Investigations Directed Toward the Total Synthesis of Shionone Citation Tilley, Jefferson Wright (1972) Investigations Directed Toward the Total Synthesis of Shionone. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/em00-jn68. https://resolver.caltech.edu/CaltechTHESIS:08292025-151007913 Abstract An approach to the total synthesis of the tetracyclic triterpene shionone i is described. The key intermediate ii was prepared in 17 steps (3.0% overall yield) from 2-methyl- 1,3-cyclohexanedione. Generation of the essential trans, disubstituted C/D ring fusion of ii was accomplished via the stereospecific formation and cleavage of a fused methoxy- cyclopropane system. An additional 12 steps served to convert the ketone ii into the ketal-ketone iii (12.5%) which requires only addition of the side chain to complete the total synthesis. See abstract in PDF for figures i,ii and iii Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Ireland, Robert E. Thesis Committee: Unknown, Unknown Defense Date: 7 December 1971 Funders: Funding Agency Grant Number NSF UNSPECIFIED Record Number: CaltechTHESIS:08292025-151007913 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:08292025-151007913 DOI: 10.7907/em00-jn68 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 17659 Collection: CaltechTHESIS Deposited By: Benjamin Perez Deposited On: 03 Sep 2025 15:49 Last Modified: 03 Sep 2025 15:50 Thesis Files PDF - Final Version See Usage Policy. 80MB Repository Staff Only: item control page

TOTAL SYNTHESIS OF SHIONCNE Thesls by Jefferson Wright Tilley In Partial Fulfillment of the RequireGsnts For the Degree of Doctor of Philosophy California Institiute of ~echnclogy Pasadena, California 19'(1 ii To Ka thy iii ACKNOWLEDGEMENTS I wish to extend my appreciation to Professor Robert E. Ireland for his guidance and support. To my colleagues goes my gratitude for their suggestions. Support by a National Science Foundation fellowship (1968-1971) is gratefully acknowledged, iv ABSTRACT An approach to the total synthesis of the tetracyclic - triterpene shionone i is described. - The key intermediate ii was prepared in 17 steps (3.0% overall yield) from 2-methyl1,3-cyclohexanedione. Generation of the essential trans, disubstituted C/D ring fusion of .._ ii was accomplished via the stereospecific formation and cleavage of a f'us r1d methoxycyclopropane system. An additional 12 steps served to con- vert the ketone ii into the ketal-ketone iii (12.5 %) which requires only addition of the side chain to complete the total synthesis. 0 ii i - CT <0~l ' yi t \_, 0 iii 0 V TABLE OF CONTENTS page Tit le Page . . . . . . . . . . . . ~ . . . . . . . . . . . . . . . . . . . . . . . . . J i Acknowledgements .......••.....•....•..........•..... iii $ •• Abstract . ............... e • • • • • • • • • • • • • • • • • • • • V•• ,. ••• Introduction . ............ , . , ............ , ........... . 1 ~ 21 Experimental Section ......••...•.•.•.•.....•..•. &e•• 99 • BaP-Methyl-l,2,3,4,6,7,8,8a-Octahydro-1~Naphthol (I-4) (61) .••. ••••••••••• • •••• lOJ. 3,~ ,6, 7 ,8,8a-Hexahydro-8a0-Methyl-1 (2H) Naphthalenone (I-5) ................... . 101 l/3, Baj.? c•Dimethy 1-1, 2, 3, 4, 6, 7 , 8, 8a-Oc tahy dro-locNaphtho l ( I-7) . . . . . . . • . . . . . , . . . . . . . 102 DiscuGsio11 ....•......... CJ •••••••••••••••••••••• c ••• e ••• lv., 8aP-Di'l1e t l1 yl - 1, 2 1 3, lt: 6, 7, 8, 8a~Octahydro-lP,Pat~"' ·f- '~o1 •l _.,.\ ,V!J (I - 7) • ~ • a 1 1 c 1 1 c 1 1 s • • • • • • . l - c " • • • 104 General Procedure for Simmons-Smith Cyclo prop Ly",J.. a"·l• -I..4v tJ,. n··O (~ ..,) t • • ,1 • • c t • a • • • , • • • ., • • e • • • >r • ~-' _) 1 s 2 s· 3 ,, 4 -' 1i a ~ 5 s 6 , 7 ·• 8 » 8a , De c ah y d r o =• l ,B, 82. J3·~ • • Dj_m~ thy l-5r.x, 4a--Methano-}o;·-l'Japh t:101 ( I-8) 11._,J ,.r 5_ I',.l11 e_., thr.x q,, ,-; rt1Cn t~y]~~ 3 f 4 j_..'....,.:,;.J-':'-_,1 i.l J 8 j 8- '",;:,t· ra n' ya'~,c ct,r.-tJ....., J ,. .l . 7 - - · ) 6 104 106 J (J-3) .•••••••• 106 5-Methoxy -8al3--M2thyl-l 1 2i3,4,6:i7,8$8a-Octahydro~lj\ 6-Naph tba.lenedio l ............... . 109 (2H , 7H)-~Naphthal enedione 5-Methoxy-8aj3-Me thy 1-1, 2, 3, 4, 6 7, 8, 8a-Cie; tahy 1; dro "• lfoJ 6-Naphthalenediol Diaceta te ..... . 110 1/3- Hydroxy-,5 -Me thoxy-, 8ap-Met h y l•n 1 , 2, 3, 4, 6, 7 s 8,Ba-Octahydronaphtha lene (N-4) ....... . 111 vi page 5-Mcthcxy-8afo-Methyl-3,4,5i6,8,8a-Hexahydro1(2H)-Naphthalenone (J-4).............. 112 Spiro-l~-Oxironyl-5-Methoxy-Bafo-Met hyl-1,2,3 1 4,6,7,8,Ba-Octahydronaphthalene......... 113 l fo , 8 a,S-· Di met hy 1- 5- Meth o xy -1 , 2 , 3 , 4 , 6 , 7 , _8 , 8 a0 ct ah y dr o- liX- Nap ht ho l (J -5)..... ....... llli 10<,8/3-Dimethyl-5-Methoxy-l,2,3,4,6,7,8,8aOctahydro-1P-Naphthol (J- 6)............ 115 l,2,3,4,4a,S,5,6, 7 ,8,8a-Decahydro-1fi,8ap-Dimethyl-5fo-Methoxy-l~-Naphthol Ketal (J-7)••••••••••••••o•••• •••••e•a••e•~"•• 115 1,2,3,4 ,Lia,5 ,6, 7, 8, Ba-Decahydro.;..1,B,Ba,B-Dimethy 1-5 «, Ll a-Methano-5{3-Methox.y-l!JC-Naphthol (J-8) ••••. •••••••••••••••••••• 116 3,. 4, 4a ;r Jl 8, 8a-Hexahydr o~ 1, 4ati., 82.p-'I'rimethy 1-~ 5(6H)-Napht ha lenone (J-9 )......... ..... 117 1 , 2 • 3 , 1! JI L1 a si 5 , 6 , 7 , 8 , 8a-Dec ah yd r o- 1 )3j 4 a c<i 8 a pTr 1 met h y 1- ltY. - Nap ht ho l (K-9)............ 118 3, 4,. lJa 1 5, 6, 7 • 8, Ba-Octahydro-1, 4a«1 8ajl-Trimethy lnaphthalene (K-10)............... 119 5,5 -Ethylenedioxo-3,4,4a,5 , 6,7,8,Ba-Octahydro-l, 4acx, Ba~-Trimethy lnaphthalene ( L-1) 121 l , 2 , 3 , lt i 4 a ., 5 , 6 , 7 , 8 , 8 a-De c ah y d r o- 4a ti( , 8aJ3- Di methyl-5,5-Ethylenedioxo-l- Me thylidene28-Naphthol (L-2)•••••••••••••••••••••• 122 Perhydro~9b-Boraphena1ene ....... e • • • • • • • • • • • • 12 3 Lithium Perhydro-9b-Bc r aph en alyl Hydride ( N-1) 124 8,41-Me thy 1-1, 2, 3, 4 ., 6, '(, 8, 8a-Oc ta.h y dro-ltx'Naph thol ( N-2 ) ••• ~ ••••••• • , , . . . . . . . . . . . 1.2~ 5-Methox y- 8ap-Me thyl-l ,2, 3, l~, 6, 1 • 8 r 8a-Octahy- dro-l~-Napht hol......................... 125 l t 2 t 3 J: 11 ~ lj a /z1; 5 , 6 , 7 11 8 /) 8 a. - De c ah yd r o ~- 5,13- Meth ox y8ap-M ethyl- l~- Nap ht ho l Ketal (N-5)..... 126 vii pa.ge l,2,3,4,4a,5,6,7,8,8a-Decahydro-5c(,4aMethano-5P,-Methoxy-3aP-Methyl-J.«Naphthol ( N-6 ) .. ~ ...•..............•.... 127 4a C(, BaR-Dlmethy 1-lr<-Hydroxy-J., 2, 3 » 4, 4a, 7, 8, 8a-Octahydro-5(6H)-Naphthalenone (N-7). 128 l,2,3,4,4a,5,6,7,8,8a-Decahydro-4a~,8ap-Dimethyl-loit-Naphthol (K-6) •• , •.••••.••••• 4a~,Ba~-Dimethyl-3,4,4a,5,6,7,8 ~8a-Octahydrol ( 2H )-Naphthalenone ( K-8) .••..•..•.•.... 130 1,2,3,4,4a,5,6,7s8,8a-Decahydro-4ao(,8a~-Dimethyl-5,5 -Ethylenedoxo-l--Naphth ol (0-1) 131 4a~,8a~-Dimethyl-5,5-Ethylenedioxo-3,4,4a,5, 6,7 ,8)8a-Octahydro-1 (2H)-Naphthalenone • 132 Attempted addition of 2-m-Methoxyphenylethylmagnesium Bromide to the Ketone 0-2 ..... 132 4a OC, 8aft-Dimethy 1-5, 5-Ethy lenedioxo-1-( 2 '-mMethoxyphenylethyl)-3,4,4a,5,6,7:8,8aOctahydronaphthalene (0-~) •.•.•.•.••.•. 133 4ao<., 8al5- Dimethy 1-5, 5-Ethylenedioxo-1/3- ( 2 '-mMethoxyphenylethyl)-l~,4,4a,5,6,7 9 8,8aOctahydro-2 (3H) -Naphthalenone (L-4 ) .... 135 Attempted Methylation of Ketone L-4 ......... . 137 ( 0-=- 2 ) o • • • • • t • • • • • • • • • e • • • • • e • • • • • • • & • • • 5 <i•, 4a-Met}-iano-5~.aMe thoxy- 8afl-Methy 1-3, 4, 4a, 5, 6,7,8,8a-Octahydro-1(2H) - Naphthalenone _ ( P-1) . t • t, • I O • " •• ~ • ,s • • • • • • • • • • .., Cl • • • • • • • ,. • 1,2,3 1 4,4a,5,6,7 , 8,8a-Dec ahydr o-5M,4a-Methano5ft-Methoxy -8at:>-Methyl-lfo- (2'-phenylethyl) l«••Naphthol ( M•-3, H=H) •••.•••• , • , ••••.•. 1,2,3,4 1 4a,5,6,7~8~8a-Decahydro-5~~4a-Met hano5/J-Methoxy---l~ .. ( 2' -m-methoxypheny le thy l )8a,eL;+·: t!~.y l -J.G{.-N aptthol ( M-3, R=Orne) .... 138 138 viii page 4a °', 8af3-Dime thy 1-3, LI, 4a, 7, 8, Ba-He xahydro-l(2'-m-Methoxyphenylethyl)-5(6H)-Naphthalenone ( M-5) •...•................... 146 l,2,3,4,4a,5,6,7~8,8a-Decahydro-l-(2'-mMethoxyphenylethylidene)-5~,4a-Methano5j3-Methoxy-8a~-Methylnaphthalene (P-4) .. 5«,4a-Methano-5J-Methoxy-l-(2'-m-Methoxypheny le thy 1) - 8a,B'-Me thy 1- 3, 4, I-J a, 5, 6, 7 .~ 8 1 8a-Octahydronaphthalene (P-3) .......... . l«,2~,3,4,4a,5,6,7,8,8a-Decahydro~5~,4aMethano-5,S-Methoxy-•l,8-( 2 '-m-Methoxy- phenylethyl)-B~P-Methyl-2~-Naphthol (P-5) •••••• "•••••••••••••••••••••••e•••• 5 a, 4a-Methano-5i8-Methoxy-l P- ( 2 '-m-Methoxypheny lethy l )-8a,B-Methy l-lo<, 2, 3, 4, 4a, 7, 8, 8a-5(6H)-Napthalenone (P-6) ... , ....... . 150 lOC, 2, 3 s 4 P 4a, 5 7 6? 7 s 8, 8a-Decahydro•"2ct, 8a;€-Dimethy l-5oc i 4a-Methano-5)1-Methoxy-l;B-( 2 ' m-M.ethoxypheny le thy 1 )-2,6'-Naphthol ( P-7) 151 8aft-Cyano-l,2,3,4,4a,5~,6 1 7,8,8a-Decahydro20{~ 4a~-Dimethyl-lfl-( 2 '-m-Metr;oxyphEnylethy 1 )-2,8, 5j1-Naphthalenediol. .......••.. 151 8a/3-Cy ano-1, 2, 3, 4, 4a, 51.)(', 6, 7, 8, 8a-Decahydrov• 2c<, 4a«-Dirnethy 1~ l/3-( 2' -m- Me thoxypheny 1) 2fot~~-Naphthalenedicl 5-Acetate ........ . 153 8a/]-Cyano-2, 4a~-Dimethyl~l_t-( 2 '-m-Met hoxy~~ 1'a ~ N ~, ,. "'11'-i ii ~ 7 $:'--')~• R ~a-rJc~~·nu'v ,~.1.,y . . - _ t, ,Y-'""''-J ~,.. . •• ,.I Pr',... a...., 1,v]eth,,1, r , N ~. 1,.-.. .. _ • ... ,,,. 1 r. •::. ;_ r\~£:av). r, >": , C • • • • tt • • d ro--:;,~,-l a r..J .lit, .~.-.......!., ,,. ,., ,_v.J. ...Gc:a. 153 lfo{2'-m-MethoxyphenyJ.cthyl)-3,4,4a~5«t6,7,8~8aOc tahyd!"' o- 2 t 4a ~ ~ 8a,8-~'Irimethy l-5t<-Naph thol ( Q-9 ) ♦ 154 ~w ...., ..,...i, '1 'Cl I 8 • t S t • C: 4 C C C 6 • t C e e • C t t e • # • 'ii • • e O t t t 156 ix page 4a,5,6,6a,9,10,10a,10b~,ll,12-Decahydro-2Methoxy-7 ( 8H )-Oxo-4b IS, 6a«, lOaf,-Trimethy lchrysene ( P-9)................... 157 Attempted Reduction of the ketone P-9 with Sodlum Borohy~ride...... . . . . . . . . . . . . . . . . 160 4b , 5 , 6 , 6 a , 7 , 8 , 9 , 10 , 10 a f 10 b o(, 11 , l 2-· Dode c ah ydro-7~-Hydroxy-2-Methoxy-4b~ 1 6a~,lOa~Trimethylchrysene (S-1)................ 160 Attempted conversion of the alcohol S-1 to 4b, 5,6,6a,7,8,9,10•10a,10b~,ll,12-Dodecahydro-7_B-Hydroxy-2-Methoxy-4b,S, 6aot, lOaBTrimethylchrysene Methane Sulfonate ( s- 2) •••••••••••••• 4t • " ••••••• •· • • • • • • • • • • 161. 4bj5,6,6a ~9, 10,10a,10b~,ll,12-Decahydro-7-Hydro x:,; -2-Methoxy-4b~, 6ao<, lOa~Trimethylchrysene Tetramethylphosphorodiamidate { T•-'•l ) • e • • • • • • t • • • • • • • • • 'i 16 2 Hydroxy-4b~,6a«,10b~-Trimethylchrysene (T-2)e••••••o•t•••••••••••c:- 11>••••••••••* 163 3,4,4bs5,6,6a,9,10,10a , 10b~,ll,12-Dodecahydro-2(1H)-Oxo-4b~,6a~,10a~-Trirnethylchrysene (T-3)•••••••••••••·••••••·•••• 164 3, 4, 4b, 5, 6, 6a, 9, 10, J.Oa, 10b 11, 12-Dode cahydro2(1H)-Oxo-l,l,4b~,6a~,10ap-Pentamethylchrysene (T-4)••••••••••••••••••••••••• 166 b • • • • • ,, • • • e, e • <:. • , ~b,5,6,6a , 9,10,10a,10b~,ll,12-Decahydro-2- o<j 4b,5,6 1 6a,9,10,10atl0b~,ll,12-Decahydro-2Methoxy-4b fJ, 6ao:, lOa#~Trirnethy lchrysene (S-3) ......••.... s•••••,.••••• .. "••t.•••••• Jt, 4a ti!, 4b, 5, 6, 6 a 1 9, 10 ~ 10 a, lOb m, J.l io 12-D ode cahydro - 2 ( 3H) .,Qxo 4b,S, 6aet~ lOa,8-'l'rimethylchrysene (U-1) 0,.,'1 ••·······••e••·••o••··•$C~ 0 167 • 168 4b ,5 ,6 ,8a Ol,9, 10-t!sx ahydro:.2-Methoxy-•7 ( BH)- Oxo- 4bfi, 8, 8- Trimethylphenanthrene (V-2) 171 X page 2--Methoxy--4b, 5, 6, 7, 8, Sat'!, 9., 10-Octahydro-~4b p, 8,8-Trimethylphenanthrene (V-3)........ 173 4 , 4a oc', µb , 5 , 6 , 7 ., 8 , 8a ~, 9 , 10-De c ah yd r o- 2 ( 3H ) Oxo-4bp,8,8,-Trimeth y 1phenanthrene (V-lt). 174 4,4a~,4b,5,6,7,8,8a~,9,10-Decahydro-2(3H)Oxo-l, 4b P> 8, 8-Tetramethy 1phenanthrene (V-6) ........................... "«· •••••••• 2,3,4 , 4ad »4b, 5 , 6 ~7 ~8,8a ~ 9 9~10-Dodecahydro-2%Hydroxy-l ,4bp,8,8-Tetrame thy lp henanth rene (V-8), and 2,3,4,4aoc.,4b,5,6,7 , 8,8at(,9,10Dodecahydro-2~-Hydroxy- l, 4bp,8,8-Tetramethylphenant hrene (V=7)............... l'/5 176 Reoxidation of the Alcohol V-7 to the Ketone V-6•••••••••••e ·••••••••••••••••••o•••••• 179 20{-Hydroxy-10(, l0a-Methano-1,2, 3, 4 i l-1aoc, 4b, 5 11 6 s 7 r, 8, Sal!(, 9, 10, l0a-Tetrad ecah ydro-lfo, 4bp, 8,8-Tetramet hylphen anthre ne (W-1)...... 179 l,4,4a~,4b,5,6 , 7,8,8a~,9,10,10a-Dodecahydro1«~10a-Methano-2(3H)-Oxo-ll,4bp, 8,8Tetramethylphenanthre ne (W-2).......... 181 l,4,4a~,4 bi5,6, 7,8,8a~,9sl0$10a-Dodecahydro- 2(3H)-Oxo-l,4b,S,8,8, l0a«-Pentamethylphenanthrene (W-3)..................... 181 Attempted equilibration of the Ketone W-3.... 183 2P-Hydroxy-1J3, 10a-Me tha.no-l,2 : 3,4,4ao<.s,4b ,5, 6, 7,8 ,Ba~,9,10~10a-Tetradecahydro-l- ,4bfo, 8,8-Tetramethylphenanthrene (W- 4)...... 183 l,4:4 a~,~b,5J6, 7 ,8, 8a~, 9,l0~10a-Dodecahydro1$,10-Me thano-2(3H) -Oxo -1~ 1 ~b~ ,8,8-Tetrarr.et.bylphen anthrene (W-5) .......... ~.... 184 2, 3, 4 ,, 4adii 4b, 5 .~ 6 , 7 i 8 :1 8a~11 9, l0-Do d 2 C!ahydro-;~).iHyd r•oxy-l~bpi 8 , 8~-TJ:-i me thy lp henon threne Y v.. 2) an d ') ') , i' lt c1 v,. ~ l'b ° ' ,;Q a,-,~ ~ 9 ' ·Lo ( ,,_ c.. $ .) -I J r:: ) 16 ~ 7 , 0 . 1 j 1• ._,, Dodecahydro - 2 ,<-~Hv droxv-4bfo'i,,8 . 8-Trimethyl- phenanthrene ( X~l )&o:~ ..... :.~~4•~•••~• 185 xi page Reoxidation of the equitorlal alcohol X-1 to the enone V-4•••••••••••••••·••••••••·•• 186 l~,2,3,4s4a~,4b,5,6,7,8,8a~,9,l0,l0a-Tetradecahy dro-2p-Hy droxy-lfo, lOa-Met hano-4b_#t 8,8-Trirnethylphenanthrene (X-3) ... c•••• 187 1, 4, l!ae,<, 4b, 5, 6, 7, 8 1 8a«, 9, 10, lOa-Dodecal:ydrolft, lOa-Met hano-2 ( 3H ) -Oxo-4bf5, 8, 8-Trirnethy lphenanthrene (X-4) .. <•••••••••••• 188 3,4,4a~,4b,5,6,7,8,8a~,9,l0,10a-Dodecahydro2-Hydroxy-l ,4bft,8,8, 10ap-Penta.r.1ethylphenanthrene Acetate (X-5)............. 189 Preparation of the saturated ketone 59 from X-4 .• 6•••••••••••••••••••••••••••••••••1! 191 1p, 2, 3, 11, 14a or., 4b 9 5, 6 .- 7 s 8, Bao(, 9, 10, 1 Oa-Te tra •• decahydro=2)3-~Hyd.roxy-lci(, 2-Me thano-4 b/3~ 8 » 8 • 10aj3-Tet ramethy lphenanthrene ( X-6). . . 191 1~,4,4a~,4b,5 9 6,7 9 8,8 a~ , 9,10,10a-Dodecahydro2 ( 3H )-Oxo-1)3, 4b,B, 8, 8 i lO a,8-Pent amethy 1phenanthrene (W-6)................... .. 194 2«-Hy droxy-•2 /3, 3, 4 1 4a o<, 4b, 5 , 6, 6 a 5 9, 1 O, 1 Oa 7 1 Ob<X, 11, 12-'l'e trade ca.hydro- L!bfos Gac<, 10 afl-T rimethy lchry sene ( Y-1) and 2.P-Hydroxy2 oc" 3 , 4 , 4 a ~, -1-1 b , 5 , 6 ; 6 a , 9 , l O :1 J. Oa , 1 Ob 0( , 11 , 12Tetradecah ydro-4b~,6a~$ 10aP-Trimethylchrysene (Y ~-2 ) •••• e•••••••••••••••••••• 199 Oxidation of the alcohol Y-1 to the eno~e U-1 201 2-Hydr oxy-3,4 ,4a~,4b,5r6,6aj9~10,10a,10b~ $11, 12, 12a-Te trade cahydro-lfo/3, 6 at'!, l Oa{~, 12 aj3Te tramethy lchry s ene ~cetate (Y-5)...... 203 Cleavage of the Encl Acetate 67 to the Ketone Y-4••••••••••~•••••••••••••••••••••••••• 206 xii page l/3, 2, 3, 4 , ~ a c1-, 4b , 5 _, 6 , 6 a, 9 , 1? , 1 Oa , 1 Ob()(, 11 , 12 , 12a-Hexadecanydro-2~- Hy drcx y- l~,2Methano-4b,8,6ac,.,10a/3,l2a,B-Tetramethy lchrysene (Y-6) ..................•... ,.. 206 2(3H) -Oxo-lp,4bJ3,6acx,1oap,12aJ3,-Pentamethylltx i; 4 ~ 4aC!(, 4b, 5, 6, 6 a 9, l O, 10a, lOb o< , 11, 12pl2a-Tetradecahydr0chrysene (Y - 7).... 210 2;2-Ethylenedioxo-l,2~3 ,4,4a~,4b ! 5,6,6a,9,1D, 10a ,10b~,llsl2,12a-Hexadecahydro-l,4bfi, 6a'-', lOap, 12ap1-Pentamethy lchrysene ( Y-- 8 ) 210 Attempted hydroboration of Y-8 with disiamylb or an e . . . • . . . . . . . . . . . . . . . . . . • . . . . . . . . . . . 211 2~2-Ethylenedioxo-la,2,3,4,4a~,4b:5,6,6a,7~10, 10e 1 10b~,ll,12~12a-He xadecahydro- 8(9H )Oxo - lf3, 4b?, 6a<r,., 10aj3, 12 a,8-Pentamethy 1chrysene (Y-9)... . .. . .................. 212 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Proposition I....................................... 223 Proposition II ............................. ,. ........ 233 Proposition III ................. ~................... 246 Propos:i.tion I .,l. .. , . , o , , . , t • • • · ., •••~,~••••••••••f)••••• 253 Prop()Sition. v .. e 263 j t -0 • ... ~· • • t .... •••• C, 0 ~· ......... , •••• ,J. l Introduction The triterpenes consist of a diverse group of C~30 isoprenoid compounds which are biologically derived fr om squalene. They are, with rare exception, tetra - or penta- cyclic molecules bearing numerous asymmetric centers. The triterpenes are widely distributed in the plant kingdom although a few such as lanosterol (1), have been isolated from animal sources (1). "" Although the first member of this class of compound s betulin (2) was isolated in 1788 (2), the combination of their great size and varied stereochemistry coupled with their pa ucity of suitable reactive centers ren dered the triterpenes resistant to structural elucidation for over 160 years. 1 2 2 In 1949 Ruzicka and Jeger (3) determined the gross - structure of oleanoic acid (3) culminating a 20 year effort and launching a period of rapid progress in the field. Building on the data acquired during the previous 30 years relating the various triterpenes to a few widely occuring examples, most of the basic triterpenoid skeletal types were quickly deciphered. In a parallel development, the combination of Barton's (4) application of conformational analysis and Klyne's (5) utilization of molecular rotation data led to the determination of the relative and absolute stereochemistry of the pentacyclic triterpenes. This work on the structural and stereochemical elucidation has been adequately reviewed (1, 6-9). H This increas e d structural knowledge coupled with preli minary biogene tic studies prompted Woodward and Bloch (10) to propose that lanosterol and the steroids were biosynthe- 3 sized through a specific cyclization of squalene followed by methyl and hydrogen rearrangements. Since then their hypothesis has been fully confirmed and extended (11, 12). Eschenmoser et ~l. (13) and Stork (14) independently advanc ed a detailed theoretical model for the formation of the pentacyclic triterpenes via a concerted cyclization of squalene followed by a series of Wagner-Meerwein 1,2-s hifts. Again labeling experiments have proved to be fully in accord w:l.th the theory at least in the cases tested (15) and this theory if: now generally accepted for al1 the triterpenes. C0r•nf' c~:th (16) has proposed that the theory be modified to include~ reversible enzymatic trapping of certain of the carbonium ion intermediates. He argues that pauses are required, particularly during formation of ring E, to allow the system to adopt the conformation necessary for furt her rearran g ements. More rec en tly 2,3 - oxidosqualene has been jrnplicated as the substrate in the enzymatic cyclizations (17, 18) accounti ng for the presence of the C-3 oxy gen, which is almo st cath olj.c among the trit erpe nes and steroids. In oth e r developments the mechani sm of the for mation and incor-porat.i.on of mevalonic acid into farn esyl pyrophosphate has been throughly worked out 1 largely through the efforts of J. w. Cornforth. This work is described by Clayton in his excellent revie w (1 2). Finally, the precise r~e chanisn of the reductive couplin g of t wo farnesyl pyrophosphat e units to form squa l enc has 4 yielded to intense scrutiny, particularly by Rilling (19-21). In ~hart A squalene oxide (A-1) ....,_ 1s shown in the chairchair-chair-boat form, which according to the Eschenmoser theory, can cyclize directly to the carbonium ion .__.., A-2 with the stereochemistry shown. Other conformations of sq~alene are possible which can give intermediates with different stereochemistry, For instance, lanosterol (1) ........ arises from a chair-boat-chair-boat cyclization followed by a se~ies of 1,2-shlfts and loss of' a proton. Hydroxy hopanone (l..J) on --- the other hand is formed by an all chair cyclization with trapping of the resultant C-20* carbonium ion by water. 0 4 ..,.., ·------------------------- - - - * The naturally occurr1ns triterpenes discussed herein are numbered ac cord l n g to 'cl1e scheme sus g e s t e d by S. Allard and t. Ourisson, Te trahedron, 1 . 277 (1957), The dicyc:lic corm:,c, :J,nd.'s' described. herein a.re named 2.nd numbered as d e r1.vati,, e s of naphthalene, the tricyclics 2s derivatives of ohenanthrene or phenalene as appropriate, and the tetracyclic~ a s derivatives of chrysene as indicated in "The Hing Ind e ;,: 11 ( A. M. Pat t e rs o11 , L . 'r . Cape 11 , a !l d D• F' • Walker, "The rU.ng Inde x", 1\rner-ic,Jn Chemical Society, Washin i ton.t D. c., J.960. Althou ~h onl y one enantio~e r is depicted in the structural formu i as 3 al l synthetic intermediat e s are ra c emic. 5 Chart A {f+ A-1 '-"'-"' H A-4 ----.,..... A-5 \.----. Shion one A-6 --------- 6 Chart A (continued) A-3 '""- H A-7 -...--.. Euphol 20 (J-H Dammarenediols A-8 Tirucallol 20 ~-H (20 d.- or ~-OH) 7 Chart A (cont,) HO A-6 ..._....,.,_ HO H 1' ' ,, J Alnu s enone A-13 ----- _ A-12 ___,... Germanicol A-11 ft III I "'~ ~j H;;7"-1 ➔ ',) ~ -,~ ) ~-- 1~ -- 15 , .... A-16 ,___.,..... Fr1e del in 8 -- The carbonium ion (A-3) serves ae, the key intermediate for a number of classes of triterpenes. It can undergo attack by water to give either of the dammarenediols (A-9) directly or the C-17 hydrogen can migrate initiating a - backbone rearrangement leading to euphol (A-7) or tirucallol (A-8 ...-- ) depending ort the stereochemistry at C-20. Alterna- tively, the C-16--C-17 bond can shift giving the cation ( A-4) ....--............ which can suffer either of two fates. Eight more l,2~•r:h.-lf'ts starting with the C-13 hydrogen leads to shionone (A-5) --- while attack of the side chain double bond on the carbo~ium ---- ion gives a new carbonium ion A-6 which can lose a protc n to give lupeol (A-10) or through a shift of the C-19--C-2 1 bond give . A-11, . . - the immediate precursor of germanicol (A-12) ._,.._, A sequence of additional Wagner- Meerwein rearrange ments can __ then lead ultimately to alnusenone (A-1 '"-',., 4 ) or friedelin ---- (A-16). It should be emphasized that triterpenes arisin g from loss of a proton from each of the potential carbonium ion intermediates between A-11 and A-15 have been isolated and characterized (6). Rearrangements similar to those proposed in the biosynth e tic scheme have been observed in vitro. Both friedelene (5) (22) and alnusenenc (6) (23) give the same mixture of 612 and 4 13 (lB ) _olanenes (7) on treatment with ac!d . ........ Apparently the drivin g force for this r e arran ge ment is t he strain associated with the cis D/E ring f us ion (23 ) , 9 6 ...... 7 Whitlock (24) has investj.gated the nature of such backbone rearrangements and his data i n dicate that there is a rapid equilibrium of a ll the possible carbonium ions accessibl e by 1 1 2-shifts and that the products are formed throu gh the most stabl e of the se . Thi s result would ascribe to the enzyme the ability to moderate such rearran geme nts through either control of the conformat ion of the nascent triterpene making the proper carbonium ion the most stable or by pro vision of a basic site at the appropriate point to interrupt 10 the equilibrium by removal of a proton. These questions regarding the microscopic mechanism of the cyclization of squalene and the subsequent rearrangements are still under intensive investigation in several laboratories. Synthetic efforts in the triterpene field have been scant, probably due to the same factors that hindered structural elucidation plus the apparent general lack of biological activity among the triterpenes. -The early synthetic work has been ably reviewed by Evans (25). The initial attention was directed toward the symmetrical tri- - terpene Cl( -ononce1•in ( 8, R=R' =OH) since this compound cou l d in principle be obtained by the coupling of two identical subunits thereby sharply reducing the number o f' synthetic steps r e quired. The discovery made by Barton a nd Overton (26) during their structural studies that ~- ononcerin diacetate gave the unnatural pentacyclio isomer 'C - ononce r ln - (9) on vigorous treatment with acid was also a key factor since this assured an entrance into the pentacyclic triterpenes, During the middle 1950s both Eschenmoser (27) and Corey ( 28) prepared the hydrocarbon CA. - ononcera.diene ( §., R=R' ::::H) ~ the dirne rization of different inter-mediates derived from sclareol (10) . ""..,.. The first tri terpene total synthes:1..s was achieved by Stork (29) who prepared ~ - onon cerin in 16 steps from 6- - methoxy -~- tetralone (B-1) (Chart B). The major advance in 11 AcO R OH 10 this work was the preparation of the keto-acid __,., B-7 by oxidative cleavage of the Cring of the tricyclic ketone ,_._ B-5. Decarboxylative coupling of ~ B-7 , , was carried out electrolyt£ ically using the procedure developed by Corey (28) for ononceradiene to give the dione ........,... B-8. ~- Addition of ethcxy- acetylanet acid cataly zed hydratj_on, and thermal de c arboxy1ation then l ed to o<.-ononcerin ..... 8. The key interme d:tate .........3-7 has subsequently been sy nthesiz ed more e fficiently by Ireland ( 30) and Sondhci~er (31), Stork!s accomplishment also provided s formal entry into t he hydroxyhopanone [;y ste r:1 12 Chart B 0 0 CH 0 3 B-1 ---- B-2 ............. OCH B-3 ----- 3 B-5 CO H 2 ------ Ac AcO B-7 B-8 ._. . ..,.,.,,. 8 13 since Schaffner and coworkers (32) had already converted -- - ~-ononcerin diacetate (9) to the keto-alcohol C-1 (Chart C) which on heating in the presence of Fuller's Earth gave the keto-olefin ...._,.. C-2 which was also obtained by a similar treatment of hydroxyh opanone (4). Chart C C-1 ....,._,.... 9 --- I~~~ '(oH I ,. 0 ::: , : j .,.) I / O: 4 ...... C-2 ,.,._ Unfortunately, this approach was applicable only to symmetrical triterpenes and the limited number of triterpenes which are derivable from symmetrical intermedi ates. A second ma jor drawback is the low yield associated with 14 the acid catalyzed cyclization forming ring C (2-20%). Halsall and Thomas (33) were the first to . suggest joining dissimilar AB and DE portions followed by cyclization to get into the ol~anane system. This approach has been successfully applied in three different laboratories (34-36), but in each case the inefficiency of the last step severly limited the yields. Also the cyclizations were generally non-specific leading to mixtures of double bond isomers such as 7. -- Barton (37) has subsequently completed a partial - synthesis of p-amyrin (11) from olean-13(18)-ene completing a formal total synthesis of the former compound. Unfor- tunately, however, this synthesis albeit elegant was too long and inefficient to serve as a general entrance into the series of triterp e nes related to ~-amyrin such as the pentacyclic compounds in chart A. •· • · .. 15 During the last several years a sig_"l.ificant portion of the synthetic endeavor in the Ireland labor·ato.ries hF..s been directed toward the development of more efficient and versatile routes to the triterpenes. Recently, this goal has been realized and publications describing totally synthetic schemes leading to germanicol (A-12) (38) and alnusenone (A-14) (39) have appeared. '"'---~ • The initial problem in the route to germanicol was the -- preparation of the tricyclic intermediate D-3 (Chart D) possessing the cis axial methyl groups at C-4a and C-8a. This was accomplished by a sequence of Robinson annulat ions of 2-methyl-1,3-cyclohexanedione and ethyl viny l ketone to -- give first the enone D-1 and then D-2 . ....- Reductive methylation at C-1 of D-2 D-3 ........... and catalytic hydrogenation gaye the ketone ....._ whose structural assignment was confirmed by co mpar ison of a derivative with that obtained from a natural product. Attention was next directed at the introduction of the side chaln beal'ing r·ing E and the an gula Y' me thy 1 gr oup at C£•8. The difficulties associated wi t h the preparation of an array of adjacent quaternary centers bearing trans orie nted methyl gr oups :.drntlar to that requ1red at C-1 2a and C-l2b of ..,_,... D-6 thwarted an early foray aimed at alnusenone (40) . Attempted a]kylation of the ketone 12 with iodomethane under the optimum conditions led to only 17 % o f the required intermediate ........ 13 together with 60% of O-methylated prod uct 16 OEt MeO OEt MeO ---13 12 ---- and 21% of starting material. This and later work have demonstrated that the stereospecific introductio~ of such combinations of angular methyls constitutes a weighty synthetic ch8.llengE.' and that provisions for their generation must form an integral part of the synthetic plan. While many of the problems pertaining to triterpene synthesis have been encountered in work on the steroids, this one has received little attention (41). In the present case the problem was solved by formation -- of the exocyclic enone D-4 which was available in four steps from -~ D-3. Conjugate addition of m-methoxybenzyl Grignard with trapping of the enolate anion thus formed by acetic anhydride then gave the enol acetate D-5. The enolate anion could subse que nt).y be regenerated in a different solvent and selectively alkylated with meth yl iod ide at C-8 with the methyl group approaching from the le ss hindered face of the 17 Chart D + 0 0 0 0 D-3 ,.,.._.__ ~OCH ~OCH 3 I I ...',~,,,,,.;,, ORY D-5 ----0 HO ---A-12 3 18 molecule to give, after acid catalyzed cyclization~ the penta- - cyclic ketone D-6. Further transformations into germanicol involved a B1rch reduction to give the ketone E.:.J and introduction of the C-17 methyl group by the conjugate addition of cyanide. Dimethylation and removal of the carbonyl from C-22 gave the natural product. For the synthesis of alnusenone (39) (Chart E) the subunits ...,.._ E-1 and .......,._ E-2 were joined by a Robinson annulation to - give the tricyclic enone E-3. The . problem of introduction of the C-lOa angular methyl group was solved neatly by the conjugate addition of cyanide using the procedures developed by Nagata (42). By appropriate choice of reaction conditions either the thermodynamic cis _ fused product or the k:Lnetic, desired ~-trans isomer ....-..... E-4 could be obtained in high yield. The cyano group was reduced to a methyl providing E-5 which ----- was cyclized in pclyphosphoric acid to give the pentacyclic - E-6. Selective reduction of the aromatic rings was achieved by the conversion of the methyl ether to the corresponding phenol, Birch reduction of the ethoxy substituted ring, and re-etherification of the phenol. The E ring was then con- structed and the second aromatic ring was reduced and dimethylated to give alnusenone. Very recently Stork (43) has communicated a total synthesis of Lupeol (A-10). Certain aspects of this synthesis will be mentioned in the discussion section. In light of these initial succe s ses a more versatile 19 OCH Chart E 2 ---E-1 CC H 5 2 E-3 E-2 ....__,__,.. ~ -E-5 E-4 ----OCH 2 0 5 CHO 3 ~ -- E-6 ... --- - - - 0 E-8 ------- A-:J. i~ ~..,.- ... 5 20 approach to triterpene synthesis was desired that would be applicable in the preparation of tetracyclic as well as pentacyclic triterpenes. The development of one such approach and its application to the total synthesis of shionone (A-..-. - 5) is the subject of this thesis. 21 Discuss:ton After apraj.sjng the manifold approaches to triterpene synthesis we had decided to direct our efforts at the class of compounds possessing trans fused, diangularly methylated C/D ring fusions. This decision was made first because there are a large number of triterpenes which incorporate this feature such as the tetracyclics lanosterol (l)j euphol _..., -- --- (A-7), tirucallol (A-8), and shionone (A-5) as well as the --.. pentacyclics alnusenone (A-14) and friedelin (A-16) (6). - -- Secondly, a potentially general procedure for the generation of the system of anti vicinal quaternary centers chr.. ract er- - istic of many other triterpenes including gerrnanicol (A-12) had already bee~ developed and applied in these laboratories ( 38). The initial goal of this work was to develop a synthetic route to a simple compound containing the desired disubstituted C/D ring fusion which could then be elaborated into the various triterpenes. It was evident that an indane or decalin derivative which bore suitably differentiated functionality far the selective modification of both rings was required~ since the A, B, and C rings of the different n a tural products bear litt1e resemblance~ A second ambition wa.s to demonstrate the utlli ty of this intermediate throu gh the total synthesis of a t r iterp e ne . 22 For this phase, the tetracyclic triterpene shionone (A-5) was deemed to be an ideal challenge since work was already in progress toward the pentacyclic alnusenone through a pentacyclic intermediate (vide~ suora) and also because it seemed probable that one of the tetracyclic intermediates in the shionone scheme could be elaborated into the pentacyclic series. Shj_oncne occurs in free form together with friedelin in the roots of Aster Tataricus and can be isolated by extraction with benzene and chromatography of the crude extracts on alumina followed by recrystallization (44). The optical rotary dispersion curve of shionone was superimposible with that of friedelin leading Ourisson and his co-workers (44) to propose that the A rings and A/Brin g fusions of the two compounds were the same. The validity of this proposition was demonstrated by oxidative degradation of the A ring of shionone employin g the procedure used by Corey (45) in his structure elucida t ion of friedelin. The above results coupled with an nmr analysis of the side chain prompt e d Ourisson et al, (44) to assign the str ucture 14 to --·- ._,_ shionone on the assumption that it arose biosynthetically via a backbone rearrangement similar to that leading to ot her -- ---- tetracyclic triterpenes starting with the cation A-3. A few months later the same authors (46) published the re v ised, correct structure ........... A-5 b a sed on their c hemica l 23 ...... ...... - 0 0 A-5 14 ------ ---- degradation of the side chain. They were able to con ve rt -- the side chain F •-1 through a series of standard transfermat.ions to the allylic bromide F-~ (C h a :ct F), but were unable ~ Chart F CH CH I 3 ,CH R-C- CH - CH - CH~C ' 2 • I 3 3 CH3 2 R' -- F-2 CH L3 0 R-C-CH-CH=C" -~~I \ '0 R' Br .,0 R-C-CH 2 -CH=C l '0 R' F-3 CH I 3 / 0 R-C::CH=CH =C l '0 Rt 24 to dehydrobrominate ..,_.__ F-4 to the anticipated diene F-5 suggesting that the carbon bearing the meth y l group was quarternary. These data implicated the cation~ as the bicgenetic precursor to shionone leading to the proposal of the correct structure. The structural assignment was placed on a firm chemical ground in 1967 by an exhaustive degradation of the side chain and mass spectroscopic studies on the tetracyclic molecule remaining, verifying the position of attachme~t of the side chain (47). In an accompanying paper Takahashi and co-wcrkers (48) related shionone to friedelin by the preparation of the olefin 15 from shionone by a variation of the route that ......... gave F-3 and from friedelin by oxidative cleava ge of the E -------- ring, In considering a synthesis of the length and complex i ty required for a mol e cule such as shionone, it is convenient to wor k b ac kwards from the natura l product toward readily avail a ble startin g materials, In this way one can si mplify the structure one step at a time in a ''rever se s y nth e tic ally 25 plausible manner" to ar-rive at intermediates which are more am.~enable to direct attack. To illustrate this process in the case of shionone consider chart G. Removal of the side chain gets rid of one asymmetric center and a potentially troublesorr.e double bond while leaving behind most of the backbone of shionone as well as alnusenone and friedelin. At the same time, it is reasonable to assume that, with suitable functionality in - the D ring of G-1, the side chain could be introduced near the end of the synthesis without affecting the rest of the molecule. A second major simplification can be achieved by the presumption that the A ring could be derived from the anlsole - derivative G-2. It is well known that Birch reduction of anisole ringtof this type gives the corresponding 2-keto-lenes which have an oxygen atom in the required position for all the triterpenes of interest and a double bond activating the carbons that will eventually have to carry the vicinal methyl eroups. -- Thus it appears that the tetracyclic G-2 would serve as an admirable key intermediate for both shionone and the related pcntacyclic triterpenes. It is further appreciated that aro ma tic r ings are stable to a wide vc:riety of chem~. cal reactions and that the Bring of ...__ G-2 ccu ld .cotentially be closed bv "' an intramolecular cyclo a l ky latlon r eaction . The utility o f this approach to pol jcy l i c systems is evident f rom its exten s ive 26 Chart G 0 G-1 ............... A-5 ..........,-- l q j ( G - )_ _ _ ____.. CH 0 f' ( G) 3 l Sta1· t1· n g .N'iat e rials 27 application in steroid synthesis (49) and has recently been extended to systems of more immediate interest by the model studies carried out by Ireland, Baldwin, and Welch (50). These workers examined the outcome of the acid promoted - C~icllzations of the b1cyclic compounds 16-18 and found that, ....... regardless of the starting material, the product consisted - of . a 3: 1 ratio of the trans, anti, tran~ l<etone 19 and the ~ , anti, tr·ans isomer ~. They also presented a detailed theoretical argument to account for the stereochemical out come of this reaction. This argument will be summarized later ---- for the case of the ketone G- 2, f'(g)=O. 0 Q + CH o 3 CH 0 3 CH 0 3 19 ......, 16 .__ Z=CH 2 17 ..,.._, Z=3 - OH ,3 -CH 3 18 Z=3 - 0Ha3 - ctt --- 20 ___,. 3 Finally, with the favorabl e result of th e cycliz2tion indicated,, it car: be assumed that the A and B rings c an be genera ted by the addition of a~-phenylethyl side chain to th e decalin derivative G-3. ,......,_ This derivative is precisely the type of intermediate which was the first goal of this work. 28 It is anticipated that analyses similar to that above starting with other triterpenes would verify the versatility ~-- of G-3 as a synthetic intermediate. A possible approach to cor.1pounds of this type was suggested by Wenke rt's (51) successful ~ynthesis of val e r anone (H-'0 in which a fused methoxycyclopropane was used ....,.,._ as a source of an an gular methyl group. Wenkert prepared the equatorial allylic alcohol ...,_ H- 1 (Chart H) by l i thium Chart H '''( II HO 0 Z=3 -OH,3 - H H-4 ----- H-3 z-- H2 ----- H- 5 -----· H-6 ~ H- 7 ~ 29 aluminum hydride reduction of the corresponding ketone. This alcohol was then stereospecifically cyclopropylated with the ... Slrnmons ~Smith reagent to give the alcohol ___ H-2o The Simmons - Smith reagent can be most ea s ily formulated - as icdomethylzinc iodide 21 and is formed by the action of dilodomet h ane on z inc-copper couple (52). This reagent will 21 transfer methylene to olefins under mild conditions to give th e derived cyclopropan es (53) and is directed by allylic (54) and homoallylic (55) alcohols to give the products of ~ - addition presumably through a prior coordination of the zinc atom with the hydroxyl oxygen. There are no known exceptions to this directing effect in six membered rings (56) so Wenkert was assured of the stereochemistry of the methoxycyclopropane ,..._ H-2 on the basis of the known stereochemistry of th e alcohol H=l. ............. after removal of the ,.., ? '-'-.J Finally, oxygen by oxidation and Wolff- Kishner reduction of the resultant ketone, the methcxyc:yclopropane system of H- 3 was cleaved in acid to g ive vale~anone --, -- (H-4) in g eed yield. It appea red that jf this method could be extended to th e axial homoallylic alcohol H-5, it would provi de a route .__,.. 30 - to the t r ~ fused di,u1gularly substituted naphthalenone H-7 with the required differing functionality in each ring. Unfortunately, preliminary attempts to prepare the alcohol !:.:,_5, H=CH 3 ran i::1to difficulties due to the ser~si ti vi ty of the enol ether and it was decided to carry out a model study on the more stable analogue I-6 ....,._ to see if the SimmonsSmith reaction would indeed work as hoped on this system. Molecular models indicated that the ~-face of this compound was significantly less hindered than the ~-face and it was feared that the adverse steric effects might overwhelm the directing influe nce of the axial alcohol, particularly since the Sin~ons - Smit h reagent is known to be responsive to steric hindrance ( 5 7) . 'Ihe di one j nMies cher' s ketone" (........ I-1) ( 5 8) was reduced ...__ with lithium aluminum hydride and was acetylated to give the known dlacetate .,._ I-2, R=OAc (59) (Chart I). The diacetate was carried on without isolation by treatment with lithium in ethylamine to affect allylic cleavage of the C-3 acetate according to the general procedure of Hallsworth and his - co .... workers (60) giving the alcohol I-4 which had been prev:Lously prepared by Marshall (61) in a similar manner. Oxidation of the crude cleavage products with chromic acid in acetone (62) then gave, aft "~ ~· column chromato gr•aphy, 3% of th_e hydrocarbon ---~ I-3 which was identified on the basis of its nmr and ir spectra (63), and 35% (from the dione ..__.., I-1) of the anticipat ed 31 Chart I OR 0 I-2 I-1 ------- OH + I-4 I-3 ...,__ ._._.,- + I-6 ~ I-7 .............. I-5 ~ 32 -- ketone I-5. The olefin ---...,,. I-3 apparently arose by homoallylic cleavage - of the 1-acetate during the dissoJ.ving metal reduction of I-2, R=OAc to give the cyclopropyl radical~- There is precedent for such homoalJylic reductions in the literature. Reusch (64) has recently reported that the action of lithium in -- ammonia on the d1one I-1 gives 80 % of the cyclopropyl ketone - 27 which result s from protolysis of the enolate anion 26 ...... during isolation. In the present case, the first formed - product 22 can react further. Acquisi t ion of an electron by either the acetate or the C-5 radical could lead to the cleav- - a ge of the second acetate to give the olefin 23. This vinyl cyclopropane is isoelectron i c with the ~-c a rbony l cyclopr opyl ketones which are known to undergo ready reductive cleava ge - to products relat~d to I-3 (65). Successive re a ction of the major oxidation product, th e ketone I-5, with dimethyloxosulfonium methylide and lithium -- aluminum hydride provided a 6:1 ratio (nmr) of the axial and equatori a l alcohol s .....I._....... - 6 and .___..._ I-7 respectively, The stereo- chemistry of the addition wa s p r edicated on the results of Corey and Chayko vsky (66) and Cook, Corleyi and Wall (67) re gardi ng the stereochemistry of the attack of sulfonium yli des on various cyclohexanones and s t e roidal ke tones. Sp e cifical l y, th e y f ound t ~at dirnc th y lo xos u l fo ni urn me th y l ide ga ve almo st exclu.s i ve ly the ox:!.ran e resultins f rom eq uat orial appro a ch o f th e reagent whil e with the le s s bulky no noxygena t e d 33 OAc AcO AcO I-2 22 25 24 23 0 I-1 26 27 analo gue, ci1methyls~lfoni~m methylide, the product of axial attack was obtained. The stereucl\emistry of the alcohols was further established ori the basis of the followin g data. The major isomer exhibited a hl ghs r r.f . on silica gel tlc indicating that it was the more hindered axial isomer. On dehyd rat ion with 34 phosphorous oxychloride in pyridine, the major isomer gave an endocyclic olefin with one vinyl proton in the nmr, a result characteristic of axial alcohols. On the other han d, the minor isomer gave a 2:1 mixture of exo- and endocyclic olefins (nmr) since the most favorable trans i tion state for the dehydration involves a trans, diaxial elimination of water and there is no proton in the ring which is axially disposed with respect to the equa torial oxy gen. The valid- ity of this procedure for the distinction of axi a l and equ~torial alcohols was established by Barton (68) dur in g his conformational studies of steroids. A compound wh i ch was identical with the minor isomer ........... I - 7 was prepared by the addition cf met hyl lithium to the ketone ..._... I - 5, a pro c ess wh i ch according to th e Felkin pr inciple (69) sho uld occur by axial entry of the r e a gent to give the equatorial alcohol. Treatment of the isolated axial aJ.cohol I - 6 with a t en fold ex ce ss of the Simmons-Smith reagent resulted in a very facil re a ction. It was complete in less than an hour at room te mperature and gave a sin g le cyclopropyl alcohol in 63% yield. ~- This was a s s ume d to be the desired ~-isomer I-8 becau s e of the rat e and stere ospe c i ficit y o f the reacti on. The re a ctions of t he Si mmons-Smith r eagent with unactiva ted double bonds such as that availa.b l e for ~ -a t t ack in !:.§ is known to re qui re severa l hours at reflux (53) so that it i s reasonabl e lo suppose t hat the reaction i n this case wa s 35 facilitated by coordination of the reagent with the axial oxygen demanding that attack occur from the o<.-side of the molecule. With the successful conclusion of the model study, attention was once again directed at the synthesis of the alcohol H-5. ~ 1,4-Dirnethoxybutanone (J-1) is available from ..,,,,,,,.,,,,,...,, butyne-1,4-diol in two steps in 55% yield (70). It was nece~sary to eliminate methanol from this compound to give --- the corresponding vinyl ketone 28 which was to be used in an Robinson annulation with the dione J-2. This process was ----attended with some difficulty. however~ and various methods were explored including pyrolysis in silicon oil~ flow py~olysis throu gh a packed tube, acid catalyzed elimination, and pyrolysis in a slurry of sodium benzoate. The packed tube method appeared to give the best yield, but was too slow using the available equipment. The method adopted involved the rapid heating to 180-200° of a rcu.nd bottom flask contaj.nin g about equal weights of sodium benzoate and 2-::l. with vig:orous st:trring and continuous distillation of the products (71). This procedure provided a 35% yield - of the vinyl ketone 28 as de termine d by nmr analysis of the distillate which also contained th e liberated methanol and -- a small amount of the startin g material J - 1. The vinyl Ketone was condensed directly with 2-methyl1,3-cyclohexanc dion e (J-2) (Ch ar t J) in the presence of " ...."'"~ ,;irox·'J. ,;i"' ( '-8) P(.I·,,· a"'"'-;1..· = h' 1 l.i. ? The additio~ product ....... 29 was \.I' ! ' ..:.. 1 ., .-',, .{ l!J .;,, 1.., \..- C 36 resistant to cyclodehydration under the usual conditions of pyrrolidine catalyst in refluxing benzene (58) giving only -- the alcohol 30 which slowly decomposed under the reaction oonditions. This alcohol could be dehydrated with thionyl chloride in pyridine (72), but this two step process was 0 0 29 .......... ~ inferior to the method employed by H. Smith and co - workers (7 3), who carried out similar cyclodehydration s as part of their synthetic endeavors on estrone, Exposure of the cr ud e addition product ......... 29 to triethylammonium benzoate in refluxing xylene resulted in a smooth cyclizatj_on and a 19% yield of -~ the dione J - 3 (from the butanone J-1) was obtained after an ~ aque ous workup and recrystallization. ---- As the demand s for the naphthalenedione J-3 gre w, a procedure which was shorter and more amenable scale preparations \<Ja5 sought. to large It was gratifying to dJ i,c over ---- that the pyrolysi s of J-1 could be carried out in refluxin~ ----- xylene cont aining an excess of the dihydroresorcino l J-2 and a catalytic amount of tri ethyl~mi~e tc g ive the condensation 37 Chart J OCH 3 + OCH 0 J) 0 OCH 3 J-3 J-2 J-1 ------ '-"-"'"' OCH 3 OCH CH o 3 3 J-4 .........,_. J-5 .......__ ------- l j l O1.,"'TI _· 3 J-6 ....,__.. TJ Ct1 O ,, -3 ~ j '' O..... 3 .T-8 38 addition of the triethylammonlum benzoate catalyst, and overnight reflux followed by an aqueous workup then gave a crude solid from which 52-59% of the dione ~J could be obtained on trituration with ether. In addition to the superior yield, this process required only one rather than three days and could be adapted to almost any scale. TI1e reduction, acetylation, and allylic cleavage of -..J-3 proceeded as in the model compound except that the cleavage gave extensive side products unless the lithium wire was fresh,ly cut into smalJ pieces P.nd added rapidly to the solution of the diacetate in ethylamine. It was also ne cessary to have ~~-butyl alcohol present to prevent the formaU.on of lithium ethylamide which could displace the methyl group cf the encl ether givin g an enolate anion which would provide the correspondin g ketone on protolysis. The yields were variable: but under optimum conditions 65% of a crystalline alcohol was available after chromatography. Oxidation with chromium trioxide dipyridine complex (Collins reagent) (74) ga ve 83% of the ketone __... J-4 which was generally treated with dime thyloxosulfonium methylide withou t further purifjcation. The resultin g mixture of epoxi des was reduced im~ed iately with lithi um aluminum hydride in pyridine to g i v e 77 ~; of the de s i re d ax:i.al alcohol ~ to get her -- with a small amount of the equato r ial epimer J-6 which was aJso available in quantitative yi e ld by ad d ition of methyl li thi~m to t he ketone ...........,.., J--4 . ' When t he reduc ti on wa e con duct ed 39 !.nether, format1on :Jf the cyclic ketal ~ occurred as a side reaction. This ketal was formed in 80% yield when a slightly acidic solution of the crude alcohol .__ J-5 in chloroform was allowed to stand for several days at room temperature. Formation of this ketal, although troublesome at first, . was providential in providing an unequivocal proof of the stereochemistry of the axial alcohol ._..._ J-5 since such a cyclization would be sterically impossible for the equatorial - isomer J-6. Use of the pyridine solvent in the hydride reduction served to complex the aluminum thus preventin g lewis acid promoted processes. - The Simmons-Smith reaction of the axial alcohol J-5 was carried out in the presence of one equivalent of dimethoxyethane to precipitate zinc iodide as it formed (75) in an effort to avoid the problems encountered aboveo The reaction was complete in less than 30 minut es and gave a single methoxycylopropane in 83% yield. In order to cleave the cyclopropane ring, it was nec e ssary to treat it with 7% hydrochloric acid in refluxing meth,rnol for two hours. These cond it ions resul te d in extensive dehydration of the tertiary . alcohol and it was most convenient to allow the dehydration to go to coinplet :i.o n to give 74% of the keto-olefin ........_... J~9 • Although the stereochemistry of t h is conpound scern0d assured on the b8.sis of the above results, Jt was desi ra ble to have a positive proof of the assigned structure. A sOlt able con~0und for comp~rls on had been prepared p revious ly 40 by Ireland and Dawson (76) in connection with their polyene cyclization expe r iments. As part of a program to prepar-2 - ccmpounds like the key intermediate G-2, they needed to determine whether a concerted polyene c y clization could proceed through a tetrasubstituted double bond to give a ~r!ns fused decalin or If the cyclization would be interruoted at the initially formed tertiary carbonium ion. -- Bromi~ - nation of 2,3-dimethylbutadiene (K-1) an d coupling with allyl --- gri gnard preceeded well to the sy mmetrical triene K-3 (Ch a rt KO. Hydroboration with one equivalent_of disiamylborane and oxidation ga ve a statistical mixture of starting mater i al, mono-alcohol and dial which was readily separated on flo r isil. Collins oxidation of the isolated mono - alcohol ther. gave the -- cyclization substrat e K- 4 in 26 % yield (from the bu t adiene - K- 1). The best conditions for the cyclization were found to be stannic chloride in ice cold nitro methane follo wed by catalytic hydrogenation of the resultant olefin mixture to provide, after preparative tlc, 40% of the equatorial alcohol - K-5 and 5% of axial alcohol K-6. ~ The s t ereoche mis try of t h e major isome r was proven by x- r ay crystallo gra phic analysis of ---- the p- bromob e nzoate derivative K-7. ln orde r to rel a te the st ereoche mistry of ............. K-5 wi th t ~ a t of the prod u ct of t he cyclopro pane c l ea vage , th e a l c oh ol was -~ oxidize d to th e corr e spondi ng k etone K-8 which wa a tre a te d with m8 thy l lithiu m, Enoliz at ion co mpete d effec t ive ly with 41 Ch a.rt K X K- 1 ..__..__ ~ MgBr Br x Br K-2 OH OH K-5 K- 4 ............... ----0 ---K- 9 ---- K- 8 l '~ a ~ 0 K-10 ,.__..._._ ...... '' ' -J-9 K-6 ----- OPBr B K- 7 ....,,__,_ addition in this case, and it was necessary to repeat the treatment to obtain a 79% yield of the tertiary alcohol ............ K-9 . It was anticipated that the steric hinderance offered by the C-4a methyl group would require the reagent to approach equatorially to give the axial alcohol (69). In support of this expectation, the nmr spectrum of the product K-9 revealed --- that the C-4a angular methyl was deshielded by 20 Hz from its position in the equatorial alcohol K-5, presumably due to its '-- proximity to the axial o xyge n. Thionyl chloride dehydration of the alcohol went smoothly to give hydrocarbon .............. K-10. 42% of the volatile A hydrocarbon which was identi cal in all respects ( i r, nmr, mp, mmp) was obtained ~ia Wolff-K:1.shner reduction of the keto-olefin .J-9 . - thus confirmin g the structural assignment. The initial plan for the conversion of the d i cyclic keto-olefin ~ tc the tetracyclic keton e \G.,.:1 9 f(g)= =-0 called for prepara t ion of the exocyclic ~,~-unsaturated ketone k.~ (Chart L). For this synthesis we proposed the - photo~xygenation of the olefin L-1 which was available in nearly qu rintitatj_ve yield by careful ketalization of J-9. '-'-"" The photoBxygeuation reaction has been widely studied and it has been estahlished that cyclic olefins bearing a - methyl group such as 31 (7?) give ma.inly the product of • hydrogen abstraction from the methyl group, ..... 32 whic h provides ~ the corresponding allylic alcohol ....... 33 on reduction. The data available at the time favored an "ene" type mechanism involving a concerted attack of one of the oxygen atoms along a p orbital of the double bond simultaneously with hydrogen abstraction by the other oxygen atom. Q a a 0-0H 9 31 ----- 0-0H 1 The argument a 32 rnr --33 accounted for the selectivity of the reaction on the basis that only the methyl hydrogens could rotate so as to maintain continuous overlap of the breaking C-H bond with the~ system. The more recent results of Fenical, Kearns and Radlick (78) have implicated tlie intermediacy of perepoxides such as ........ 34 in this reactio~; however, it appears that the reasoning invoked above to explain the selectivity would also be valid fer the decomposition of 34 to products . .....--.. Unfortunately, the olefin ..____.. L-1 proved to be extremely resistant to photocixygenation under a variety of conditions. Using either rose bengal sensitizer in isopropanol (79) or the ozone-trj.p henylphosphit e complex (80) to generate singlet oxygen 1 only starting material and tar were recovered. The Nickon and Bagli (81) conditions of h emat ophoryn sensitizer j n py ridine at room temperature gave better res 11lts and after 132 h ours, gas liquid chromatography indicated that Chart L J-9 L-1 ----- · '-'- ---------- ----------➔ 0 L-3 ---- ---L- 2 I\ 0 L-4 45 H ~ ~ 34 about 2/3 of the starting material had been consumed. The crude hydroperoxide was reduced with lithium aluminum hydride to give 31% of a single allylic alcohol which was assigned -- the structure L-2 on the assumption that the singlet oxygun would approach the molecule from the side opposite the C-4a angular methyJ.. Apparently the steric hindrance presented by the two an g ular methyl groups is sufficient to slow the reaction drastically permitting side reactions to compete. Such a conclusion is in accord with Nickon's results (81 which indicate that the attack of singlet oxygen is quite sensitive to steric effects. While the results obtained by Ireland, Baldwin, and Welch (50) on a related allylic alcohol indicated that the proposed oxidation and 1,4-addition of m-methoxybenzyl grignard would proceed as desired to give the ketone L-4, the ------ inefficiency of the pho t o6xygenation step made other routes appear more attractive. One potentially promising approach to the allylic alcohol L-2 which avoided the photo6xygenation ------ step, the strong base induced cleavage of the epoxide ....35 (82), was considered only briefly before moving on. Later work by D. Dawson (83) has demonstrat ed the feasibility of this procedure in the presence of a more stable protecting group for the ketone. r--\ 0 0 35 .....,_.. One inviting method for the introduction of the side chain possessing the A ring was cleavage of the epoxide ......,..._., M-1 (Chart M) with a dialkyl magnesium. Some preliminary exp eri- ments showed that ether solu ti ons of dibenzyl - or di-m-methoxybenzylma gnesium could be prepared fro m solutions of the corresponding Grignard reagents by precipitation of the magnesiums halides with one equivalent of dioxane in a mo dification of the Christensen (84) procedure, When stirrin g was halted, the precipitate settled rapidly and the s upe rnatan t could be withdrawn with a syringe and added to a solution of the epoxide in dioxane, Usin g dibenzyl magnesium, the cleava ge went smoothly to give the axi a l alcohol M-2$ R~H in 80% yield. ----The al..:!ohol was generally treated directly with the Simmons - Smith reagent to give 45% of the desired methoxycyclopropane M-3~ R=H together with 12% of the cha ra cteri s tic cyclic ,-. 47 Chart M ~\ ~ J-4 ,..__..... M-1 ----- -- M-2 M-4 ----- Mg 48 ketal M-4., R=H. """'"""'' When di-m-methoxybenzylmagnesium was employed in the same reaction, the very first attempt resulted in an yield of the alcohol~, R=OCH give 3 which was carried on to 66% of the cyclopropane ~ , R=OCH ketal Vv"-' M-4, R=OCH 3 as exoected. • 86% 3 and 8% of the Cleavage of the methoxy- cyclopropane in acidic methanol as before gave only 46 % of the contemplated product., the keto-olefin M- 5, probably due ~ to competin g attack of the anisole ring on the carbonium ion formed during the dehydration of the tertiary alcohol. The initial favorable result in the epoxide cleavage with di - m-metho xybenzylmagnesium was not reproducible. Subsequent reactions proved to be highly capricious givin g from 24 - 57% of the required alcohol ~ R=OCH with a host of side products. 3 together A great deal of effort was expended in trying to ascertain the cause of this variability without success. The di-m-•methoxybenzyl magnesium was always titrated (85) prior to use and the a mount of rea gent formed did not vary appreciably from rur! to run. Also the relative amounts of solvents and the reaction ti mes were varied to no avail. After this work had been abandoned, a report by Mo r r is on, At k ins, and Tamaszews k i (86) su gge sted that suspended magnesium chloride dio xinate can be a source of variability in these reactions~ A r e investigation of this epoxide cleava ge should tak e this possibility into account. 49 While the above experiments were in progress, a paper by Brown and Dickason (87) appeared describing a new reducing agent for the preparation of axial alcohols from cyclohexanones opening new avenues to the synthesis of the tetracyclic intermediate ....___ G-2. Several reduction experiments were - carried out on the ketone I-5 to investigate the utility of the new reagent, llthium 9b-boraperhydrophenalyl hydride (!~.::_!), in systems of immediate interest. A typical yield was 64% of a 56:44 ratio of the axial and equitorial alcohols .._...._ N-2 --- and I-4 respectively (Chart N). The ratio of isomers was insensitive to tem~erature between -78° and 25° so the reactions were usually run at 0°. Fortunately, it was soon dis- covered that the poor yields could be improved by modifying the preparation of the reagent. Brown reported that the reagent could be obtained by heating a solution of 9b-boraperhydrophenalene (88) in tetrahydrofuran at reflux in the presence of "a moderate excess of lithium hydride" for three hours. Experience has shown that it is necessary to use a large excess (>than 20 fold) of lithium hydride and to extend the reflux period to six hours to obtain a reliable reagent; it is also advisable to run this reaction under an argon atmosphere since the trtalkylborane is sensitive to even traces of oxygen. With the borohydride prepared in the above manner, it was pos sib le to routinely achie ve a quantitative yield of a 70:JO mixture of the alcohols ..__.,__ N-3 a nd N-4 on reduction of the ~ 50 Chart N 0 N-1 X I-5 X=H ---- · X::::OCH OH 3 OH + X. - OH 0 N-2 X=H N-3 X==OCH .......-- N- 7 3 cn 3o o N-6 ,.___.... '--'- 1ll ....OH ~ .> K-6 N-4 ......_.... = CH l 3 OH K-8 .._,..__.. N-5 -- 51 ketone J-4. ~ The major isomer readily cyclized to the ketal N-5 on standing overnight in deuterochloroform in an nmr tube ~ while the miner isomer had been prepared previously so that the stereochemicaJ outcome of the reduction was clearly defined. When the crude mixture of alcohols was treated with an excess of the Simmons-Smith reagent, once again a facile reaction ensued providing 59% of the methoxycyclopropane N•~6 ( f'.r•om the ketone ~ J-4,'I after chroma to crraphy. ~........... The c ...y clo,, 0 propane ring cleaved as expected on treatment with acid to give 80% of the keto-alcohol ..._ N-7. ... With the more s t able secondary alcohol at C-1, it was possible to achieve ring opening without concomitant d2hyd r ation by following the reaction and sto ppi ng it when the desired transf ormation was co mplete. This represents a more versatile synthesis of the traE~s_-fused, di a ngularly substituted n3.phthalene of the ----- type G-3 than that accomplished before (Cha r t J). The keto- olefin N- 7 should be an admirable synthetic inter med iate since it is potentially a masked, symmetrical diketone. In or der to p~ovide unequivocal proof of the stereo- - chemistry of the ring fusion of N-7 it was necessary to -- relate it to the alcohol of known configuration K-5. Wolff- K:l.s hner reduction of N-7 preceeded poorly s presumably due to ---- the steric hindrance to hydrazone formation associated with the angulQr methy l gro ups and the axial alcohol, b ut did 52 prcvide 23% of the alcohol ...,_,_ K- 6 which was spectrally identical (rnnr, :tr) to the minor i5omer obtained by Ire l and and Dawson Chromic acid oxi-dation gave the ketone K-8 which was identical in all resfrom the cyclization of the aldehyde K-4 . ·- pects (ir, nmr, mp, mmp) to that prepared by a similar oxidation of the equitorlal alcohol .!S.::.2.• With the successful culmination of this phase of the work, it was appropriate t o consider methods for adding the A and Brings to the ketoalcohol tt:l• The most direct approach would be to add a p-phenylethy l side chain to the carbonyl and then to manipulate the rin g functionality to provide a suitable substrate for the acid catalyzed closure to the tetracyclic ........._ G- 2. In order to impli- ment this plan, it was first nec e ssary to convert the alcoh o l to a more stable group. Taking advantage of the symmetry of N-1t the ketone was protected as the ketal, , a reaction which ~ was accompanied b y extensive dehydration of the seconda r,y alcohol. Thus ketalization of ~..::] gave only a 68 % yield of ---- the ketal 0-1 which was oxidized qua ntitatively to the keto~ e 0- 2 with chromic acid (Chart O). ,.__.., The dehydr a t i on products proved to be a complic a ted mixtur e in contra st to the situation encoun te red be f ore with t he alcohol J-8 ( Chart J). -~ One poss ib le e x plan a tion for this 36 could result is th a t t h e i ni t i al l y formed c arb cni um ion ,..,_ loos e a pro ton fro m re arra n geme nt t o th e mo r e s t a b le t e r t i ary carbon ium ion ,37 ...... wh ic h co uld loc~ e a 5.3 proton in either of two directions or rearrange further. There is no __ a ..____._ oriori reason to expect a single process to predominate. -r'I+ An atte:np'~ to add the side chain by trer,.t.nwnt of the ketal 0-2 with 2-m-methoxyphenylethylmagnesium bromide led only to ----reduction of the ketone. Such a result had heen encoun t ered previously by Barltrop a nd Rogers (89) in their attempt to add the Grignard reagent to the cycloh~xanone 38, These worlcers turned to the less hindered potassium m-me thoxy- phenylacetylide (0-3) which they formed by addition of the ----... corresponding acetylene in ether to a sclution of potassium amide in liquid armnonia. Addition of an ether solution of the ketone 38 gavet after catalytic hydrogenation over --- palladium on carbon and distillation, 80% of the alcohol 39. ·- In the present case, it was more conveni ent to form the acotylide by the dropwise addition of one equivale nt of the acetylene to an ethereal s olution of n-butyl lith i um. The svbt'>t:rate could then b e added a nd the ensuing react1on coulcl be followed by vpc, After four hours no f urther c hange was 54 Chart O 0-3 ......_... z OH N-6 .....__ CH ---0-1 Z=5«--0H, 5~-H 0-2 Z= =0 o 3 0-4 0-7 ......... -.:... 55 OCH 38 ......... 3 39 discernable and the product was obtained as a 60:40 ratio of the addition compound and starting material after chromatography. The mixture was hydrogenated under the published conditions to give a similar mixture of the alcohol O-4 and ~ the starting ketone 0-1. This crude product was dehydrated with thionyl chloride in pyridine to give an overall yie!d of only 38% of the olefin 0-5 tha t was readily separable ............... Once again it appeared that --the steric hindrance attendant with the disubstituted ring from the starting ketone 0-1. fusion, in this case butressed by the axial oxygen of the ketal, reared its ugly head to render a promising route mediocre. In spite of this setback it was decided to press on in hopes of obtaining a sample cf the tetracyclic 'G-2 for comparison --'~ with the product from other more efficient routes. Hydroboration of the olefin 0-5 proceeded slowly and ----- after two hours at ro om temperature 37 % af the secondary alco- hol 0-6 was obtained on oxidation along with ------ of recovE,red 56 starting material, while longer reaction times led to lower yields. Chromic acid oxidation of the alcohol did go well to give a quantitative yield of the ketone~- This ketone, unfortunately, was resistant to attempts to add a methyl When it was treated with ---methylmagnesium iodide, dimethylmagnesium, or methyl lithium group and form the alcohol 0-7. at temperatures ranging between -78° and 25°, only recovered starting material was isolated. At the time it was concluded that enolization of the ketone was occuring, again due to the bulk at the ring fusion, and this route was abandoned. In light of the reasoning that most of the problems with the above scheme were associated with the steric bulk of the ketal and angular substituents, it appeared that the route could be resurrected if this factor could be controlled. One simple method to achieve this would be to delay the - cleavage of the methoxycyclopropane system of N-5 until the other transforma tions were complete. The intact cyclopropane ring should have the effect of flattening the ring system while at the same time tying back the carbon atom that would later become the C-4a angular methyl. An additional advantage of this innovation is that it would avoid the inexpedient ketalization of the keto-alcohol N-7. --- In accord with the abcve plani the methoxycyclopropane N-5 was oxidized with chromic acid to give 73% o f the ketone ---P--- 1 (Char t P). On treatment with 2a•m-rneth oxyph e nyl ethy1- 57 of the reduction product, the alcohol N-6, and the addition ---- product M-3, R=O Me. ----- When lithium m-met h oxyphenylacety l id e was employed under the same conditions used before and the crude propargyl alcohols were hydrogenated, 44% of the a x ial ---- alcohol Ii:) s R=OMe and 1~6% of the equatorial iso mer P-2 were recovered, The stereochemical assignment of these products was based on the higher tlc mobility of the axial isomer and was confirmed by the dehydration experiments described below. It is possible that a higher portion of the desir e d axial alcohol could be obtain~d by running the reaction at a lower temperature than 25°, This point was hot pursued in the present work because a shorter and preparative ly more useful - route to the tetracyclic ketone G-2, f( g )~o had just be e n complete by C, Kowalski (90) in the Ireland laborat orie s changing the purpose of this work to that of provi d in g a sample of the same co mpound whose stereochemistry ab out tr. e C/D ring fusion wa s ri g orously defined for comparison. Both the axiaJ. a lcohol M-3 , R"' m 1e and the equatorial ~ lsome r P-2 were c c h yd r ated with thi ony 1 chloride in pyrid 1 :-1e ~ P~4 respecti vel y . to give 91% and 43 % of the olef:L ns ~P~ 3-- an d .................. --- The assi gnme nt of P-3 a s the end oc y clic clefi n was based on the relat1.ve w:i.d.tbs of the vi.ny l p roton pe a ks in t he fo:J.I' spectra., 12 v s 20 Hz for the exoc y clic olefi n -- as t he fu ~ther r eactions of P- 3, The ex oc yclic ole f i n is ex p ected to e xhibit a bro a d e r v i nyl r esona nce si nce themmctho xy b e nzyl sv.b stituE,n t can rotate fri~ely all owi ng E·.f:C:iclP.nt. 56 coupling between the benzyl and vinyl protons, while in the relatj_vely ri g id ring, the various protons exist at fixed dihedral angles. The result of the dehydration experiments verifies the stereochemical assi gnment of the alcohols o~ the strength of Barton's criteria (68). Hydroboration and subsequent oxidation of the olefin t::] ---- proceeded without incident to the ketone P- 6 in 62% yield. Treatment of P-6 with ten equivalents of methyl lithiu m at room temperature provided 90% of a single tertiary alcohol assigned the structure ..,..., P-7 on the assumptio~ that the methyl anion would approach equ a torially to avoid a 1,3-diaxial interaction with the C-4a angular methyl. The facilit y of these transfo r ma t ions provides support f or the hypothesis that the proble ms associated with the previous e fforts (Charts Land 0) were indeed steric in nature. The alcohol ._._ P-7 was treated under the conditions used previously to cleave t h e methoxycyclopropane rin g syst e m and the reaction wa s followed by analytical tlc. The tertiar y alcohol dehydrat ed fir s t g iving rise to a very mobile spot which slowly gave way to a sli ghtly less mobile spot corre- ---- spending to th e mixture of ol e finic k e tones P-8. Preparative tlc of the crud e p roduct g ave 91 % of a colorless oil which consi s ted of a 'l 0 : 30 mixt ur e of th e t e trasubstituted and tri s ubstltutcd double bond i s cm (~ rs by nmr inte gration of' the a n g ul n:r methyl regi on. 'J.' h e olc fl n m:!.x t u r-e ViH~' na.:l. nt ~: n~d a t r•e f lltx for s ev e ra l 59 Chart P QH 0 0-2 ----,, CH -o CH 0 3 3 ---- P-1 N-5 ~ + ClLO j M-3 ,__.... R==OCH 3 P-2 l l P-3 --- ------ P-5 P-4 60 Chart P (continued ) P-7 ---·- P-8 ------- + CHO 3 P-9 P-10 ~ II I 111 OCH "0 OF·3 ...... ...'-... 3 61 hours in a 20% solution of p-tolulenesulfonic acid in tolulene to effect cyclization. Chromatography gave 78% of an 80:20 ratio of' two compounds which were assigned as the ~::1s, ~E-~, trans and~, ~nti, trans ketones ~:2 a n d ~ respectively. Later, for preparative purposes it was found t hat the cyclization went better in refluxing trifluoroacetic acid and that it wac possible to achieve a 94 % yield o f a 85:15 mixture of the two ketones from which 65-70 % cf t h e desired ketone ....,..._ P-9 could be obtained by djrect cr y stalliz a tion fro m ethanol. The components of the mother liquors were extre mel y resistant to separation, but could be partially pu r ifi ed b y careful chro ma t o graphy on grade I alumina (91). The overall yield of the ketone ..___ P-9 from the dibne .....__ J - 3 was 3.3% in 15 steps. That both the ketone isomers were the products of c y cli za tion E3:..E_a to the methoxyl group was evident from their ir spectra which exhibite d aromatic bands at 1600 and 1500 cm-1 . - A small sampl e of the 4-methoxy - isomer of P-9 resultin g fro m ortho cyclization was obtain e d b y C. Lipinski (92) from a concerted cycll za t:l.on (vij _t ~ ) 8.nd th i s ma teri ,.1.l had 1 aromat~c bands in the i r a t 15 9 5 and -r~~ l ~( J cm -1 . Of the four p os si ble tetra cy clic 2-me t h ox y- i some rs, the two syn isomer s coul d • ..i..-,. 0€ d ro p ped from consi dc r a.tlo :--1 t. c c a u se thei 1• formation wo ul a r e q uir e eq u itori a l protonat i o n a t C-5 of ~0 and r e qu i r e t h a t the Cr i ng adop t a n un favo r a b l e twist '-'- 62 boat conformation or suffer a secere 1,3-diaxial interaction between the C-8a angular methyl group and the axial side chain. Both of these processes are expected to be of significantly higher energy than the alternatively possible stereoelectronically preferred axial protonation at C-5 of 40 leading to CH 0 3 CH - 3 the conformers 41 and 42 both of which have ring C in the ---- more stable chair form. Of the two, cyclization is predicted to occur mainly through the conformer:!]- to give the trans, £!:}ti, trans tetracyclic P-9 because the developing 1,3- ----- diaxial interaction between the incoming aromatic ring and the C-4a angular methyl group in ~2 should ma:.-~e cyGlization '-" th1·ough thts conformer· a less fa,vorable process (50). That the requJ.r8d trans_, anti, trans isomer did p::•edominate was readily appa1·ent from the nmr spectra of the two :1.soated ketones. As can be ascertained from the conformational drawi.ngs, the cis isomer P-10 is folded s~ch that t~ere is -------- 63 CH I 3 41 ,._,.._ - CH , 3 42 a 1,3-interaction between the aromatic ring and the C-lOa an gu l.ar methyl group so the methyl should be strongly shielded in the nmr. No special effects on the methyls of the flat t.~- isomer are expected so that the two sho uld be clearly differenti ated by their spectra. ont fully as shown in tnb le 1, This presumption was born The chemjcal shifts of various methy l gro ups are reasonably si~ilar ex ce pt for the C-lOa methyl which appears 29 Hz up fie l d Jn the r:-::!nor, ~i~- isomer ,.__...__ P-10. ___ I n support of this analysis a similar result has been observ ~d in the cyclization of the tertiary alcohol de rived fr•om thF. a:J.cohoJ. E-5 (Chart E ) during r.:.h2 synthesis of alnusenane (39), 64 TABLE 1 NMR 60 MHz trans B/C (P-9) cis B/C (P-10) 224 Hz 224 Hz C-4b CI-I3 71 Hz 70 Hz C-6a CH 3 73 Hz 78 Hz C-lOa CHJ 1i9 Hz 20 Ez C-2 OCH 3 Almost simultaneously with the synthesis of the ketone P-9 in this work, the same compound wa s prepared by two ---..;. alternant routes by C. J. Kowaiski (9 0 ) and c. A. Lipins k i (92) in the Ireland laborator,ies. The products from all three syntheses were identical ln all respects (irj nmr, mpt mmp) and neatly correlated th e individual efforts. The scheme developed by Kowalski (Chart Q ) i n volved generation of the crucial C/D rin g fusion by a stereoselective hydrocyanation of the enone Q-6 and reduction of the cyanide ------ to a methyl group. It provides a 10 % overall yield of the tetracyclic keton e P-9 starti ng from m-me t h oxy cinnamic acid in 15 steps. The third syn t he s is of P-9 wa s achieved by Li pinski ----- throu t::>ah the triene ,R-6 (Char t R) in a conti n uation o f the _____ polyene cyclization studies init ia ted by Irel an d an d Da ws on (76). This sche me provided an o verall yiel d of 2.0 % fro m th e dibro mide R-1 i n 12 ste ps. -------- 65 Chart Q co HCH 2 OCD 3 - Q-3 Z=OH,H ----Q-4 Z== =O Q-2 Q-1 .........- CH 0 ....,._,.., CH 0 3 3 Q-5 Z= =O Q-6 Z= lp -OH, lo<-H '----~--- Q-7 ._..._.._ ~ CH 0 3 Q-8 ............. P-8 ............. Q-9 '-~ 66 Chart R R I! 11 R R-1 '-"'"" X 0 ) R- 6 R-7 ....__ R.--8 67 The hydrocyanation route is the method of choice for preparative scale synthesis of !:2 both from the point of view of overall yield and ease of isolation of the intermediates. Assurance of the 3tereochemistry of the C/D ring -- fusion of P-9 rested on the experiments conducted in the - present work relating the dicyclic keto-alcohol N-7 to the - alcohol of known stereochemistry K-5. In the hydrocyanatio~ - scheme the C/D ~ and trans isomers of Q-7 were distinguished only on the basis of the relative intensities of the nitrile stretching band in their (93), and in the polyene cyclization route the C/D trans configuration was assigned on the precedence established during the earlier cyclization experiments ( 76). In view of the importance of the tetracyclic ketone ,_.._.... P- 9 as the common product of three synthetic schemes and as the potential key intermediate j_n the total synthesis of the triterpenes shionone, alnusenone, and friedelin, an unequivocal proof of its structure was sought. This was obtained through a sin g le crystal X-ray structure analysis performed by Benes L. Trus, Gary Frank el, and Richa~d II. Stanford on a sample of the ketone (mp 153-154°) which was prGpared by the Simmons-S~ith route (fi gure l). The ketone crystallized 0 (ether) in space group Pna 2 with cell constants a=29.922 A, fou r molecules cc~ur in the unit cell. The struct ur e anal ysis was bas2d on 1 9 70 nonzero reflections of which 1 35 were 68 emitted from the least squares refinement. F5.gure 1 STEREODRAWING OF THE TETRACYCLIC KETONE P-9 With a satisfactory supply of the tetracyclic ketone p_g ...,..:. assured by the foregoing worki attention was directed ~ at the const:r-uction of the A ring of shionone ..__. 43. It appeared _that the most direct approach would be first to rnonoalkylate the C-1 position of the enone 411 ...,._ resuJ.tj_ni:; from Birch reduction of the aromatic ring of ..._..._ P-9 followed by introduction of the C-=12a angular methyl group Y. ?-:. A a hydrocyanation or a cyclopropane cleavage. Since the potential efficacy of this procedu r e could be simply tested by the atte mpted pre paration cf th e monoalkylated product 45., consideration of alternative path- '"'"" ways was deferred pending the outcome of the initial experiMi:!nts. 0 R 44 R:;,H 115 '-""' R-CH - 3 The problem of monoalkylation of «,p-unsaturated ketones similar to ....... 44 has been investigated at length in the steroids . Until recently the only successful solutions involved cleavage of the A ring and recyclization (94) or careful alkylation with methyl iodide--potassium tert-butoxide (95) and neither of these procedures were applicable for small scale preparations due to the poor yields generally realized. However, hopes for the sucessful conclusion of this endeavor were heightened by Wendler's (96) communication that a transformation such as that desired was achieved startin g with the ~,i-unsaturated ke t one!:.§ u ~in g one equivalent of a strong base (lithium triphenylmethide). A second method . was also available from the work of Kirk and Petrow (97)~ who prepared steroidial C- 4 thio -Mannich derivatives such as ~7 by --- treatment of the correspondin g enone with form a ldehy de and thiophenol in the presence of a basic catalyst. Desulfurlzation 70 then gave the desired monoalkylated products in up to 80% yield. 9 46 '-- 47 --- Before the A ring synthesis could be tackled, it was necessary to consider means of modifying the ketone in the D ring of ....,.._,,_ P-9 so that: 1) it would not interfere with the anticipated manipulations, 2) it would be differentiated from the C-2 ketone which was to be generated in the A ring, and 3) a suitable substitution pattern for the introduction of the side chain would remain. Conversion of the ketone to ---- the 41 7-olefin S-3 appeared to be an ideal solut:ton to the problem. It was anticipated that the steric bulk of the neighboring angular methyl grou ps would serve to help protect the double bond and, when required, to assist efforts to functionalize it selectively at c-8. Initially 1 it was planned to prepare the olefin S-3 ~ through dehydrosulfonat ion of the mes:y·late S-2. . .......,__ The ketone P- 9 was re covered q uan ti tat i ve l y frorn trea trr:en t ',vi th an .._.,_,._ excess of sodium borohydride in ethanol at room temperature er.ha.ne:ing our confi de nce in the steri c shieldi.n g afforded the 71 C-7 carbon atom by the ring fusion substituents. When the ketone was reduced with lithium alum~nurn hydri.de in tetrahydrofuran, a 97% yield of the axial alcohol ....._,_ S-1 was obtained without incident. The stereochemical assignment of the alcohol was based on the steric hindrance to axial attack of the rea gent (69) and was supported by the nrnr spectrum of the reduction product which revealed that the C-lOa angular ~ethyl group was deshielded by 14 Hz from its position in the star t ing material. Unfortunately, efforts toward preparation of the mesylate .__ S- 2 led only to formation of a dark oil that consisted of a variety of decomposition pro duc~s according to its nmr spectrum. Rather than pursue thls u.nele gant approach, lt was decided to turn to a new pr~1cedure for the conversion of ketones to olefins which was developed by D. Muchmore (98) in the Ireland laboratories. This method consisted of the alkali metal induced reduction of alkyl or encl phosphorodiarnidate esters to the correspondin g saturated or olefinic compounds. In order to apply th e new procedure, the phosphonate ester ,.,...._ T-1 (Chart T) was prepared in 88% yield by the addition of N,N,N' , N'-tetramethyldiarnido- phosphorochloridate (99) to an ethereal solution of the enolate anion generated from ...__ P-9 by the action of lithiuffi diisopropyl amide. When this ester was reduced with a large exce ss of the lithium biphenyl adduct in tetrahydrofuran under the conditions prescribed by Muchmore (100)} the product obtained in 62% yield wa 5 the phenol ............ T-2 rather than the correspondin g 72 Chart S CH 0 CH 0 3 3 CH 0 3 S-3 ---- S-' 1 ---- R=H 73 methyl ether .__... S-3. Such a r e sult is precedented by the re3ults of Eisch (101) who has found that anisole is cleaved to phenol by the action of the lithium biphenyl adduct in refluxing tetrahydrofuran over· the course of four and one half hours. It was hoped that this cleavage would not compete with the desired transformation in this case since the reaction concitions were more mild (1 hour, room temperature). The use of the lithium biphenyl cleavage was not precluded by the above result since the phenol ....,.._ T-2 could be remethylated to give the desired anisole derivative S-3, and it is possible ----- that the selectivity of the reduction could be improved by limiting the amount of reagent or the reaction time. How- ever, in order to avoid an extra step$ it was decided to explore the attractive prospect of carrying ou t the phosphonate cleavage and Birch reduction simultaneously. While Muchmore (102) reported that the phosphorodiamida te esters ......,_ 48 and '--" 49 were inert to lithium in ammonia, the preliminary reduction experiments on ....__ T- 1 were carried out ln ammonia sinc e mo st Birch reduction proc e dure s employ this solvent. In an early experiment usin g an e xc e ss of lithium and ~ - b u t y l alcohol as the p r oton s ourc e to promote reduc:tion of the aromatic rin g , t he i n te r me d i ate dihydroanisole obtained was hydrolyzed with aqueous oxalic acid to provide 42 % of' the f3 ,'(,••unsatu r ated k et or:e ~ ve r ifyin g that the cleava ge of encl phosph0diamida. t es wa s feasible wi.th lithium in a~non ia , Att e mp ted alkyla t i on o f T-3 u nde r t he Wendl e r ~ 74 0 R OP [N ( CH ) ] • 3 2 2 48 .....- OP[N(CH ) ] • 3 2 2 49 ..... conditiohs led only to the dialkylated product T-4 in 61% ~ yield, possibly due in part to the small scale on which the reaction was conducted. The outcome of these experiments prompted a more extensive investigation of the reduction steps and a search for a more efficient monoalkylation procedure. Muchmore (103) found that for the lithium in ethylamine phosphonate cleavage reactions, added tert-butyl alcohol was necessary to supress the formation of side products, Thus during the initial experiments on the reduction of T-1 '--"-~ this proton source was included from the start of the reaction. From an intermediate scale rectuction (110 mg) 40 % of the anticipated product 'U-1 was isolated to get her with --- 35% of the diketone 50 which arose from P--O cleavage of the phosphonate ester T-1. '-"~- It was quickly ascertained that formation of th1s cU.ketone- was dependent on t he presence of the proton source. When the cleavage was allowed t o proceed for five hours in the presence of a moderate exc ess of lithium an d the re rnaini n G lithium was decompos e d Ly addition 75 Chart T CH..,O CHO 3 J P-9 ------ \\ -::::- -~ l1 b -- - T- 3 T- 2 ....... 0 1 ) 76 50 '-'""' of sodium benzoate (104), an 82% yield of the olefin reali z ed. This could be further reduced in a normal Birch r6action to g ive 78% of the unsaturated ketone .._..._..... U-1, or ~ore conveniently, the two steps could be tel es coped together by allowing the reduction to proceed five hours ~nder anhydr ou s conditions and then for two hours more after addition of l£Ei-butyl alcohol. ~ This procedure netted 78 % of the enone after chromato graphy implying that very little of the phosphodiamidate could have suffered P--O cleava ge. Products of P--OR bond cleava ge have been observed by - other workers. Kenner and Wil li ams (105) obtained small amounts of phenolic and water soluble materials in addition to aro mat ic hydrocarbons from their pioneering reduction experiments on phenolic diethyl~h os phate esters. ( .1.... I0 u c. I' l' 1 ....;1 h. 1· R,. at t·•,, c; l"' ' !YJ t Muchmore t o' r .:... d u c ·- t he '-4 "- 2 - c n· ,~. , 1· e ~c:. t P-- r1• y ]_ ,--c .·n o c:~ _,-_) h a•. t.- •">~ O O 51 with either the lithium biphenyl or lithium naphthalene •...,..-. adducts in dimethoxyethane, obtained essentially only 77 Chart U 0 OP[N(CH) ] 3 2 2 ~ S-3 rr-1 .........__. ~ i~1 i I '--✓ 0 U-1 78 0 (EtO).,._PO C. 52 51 .......... cholestan-3-one ......,.. 52 which he demonstrated did not arise by hydrolysis of the ester during workup. The dramatic shift in reduction products in the presence of a proton source has no precedent in the previous work and indeed, runs contrary to the results obtained by Muchmore from reductions carried out in ethylamine solvent. The cause of the anomalous cleavage is obscure and was not pursued in the present work since an excellent reduction procedure was developed to get around the problemo With a good route to the c(,~-unsaturated ketone~ in hand, it was decided to carry out a model study on the more plentiful analo gue ~_l, particularly since preliminary experiments applying the Kirk and Petrow (97) alkylation procedure to the unsaturated ketone ,.__..___ T-3 gave .poor yields. The tricyclic ke tone V-4 hed been prepared previously by ------ Church, Ireland~ and MarBhall (107) and appeared to be an 79 ideal model as it possessed A, B, and C rings which were -- identical to those of the tetracyclic ketone U-1. Rather than prepare the model compound by the original route, a more efficient alternative seemed to be available based on the reductive alkylation results achieved by D. Evans (108) in the Ireland laboratories. The tricyclic -- enone V-1 (Chart V) was prepared accordin g to the procedure described by Evans and was added to ge ther with one equivalent of water to a solution of lithium in ammonia and tetrahyd:rofuran, Addition of methyl iodide to the still blue solutio~ ---- then led to formation of the ketone V-2 in 80 % yield, The Wolff-Kishner modification developed by Nagata (1 09 ) in which hydrazone formation is carried out under buffered conditions - was employed to obtain 88% of the anisole derivative V-3, and Birch reduction as described by Ireland (107) provided 78 % of the desired c<..~ .,, unsaturated ketone ~ . yield for the three steps was 'J'he overall 55%. Attention was first directed toward monoalkylation at C-1 of the ~,~-unsaturated ketone V-4 using the Kirk and '-- Petrow (97) procedure discussed ab ove, Of the two variations they developed, the one emplo yinf formaldehyde and thiophenol with ethanol as the solvent and triethylamine ns the basic catal ys t proved to be superior to the one using triethanolami~e as both the catalyst and solvent, possibly due to the difficul ties associated with ha~dling the small amounts of trieth ano lamine required (0.5 ml). The thioe th er V-5 was ....----. 80 Chart V CHO CH 0 3 3 V-2 -- CH 0 0 3 V-4 ............... V-3 -------- V-6 '--""""' + Ho'' V-7 ~ 61 freed of polymeric materials by chromatography and was desulfurized with raney nickel in ethanol at 0°. The desul- furization conditions used were those described by Coates (110), because the Kirk and Petrow conditions, raney nickel in acetone at reflux, did not give as reproducible results. --- Even under the optimum conditions, the overall yield of V-6 was only 36% for the two steps. The low yield may be due to - concomitant aromatization of the A ring of V-4 during the condensation even though oxygen was rigorously excluded from the reaction mixture; such a side reaction was not likely in the cases tested by Kirk and Petrow since the compounds all possessed stabilizing C-19 methyl groupse In spite of this disappointing result, it was decided --- to continue with the ketone V-6 in order to provide a sample of the tricyclic with a completed A ring and to ascertain the desirability of developing new methods for monoalkylating the ----- C-1 positions of the unsaturated ketones U-1 and V-4. '-- The most direct approach appeared to be preparation of an C-2 axial alcohol from V-6 by reduction with the trialkylborc'-'- hydride reagent ~-1. ~,..... It was anticipated that this alcohol would direct attack of the Simmons-Smith reagent to the desired p-race of the ~ 1 -ctouble b ond to give the A/B trans fused product. Oxidation would then give a cyclopropyl ketone, which acccrd:\.ng t.o the res u.l ts o-f Dauten ( 6 5) should be susoeptib le to reduc t ive cleavage to provide a tricyclic derivative possessing th e required A ring. 82 When the cr..,~-unsaturated ketone ~ was reduced with lithium perhydro-9b-bo~ophenalyl hydride (N-1), the isolated ......,_ yields of allylic alcohols was an unfortunate 63% of the -- equatorial isomer V-7 and only 20% of the axial isomer V-8. '-""""' The stereochemical assign ment was based on the hi g her tlc mobility of the minor isomer ind the relative widths of the nmr absorbtions of the C-2 hydrogens, 18 and 10 Hz for the major and minor products respectively. That the larger coupling is associated with the equatorial alcohol is a well established result in six membered rings (111) since vicina~ axial protons couple more efficiently than equatorial protons. A final assurance of the stereochernical assi gnment was pro- vided by the lithium aluminum hydride reduction of the keton e V-6 which led to a 93:7 ratio of the equatorial and axial ---- alcohols as anticipated (69). The eauatorial alcohol V-7 • --- ----- could be oxidized with the Collins rea gent back to V-6 in 97% yield making the total yield of the axial isomer 40% when the equatorial alcohol is recycled twice. Both the allylic alcohols were carried on in order to provide samples of both the cis and ~S.. fused analo gues of the natural A ring '-' 43. ...... The equ a tori a l alcoh o l V7 wa s ~ ,..... treated with the Simmons -Smith r eage nt i n a r e a cti o n th at was complete in two ho ur s to give 90 % of the d e r ived ~Jic1 o propane W-1 (Ch a rt W). ~ Th is a l co h ol wa s readily ox i d i ze d with the Jona s reag ent to give 93 % of the cyclo pro py l keto ne Dauben and Deviny ( 65) have st udi e d t he r e duc ti ve 83 Chart W V-7 ...._..__ W-1 ...______ W-2 ----- HO W-4 V-8 ..___, ------~ ()~ w-5 ....,._,-,. W--6 53 54 __..,. 0 0 --56 55 ,..._,.. cleavage of cyclopropyl ketones and have shown that the cyclopropane bond that best overlaps the carbonyl 'ii' bond is preferentially cleaved. methanccholestanones Both the 4~,5- and 4~,5- 53 and 55 are reduced to the corres- ponding methyl compounds 54 and 56 in good yield. ---- Thus it was somewhat surprising to find that the cyclopropyl ketone W-2 was cleaved only with difficulty by lithium in ammonia ,._,_._ and gave only 37% of the ketone W-3 a.nd 18% of a second irnpu1·e ~ ketone which may have been the alternat e cleavage product with ·a seven membered A ring. The major product was recovered unch a nged from an attempted isomerization with ethanolic potassium hydroxide i ndi cating that essentially only one C-1 isomer of W-3 exists at equilibrium. ------- The Simmons-Smith reagent reacted more sl owl y ·,d.t h axial alcohol V8, requiring four hours to g ive -..,...._._ 61 r of v!le 4- • 85 58 57 ......---- ---- cyclopropyl alcohol W-4. The greater difficulty in carrying ----out the Simmons-Smith reaction with the axial allylic alcohol is in accord with the results obtained by Chan and Rickborn (55) who found that the allylic alcohoi 57 reacted n.t abo"'i 1.: 1/3 the rate of the isomeric alcohol 58 in competition experiments. ---- Jones oxidation of the alcohol W-4 gave 89% of the correspondin g ketone which was reduced smoothly to the ketone W-6 in 78% yield using the same conditions as above for the ---- ----- isomer W-2. Assignment of the C-1 methyl group of ,___.... W-6 as 0 • was predicated on the results of Tsuyuki and co-workers(l12) who prepared 4~-shionone and friedelin by photoisomerization and showed that these were converted quantitatively to the natural l!t>-isomers by base treatment. 1-'he conformational forces requiring the secondary methyl group of the natural products to be in the ~-position a~ equilibrium should be ~- W-6 . and 1-7 very similar in the synthetic int e rmediates . ~ infra) since the A, B, and C rings are identical. ---- With the syntheses of the required isomers ~-3 and W- 6 successfully ------ 86 --- negotiated, a new route to W-6 was sought which would avoid the inexpeditlous thioma!1.nich condensaticn aild borohydride reductj_ons. One attractive approach would be to prepare the cyclo- --- propyl ketone X-4 and to reductively methylate it by trapping the enolate anion formed from the Birch cleavage of the cyclopropane ring with methyl iodide. Some preliminary experiments carried cut by D.R. Marshall in the Ireland laboratories indicated that the borohydride reduction of the enone V-4 gave a more favorable ratio of isomers than was ~ obtained from V-6, so that a reasonable synthesis of ~-... X-4 ___,._...._ appeared feasible. Althou gh the only reported attempt to trap the enolate anion formed from a reductive cleava ge of a cyclopropane ring gave poor results (113) 1 the potential efficiency of this route made the point worth reinvesti gation. Reduction of the enone ~-:3. with the borohydride r e,~gent - N-1 gave 41% of the desired axial alcohol X-2 (Chart X) ............ together with 54% of the 8quitorial isomer 'X-1 which could --- be recycled by Collins oxidation (96 %) back to the enon e V-4 ...,._,. and reduction to give a total of 63% of the isolated axial. alcohol X-2, The two alcohols had previously been prepare d by Irciand and co-workers (107) who established thei~ stereochemi3try. The S:L ;nm::rns-Sid. th reaction proceeded better on the aJ.lylic alcoho l X-2 than lt di d on the corre s pc~d!ng ax i al '-".....,_v-,_ 87 alcohol V-8, perhaps due to the reduced steric hindrance '--- about the double bond in the former case, giving 83% of the alcohol X-3 which was oxidized directly to the ketone '--- X-4 in 93% yield. When the ketone was reduced with lithium -----in ammonia and the blue solution wa.s quenched directly with methyl iodide, only starting material and the unalkylated product 59 were recovered. -...-. 59 .___.... Very recently, Stork (43) renorted a successful reductive alkylation of the cyclopropyl ketone ........... 60. When the reduction was carried out in the presence of tert--butyl - alcohol, 60% of the methylated product 61 could be obtained if the reaction mixture was warmed to 0° as most of the ammonia evaporated and the methylation was conducted with added hexamethylphosphoramide (HMPA). Before the Stork paper appeared, it was decided to -- attempt to trap the enolate anion formed by cleavage of X-4 as the enol acetate in order to verify that the required anion was indeed present and to ~rovide a source from wtic h the enolate anion could be regenerated under rigorously defined conditions. The reduction was carried out as be f ore 88 OH OH -- 61 except that the ammonia was evaporated in a stream of argon and the tetrahydrofuran was heated to reflux to drive out the last traces of ammonia before the reaction mixture was quenched with acetic anhydride. Thick layer chroma tography of the crude products then gave 72 % of the encl acetate X-S. ------=-- When the enolate anion was regenerated and alky lated in dimethoxyethane under the House (114) conditions, by treatment of X-5 with two equivalents of methyl lithium followed '--- by an excess of methyl iodide, only 20% of the desired product W-6 was obtained after preparative thick layer chroma- ----- tograp hy tog ethe r with 10% of the unalkylated material 59 and 40% of polyalkylated products. While it seemed probable th at a more favorable p ortion of the monoalkyl a ted product .._,..._.. W-6 c ould be a t t ained by a careful control of the reaction condit ions, a report by Whi tlock and Ove rman ( 1 1 5) describing the a l kyl ati on of the enolate 89 Chart X 0 HO'' X-2 X- 1 ----- V-4 ---- ,,,,, ,, ,,, \ .. - 0 HO X-ll X~3 ............... -----. I ,,,,, ·-'> HQ ..... ,,, ,,' Y.-5 ...__ X-- 6 90 anion 62 by treatment with the Simmons-Smith reagent attracted '"" us to the possibility of using a variation of this procedure for the alkylation of the enolate derived from X-5. ----- Whitlock and Overman obtained directly 65-75% yields of the monoalkylated product 63 as a 3:1 mixture of the cis and trans "-" fused isomers. The enolate anion was regenerated from X-5 ----- as before in dimethoxyethane and the solution was treated with a large excess of the Simmons-Smith reagent in ether. The crude product wa s dried briefly over magnesium sulfate and the residue~ following concentration, was chromatographed on grade III alumina to give 73% of the cyclopropyl alcohol o62 ----Whltloc Jt was urw.ble to isolate the corr2spondlng aJ.c-.ohol which mt.:st have b2en an intermediate between the cnolate anion 62 and the ketone .......... 63 and could not 2ccount for this x-csul t. When he u se d diiodomethane-d2 t o forr:·i the Simmons- Smith reagent, exactly two deuteriums were incorporated into the ketone 63. '-'"'· Als o: when the reaction mixtures were quench ed 91 with deuterated acids, no deuterium was incorporated. A possible explanation for these results is that the rearran g ement of the intermediate alcohol to the methylated ketone 63 ...... was promoted by iodine formed by decomposition of the unreacted diiodomethane while the solution was drying. In support of this argument, when an ethereal solution of the cy~lopropanol ,.,...._ X- 6 was treated with a catalytic amount of iodine, 55% of the ketone 't!.:;.§ was obtained after base cata- lyzed equilibration. This rearrangement may be caused by hydrogen iodide formed from the attack of iodine on the cyclopropane rin g . result~ Dauben (116) has observed a rela t ed When the crude product from the Simmons-Smith reac - tion of the allylic: alcohol~ was allowed to stand over sodium sulfate, it d iMe rized to the ether .,_ 65. ether was formed in The same 64 % yield when a solution of the puri- fied alcohol .,_,. 64 was treated with a catalytic amount of iodine in methylene chloride for 12 hours at 0°. In the present work suc h problems were avoided by routinely dry ing the Simmons - Smi t h products 1-5 min and immediately chromatographying the conce ntrated residuea. 1'he cyclopr·opy l a lcohol 0 g av e , on b r ief treatment with ethanol i c hydr o c hloric acid, 86% of the desired ketone W-6 which was id e ntic a l to that prep ared ea r lier. '--- It was furth er discovered that the cyclo p ro pyl alcoho l c ould b e formed dire ctly in 57 % y i eld from th e k e ton e -..X- 4 b y q ue nc h - j_n g the B1rch prod u ct, fo 1 lowi n rr, removal o f the a mmo nia , wi th 92 HO 0 ---64 the Simmons-Smith reagent. yield from the enone ~ Using this procedure, the overall to the ketone~ possessing ti10 intact A ring of the natural product was 24 % in five ste ps . With the successful conclusion of the model study, we again turned to consideration of the tetracyclic unsaturated ketone U-1. ------- The allylic alcohols resulting from reduction of U-1 were mor e difficult to separate than their tricyclic --analogues. It was only possible to isolate 38% of the impure axial alcohol Y-2 and 50 % of the equ~torial isomer -------- ---- Y-1 which could be oxidized back to the enone in 91% yield -so that it is necessary to recycle the equatorial alcohol twice in order to achieve a 63% yield of the axial alcohol Y-~2 (Chart Y). -...-- The stere ochemical as sig:ment of the two alcohol s res~s on the sa me crit~~ia employed for the a.1cohols V-7 and V-8. 'the minor j_scmer Has the more mc,b:il!? on silica gel tlc and exhibit ed a C-2 peak width of 12 ~z 93 in the nmr as opposed to 21 Hz for the equatorial alcohol ---- Y-1 (111). -- The Simmons-Smi th reaction of the axial alcohol Y-2 proceeded as before, but it was found that the Collins oxidation procedure gave a better overall yield ketone Y-4 than Jones oxidation. (77 %) of the Birch reduction of the ketone and trapping of the enolate anion for me d wit h acetic -- anhydride gave 72% of the enol acetate Y-5 to gether with 5% of the ketone 66 and 8% of the cyclopro pyl enol acetate 67. The structural assignment of ....... 67 was ba.sed on its ir spect rur:, which indicated it was an enol acetate (1755, 1685 c rn- 1) and the nmr which showed only three angular methyl groups. Tre at ment cf a portion with ethanolic potassi um hydroxide overni ght gave a 61 % yield of the starting cyclopropyl ke tone The enol acetate Y-5 was converted to 71 % of the cyclo- - propanol Y-6 by addition of two equivalents of methyl li thium to a dimethoxyethane solution followed by an ex cess of th8 Simmons-Smith reagent as before in the model system. The alcohol was algo available in 69% yield by the direct reductive cl ea vage - -cyclopropylation proced ure, but the product was l ess cle2.n than that ob tained from t:1e enol acetate. Y.-6 oreAc id cat alyzed cleavage of the cyclopropy l aJ.co.'lo1 ....._· pared fr om the enol ace tate gave S8% of the desir e d ketone Y-7 while a 72 % yield was obtainej starting with the alcoh o l ....__.. Chart Y 0 ---- U-1 / -+ HO - --- Y-2 Y-1 HO 0 Y-4 __ _____,.,. , 95 Chart Y continued Y-6 ---- Y-7 .........._. - Y-9 Y-8 -.;.- 96 .AcO 66 67 prepared by the direct method. The overall yield from the ---- cyclopropyl ketone Y-4 to the methylated ketone Y-7 was 49% by either procedure. In order to carry out the addition of the side chain the C-2 ketone of .__,.._ Y-7 was protected as the ketal derivative 1 (quantitative). The synthetic plan called for functionali- zation of the A7-double bond by hydroboration, taking advantage of the steric hinderance offered the C-7 carbon by the angular substitucnts to direct the boron atom to the C-8 carbon. While only starting material was recovered from reaction of the ketal Y-8 with disiamylborane, it did react ~ slowly with borane in tetrahydrofuran at 0° and after 5 hours the starting material was consumed. The alcohol obtained from oxidation of the borane was treated directly with the Collins reagent to give an overall yield of 84% of a sin gle ketone which was presumed to be the desired product .._..__ Y-9, The pro- duct gave a single spot on analytical tlc and wa5 rspresented 97 by a single peak on glpc. The nmr spectrum and sharp melt- ing point (271-273°) also indicated that a single product was formed. It was assigned as the 8-keto isomer since the 7 position is clearly the more hindered so that one would expect either a mixture of ketone isomers or only the C-8 ketone from the hydroboration oxidation (117). desired The over- all yield of Y-9 from the ketone .............. P-9 was 12.5 % in 12 steps . It yet remains to add the side chain. Plans for this transformation involve preparartion of the aldeh y de Z-1 by ------- either an epoxide cleavage or a suitable Wittig reaction. Alkylation wj_th methyl iodide should proceed with attac k of the reagent from the equatorial side to avoid a 1,3-d i axial interaction with the C-6a an gular methyl group to give the required f3 -me thy lated product ~ . It should then be a routine matter to add the remainder of the side chain t o form shionone ketal Z-3 by one of a variety of possible means, ---- Deketalization would then give the natural product. 98 Chart z CHO 0 0 99 Experimental Section Melting points labeled (vacuum) were taken in evacuated capillaries on a Hoover Capillary Melting point apparatus; all others were determined on a Kofler Micro Hot Stage melting point apparatus. All melting points and boiling points are uncorrected. Infrared spectra (ir) were run on a Perkin Elmer 237B grating infrared spectrometer and are reported in cm-1 . Nuclear magnetic resonance spectra {nmr) were recorded using either a Varian A-60A or T-60 spectrometer and are referenced to tetramethylsilane as an internal standard. Gas chromatographic analyses (glpc) were conducted on a Perkin Elmer 881 gas chromatograph using 4% SE-30, 6' xl/8 11 colu.mns with a helium flow rate of 60 ml/min. Preparative thin layer chromatog1... aphy (ptlc) was carried out on 20x20 cm glass plates coated with a ~l rrun layer of silica gel PF 25 4+ 66 as supplied by Brink~an 3 Instruments Co. Analytical thin layer chromatography (tlc) was conducted on l"x3" microscope slides coated with the same silica gel. Alumin a refers to the gr ade I, neutral variety manufactured by M. Woelm, Eschwe ge , Germany made up to grade II or III as indicated by addition of 3% or 6% water pr:tor to use. Silica gel columns used the 0.05- 0,2 mm stJ.ica gel "for column chro m21tography 11 mf-~nufactured by E. Merck, DaMnstadtj Germa ny . 100 Where anhydrous solvents are indicated they were dried by the following methods. Benzen~, toluene, pyridine, tert- butylalcohol, and xylene were distilled from calcium hydride. Ether and tetrahydrofuran wer~ refluxed several hours over lithium aluminum hydride (LAH) and distilled. Dimethoxy- ~hane was distilled twice from LAH under an argon atmosphere. Dioxane was refluxed for 4 days over sodium metal and was distilled from sodium immediately before use. Dichloro- metha11e was distilled from phosphorous pentoxide. Petroleum ether refers to the fraction bp 30-60° as supplied by J. T. Baker Chemic al Company and required no special drying. Reactions described as run under nitrogen or argon employed a mercury bubbler arranged so that the system could be alternately evacuated and filled with the inert gas and left under a positive pressure. Microanalyses were performed by Spang Microanalytical Laboratorie3, Ann Arbor, Michigan. Since all compounds reported herein are racemic, the prefix 9_d has been omitted for convenience. The brine used in the workups refers to a saturated aqueous solution of sodium chloride. 101 ~aj,-Methyl-1 , 2, 3, 4, 6, 7, 8, Sa-O_ctahydro-1_(: -Nap~~l ~ ( 61). Following the general procedure of Hallsworth and coworkers (60) 1 1. of monoethylamine was distilled throu gh potassium hydroxide into a dry 2 1. flask fitted with a mechanical stirrer and a dry ice condenser and containing 34.5 g (0.126 mole) of 8~-methyl-_l,2,3,4,6,7,8,8 a ~octaLydrcl~.6-naphthalenediol diacetate (I-2, . .............,. R~OAc) ( 59). Over the course of five minutes 11.0 g (1.56 moles) lithium wire was added with vigorous stirring. After 20 min the dark blue color was discharged with solid ammonium chloride and most of the solvent was removed in a stream of nitrogen. The gray residue was dissolved in 300 ml of water and was extracted with ether (5xl00 ml). The ether solution was dried (Mgso 4 ) and evaporated to dryness to give 17.5 g of a yellow oil. Re - extraction of the aqueous phase yielded an additional 1.5 g. The combined products contained 90 % of one major volatile component by glpc and were used in · the next step without further purification. --------~---To a solution of 19.0 g 0 ~114 mole) of the crude 3,4,6,7,B ,8a-Hexahydro-8a~-Methyl-1(2H)-Naohthalenone (I-5). "---"-~""""'-'~-............ .... ....- alcohol I-4 from above in 450 ml of ice cold acetone (previous ly distiJ.J. ~d from potassium p ermanganat e) was added 31.6 ml (0.126 meav) of 8N chromic a~id solution (62) ov1::X' a. period of 30 mln. Th~ rea ction mi xture wa s s t5-rred 5 Llin a nd dilut ed with 100 ml of sat u rated aqueous sodium 102 bicarbonate and sufficient water to dissolve the chromium salts. The aqueous solution was extracted with ether (4xl00 ml) and the combined ether layers were dried (Mgso ) and evaporated. 4 The residue was chromatographed on 450 g of grade II alumina. Petroleum ether eluted 8.71 g of a fragrant, colorless oil which was further purified by chromatography on 250 g of grade II alumina. Elution with petroleum ether gave successively --- 0.56 g (3% from the dial I-2, R=H) of Ba-methyl-1,2,3,4,6,7,8, Ba-octahydronaphthalene (I-3): ir (CHCl) 1000, 980, 810 [lit ....,._ 3 (63) 1665, 1010, 980, 810]; nmr (CDC1 ) l.03~ (s, 3, C-8a CH ), 3 3 5.25-5.421 (m, 1, vinyl) and 6.73 g (35 % from the diol I-2, ---~ R=H) of the ketone I-5. Ptlc (10 % ether-petroleum ether) and ---evaporative di.stillation (46°, 0.03 mm) gave a sample for analysis: ir (CHC1 ) 1700 (C=O); nmr (CDC1 ) l.32~ (s., 3, C-82. 3 3 CH )t 5.25-5.425 (m, 1, vinyl). 3 Anal. Calcd , for c 11 H1 50: c, 80.44; H, 9.82. Found: C, 80.47; H, 9.89. lp, 8aJ3 -Dimethy 1-1 , 2, 3, 4, 6, 7, 8, 8a-Octahydro-l~-!·Iaph thol ( I -7) ----- -pro~edure ------- - - - - -by - -Corey ---- -Chaykovsky - - - - - - (66) ----The described and was employed for the epoxidation. A dry 100 ml flask cont 2.in- ing 1. 80 g ( 113 rmnoles) of 57 % sodium hydride dispersion was flushed with ar gon. The hydride ~as washed by decantation with four 5 ml portiom; of petroleum ether and the remaining sol- vent was removed in vacuo, Wi th an eir,erging stream of ar-gon, 9.91 g (l15 rrunoles) of trimethyloxosu~tfonium iod:tde (118) was ad ded followed by 60 ml o f dimethylsulfoxide (previously distilled from calcium hydrid e). 103 The resulting mixture was stirred 2 hours at 25° until hydrogen evolution had ceased. A solution of 3.42 g (21.5 mmoles) of the ketone I-5 in 10 ml of dry dimethylsulfoxide ~ was introduced all at once and the course of the reaction was monitored by glpc. After 5 hours the peak representing starting material had disappeared, and the reaction mixture was diluted with 100 ml of ice and water and was extracted with ether (4x30 ml). The ether layer was washed with water and brine and was dried (MgS04). Evaporation t o dryness afforded 3.43 g (89%) of a pale yellow oil which was used directly :i.n the next step: ir (CHCl3) nmr (CDC1 ) l. 22~ ( s' 3 3, c-8a methyl), 2. 3oi 1655 (C=C); ( d, 1, J=4 , oxirane), 2.65~ (d, 1, J=t4, oxirane), 5,37£ (m, 1, vinyl). The crude oxirane from above in 15 ml of dry ether was added over a period of 15 min to a solution of 850 mg (22.4 mmoles) of lithium aluminum hydride in 90 ml of dry ether. After an additional 20 min, the excess hyd~ide was decomposed with 3.0 ml of ethyl acetate followed by the sequential addition of 0.9 ml of water, 0.9 ml of 10% aqueous potassium hydroxide• and 2.7 ml of water. ; The mjxture was filtered and concentrated to g ive 2.70 g (80%) of a water white oil consistin g of a 6:1 ratio of axial to equatorial alcohols by nmr integration of the C-Ba and C-1 angular methyl peaks. The pure axial alcohol wa s obtained as needed by ptlc (15 % ether-benzene): ir (CHC 1 3 ) 3550 104 (0-H)s 1655 (C=O); nmr (CDC1 ) l.18S(s,3,C-l-CH ), l.13~ 3 3 (s,3,C-8a- CH ), 5.47-5.70! ( m,l,vinyl). A sample was 3 evaporatively distilled (40°, 0.025 mm) for the analytic a l sample. Anah_ Calcd for c12 H 20 o: c, 79.94; H, 11.18. Pound: c, 79.84; H, 11.19, lo.:., 8a~ -Dirnethyl-1, 2, 3 , 4 ,6, 7, 8, 8a-Octahydro- l~ -Naph.th ol ( I-7). ~,.._,...,,,.,...,,.....,~.~"'-"'~---.........-"""""-------'-~,,..._.,._,, .~ ....................... ,.,,___ \,.~ A solution of 56 mg (0.34 mmole) of the ketone 1-5 in "'""""""' 2 ml of dry ether was added dropwise with stirring to 1.5 ml (3 mmoles) of a 2 M solution of methyl lithi~m in ethe r (Alpha Inor gan ic, Inc.) in 6.5 ml of dry ether under a nitrogen atmosphere. After 5 min the r eaction ffiixture was coole d in an ice bath, and the excess reagent was d estroyed with 0.5 ml of water. The solution was diluted with 70 ml of ether, washed with brine (lxl0 ml) and d rie d (M gS O4). Evaporation to d ryness and ptlc cf the residue (20% etherpetroleum ether) afforded 24 mg (43%) of the analytically pure alcohol I-7. '-"""- Evaporati ve dist illation (60°, 0.05 mm) give the analytical sample: ir (CHCl3) 3610, 3450(OH), 815 (C=C); mnr (CDCl . ., ) 1.16$ (st 3, C-1 me thyl); l.22S (s:; 3, .:i Ba methyl), 5.32-5 .S 0J (m, 1, vinyl). Found:, Anal. Gener a l Pro cedu r e for Simmons-Smi th Cyclap rooyl2tlons (53) -.w ~ ... - - - - -..- · - ~ - - . __,,, _ _ _ _ ,_....,,,._ .. . • ...._.._, ______,. .,,...,_,.... ............... _ .... ___ _ The zi~c-co pp er couple was prepared by a variation of 105 the LeGoff method (52). In a typical experiment 15.0 g (0.23 mole) of zinc dust was added to a stirred solution of 2.2 g (0.011 mole) of cupric acetate monohydrate in 50 ml of glacial acetic acid which had been preheated to 80-90°. After two min the gray suspension was filtered and the powder was washed with two 100 ml portions of glacial acetlc acid and six 100 ml portions of ether. The washings should be colorless; light blue washin gs indicate that the cou.ple was not heated long enough. The last traces of solvent were removed under high vacuum to give a fluffy, gray powder which was used immediately. In a dry 3-neck, 500 ml flask was placed 12.8 g (0.183 mole) of the couple and a small crystal of iodine. The atmosphere was replaced with nitrogen and 250 ml of dry ether was introduced, followed by 14.7 ml (0.181 mole) of diiodomethane. Spont eo.neous refluxing commenced upon ge ntle heating and continued about 10 min. Reflux was maintained an additional 30 - 35 min by heating with an ir lamp. Upon cooling the solution could be transferred via syrin ge to a second f las k containin g the olefin in ether, or an ethereal solution of the olefin c ould be added to the initial fla s k. affect t h e y ie lds. The choice of method does not s eem to 106 l 1 2,3,4,4a,5,6,7,8,8a,Decahydro-l~,8a~-Dirnethyl-5~,4a- ~ ... ~ - Y¼. ,._,,-, y W "-" ,., -"" -~ - ~ - - : q ....... Methano-lor__-Naphthol ( I-8). \,,a ~ ~__....._ ~ To the Simmons-Smith reagent (53) prepared from 980 mg (14.1 mmoles) of zinc-copper couple (52) and o.80 ml (10.0 mmoles) of diiodomethane in 5 ml of dry ether was added a solution of 222 mg ( 1. 23 mmoles) of the alcohol I-6 in 2 ml of dry ether over the course of 1 min. ~ After 1 hour at room temperature the excess reagent was destroyed with 1.0 ml of 10% ammonium chloride and the resulting mixture was filtered through a glass wool plug which was then washed with 30 ml of ether. The ethereal solution was washed with saturated aqueous potassium carbonate (2xl0 ml) and with saturated sodium chloride (3xl0 ml) and was dried over Mgso 4 . Evaporation to dryness and ptlc (benzene) afforded 151 mg (63%) of a colorless oil: ir (CHC1 ) 3575 (O-H ); nmr (CDC1 3 ) Oc25-0.66 3 pane), l.04f (sj (m~ 3, cyclopro- 3, C-8a methyl),. 1.17c) (s, 3, Caal methyl), 2.38S (ss 1, O-H). A portion was purified by preparative glpc (5% SE-30s 150°) and evaporatively distilled (42°, 0.025 mm) for analysis. Found: Anal. C, 80.43; H, 11.50, 5-Me th oxy-8 a(l =Met hy 1- 3, lJ , 8, 8a-'I'ct rahy dro-1, 6, ( 2H ~ 7ll )'--"""""'"""'-".....,,.,.,,_,"""'~~~~· ~ ~ ~ - ~ ~ " " " '..............._______ , __ Naphth a len edione (J-3). '--.......... ~-'-""' ........~__..,,_,..._,..,,,_-..-...,. ' -""",,.._,, . _4 o - ~1i'rire e-:St.et) P1... oce durc! - ~ - , . . . ,,,.,., ..,,.,......, . _.u ,. ,.._ .,_.,. . _ ....,,, _ ,,._.,....,..-.~ •- 107 The pyrolysis was carried out using the general method of Archer (71). In a 200 ml flask fitted with a short-path still head and a Hershberg mechanical stirrer was placed 200 mg of hydroquinone, 30.5 g (0.231 mole) of 1,4-dimethoxy2-butanone (J-J) (70) and 40 g of sodium benzoate. ~ receiver contained 200 mg of hydroquinone and anhydrous magnesium sulfate. The 2 g of The apparatus was plunged into a hot oil bath, and the temperature was brought to 180185° and held there 1 hour with vigorous gtirring as the products distilled. When the pot was dry, the reaction was stopped; the receiver contained 17. 8 g of a mixture consisting mainly of methanol and l-methoxy-2-ketobutene along with a small amount of starting material by ir. An adaptation of the method of Ramachandran and Newman (58) was employed for the Micheal addition~ The material from above was dissolved i n 75 ml of methanol and added to a flask containin g 17.0 g (0.135 mole) of 2-methyldihydroresorcinol (J-2) and 50 mg of potassium hydroxide. ~ The mixture was refluxed 1.5 hours while most of the 2- methyl dihydroreaorcinol went into solutio~. removed ~~ Y..£.?2.9.., the product 1 11<.i~Y The methanol was ta.ke-:1. up in 50 ml of chloroform an d filtered, and t he filter cake was washed. The concentration filtration procedure was reoe~ted t o glve a total of 8. 9 7 g ( 53%) of re co vered 2,-. methy ld.ihydro-- res orcinol (mp 204- 206 d,). 108 The cyclization-dehydration step was conducted in buffered xylene as outlined by H. Smith (73). Concentration of the above chloroform solution gave 19.65 g of an oil which was dissolved in 300 ml of xylene in a 500 ml flask fitted with a Dean Stark water separator, and 20 ml of xylene was distilled. The solution was cooled, 11.5 ml (0.083 mole) of triethylamine and 11.8 g (0.097 mole) of benzoic acid were added, and the mixture was refluxed with separation of the water formed. After 15 hours, the solution was cooled, washed with saturated aqueous sodium bicarbonate (2x50 ml) and water (lx50 ml) and was dried (MgS04). Distillation of the xylene under vacuum affo~ded 13.5 g of a dark, partly crystalline oil; trituration with ether gave 9.2 g (19% based on 1,4-dimethoxybutancne) of buff colored crystals mp 66-74° that were sufficiently pure for use in the next step. 'Iwo crystallizations of a portion from ether-h exane gave anaJ.ytically pure material mp 78-80°: ir (CHCl3) 1715 (C=O), 1680 (C=O), 1615 (C=C); nmr (CDC1 ) L 1HS (s, 3 t C-8a-cH ).& 3.61S (s, 3, O-CH3). 3 3 A_naJ:;,•. Calcd for c 12 H16 o : c, 69.21; H, 7.75. Found: 3 C, 69.10; H, 7.81. B • - ~ ~~f o S'~_d u re To a 2 1. flask containing 70 . 0 g (0,555 mole) of 2methyldihydrore so rcinol (J - 2) was added a solu tion of 69.2 ......- g (0.522 mole) of 1J4-dimethoxy-2-butanone (J -l.) and 16 .0 ~- 109 replaced with nitrogen and the mixture was heated to reflux. After 1.5 hours, 50 ml of solvent was removed by distillation, and 23.6 g of benzoic acid and 23 ml of triethylamine (73) were added. Reflux wao cont i nued for 15 hours while the water for med was removed with a Dean Stark apparatus, Upon cooling, the solution was washed with three 250 ml portions of 5% aqueous potassium hydroxide and was dried (Na 2 so 4 ) . Vacuum distillation of the solvent afforded 51 . 3 g (47.2%) of yellow crystals mp 66 - 71°. Extraction of the aqueous washin gs with chlorororm yielded an additional 5,30 g (4c8%), The overall yield from 1,4-dirnethoxy-2- butanone \~as 52%;in another experiment a 59% yield was realized. 5- Me thoxy -8a~-Me thy l-l , 2 , 3,4 , 6 , 7 , 8 , 8a - Oct a hydro- l~,6- ~...,,,...,,,...,,,,...,,..__......""""""~.,._ .... ,._._.._,.,, ""'"' -......... __ ,....__.........._.,,,_,,, Na phthalenedio l, ~ A solution of 37 ~70 g (0.181 mole) of dione ---.... J - 3 in 250 ml of ether was added to a stirred solution cf 15.70 g (0.413 mole) of lithium aluminum hydride in 2 1. of ether over the cour se of l hour. The solution was stirred ove r- night, ~ooled to 0°, and the excess rea gent was decomposed with 50 ml of ethyl acetate. The aluminate esters were hydrolyzed by the consecu t ive addition of 16 ml of water, 16 ml of } 0 % aque ous potassium hydr o xid e , and 45 ml of wa t er. The m1 x t u r e wa s filtered, dr ie d ( MgSO4) and eva porated to dPy rie ss to g ive 35. 8 ~; (95 %) of a wh i t e crystalline solid , mp 88- 92° ( partl y rnel t) a nd 13 4- 140 ° that cons i s ted of a 110 2:1 mixture of 6P and 6~ isomers by nmr integration of the C-Ba angular methyl peaks. Two crystallizations from ethyl acetate provided a pure sample of the 6~ isomer mp 147-150°: ir (CHC1 ) 3600 (OH), 1665 (C=C); nmr (CDC1 3 ) l.22J (s, 3, 3 C-8a--cH 3 ), 3.706 (s, 3, O-CH ). 3 Anal~ Found: 5-Meth0xy-8aP-Methyl-l,2,3,4,6 1 7,8,8a-Octahydro-lP,6- -~-----~ Naphthalenediol Diacetate. ______________., A solution of 35.B g (0.169 mole) of the crude dial from above in 600 ml of dry pyridine was treated with 62.5 ml (0.85 mole) of acetic anhydride. The reaction mixture was stirred 17 hours at room temperature and was diluted with 500 ml of saturated aqueous sodium bicarbonate. The aqueous solution was extracted with ether (4x200 ml) and the combined organic layers were washed with water (2x200 ml) and brine (lx50 ml) and were dried (Mgso ). 4 Concentra- tion gave 50.l g, (quantitative), of the diacetate as an oil, Ptlc of a portion (40% ether-petroleum ether, dcuble elution) and evaporative distillation (100°, 0.025 mm) gave the analytical sample of the mix t ur e of C-6 isomers: ir (CHC1 3 ) 1725 (C= O), 1655 (C=C); nmr (CDC1 3 ) l.08~ (s, 1, C-8a-cH , 6~ isomer), 1.15J (s, 2, C-8a-CH 3 , 61 isomer), 3 2.03 and 2,05J (pair of s, 6, acetate CH )s 3.~8$ (st 3, 3 o-cH 3 L 111 Anal. Calcd for c16 tt 24 o5 : c, 64.84; H, 8.16. Found: C, 64.88; H, 8 . 24. __ naphthalene (N-4). ---~--- ~ ~~ - Hydroxy - 5-Met ho>:y-8a~ -ME:_thyl-1, 2-----..,.... , 3 , t1, 6,..... 7, 8, 8a-Octahyd r o- A modification of the Hallsworth procedure (60) was utilized for the cleava~e. In a dry, 2 1. flask fitted with a mechanical stirrer and a dry ice condenser and containing 23,7 g (0 . 080 mole) of the diacetate from above was distilled 1 1. of monoethylamine through potassium hydroxide. The solution was cooled in an efficient ice- salt bath after injecting 60 ml (0.63 mole) of dry t-butyl alcchol through a septum. E.Feshly_ cut lith ium wire, 5 . 5 g (0.80 mole) was added over 5 minutes with rapid stirring. After 20 min the characteri sti c blue color developed and the excess metal was decomposed with solid ammonium chloride. Most of the solvent was removed overni ght in a stream of nitro gen and the residue was dis s olved in 600 ml of ether. The ether ~il solution was washed with water (2xl00 ml ) and b~ine (l xlOO ml) and was dried ( Mg30 4) • rrhe p roduct, follow:tng cone en,·~ trationi was chromatogr aphcd on 920 g alumina. Elution with 3 1. of 10% eth e r-petroleum ether gave 703 mg (5 %) of an oil w~ich was an enol ether possessin g neither alcohol nor ket one functi onal ity. Further elution with 17 1. of ei.;l1c:t afforded l:i.'(8 g (58 %) of t he alcohol (N - 11) rnp ...,__,~ 112 83.5-86.5: A portion was recrystallized 3 times from ether-hexane tc provide analytically pure material mP 85.5- 86.5°: ir (CHC1 ) 3610 (OH), 1645 (C=C); nmr (CDC1 3 ) 3 l,02J (sj 3s C- 8a-CH3), 3.47~ (s, 3, O-CH 3 ). Anal. Calcd for c12 H20 o2 : C, 73 . 43; H, 10.27. Found: 5-Meth_.Yoxy~8~ - Me thy 1-3 , 4, 5, 6, 8, Ba- He xahydro - 1 ( 2H )~--~-----------~__... - - .,.....____ Naphthalenone (J - 4) . --.-.-~w--- To a rapidly stirring solution of 6.10 g (31.1 mmoles) of the alcohol (N- 4) in 50 ml of dry methylene chloride -------- under ·a nitrogen atmosph e re was added all at once 900 ml (0.175 mole) of a 5% solution of ch r o mium trioxide dipyri - dine complex (74) in dry methylene chloride. After 1 0 min at room temperature the blac k react i on mixtur e was filtered through a 600 ml B~chner funnel filled three - fourths with grade II alumina with suction, washing the alumina with 1000 ml of ether . Dryin g ( MgSO4) and concentration af f orded 5.86 g of a red oil which was chromato g ra phed on 150 g of grade II alumina elutin g with 700 ml 10% ether-petrole u m ether to give 5 . 02 g (83 %) of a water -W hite oil which contained a single volatile component by g lpc. Ptlc (5 % ether-petroleum e t he r) a nd evaporative d i sti l lation ( 5 0°, 0.025 mm) provid('. d th e a.n a l y t :i.c al sampl e : ir (C HC1 3 ) 1705 n mr 113 Anal. Calcd for c 12 H18 o2 : C, 74.19; H, 9.34. Found: C, 74.0l; H, 9.49. Octahydronaphthalene. -. * ------- Following the procedure of Corey and Chaykovsky (66) a dry 100 ml flask containing 79 8 mg ( 19. O rnrnoles) of 57% sodium hydride dispersion was flushed with nitrogen and the sodium hydride was washed with three 10 ml portions of petroleum ether. The excess solvent was removed in vacuo and 4.25 g (19.3 rnmoles) of dry trimethyloxosulf'onium iodide (118) was added followed by 40 ml of dimethylsulfoxide (previously distilled under vacuum from calcium hydride)~ 'l'he reaction mix ture was stirred 40 min at 23° until hydrogen evolution was complete and the solids were allowed to settle 1 hour. The supernat a nt was transferred vi~ sy r inge to a 50 ml flask containin g a solution of 361 mg (1.86 mmoles) of ketcne ........_.._ J-4 in 4 ml of dry dimethylsulfoxide under nitro ge n . The course of the reaction was monitored by glpc and it was stopped after 7 hours at 23° when the - peak repres en ting starting material had disappeared. Lon ger reaction times lead to lower yields. The excess reagent was carefully deco mpose d with 1.0 ml of wat~r, 15 ml of water was added and the aqueous solution was extracted with ether (6xl5 ml) . The combined or ganic layers were to dryness. Ptlc (20% ether-petroleum ether, double elution) afforded 315 mg (81%) of the~-oxirane r.f. 0.7, which crystallized on standing at -10°: ir (CHCl~) .., 1670 (C=C), 1130 (C-0), 1055 (C-O); nmr (CDCl3) 1.20! (s, 3, C-8aCH 3 ), 2.33J(d, 1, J=S.5 Hz, oxirane), 2.70~ (d, 1, J=5.5 Hz, oxirane), 3.42J (s, O-cH 3 ). 3$ -- 1~,8 a~-Dimethyl-5- Methoxy-l , 2,3,4,6,7,8,8a-Octahydro-:lcl.......... ,.., ............---. Naphthol (,T-5) • .............. ............... - ~~-~ ~ ~w"'- To a solution of 7~0 mg (3,55 mmoles) of oxirane from above in 25 ml of dry pyridine at 0° (ice bath) was added 440 mg (11.6 mmoles) of lithium alurr.inum hydride. The mixture was stirred 10 min at 0°, then 1 hour at room temperature. The muddy-green solution was diluted with 25 ml of ether, the excess hydride was destroyed by the consecutive addition of 0.45 ml water, 0.45 ml of 10% aqueous potassium hydroxide solution and 1.35 ml water and the solution was filtered, The filtrate was washed with water (2x20 ml), saturated aqueous cop per sulfate (2x20 ml), and brine (2x20 ml) and was dried ( MgSO~ ). Fi ltration throu gh 30 g of gra d~ II alumina ( 50% ethe:.r•-petrcleum ---- ether) afforded 690 r::g (9i.\%) of the alcohol .J •• 5 as an oi l . wh i(!.r.i was contarr:J.nated wit h less than 5% of the equ.2.tor·lal isomer ,J=6 by wr.r i nte gration of the C- 1 and C-8a angular ------ The alcohol is quite labile and waG used without methyls. further purification: -{ .J. r ( c:_,,u C1- .)- . ) 3 r:;_, 0 0 i.'b roaa): ' ',s: ea .' ..-. ) ( OH· . ) > 115 1665 (C=C); nmr (CDC1 3 + l drop pyridine) 1.111 (s, 3, C-8a-CH l.13~ (s, ) , C-l-CH 3 , 3.47~ ) , (s, 3 , O-CH 3 ) . 3 3 1~,8~-Dimethyl-5-Methoxy-l,2,3,4,6,7,8,8a-Octahydro-lp~""""'--"'" ..,.,,,., - ~. . ..., -'U,..., ,,l>.,.._,,...,.,, .., ... .....,.,...,,.., ,_. -- Naphthol (J-6). ~ To a solution of 2 ml (4 mmoles) of a 2M solution of methyl lithium in ether (Alpha Inorganics, Inc.) in 5 ml of dry ether was added dropwise 109 mg (0.53 mmole) of the ketone atmosphere. - J - 4 in 1.0 ml of dry ether under a nitrogen After 1 min the mixture was cobled in an ice bath and the remaining reagent was decomposed with 0.50 ml of water. The solution was diluted with 60 ml of ether and was washed with water (lx5 ml) and brine (lxlO ml) and was dried (Mgso 4 ). Evaporation to dryne3s afforded 118 mg, 100% of a colorless oil which was represented by a single volatile component by glpc; ptlc (20% ether-petroleum ether) and evaporative distillation (60°, 0,005 mm) gave a sample for analysis; ir (CHC1 3 ) 3600 (OH), 1665 (C=C); nmr (CDC1 ) l.15J (s, 3 , C-8a-CH ) , 3 3 1.2oj(a, 3~ C-l- CH3)1 3.45J (s, 3, OCH3). Found: An al. C, 74,33; H, 10.51, l,2r3 f4,4a~ 5 t6, 7,8 ,Sa-De cah y d r o-lp, 8a? - Di methyl-5p-Me thoxy~ ~-~"""'-,..,.,...-~ ........._v'.._,,• ......_,,i-¥._.....,, . . . . _ . . . . , , . . , . . . ~ , ~·~ ,~....,.._-.,..,.~.-ll.t"V._,,.,,,,.,,,,..,t.Pt..ft"'t.-.,,, .,~_. 1,~Naphthol Ketal (J-7). ~,~~~--- VV'tJ-~ ~~ In an nmr tube was dissolved 79 mg (0.38 mmole of the alcohol :tn l ml o f ch loroform~-d. After 5 d8ys at room 116 temperature nmr spectra indicated startin g material had disappeared forming a single major product. Evaporation to dryness gave 63 mg (80%) of an oil; ptlc (15% ether-benzene) afforded 43 mg (55%) of the analytically pure ketal which was evaporatively distilled (55°, 0.05 mm) for the analytical sample: ir (CHC1 ) 1085 (C-0); nmr (CDC1 ) 0.92A (s, 3, 3 3 C-8a-cH ), 3.37~ (s, 3, O-CH ). 3 1 An~l. Calcd for c13 tt o : C, 74.24; H, 10.54. Found: 22 2 C, 74.26; H, 10.56. ~~------ l,2,3,4,4a,5 , 6 , 7,8,8a- Decahydro-l~)8 a ~-Dirnethyl-~,4a...--,--..,....,...,-.,_,,..,,...,_..........,~__.. _ Methano- si- Me thox y-1-;(-N a phthol (J-8). ~~ ~~~'"""'~.......,..... ...,.._..,., ~ To a solution of the Simrnons-Smith re a. gent ( ?3) prepa r ed from 12.8 g (0.183 mole) of zinc-copper couple (52) and 14.7 ml (0.183 mole) of dliodomethane in 250 ml of ether was added a solution of 4.04 g (0.019 mole) of th e tert-alcohol J-~ in 20 ml of dry ether and 15 ml (0.17 mole) of Vo,.~ dry 1,2-dimethoxyethane over a period of 10 min. After 40 min at room temperature the flask was cooled in an ice bath and the excess rea gent was decomposed with 3.0 ml of 10% aqueous ammonium chloride. The solution was diluted with 600 ml of ether and washed with s atura t e d aqueous potassium carbonate (3 xl50 ml) a n d brine (2xl50 ml). The organic phase was dr i e d (Mgso 4 )> concentrated. a nd chromato graphed on 300 g of grade I I alumina. Pe troleum ethe r el ut e d 5 g di i odome th z ne ; fur t her elution o f the dolumn with 1 200 ml 117 of 50% ether-petroleum ether gave 3.54 g (83%) of crystalline cyclopropane mp 58-60°. Crystallization of a sample from ether-heptane, then from ethanol-wa.ter, yielded the analyt- ical sample mp 60-61.5°: ir (CHC1 ) 3600 (OH), 1075, 1060 3 {C-O); nmr (CDc1 3 ) o.52l (d, l, J=5.5 Hz, cyclcpropane), 0~82~ (d, 1. Jm5.5 Hz, cyclopropane), 1.031 (s, 3, C-8aCH3), l.15~ (s, C-l-CH 3 , ) , 3.23J (s, 3 , O-CH ) . 3 3 Anal. C, 74.95; H, 10.78. Found: C, 75.01; H, 10.78, 3,4,~a,7,8,8a-Hexahydro~l,4a~ ~8a~~Trimethyl-5(6H)-Naphthal~ ' " " " ' .. .,,..,,_....,_,._~ ~ . _ . . _ ~ . , ...' " ' W " ~ ~ " " 1 r . r v ...~ - " .. enone ( J -9). -...._ A solution of 595 mg (2.65 mmoles) of cyclopropane ,_..._ J- 8 in 20 ml of methanol and 2.0 ml of 37-38% hydroc!1loric acid was refluxed 4 hours, cooled, and neutralized with saturated sodium bicarbonate. After most of the methanol was removed in vacuo; the residue was taken up in 200 ml of ether and was washed with saturated aqueous sodium bicarbonate (lx25 ml), and dried (MgSO4). Concentration gave 510 mg of a yellow oil that was chromatographed on 20 g of alumina. Petroleum ether eluted 376 mg (74%) of the des ired k~tone 1 mp 67-68°. eth a nol-water and analyti~al sample mp 68-69°: ir Recrystallization from the 118 Anal. Calcd for c 13 H20 o: C, 81,20; H, 10.48. Found: C, 8lc21; H, 10,57, In one experiment which was stopped after 3 hours, a small amount of the highly crystalline alcohol, 1:L,-hydroxy- 1,2,3,4,4a,7,8,8a-octahydro-l~r-48.d..,8a~-trimethyl-5(6H)naphthalenone was obtained as a by-product. Glpc indicates that this compound forms first from cyclopropane cleavage followed by a slow dehydration to the keto-olefin ...,__ J-9. One crystallization from ether-petrol.eum ether gave analytically pur material mp 92-96°: ir (CHC1 ) 3610 (O-H), 1700 (C=O); 3 nmr (CDCl3) 0,85t (s, 3, C-8a- CH3), l,13J (s, 3, C-l-CH ), 3 1. l! 5 ~ ( s , 3 , C- lt a-CH ) • 3 ~1l,al. Calcd for c 12 H 22 o2 : c, 74.24; H, 10.55. Found: C, 74.15; H, 10.53. 1, 2, 3 $ 4, Ila , 5, 6, 7 , 8, 8a-Decahydro-lf?, 4a11.., 8afs-Trimethy 1-ld..- ~__,_ . . , . , . ~ ~ ~ ~ ~ . , , . . . , , , .... ~~ Naphthol (K-9 ). " ~ """"~ To a solution of 4 mrnoles of methyl lithium (2 ml of a 2M solution in ether ( Alpha Inor gan ics 1 Inc,) in 20 ml of dry ether was added 59 mg (0,33 mmole) of 4a~, 8a ~-d imet hyl3,4,4a,5,6,7,8,8a- oct ahydro- 1( 2H ) -naphthalenone ( K-8 ) (76) ·~ in 2 ml of dry ether with a syringe under a nitro gen at mosphere. After 10 n~.n at room temperature the remaining methyl lithium was carefully destroyed with 0.6 ml of saturated ammonium cl!1or•ide. rrhe solution was cJ.J.uted w:t'ch 75 ml o f ether, washed with va t er ( lx5 ml) and tr!~~ (l x5 119 ml), and was dried (Mgso 4 ). Evaporation to dryness and evaporative distillation afforded 59 mg (94%) of an oil which consisted of 25% starting material and 75% of a single higher boiling product by glpc. Repetition of the methyl lithium treatment provided 49 mg (79%) of a partly crystalline product that was greater than 95 % one volatile component by glpc. Ptlc (benzene) and evaporative distil- lation (60-70°, 0.25 mm) gave analytically pure crystals mp 40-41°: ir (CHC1 3 ) 3600 (OH); nmr (CDC1 ) l.03j (s, 3 3, C-8a-cH 3 ), l.08~ (s, 3, C-l-CH 3 ), l_.30S (s 1 3, C-4aCH 3 ). Anal. Found: C, 79.41; H, 12.33. 3,4j4a,5,6,7,8 -8a-Octahyd ro - l,4a~ ,8 ap -Trime th ylnaphthalene ·------.-.,-------------...............------~-------~~~~~......,,...- ( K-10) . ...._.._,_ A. Wolff-Kischner of J-9 The Haung Minlon modification (119) of the WolffKischner reduction was used. A 10 ml flask was fitted wi th a short path mi crostlll, and a nitrogen inlet arranged sc that nitro gen wou ld flow from the pot, through the still, into the receivAr an d out to the atmosphere. The flask was cha:r· e;,~d with 141 mg (0.7 35 mmole) of ketone J-9, 500 '-'··- mg of cru3hed potassium hydroxide, 0.40 ml of 85 % hy draz!ne hydratej and 5 ml of diethyleneglycol. With the nitr ogen flowi~ g it was heate d tc 100~1 0 5° fo~ 30 min 120 and then to 200-205° for 120 min while the volatile products distilled ~ The ap p 2ratus was cooled, and the contents of the pot and receiver were combined and extracted with ether. The ether solution was dried (Mgso ) and the solvent was 4 distilled at atmospheric pressure; the crude product was sublimed (40°, 0.025 mm) to afford 60 mg (46%) of white crystals mp 45- 50°. Ptlc (petroleum ether) and sublima- tion gave the analytical sample mp 52 ~ 55°: ir (CHC1 ) 3 16~0 (weak) (C;C); nmr (CDC1 ) o.90J (s, 3, c - 4a-cH ) , 3 3 l.03~ (s, 3, C- 8a-CH ), l.58~ (d, 3, J=l.5 Hz , C-l- CH3), 3 5.03-5,23t (m, 1, vinyl). Anal. Calcd for c 13 H22 : C, 87,56; H, 12 . 44, Found: C1 87.36; H, 12.48. B. Dehydrat ion of K- 9 To a solution of 50 mg (0 , 25 mmole) of th e alcohol K- 9 ""·""-"' in 5 ml of dry pyrldine was added 0.30 ml (4.1 mmole s) of thionyl chloride at - 10° (ice - salt bath) . The solutio n was stirred at -10° for 45 min and warmed to room temperature over 15 m:ln~ It was pcured in t o 25 ml of saturat ed aqueous sodium b i carbonate a n d e xtracted with et ~e r (4 x 25 ml). The comb i ned o r ga n ic l a yers were washed wi t h wa t er (lxl5 ml) , sat ura t e d aqueou s c o pp e r s ul fate and b~ine (l x l5 ml) . ( lx l5 ml), Dryin g ( MgSO4)s removal o f the solvent by distil l at i on a t at mos p heric pres s ure, and c hro ma to gr a?h Y on 5 g cf alumina ga ve with 15 ml of pe n t a ne 19 mg (42 %) 121 of a white crystalline solid mp 50-54° that was spectrally identical to that obtained in Part A, above. A mixed sample of material from Part A, ~p 45-50° and Part B, mp 50-54°, gave mp 45-50°. 5, 5 -Ethy lenedioxo-3, li, 4a, 5, 6 ~ 7, 8 ~ Ba-Octahydro-1, 4ac,., 8a~ - .,,,.., ..... ,...,'-'"""",.... ---------- . -~ - . , . . , , ~ ~ ......... ....... Trimethylnaphthalene (L-1) . ...,.,.._,_ -..-..,..___.~ .......... .... --- A solution of 502 mg (2.62 mmoles) of the ketone J-7 and 10 ml of ethylene glycol in 110 ml of benzene was placed in a flask fitted with a Dean Stark water separator and 10 ml of benzene was distilled. The solution was ~efluxed 20 hours after adding 40 mg of p-tolulenesulfonic acid. It was then washed with water, satur ated aqueous sodium bicarbonate. and brine. Drying (Mgso 4 ) and evaporation to dryness yielded o.64 g of an oil which was chro~atographed on 30 g of grade II alumina. Petroleum ether eluted 510 mg (83%) of the ketal .......,,._.. L-1 (mp 37-40°) • Further elution with 10% ether-petroleum ether afforded 55 mg (11%) of starting material. The ketal was recrystallized three times from hexane to provide an analytically pure sample mp 45-116°: ir (CHC1 ) 1660 (C=C); nmr (CDC1 3 ) 1.09i 3 (s, 3, C-4a-cH 3 ), l.22i (s, 3P c~Ba-CH3) 2 l.65i (s, 3P C-l-CH )i 3.88~ ( m, 4, !<etal), 5,101 (m, 1, vinyl). 3 Anal!.. Ca.led for c 15 H24 o2 : C, 76.c1 2; H., 1 0.24. Found: 122 1,2,3,4,4a,5,6,7,8,8a-Decahydro-4or.(,8a~-Dimethyl-5,5 · --•.............~~....,_.....,_ ~~~~__,.,...........,...__..-. -- Ethylenedioxo-l-Methylidene-2,-Naphthol (L-2). ~ ..........~~ ~..... ,..~..... ,..,......,..._.......,..._._._.., ~ ~ The photooxidation procedure described by Nickon and Bagli (81) was employed using a merry-go-round apparatus consisting of 11 parallel 15 watt fluorescent bulbs arranged in a circle each 5-6 cm from the center. A fan was set to blow air between the bulbs for cooling and a thermometer was suspended in the middle along side the reaction vessel. A solution of 510 mg (2.16 mmoles). of the olefin L-1 and 80 mg hematop0rphyrin dihydrochloride (Calbiocham) in 50 ml of dry pyridine was plac e d in a 2xl5 cm pyrex tube fitted with a gas dispersion tube extending to within 0.5 cm of the bottom. Oxygen was passed through and the solution was irradiated 132 hourr; at the center of the apparatus. During the reaction two 50 mg portions of hematoporphyrin dihydrochloride were added and the pyridine lost by evaporation was replaced. The temperature varied from 20 to 35° during the reaction period. The pyridine was removed in vacuo at room temperature and the black oil was taken up in 100 ml of dry ether; lithium aluminum hydride, 2~1 mg (6,3 mmcles) was added and the solu t i on was stirred 4 hours. l'he excess hydride, was destr oyed by successive additions of 0.24 ml water, 0.24 ml of 10% potassium hydroxide and □ .72 ml water. The 123 mixture was filtered and concentrated to give 340 mg of a crude oil which was applied to 30 g of Florisil. Petroleum ether, 300 ml, gave 83 mg (16%) of recovered starting material; further elution with 400 ml of 60% etherpetroleum ether afforded 173 mg (31%) of the crystalline alcohol L-1. Two crystallizations from ether-heptane provided analytically pure material mp 148-149.5°: ir (CHC1 ) 3600 (OH), 1645 (C=C), 895 (c~cH 2 ); nmr (CDC1 3 ) 3 1.00~ (s, 3, c-8a-cH ), 1.25, (s, 3, c-4a-cH ), 3.90~ 3 3 (m, 4, ketal), 4.671 (m, 1, vinyl), 5.02& (m, 1, vinyl). ~-1. Calcd for c H o : 15 24 3 c, 71-.39; H, 9.59. Found: C, 71.41; H, 9.48. Perhydro-9b -B oraphenalene .....~~~ ~ The borane was prepared by a modification of the method employed by Rotermund and Koster (88). A 1000 ml flask fitted with a distillation head equipped with a stopcock to permit total reflux and a 500 ml dropping funnel was flushed with argon and was charged with 100 ml of dry xylene. The xylene was heated to reflux and a solution of 40 g (0.34 mole) of triethylamine borane (Penisular Chemresearch, Inc.) and 51 . 9 g (0.32 mole) of 1,5,9- ~.!'~., ~}'cl(:,2_ , ~ra,ll~-eyclododecatriene (Columbia Organic Chemical Cu., I nc.) in 200 ml of dry xylene was added over the course of 3 hours. On compl.etion of the addition~ most of the solvent wa.s di.stilled. and th ,~ rcact:Lon mix- 124 t .ure was allowed to cool and stand overnight under argon. The mixture was quickly poured into a dry 300 ml flask and the remaining xylene was removed under reduced pressure (bath temp 40-80°, 1.5-2.0 mm). 'i'he borane was distilled bp 72-76°, 0.3 mm [lit (88) 55c, 0.1 mm] and the vacuum was broken with argon to give 44.7 g (81%) of a viscous oil. - Lithium Perhydro-9b-Boraphenalyl Hydride (N-1). ,...,,,......~.,,..._,_,._,,..., ,., ..., .............., the borane from A Eolution of 15.1 g (0.086 mole) ~~~..,,,..,..,~--- above in 90 ml of dry tetrahydrofuran was treated with 5.2 g (0.66 mmoles) of lithium hydride (Alp ha Inorganics) and the resulting suspension was heated to reflux for 6 hourn under an argon atmosphere. On coolin g , most of the unreacted lithium hydride rose to the surface and the cloudy solution below could be withdrawn with a syringe and stored in a 100 ml flask under argon. The concentration of the reagent was calculated to be 0.85M based on 100% react i on of the starting borane; it was generally used in 50-100% excess. __ ·sa.A-Me thy 1-1, 2 t 3 .!' 4, 6,......,, 7_$ 8, 8a -0c tahydro-lt(.-Naphthol (.,,,..,,,,,..., N-2 ) . ~~~_....,.. _ , - . . , - " ' " " . ~___,,......,,.~ . A stirred, ice cold solution of 128 mg (0.78 mrnole) of the keto-ol efin ---..;... I-5 in 2 ml of dry te tr ahyd rofuran was treated with 2.0 ml of a 0.77M solution of lithiu m perhydro9b-horaphe nalylh ydride (N-1) in d r y tetrahydrofuran tmd e r nitro ge n. After 30 min the excess barohyd ri de was ~es- 125 troyed by the consecutive addition of 0.5 ml of 3N sodium hydroxide and O. 7·5 ml of 30 % hydrogen peroxide. The mix- ture was poured immediate ly onto 15 ml of 20% aqueous potassium carbonate and the aqueous solution was extracted with 75 ml of ether. The ethereal layer was washed with brine (lxlO ml) and was dried (MgS04). Concentration afforded 189 mg of an oil which was filtered throu gh 15 g of alumina (ether) to give 85 mg (65%) of partly crystalline material. Ptlc (15 % ether-petroleum ether) gave two products: r.f. Oe2, 35 mg (28%) of the equitorial alcohol J.::0 and r.f. 0.5, 45 mg (36 %) of the pure axial alcohol ~ ' mp 65-66 ~5° which was suitable for analysis: ir (CHC1 3 ) 3600 (OH); nmr (CDC1 3 ) l.07J (s, 3, C-8a-CH 3 ), 3.27-3.47! (ms 1 •. C!i_OH), 5.3E-5.62S (m, 1, vinyl). Anal~ Ct Calcd for c 11 H18 o: C, 79.46; H, 10.91. Found: 79.58; H, 10~92. 5-Methoxy-8aB-Methyl-l, 2j3,4,6 j 7,8,Ba -O ctahydro -~-Naphth ol. """"--~-~---. . . . . ~~.. ~ , . . . . , . , _ , , , . . . ~ ~ ~ t . _ . - .... To a solutlon 0f ~""-""..._ 41~8 mg (2.30 rri.moles) cf the ketone J-4 in 5 ml of dry tetrahydrofuran was added 4.20 ml (3,20 ......,...,.. --- mmoles) of a 0.77 M solution cf the borohydride N-1 at -1J 0 (ice- salt bath) under a nitrogen atmosphere. After 30 mi n, the e~cess rea ge nt was destroyed by the carcf~l, dropwise a ddi tiion of 2.0 ml of 3~ sodium hydroxide fol l owed by 1,0 .·11 of de. - 30 °,·o' J..,y·v-'l_r-cge:1 - _ . r,- eY'OXl - •'_1 0 T'ne :::i• x t . ur2 '.•:2s ncu:>~ -:_• or~to 30 ml of 20% aq ueous potassium c arb on ate and was extracted 126 with ether (6x25 ml). The combined organic layers were washed with water (lx20 ml) and brine (lx20 ml) and were dried (Mgso ). 4 Evaporation yielded mg (quantitative) 4 8 3 of a colorless oil consisting of a 70:30 mixture of the axial alcohol N-3 and the equatorial alcohol ~ N-11 "'""""" 2s deter- mined by nmr integration of the angular methyl peaks. The axial alcohol was quite labile so the mixture was used without further purification: ir (CHC1 ) 3600 (OH), 1670 3 (c~c); nmr (Cc1 4 ) 0.95i (s, 0.9~ C-8a-CH , equatorial 3 alcohol), l.05S (s, 2.1, C-Sa, axial alcohol), 3.40~ (s, 0 . 9 , O-CH , equ~torial alcohol), 3 . 4 3 r (s, 2.1, O-CH 3 , 3 axial alcohol). 1, 2, 3, 4, 4a~ ~ 5 , 6 , 7, 8, Ba-De cahydro-5~ -Me thoxy-8a.(l-Mett.yl- 1{ - ' - " - ~ ~·~ _ , _ " " " " " . . . , . . . . ...~...... w..,,,, .... .. ~ ~--- Naph thol Ketal (N-5). ~~~~ ~ A solution of 154 mg (0.785 mmole) of the crude mixture of alcohols v N-3 and ,N-4 in 3 ml of chloroform-d containing ~ ~ 1-2 mg of p-tolulenesulfonic acid was allowed to stand 12 hours at room temperature. ether) gave two bands. Ptlc (30% ether-petroleum The first, r.f. 0.1, contained ·54 mg, (42 %) of a mixture of four major components as determine d by nmr: the startin g alcohols N-3 and N-4. " ' ....~ .... ....,.,.,_,,,,1 the hydrolysis product cf tbe equatorlal alcohol (vide - :L_D.f!:~_) and nn unidenti.fi (-::d compound presumably the hydrolysis p r oduct of th e axial alcohol. The f aste r moving band r.f. 0 . 3 contained 43 mg (2 8% fr om the k et one J - 4) of \.,., v ~ 127 the analytically pure ketal I.Ar-N-5. Evaporative distillation (45°, 0.15 mm) afforded the analytical sample: ir (CHc1 3 ) 1055 (C-0); nmr (CDC1 3 ) 0.97S (s, 3, C-8a-cH ), 3.30) (s, 3 3 1 0-CH 3 ), 3.77-3.90l) (m, 1, CH-0). Anal . c12 H20 o2 : Calcd for C, 73.43; H, 10.27. Found: C, 73.54; H, 10.23. 1, 2, 3, ll, 4a, 5, 6, 4a-Methan c-5-P-Methoxy~~.............-. ,. 7,., 8, 8a-Decahydro-5c<,, ..,...,_~..,,.......,,...,.-..,._,_ _ _ _ _____ _~.... ~ 8a~-Methyl-h<_-Naphthol (N-6). ~~~......., ~ WV-..,._ The Sirnmons - Smi th reagent ( 53) prepared fr·om 2 .10 g (30.0 mmoles) of zinc-copper couple (52) and 2.40 ml (30.C w.moles) of diiodomethane in 30 ml of dry ether was added to a solution of 483 mg (2.30 mmoles) of the' 70:30 mixture of alcohols ....N-3 N-4 from above in 3.2 ml (30 rnmoles) _ and '-"--of dry 1,2-dimethoxyethane under a nitrogen atmosphere. Over the course of 1 hour, the characteristic gray precipitate formed; the mixture was cooled in an ice bath and the excess reagent was decomposed with 1.0 ml of 10% aqueous ammonium chloride. The solution was diluted with 200 ml of ether, washed with saturated aqueous potassium carbonate (lx50 ml) and brine (2x50 ml) and was dried ( MgSO~ ). Following concentration,ptlc of the crude product on three 20x20 cm plates (30 % ~ther-petroleum ether, 2 elutions) gave a b~nd r.f. 0.5 cont a ining 278 mg ( 59% from the ketone Rechr omatography and evapor~tive distiJ.laticn (120°, 0,6 5 mm) gave the analytical 128 lr (CHc1 ) 3600 (OH); nmr (CDC1 ) 0.38d (d, 1, 3 3 J~5 Hz, cyclopropane), 0.785 (d, l, J=5 Hz, cyclopropane), sample: 1.lli (s, 3, C-8a-CH ), 3.17~ (s, 3, O-CH ), 3.17-3.37$ 3 3 (m, 1, CtI_OH). ~nal-!. Calcd fro c13 H22 o2 : c, 74.24; H, 10.54. Found: C, 74.32; H, 10.63. 4C0\ 1_ 8:=-13 -Dime thy 1-1«.-Hydroxy-l, 2, 3, 4, 4a, 7, 8, 8a-Octahydro-5 ~ ~ . , _ . _ , , , ............_ _ _ , . . , , , . . . , , ~ _ , , . . _ _ , - - . , ~ ~ ~ - ' (6H)-Naphthalenone (N-7). A solution of 114.2 mg (0.545 rnmole) of the cyclopropyl ether ~,0.5 ml water, and 2.0 ml of 38-39% hydrochloric acid in 8 ml of methanol was refluxed 1.5 hours. The cooled mixture was poured into 20 ml of ice and 5% aqueous sodium hydroxide, and the aqueous solution was extracted with ether (6x25 ml). The ethereal layer was washed with saturated aqueous soditlm bicarbonate (lxl5 ml) and brine (lxl5 ml) and was dried (Mgso 4 ). Evaporation to dryness and tituration of the crude crystals with ether afforded 78 mg (80%) of a white cry~talline solid mp 125-130°. Crystallization from ether-heptane gave cubes mp 158-159° which were sublimed to give the analytical sample: ir (CHC1 ) 3615 (OH), 1695 3 (C"-'O); nmr (CDCl?) 0.83~ (s, 3, C~8a-CH~), l.46J (s, 3, J Anal. C, 73.29; H, 10.17 . ~ Pound: 129 In one experiment starting with 1.79 g (8.50 mmoles) of the crude (70% pure) product from the Simmons-Smith reaction there was obtained in addition to o.820 g (54%) of the keto alcohol N-7 0.175 g (12%) of a second keto-alcohol as ~n '""-"- oi 1: 1i-hy droxy-8~-methy 1-1, 2 1 3, 4, 14a, 7, 8 • 8a-octahydro-•5 (6H)-naphthalenone which was produced by hydrolysis of the --- equitorial alcohol N-4 that occurred as an impurity in the starting material. Ptlc ( 75% ether-petroleum ether) and evaporative distillation (130°, 0.004 rr~1) afforded the analytical sample: ir (CHC1 ) 3600 (OH), 1702 (C=O); nmr 3 (CDCl3) 0,77S (s, 3, C-8a-CH ), 3.28-3.67$ (m, 1, CH-OH). 3 Anal. Calcd for c11 H18 o2 : C 5 72.49; H, 9,95. Found: C, 72.42; H, 9,91. l,2t3,4,4a 1 5,6,7,8,8a-Decahydro-48.d..,8ap~Dimethyl-1~~ " ' V - ~· ----.~ . . . . . , . . ~ ~ ~ Naphthol (K-6). ~ ~ The Wolff Kischner reduction was carried out ac above. A 10 ml flask fitted with a short path microstill and a ni t:rc,gen inlet was charged with 73 mg ( 0. 38 mmole) of keto-• alcohol N-7, 1.0 ml of ethanol, 2.5 ml of diethylene glycol, """- 0.20 ml of 85% hydrazine hydrate, and 250 mg of crushed potassium hydroxide. With the nitrogen flowin g , the flask was heated to 100-105° for 0. 5 hours~ tlH.=: n to 200 - 205° for two hours. Upon cooling, the contents of the pot and r0ceiver were combined and extracted with ether (6xl5 ml). The corrbined or ganic layers were washed wi th water (2xl0 ml) 130 and brine (lxl0 ml) and were dried (Mgso 4 ). Distillation of the solvent at atmospheric pressure and ptlc {30% etherpetroleum ether) gave 15 mg (23 %) of the desired alcohol which crystallized on standing, ~P 46-56°. Ptlc (30% ether~petroleum ether) afforded white crystals mp 70.5-72°, which were spectrally identical to a sample prepared by Ireland and Dawson (76): ir (CHC1 ) 3615 (OH), 1260 (C-0); 3 nmr (CDCl3) 0.98i (s, 3, c-8a-CH3), 1.23J (s, 3, C-4a-CH3), 3.33-3.50J (m, 1, c~-OH). Anal. Found: (76) Calcd for c 12 H22 o: C, 79.06; H, 12.16. c, 78.93; H, 12.05. 4a~,8ap-D imethyl-3i4,4a, 5,6 , 7s8,8 a-O ctahyd r o-1 (2 H)- - ......._~~~~~~ Naphthalenone(K-8) . .........,..___________ To an ice cold solution of 39 mg (0.21 mmole) of the - alcohol K-6 in 5 ml of acetone that had been freshly distilled from potassium permanganate was added 0.J.0 ml (0.40 meq) of chromi c acid solution (62). After 5 mi n the solution wos poured onto 5 ml of saturated aqueous sodium bicarbonate, sufficient water was added to dissolve the chromium salts and the aqueous solution was extr a cted with et her ( 4xl 5 ml), The combl ned etl1er 12.yers wer-? washed with brine (lxl0 ml) and were dried ( MgSO4). Atmospheric: p:cessuI'e distillation of the solvent and ptlc f \50% ether-benzene ) gave 21 mg mp 65-72°. Crysta].lization (r1 ~4 c:· ~) of white crystals~ from he~tane 1 then from 131 petroleum ether, afforded a sample mp 108-110° (sealed capillary) which on adrrdxture with an authentic sample, (76) mp 108-110° (sealed capillary), gave mp 108-110° (sealed capillary). The spectra (nmr and ir) were also in total agreement with those of authentic ketone (76). l,2J3,4.,4a,5,6i7,8,8a-Decahydro-4ac<~8a~-Dimethyl-5,5- - --------------------------------Ethylenedoxo-lo{-Naphthol (0-1). A 50 ml flask fitted with a Dean Stark water separator was charged with a solution of 117 mg (0.595 mmole) of the ketone 'N-6 and 2.5 ml of ethylene glycol in 35 ml of benzene. -'l'en ml of benzene were distilled, 11 mg of E,-tolu1enesulfonic acid were added, and reflux was continued for 7.5 hours. The cooled solution was poured onto 30 ml of water and was extracted with ether (4x35 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (2xl5 ml) and brine (lx20 ml), dried (Mgso 4 )~ and concentrated. Ptlc (50% ether-petroleum ether) afforded 66 mg (64%) of the ketal mp 89-91°. Two recrystallizations from ether-heptane provided an analytically pure sample mp 9294° which was sublir::e:d (75°, 0,005 mm) for analysis: ir (CHC1 ) 3615 (OH); nmr(CDC1 ) 1.121 (s~ 3, c 8a CH ), 1.40{ 3 3 3 (sr- 3, C-4a CH ), 3.37-3.50S (m, 1, cg_oH) 1 3.G7-4.15J 3 (m, 4 11 ketal). 7 Anal. Calcd for c14 u~,:_ 4o: 3 C, 69.96; H; 10.07. Found: 132 - .~_,,,,_,,_,...._,,,.,_,_...,,,~......,..............,. 4Gb(., 8a~-Dimethy 1-5 , 5 - -Ethylenedioxo-• 3 , 4, 4a, 5, 6 j 7, 8, Sa- ~,___ -...,........ --- Octahydro-1(2H)-Naphthalenone (0-2). ~"" ..,.........,_ ~ To an ice cold solution of 133 mg (0.554 rmnole) of ketal 0-1 in 20 ml of acetone, (previously distilled from potas- ~ slum perman ganate), was added 0.25 ml (1.0 meqv) of BN chromic acid solution (62). After 1 min,0~10 ml of iso- propyl alcohol was added, the mixture was diluted with 20 ml of saturated aqueous sodium bicarbonate and was extracted with ether (4x50 ml). The ethereal solution was washed with brine (2x30 ml), dried (M gSO4) and evaporated to dryness to yield 32 mg (100%) of yellow crystals, mp 78-82°. Two recrystallizations from ether-hexa ne and sublimation (80°, 0.05 mm) provided the analytical sample mp 88-89°: ir (CHC1 ) 1695 (C=O); nmr (CDC1 3 ) l.00~ (s, 3 3, c-4a-cH 3 ), l.35~ (s, 3, c-8a-cH 3 ), 3.70- 4.17~ (m, 4, ketal). Anal. Calcd for c 1 4H 22 o3 : C, 70.56; H, 9.30. Found: C, 70.61; H, 9.44. Attempted addition of 2-m-Methox i phe nyJeth y lma ~ne s ium - bromide to the ke tone 0- 2. -· A dry 25 ml flask containir~g 170 mg ( 7 mmole s ) of magne5i um shav1.ngs was flush ed with nit rogen a nd charged with 3 m1 of dry ether. A solut J on of' 1.44 g (6.05 mmole s ) of 2-m-me thoxyphenylcthy 1 b1·01ni d e ( 1 2 0) ir, 7 ml of dry e ther was add ed dro pwi s e so as to ma i nt ai n a steady r e fl u x 133 (10 min), and the resulting solution was stirred 15 min at reflux. A 3 rnl (~2 mmole) portion was transferred to a dry 25 ml flask - under a nitrogen ntmosphere and a solution of 56 mg (0.24 mmoles) of the ketone~ in 5 ml of dry ether was added over the course of 5 min. After l hour at room temperature, the resulting mixture was poured onto 50 ml of water. The aqueous solution was extracted with ether (4x50 ml) and the combined ethereal layers were washed with saturated aqueous sodium bicarbonate (lx25 ml) and brine (lx25 ml) and were dried (MgS04). Evaporation to dryness and ptlc (50% ether-petroleum ether) gave: r.f. 0.2, 24 mg of aromatic material which displayed no angular methyl signals in the nmr and r.f. o.4, 46 mg (82%) of recovered starting material. 4a~'L3.p.-Dimethy 1-5, 5-Ethy lenedioxo-1- ( 2 '-m-Methoxypheny le thy l) -"""' ~ _... ' · " " ' - ~ ~ - - ~· -- - • .. • .. ~ .... ... -- ... . - 3,4t4a,5,6i7,8~8a-Octahydronaphthalene (0-5). ~ ..............................~~...............~.,,,,.,._......~ ....-- . _.. _..........,_.. ~..,-,,.,. A dry 25 ml flask fitted with a condenser, dropping funnel~ and a serum cap was flushed with nitrogen and charged with a solution cf 5.0 mmoles of n-butyl lithium (2.0 ml of a 2.5M solution in hexane as supplied by Alpha Inorganics, Inc.) in 8.o ml of dry ether. A solution of 931 mg (7.05 mmoles) of m-methoxyphenylacetylene (121) in 3 ml of dry ether was added over the course of 5 min while a vigorous 11 exothermic reaction trann p ired. The ... ¥ :..-. 134 solution initially turned yellow, but became a milky color near the end of the addition. After an additional 5 min, a solution of 76 mg (0.32 mmole) of the ketone 0-2 in 3 ml ~ of dry ether was introduced through the serum cap with a syringe. After 4 hours, no further change in the peak representing starting material was discernible by glpc so 0.5 ml of 10% aqueous ammonium chloride solution was added carefully followed by 15 ml of water. The aqueous layer was extracted with ether and the organic layer was washed with water and brine. Drying (Mgso ) and evaporation to 4 dryness afforded 828 mg of a yellow oil. Ptlc (40% ether~ petroleum ether) gave 102 mg of an oil which consisted of 60% of the addition product and 40% of the starting ketone by nmr integration of the methoxyl region. In another exper- iment, carried out at -78°, a 50-50 mixture of products was obtained. The hydrogenation was conducted according to the procedure of Barltrop and Rogers (89). The crude mixture from above was dissolved in 5 ml of reagent ethyl acetate and was hydrogenated l hour in the presence of 30 mg of 10% palladium on carbon at one atmophere, Filtration through celite and concentration yielded 78 mg of a mixture of the tertnoalcohol .,_.._.. 0-4 and the starting ketone v,hich was not conveniently separable by ptl.c. To a solution of 150 mg (0.52 mmole) of the crude reduction pr0du8t f::-•om above (combirn:d. :)roduct fro m two 135 experiments), in 5 ml of dry pyridine cooled in an ice bath, was added 0.20 ml (2.8 mmoles) of thionyl chloride. The yellow solution was stirred 50 min at 0° and poured onto 25 ml of ice and water. The aqueous layer was extracted with ether and the ethereal phase was washed with water, then brine and was dried (Mgso 4 ). Evaporation to dryness and ptlc (30% ether- petroleum ether) gave two bands, r.f. 0.5~ 45 mg (28 %) of ~tartin g ketone \.--. 0- 2, and r.f. 0.7, 68 mg (38% based on starting ketone) of the desired olefin 0-5. ~ Ptlc (30% ether-petroleum ether) of a portion and f1ash distillation at 0.005 mm afforded the analytical ir (CHC1 3 ) 1600, 1585 (Ph); nmr (CDCJ ) 1.10{ 3 (s, 3, c-4a-CH 3 ), 1.25! (s, 3$ C-8a-cH 3 ), 3.78-4.oSJ (m, sa.mple: 7, ketal and O- CH 3 ), 5.15-5.351 (m, 1, vinyl), 6.62-7.3U ( m, ¼t Ph). Anal. Cs Calcd for c23 H32 o3 : c, 77.49; H, 9.05. Found: 77.35; H, 9.15. ~aor., 8ap-DiDet hyl-5, 5-Ethy lenedioxo-:ip - ( 2 '-m-Methoxypheny 1- , ~. ,. . . .~.,..,.,~""--"'-.._,p...,,.._,....__~------..~ ~ ~ ~ . . , _ , . . , , , , . . _ ethyl)-~,4,4a,5 , 6,7 ,8,8a- Octahydro-2(3H) -Naph thalenone (L- 4). ~-~.,.,,,,, ~ ... ., ~ ~-~ . . . _ ~ ~ ~ - - ~ , "'"""'...... "' The hydroboration was carried out according to the general procedure of Brown and Zweifel (l22). of 165 mg To a solution (0.461.l mmole) of olefin ---. 0~5 in 4 ml of dry tetra- hydrofuran was add1.::d 3, 0 ml ( 3 mmoles) of a lM solution of bcranc in tetrahydrofuran under a nitrogen atm. The reac tion mixt.ure waa stirred 50 min~ cooled to 0°, and the rema:!.r.::l.ng borane was destroyed by th~ careful addition of 0.20 ml of 136 water, followed by 2.0 ml 3N sodium hydroxide and 2.0 ml of 30% hydrogen peroxide. After an additional 45 min, the resultant mixture was diluted with 25 ml of 10% aqueous potassium carbonate and extracted with ether. The etheral · solution was washed with water and brine, dried (Mgso evaporated to dryness to give 107 mg of an oil. 4), and Ptlc (40% ether-petroleum ether) gave three bands: r.f. 0.2, 63 mg (37%) of the desired alcohol 0-6; . r.f. 0.3, 49 mg (28%) of a complicated mixture; and r.f. 0.5, 43 mg (16%) of recovered starting material. Longer reaction times lead to lower yields: ir (CHC1 ) 3600 (OH), 1600, 1585 (Ph): nmr (CDCl3) 3 1.07! (s, 3, C-4a-CH ), l.42J (s, 3, C8a-CH3), 3.67-4.07{ 3 (m, 8, ketal, O-CH 3 , C!:!_-OH), 6.60~7.37I (m, 4, Ph). To an ice cold solution of 63 mg (0.168 mmole) of the alcohol V..,00-6 fro □ above in 5 ml of acetone, (freshly distilled from potassium permanganate), was added 0.06 ml (0.24 meqv) - of BN chromic acid solution • (62). After 2 min, the mixture was diluted with 20 ml of water, and was extracted with ether. The ethereal solution was washed with saturated bicarbonate and brine and was dried (Mgso 4 ). Evaporation to dryne s3 afforded 62 mg (37% from the olefin a.queous sodium 0-5) of the ketone L~4. ~ """-" Pt le ( 50 % cther-,petro leum ether) and flash distillation (0.15 ~n) gave the analytical sample: ir (CHC1 ) 1695 (C=O), 1600, 1585 (Ph); nmr (CDC1 3 ) 1.05[ 3 (s,. 3~ C-lla-CH )~ l,23S (s, 3, C-80.•- ° CH ),. 3.6G - 3.97J (m, 3 3 137 7, ketal and O-·CH 3 ), 6. 60-1. 4oJ (m, 4, Anal. Calcd for C23H3204: Ph). c, 74.16; H, 8.66. Found: c, 71.!.17; H, 8.79, Attempted Methyl at ion of Ketone L-4 To a suspension of 50 mg (2 . 06 mmoles) of magnesium shavings in 2.0 ml of dry ether under nitro gen was added dropwise a solution of 0 .11 ml ( 1. 75 m,11oles) of iodomethane (freshly distilled from anhydrous calclum sulfate) in 4 ml of dry ether so as to maintain spontaneous refluxing, The mixture was stirred an additional 15 min at room tempera ture, cooled in an ice bath, and a solution of 63.3 mg (0.170 mmole) of the ketone ............ L- 4 i n 4 ml of dry ether was added over the course of 10 min, After 0.5 hours at 0° and 2 hours at room temperature, the exce s s Grigrand was decomposed with 0.2 ml of 10% aqueous ammonium chloride, the solution was diluted with 100 ml of ether, and the ethereal phase was washed with water and brine. Drying (Mgso ) and concentration yi elded 65 mg of a 4 slightly yellow oil whose nmr revealed no discernible product besides starting material. Other attempts involved the use of me t h yl magnesium iod i de a nd me t hy l li t hium at room temp e rature and - 78°. Dime thyl magn e s l u m, gene r ated by a ddition of a ntoichiomet r ic amoun t of d ry dio xane to an etherea l s ol uti on of meth y l ma gnesi u m iod i d e ( 8 11) .,was al s o e mpl oy ed a t 0 ° and 138 -78°J all with similarly negative re s ults. s~,4a-Methano-58-Meth oxy-8aP-Methyl-3 , ll ,4 a,5,6»7 , 8,8a- '-"""--.---------·- - - - - ~ - . . . - ~ ~ Octahydro-1(2H)- Naph thal en one (P-1). -..............------· -· ..........,.._ To an ice cold solution of 240 mg (1.22 mmoles) of the - axial alcohol N-5 in 45 ml of acetone (freshly distilled from potassium termanganate) was added o.40 ml (1.60 meqv) cf 8N chromic acid solution {62) over a period of 3 min. After 3 min, 0.20 ml of isopropyl alcohol and 5 ml of saturated aqueous sodium bicarbonate solution were added and most of the acetone was removed in va cuo. The residual green m~ss was dissolved in 30 ml of water and was extracted with ether (4x50 ml). The combin e d organic layers were washed with brine (2x50 ml) and were dried (Mgso ) . 4 Evap oration to dryness and ptlc (30% ether-petroleum ether) afforded 174 mg (73%) of a white crystalline solid mp 60.5-62°. Crystallization from hexane and sublimation (55°, 0.005 mm) provid ed the analytical sample mp 61-62°: ir (CHC1 ) 3075 (cyclopropane), 1705 (C=O), 1055 (C-0); 3 nmr (CDCl?) 0.38 i (d, 1, J=5.5 Hz, cyclopropane)s 0.601 .J (d, 1. J=5.5 Hz, cyclopropane ), l.38((s~ 3, C-8a-CH ), 3 3,27, (s, 3, O- CH3)• Anal. Found: l,2 , 3,~ , 4a 1 5,6~ 7,B ,8a-Decah ydro-5~,4a-Me thano-5 p- Me thoxy-8 ap \..A,:~ ~.... ~ ~ U ; / ' . . , ~ " ' " ' ~"~ ~ - " ' ~ ~ - . , . . . ~ , . . . ,·""'..,~.. , . . . . , , ~ ~-~ l l •...«a""'"- ••:..:........~~, .......""'"'""·.._ Mcthy1"-~-(2 1 ·•P l1cnyL:thyl)=l'\ - Na.phthol ( M~-3,. R""H). \r~t..P"........,...,,.,.._...._,Ji"1"c .........-ll.~~~ -~.............,.~.__,._~.......__......,,.,.,,,,(,,._.,, .-.,"V"III ..._,..,..~...- , . . : - " - ~ " " ' · 139 Benzyl Grignard was prepared using t he general method of Prout (123), Freshly distilled benzyl chloride 0,90 ml (7.8 mmoles) in 9 ml of dry tetrahydrofuran was added over 1 0 min to a suspension of 191 mg (7.97 mmoles) of magnesium shavings in 6 ml of dry ether under an atmosphere of nitrogen. The G~ignard solution was refluxed 15 min and cooled; 9.0 ml of dry tetrahydrofuran and 0.70 ml (8.2 mmoles) of dry dioxane were in,jeeted and the result1.ng precipitate was allowed to settle 20 min (8~). The supern2tant was removed with a syringe and introduced into a flask containing 207 mg (1.00 mmole) of the oxirane ...M-1 __... in 2 ml of dioxane under nitrogen. The reaction mixture was refluxed 1.5 hours, cooled, and poured into 20 ml of water. 'l'he aqueous solution was extracted with ether, and the ethereal layer was washed with water and brine, and was dried (MgS04). Evaporation to dryness afforded 385 mg of an oil which was chromatographed on 20 g of alumina: 100 ml of petroleum ether gave 56 mg of bibenzyl. Elution with 100 ml of 10% ether-petroleum eth~r afforded 39 mg (18%) of starting oxirane, and 50 ml of ether eluted 250 mg (82%) of the desired enol ether alcohol M-2, R~H contaminated with ~ two minor impurities acc0rding to glpc: ir (CHC1 ) 3550 3 (broad, weak) (OH)t 1660 (C~C), 1595 (Ph); nmr (CDC1 3 + 1 drop pyri.ne) 1.J3S (s, 3, C-8a-cH ), 3.52J (s, 3~ o-cH 3 ), 3 Ph). The alcohol is quite sens itive and wa s . 140 used directly in the next step. Cyclopropylation To a solution of the Simmons-Smith reagent (53) prepared from 600 mg (e.5 mmoles) of zinc-copper couple (52) and o.64 ml (7.9 mmoles) of diiodomethane in 10 ml of dry ether was added all at once a solution of 237 mg (0.79 mmoles) of the alcohol M-2, R=H in 3 ml of dry ether and 0.7 ml (6.7 mmoles) of dry 1,2-dimethoxyethane. After 40 min at room temperature, the reaction mixture was cooled in an ice bath and was quenched with 1.0 ml of water. The solution was poured into 20 ml of water, extracted with ether and the organic phase was washed with saturated aqueous potassium carbonate and brine and was dried (Mgso 4 ). Evaporation to dryness and ptlc (20% ether-petroleum ether) gave two products. mg The slower moving band, r.f. 0.3 contained 131 (45% from the oxirane ...__... M-1) of the desired cyclopropane . Glpc indicated a minor impurity that could not be removed conveniently by ptlc under a variey of conditions so a 90 mg (0.30 mmole) portion was dissolved in 20 ml of cold acetone and treated with 0.1 ml (0.4 meav) of • acid solution (62). SN·- chromic The mi xture was poured into saturated aqueous sodium bicarbonate, and was extracted with ether. The ethereal layer was washed with water and bri n e and was dried (Mgso 4 )~ - Evaporation to dryness and ptlc (20% ether-petrcleum ethe:r·, 2. elutions) af forded 59 mg ( 66%) of 141 the pure alcohol. Evaporative distillation (155°, 0.01 nun) gave the analytical sample: ir (CHc1 ) 3590 (OH), 1605 (Ph); 3 nmr (CDC1 ) 0.52i (d, 1, J=5 Hz, cyclopropane), o.83J (d, 3 1 1 Jc5 Hz, cyclopropane), 1.15[ (s, 3, C-8a-CH ), 3.27f (s, 3 3 , 0-CH ) , 7 . 20 ! ( s , 5 , Ph ) . 3 c, 80.21; H, 9.62. Anal. Found~ C, 80.14; H, 9.45. - l,2,3t4,4a,5,6,7~8. 1 8a-Decahydro-5~~ba-Methan o-5~- Me thox v-lp. _ -~ ... , _ _ . , . , . . . , . ~ • ( 2' -m-me thoxyphenyle thy 1 )-Sai-Methy 1-Jo(.-Naphth ol ( M- 3, H=Ome). ~ . , ~ - - ,--.. ,.. w,-_, -~ , r· ; ...,,, .,, ,,.,.,,,,, ..., • _..__...,,.._. ~ . ~ ~~ A. Oxirane Cleava ~e grignard A dry, 50 ml flask fitted with a serum cap: reflux condenser, and dropping funnel was flushed with nitro gen and charged with a suspension of 313 mg (12.9 mmoles) of magnesium shavings in 5 ml of dry ether. A solution of 1.867 g (11.9 mmoles) of m-methoxyhenzyl chloride (124) in 5 ml of dry ether was run in over the course of 15 min while the mixture reflu xe d spontaneously. After an additional 30 min reflux, 10 ml of dry tetrahydrofuran was introduced followed by 10 ml (11.7 rnmoles) of dry diox an e (84). After 2 minj stirring was halted and the precipitate was permitted to 3cttle 10 min. Titration of an aliquot with ~-butyl alcohol j_n xylene using 1, lO-pl1e n a n throlene a.s j_ndi cs.to!' as described by Watson and East ham ( 85) tndi ca tE)d the was 0.26M in dialkyma gn es ium. s () lu -:;.Jon The s up erna tant, 13 ml (3.4 142 mmoles), was transferred with a syringe to a flask containing a solution of 200 mg (0.96 mmole) of the oxirane M-1 in 1 ml of dry dioxane under nitrogen. '""-- The reaction mixture was refluxed 65 min, cooled, quenched with 1 ml of water, and poured into 50 ml of water. The aqueous solution was extracted with ether and the ethereal layer was washed with water and brine and was dried (Mgso ). 4 Evaporation to dr yness afforded 411 mg of an oil which was chromatographed on 20 g of alumina: 60 ml of petroleum ether eluted 119 mg of 3,3'-dimethoxybibenzyl; 60 ml of 10% ether-petroleum ether gave 74 mg (37 %) of recovered starting material, and further elution with 80 ml of ether afforded 181 mg (57 %) cf the desired alcohol M-2, R=Ome '-"'-- which was 65% pure by nmr inte gration of the methoxyl regions: ir (CHc1 ) 3550-3500 (broad, w) (OH), 1665 (C=C) ~ 3 1600, 1585 (Ph); nmr (CDC1 3 + 1 drop-pyridine), 1.131 ( s , 3, C-8a=CH 3 ), 3.505 (s, 3, O-CH 3 ), 3.82J (s, 3, PhOCH 3 ). The product is extremely labile and was used directly in the cyclopropylation. The yield from the gri gnard was highly variable ran g ing from 29 - 86% based on consumed starting material. In one experiment the alcohol ~- 2, ~ R=Ome was obtai ned free of impurities; i n this case the cyclopropylation pro cee ded well. In oth e r instances po o r yields were reali zed . To a so l ut io n of t h e Si mmons-S mith re age nt ( 53 ) prepar Pd 143 from 1.168 g (16.7 mmoles) of zinc-copper couple (52) in 17 ml of dry ether and 1.30 ml (16.2 mmoles) of diiodomethane was added a solution of 520 mg (1.57 mmoles) of the alcohol -- M-2, R=OMe (obtained free cf impurities from one grignard experiment) in 1.75 ml (16.7 mmoles) of dry 1,2-dimethoxy- ethane in 5 ml of dry ether under a nitrogen atmosphere. After 50 min at room temperature the excess reagent was quenched with 0.5 ml cf water and the mixture was poured onto 35 ml of saturated aqueous potassium carbonate. The aqueous layer was extracted with ether and the combined organic layers were washed with brine before drying (M gso 4 ). Evaporation to dryness and ptlc (20% ether-petroleum ether) gave two products. The first, r.f. 0.2, 352 mg (66 %), was the desired cyclopropane M- 3, R=OMe. A portion was further """"" purified by ptlc (20% ether-petroleum ether) and the oil was flash distilled (0.01 mm) to give the analytical sample: ir (CHC1 ) 3600 (OH), 1600, 1585 (Ph); nmr (CDC1 ) 0.50J (d, 3 3 1, J=5, cyclopropane), o.80~ (d, 1, J=5 Hz, cyclopropane), 1.136 (s, 3 1 -C8a-CH 3 )t 3.22[ (s, 3, OCH 3 ), 3.77J (s, 3, PhOC~ ), 6.57-7.37t (m, 4, Ph). 3 Anai. Found: C, 76.62; H, 9.22. The second band, r.f. 0.7, 42 mg (8%), contained 1,2,3, Li, 4q1 l- 5 ~ 6., 7,, 8., 2.a.-dcca.hy dro-5$ ~methoxy-1~ - ( 2 '-rn-methoxypheny 1- ethy 1 ) -6:,;~; --mt, thy l-ll'!(,-naphthol ketaJ. ( M-4, R"'OM e), which was ......... 144 purified by ptlc (20% ether-petroleum ether) and flash distillation (0.01 mm) to afford the analytical sample: ir (CHC1 ) 1600, 1585 (Ph), 1155, 1085 (C-O); nmr (CDC1 ) 3 3 o.95~ (sj 3, C-8a-CH3), 3.37J (s, 3, O-CH3), 3.77i (s, 3, PhOC,!i ), 6.53-7.25[ (m, 4, Ph). 3 Anal. Calcd for c H o : 21 30 3 c, 7G,33; H, 9.15. Found: C, 76.36; H, 9,20. B. From Ketone P~l with 2~m-Methoxyphenylethyl Grignar...9. A dry 25 ml flask was flushed with nitrogen and charged with a suspension of 34 mg (1.4 mmoles) ~f magnesium shavings in 1.0 ml of dry ether. A solution of 220 mg (1.02 mmoles) of 2-m-methoxyphenylethyl bromide (120) in 2.0 ml of ether was added dropwize so as to maintain a steady reflux. Reflux was continued 5 min following the addition, the solution was cooled to 25°, and 47.3 mg (0.228 mmole) of cyclopropyl ketone P-1 in 2.0 ml of ether was added all at """"' once. After 1 hour the reaction was quenched with 0.3 ml cf saturated aqueous ammonium chloride and the product wa$ poured into 25 ml of water. extracted with ether. The aqueous solution was The ethereal solution was washed with water and brine and was dried (Mgso ). 4 Concentration and ptlc (40% ether-petroleum ether) gave two bands. The slower moving band, r.f. 0.2, consisted cf 18.4 mg (24%) of a mixture of at least two components and was not further examined. The faster band, r.f. a.4, 45.5 mg (58 %) contained 145 a 1:1 mixture of the desire addition corr.pound M-3, R=OMe ~ ---- and the axial alcohol N-5. c. From Ketone P-1 with m-Methoxyohenvlacetylene A solution of 3.0 ml of a 2.5M solution of n-butyl lithium in hexane (Alpha Inorganics, Inc.) in 20 ml cf dry ether was placed in a dry 50 ml flask fitted with a serum cap, a reflux condenser, and a dropping funnel under a nitrogen atmosphere. A solution of 3.2 g (10 mmoles) of m-methoxyphenylacetylene (121) in 7 ml of dry ether was added dropwise resulting in a vigorous exothermic reaction. The initially yellow solution became a characteristic milky white near the end of the addition. After 5 min, 287 mg (1.38 rnmoles) of the cyclopropyl ketone P-1 in 4 ml of dry ~ ether was introduced with a syringe and the resulting mixture was stirred 1 hour. The excess acetylide was decomposed witt, 0.5 ml 10% aqueous ammonium chloride, and the mixture was poured into 50 ml of water and was extracted with 200 ml of ether. The ethereal solution was washed with saturated sodium chloride (lx25 ml), and dried (MgSO,,). '-i Evaporation to dryness and Ptlc (50% ether-petroleum ether) yielded 455 mg (96%) of a yellow oil. The crude product was taken up in 10 ml of ethyl acetate and was hydro genated (89) over 200 mg of 10% palladium on carbon under 1 atmosphere of hydrogen for 1 hour. Filtration through Celitej evaporation to dryness , and ptlc (50 % ether-petro leum ether) revealed 146 two components. The more polar band r.f. 0.3, 204 mg (46%) contained the equatorial alcoh::,l p ... 2 mp 95-98°. Crystal- '-"-" lization from ether-n-heptane gave the analytically pure sample mp 100.5-101.5•~ j_r (CHC1 ) 3610 (OH), 1600, 1.585 3 (Ph); nmr (CDC1 ) 0.53! (rn, 2, cyclopropane), l.25J (s, 3, 3 c-8a- CH3), 3.23J (s, 3, O-CH3), 3.80E (s, 3, PhOCH3), 6.57- 7 . 3 76 ( m, • 4 , Ph ) • ~ Calcd for c22 H32 o3 : c, 76.70; H, 9.36. Found: C, 76.64; H, 9.17. The second band, r.f. 0.4, 192 mg (44%) contained the desired axial alcohol ~ M-3, R=OMe which was the same as that obtained in Part A above. 4ao:. s Ba~ -Dime thy 1-3, 4 , 4a , 7, 8, Sa-He xahydro-1-( 2' -m-Methoxy- ~....- - - - - . . . _ . _ . , . _ . , . _ -- - . . - - -·.,...,,.,..,,.,.,,,,..,~.,--...-,..-,, _ , ..., ¥1 u - --~ phenylethyl)-5(6H) -N aphthalenone (M-5). A solution of 181 mg (0.525 mmoles) of the cyclopropyl alcohol M-3, R=OMe in 1.5 ml of 37-38% hydrochloric acid ~ and 15 ml of methanol wa s refluxed 4 hours. The solution was poured into 25 ml of saturated aqueous sodium bicarbonate and was extracted with ether (5x25 ml). The com- bined organic layers were wash~d wjth water (lx25 ml), saturated aqueo~s sodium bicarbonate (lx25 ml), and brine (lx25 ml), and were dri ed (M gS0 4). Evaporati on to dryness yielded 159 mg; ptlc (20% ether-petroleum et~ er) gave a band r,f. 0.3 containing 89 rng (46%) of M- 5 as a colorless oil """""' con tarnjn at ed with about 20% of th e exocyclic olef!n. A 147 portion was further purified by ptlc (20% ether-petroleum ether) and flash distilled (0,01 mm) for the analytical sample: ir (CHC1 ) 1695 (C=O), 1600, 1585 (Ph); nmr (CDC1 ) 3 3 1.02J (s, 3, C-,8a-cH ), 1.20~ (s, 3, C-4a-cH ), 3.8oS (s, 3, PhOCl:! ), 3 3 3 5.22-5~37~(m, 1, vinyl), 6.58-7.42! (m, 4, Fh). C, 80.73; H, 9,03, Anal. Found: 1 1 2,3,4,4at5,6,7,8,8a - Decahydro-l-(2'-m-Methoxyphen y leth yl i- '-""-~~~--- ~u~...,. ___...,. _ _ .,...._, w ..._.. z.., "'-i ................ ~ ~ ~ . . . . , , . . _ . . . _ . _..,,,..,....,... dene )-5-11., 4a-Methano- 5\:, ·~Me thoxy -8af> - Me th y lnaphthalene ( P-li ) . ~~~""""-'·~ ~ ~ . , , . . _ , . , . , , , .-~-- ,.., ...._, ... """-~,...,.,,,.,_ To a solution of 204 mg (0.594 mmole) of the equatorial alcohol ,._...._ P-2 in 5 ml of dry pyridine at -10° (ice-salt bath) was added 0.25 ml (3.44 mmoles) thionyl chloride~ The r·ea.c-" tion mixture was stirred in the cold 45 min and was poured into 200 ml of ether. The ethereal solution was washed with water, saturated aqueous sodium bicarbonate, and brine, and was dried (Mgso 4 ). Concentration and ptlc (20 % ether- pet~oleum ether) gave r.f. o.6, 82 mg (43%) of an olefin different from that obtained below from the axial alcohol. Rechromatog1•aphy and flash distillation (0.01 mm) gave the analytical sample: ir (CHC1 ) 1665 (C=C), 1600, 15 8 5 (Ph)~ 3 10~5 (C-0); nmr (CDCl~) ., o.37~ (m, 2, cyc loprop ane), 5.00-5,33 Anal. vinyl), 6,57-7,33~ (rn, 4, Ph). Found.: 148 C., 80.82; H, 9.20. 5~, lla•-Methano-5r-Methoxy-l- ( 2 '-m-Methoxypheny le thy 1 )-8ap~~_____....,..,....._~~~,.._.,.,,...~~ •"-"""'--~ . _ . . .___ . Methyl-3 ,4,4a,5~6, 7,8,8 a-O ctahydronaphthal ene (P-3)e ............... ~~~~¥~,,,,._,,,_..,,.~.----...-..-ww~ ,____ -.,._,..,_ To a solution of 317 mg (0.92 mrnole) of the axial - alcohol M-3, R=OMe in 7 ml of dry pyridine cooled to -10° (ice -sal t bath) was added 0.35 ml (4.5 mrnoles) of thionyl chloride. After 45 min, the reaction mixture was diluted with 300 ml of ether and was washed with wa ter, saturated aqueous sodium bicarbonate, and brine. Drying (Mgso ), 4 evaporation and ptlc (20% ether-petroleum ether) afforded 241 mg (91%) of the endocyclic olefin P-3. .......,_ Further puri- fication of 31 mg by ptlc (20 % ether-petroleum ether) and flash distillation gave the a nalytica l sample: ir (CHc1 ) 3 1600., 1585 (Ph), 1155 (C- 0); nrnr (CDC13) o.35~ (d, 1 , J=5 Hz, cyclop ropane ) o.62~ (d, 1, J=5 Hz, cycloprop a ne), l.27~ (s, 3, c-8a-~H 3)l' 3.23i (s, 3, OCH3) , 3.77~ (s, 3, PhOC!i3), 5 • 30- 5 • 50 i ( m, 1 , v i ny 1 ) , 6 . 57 - 7 • 3 7 X ( m, 4 ., Ph ) • Anal. Calcd for c 22 H30 o2 : C, 80.94; H, 9.26. Found: C, 81.17; H, 9,13. ld., 2.p 9 3, 4, 11a, 5, 6, 7, 8 :1 Ba-De c ahydr o- 5<.-:. , 4a-Vie thano-5p-~ Me thoxy"~~ ....~ ~ ~ ~,.~~......._,.....,,_,,,_,.,,,..,,......... ~ . ' -_._.,,,_.....,.._,.._.~ ~ ~-. ,._,_~-·......,.~ lp ~- ( 2' -m-Methoxypheny J.cth y l )-8a~ -Methyl•~2cx_ --N a.ph the l ~ , _ __.,__ __.._, -- .,,.._...--.. ~.J'..,,.....,,_.,...,..,,,...,, .... .... ~~ ( P··:. ) . ~ - - , 1 1 1 , u •. , . , ~ .........." " " ~ Employing the hydr obo ratio n prccedure of Bro~n and Zweifel (1 22), a 50 ml flask was flushed with nitro ge n and chargeci wl th a soluU.on of 210 mg ( 0. 6 45 mmole ) of the endocyclic ole f in .___ P-3 ..... in 6 ml of dry tetrahydrofura~, 149 followed by 2.0 ml of a lM solution of borane in tetrahydrofuran. The reaction mixture was cooled to 0° after 1 hour and the borane was decomposed carefully with 0.5 ml of water, 3 ml of 3~ sodium hydroxide, and 3 ml of 30% hydrogen peroxide. After an additional 45 min, the mixture was poured into 30 ml of 10% aqueous potassium carbonate and was extracted with ether ( 4x50 ml). 'l'he combined organic layers were washed wi th water (2x20 ml) and brine (lx20 ml) and were dried (MgS04). gave two bands. Ptlc (50 % ether-petroleum ether) The first, r.f. 0.2, contained 185 mg (84 %) of the secondary alcohol, ..._,_..__ P-5 which crystallized on stand. in g mp 90 - 97° . Crystallization from ether-hexane and further purification by ptlc (50% ether-petroleum ether) gave analytically pure material mp 100-102° (amorphous solid): ir (CHC1 ) 3600 (OH), 1602, 1585 (Ph), 1155 (C-0); nmr (CDC1 ) 3 0.35~ (d, 3 1, J=5, cyclopropane), o.58~ (d, 1, J=5, cyclopro- pane), 0.9Bi (s, ~• C-8a-CH ), 3.20, (s, 3, O-CH ), 3.751 3 3 (s, 3, PhOCH ), 6.57-7.18~ (m, 4, Ph). 3 Anal. Calcd for c22 H32 o3 : C, 76.70; H, 9.36. Found: C, 76.87; H, 9,37. The second band, ~.f. 0.3, consisted of 21 mg (10 %) of ---- approximately equimol a r protions of the startin g ole f in P-3j the equatorial alcohol ,.____ P-2, and a third, unide n tlfi a d compound. 150 2-.~.~!::_e..t~an o- ~t-~1~xy,~ 1~ : l _ ~ ~ ~ l - ~ ) : ~- --------- - Methyl-l~,2,3,4 1 4a,7,8,8a-5(6H)-Napthalenone (P-6). ........... ~ - _.....,.._-~~~ ~ To an ice cold solution of 164 mg (0.476 mmole) of - secondary alcohol P-5 in 15 ml of acetone (freshly distilled from potassium permanganate) was added 0.15 ml (0.60 meqv) of 8N chromic acid solution (62). After 5 min, 0.10 ml of iscpropyl alcohol was added and most of the acetone was removed in vacuo. The green residue was dissolved in 25 ml of saturated aqueous sodium bicarbonate and was extracted with ether (5x30 ml). The combined ether layers were washed with water and brine (lx20 ml). Drying (Mgso ) and evapora- 4 tion to dryness afforded 164 mg (100%) of a pale yellow oil~ Ptlc (50% ether-petroleum ether) gave two bands; the more polar r.f. 0.2, contained 21 mg (13%) of the equatorial alcohol P-2 which occurred as an impurity in the starting ~ material. The faster moving band r6f. 0.3 contained 130 mg (74%) of the ketone ..__ P-6 which gave waxy crystals on standing; two crystallizations from ether-heptane gave the lr (CHC1 ) 1700 (C=O)~ 1600, 3 1585 (Ph)s 1155 (C-0 ); nmr (CDCl?) 0.67J (m, 2j cyclopropane), :.) analytical sample mp 108-110°: 0.90~ (s, 3t C-8a-cH ), 3,2jtS (s, 3, 0-CH ), 3.77S (s, 3s 3 3 PhOC1,i ), 6.57 ~·7.27b (rn, h, Ph)~ 3 Calcd for c~~H r::. ,. 30 o 3 : C, 77 . 23; H, 8.87. Anai. Found: 151 1~, 2,3 4, 4a, ,..,.,,,,,..,,,_~ 5, 6, 7, 8 , 8a-Dec ahydr-o-2--<, 8a~ -Dime thy 1-So<, 4a-------........ 8 ,.,,...,._""" ~.......-...-.. ~~ Methano-5f-Methoxy-l?- ( 2' ~m-Methoxypheny lethy l )-2~ •-Naphthol ~-~~ ,.,,._,.~~ ....,..,,_ > -.........-... ....... ..,...,..._ .,.,_,,,,., ...,.., ..... ,,...,..__w-- ---- ( P-7). To 1. 4 ml ( 3. 3 mmoles) of a 2. 4t1_ solution of me thy J. lithium in ether (Alpha Inorganics, Inc.) in 10 ml of dry ether at 0° (ice bath) and under a nitrogen atmosphere was added a solution of 109 mg (0.318 mmoles) of the ketone P-6 in 4 ml dry ether. ~- After 10 min, 0.5 ml of water was introduced carefully and the reaction mixture was diluted to 200 ml with ether. The ethereal solution was washed with water (lx20 ml) and brine (lx20 ml) and was dried ( MgS04). Evaporation to dryne ss and ptlc (50% ether-petroleum et her) gave 102 r.1g (90%) of white crystals mp 87- 101°. Two crystallizations from ether-hexane gave a pure sample mp ir (CHC1 ) 3605 (OH), 1600, 1585 (Ph), 1155 3 (C-0); nmr (CDC1 3 ) o.30~ (d, 1, Jg5 Hz, cyclopropane), 106.5-107.5: 0.63o (d, 1, J=5 Hz, cyclopropane), 1.40( (ss 6 1 C-,4a and C-8a methyls), 3.25J (s, 3, O-CH 3 ). 3; 78! (s, 3, PhOC~3 )J 6,57-7.37J (m, 4, Ph). Anal.. Found : 8a.p ,... cy ano-1,. 2 d, 4, 4a, 5'-( 6 7 , 8: Ba-De cahydro-2t<, i4 a'l( -Di.me th y J.-~ .1 t " ' " ~ ~ -,lP""-...-~.-.___.....- - ~ ~ ~ " ' . . . . - i , . , , . . . _ , , , _ ~......-.#~•-.-.~•"-....,-.....·~""''"'="'--,......,.~ -·..... ..,.._.........-~- 1,-(2'-rn-Mcthoxyphenylethyl)-2p,5D-Naphthalenediol ..... ~~-~-~~- ,.. .,.....,_..~ ~ - ~ ~ ~•'t..,,......,.,,.._..,..__,....""..._.,..,-,i,~ A dry 2 1. fla s k fitted with a mechanical stirrer, a 500 ml addition funnel, and an efficient reflux condenser 152 topped with an argon inlet was charged with 15.7 g (0.645 mole) of magnesium turnings and was flushed with argon. The magnesium was suspended in 50 ml of dry ether and a solution of 34 ml (0.55 mmole) of methyl iodide (previously distilled from phosphorous pentoxide) in 300 ml of dry ether was added over 1 hour so as to maintain a vigorous reflux. The dark Grignard solution was cooled in an ice bath, and a solution of 19. 80 g ( 58 rr1moles) of 8a13-cyano-5oi.-h ydr ox y"'mr,¢ _...,... """',., --...--.... lp-(2'-m-methoxyphenylethyl)-4act_.-methyl-3,4,4a,5,6,7,8,8a~ ·••- ,-,, -- -- >I. --- - zt'"lw.,..,_,,...,._. .... - ,._..,.,..,, ,_. . _ _ • <'.II ... -~ octahydro-2(1H) -naphthalenone (Q- 7) [prepared according to ., _.. • ..,........... ,.--,...__-..,,.. -"-=' ......_ ~ the procedure of Kowalski (90)] in 300 ml of dry benzene was added over the course of 45 min. After an additional 45 min the excess reagent was destroyed by the careful addition of 15 ml of saturated aqueous ammonium chlori de solution, and the reaction mixture was partitioned between 600 ml of methylene chloride and 1000 ml of water. The lay ers were separated and the aqueous layer was extracted with methylene chloride (4x600 ml). were washed with The combined organic layers 1% aqueous ammonium chloride solut io n (2x500 ml) and water (2x500 ml) and wer2 dried ( MgSO~ ). Evaporation to d~yness afforded 20.80 g (quantitative) of a white crystalline solid, mp 1 71-175° (lit (90) 175-178°). Their spectrum of the product showed no carbonyl str~tch and was identical to th at of the authentic diol. 153 8~-Cyano-1,2,J,4,4a,5~,6~7,8,8a-Decahydro-2~l4a~-DimethyJ....." - . . - . """'....._ • aw..,., -. -- ....--,- • lf-( 2 '-m-Methoxyphenyl )-2~, 5""--Naphthalenediol ~ . . . ._ .............. "-1~..---.-- .. 5-Aeetate. - Employing the procedure developed by c. Kowalski (90), a solution of 20,.80 g (58 mmol.es) of the diol from above in 400 ml of dry pyridine was placed in a 1 1. flask under an argon atmosphere and 150 ml (1.59 moles) of acetic anhydride were introduced all at once, After 22 hours at room tem- perature the reaction mixture was diluted with 2 1. of ethyl acetate and l 1. of ether and was washed with water (2x500 ml), saturated aqueous sodium bicarbonate (3x500 ml) and brine (lx500 ml) and wa3 dried over Mgso 4 • Evaporation to dryness afforded 23.17 g (quantitative) of white crystals mp 162-165° [lit (90) 163-165°] whose ir spectrum was identical to that of authentic material. 8.aj, - Cyano~2 , 4n,,c.-Dimethyl -lp- (2'-m-Methoxyphenylethyl)-3 , 4,4a, ~ ~•----• :l"tw - - ::_; ,....._, I ·r w " ' ~· - --~-- ,-..- q · ~ - - ,_, ...... ~ - _..__.,.~ 5~,G,7,B,Ba-Octahydro-5~- Nap hthol Acetate ( Q-8 ). ~ .W ,-.,, I _p • ~ ~ Following the procedure of Kowalski (90), a solution of 23.17 g (58 mmoles) of the cyanoacetate from above in 450 ml cf dry pyridin~ was placed in a 1 1. flask under argon. The solution was cooled in an efficient ice bath and 25 ml (344 mrnoles) of thionyl chloride were added dropwise over 30 min. ~he r ea ction mixture was held at 0° for 75 min and then was allowed to warm to room temperature over 45 min. The resultin g brown solution was poured onto 2 l. of ethyl acetate, 1 1. of ether, and 500 ml of ice and 154 water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (2x500 ml), water (lx500 ml) and brine. The solution was dried (Mgso ) and evaporated to dry- 4 nezs to give 22.77 g of brown sticky crystals. Crystalliza- tion from ethanol gave 14.03 g (63.5%) mp 95-108° (vacuum) [lit (90) 89-108°] of white crystals consisting mainly of the A' isomer. The mother liquors were chromato graphed on 800 g of siJJ.ca gel; 1500 ml of ethyl acetate P.luted 10 9 '11ft of an oil which did not have any high boilin g components by glpc, Further elution with 3.5 1. of ethyl acetate gave 7.48 g (34%) of a colorless oil. consisting of a mixture of double bond isomers which was identical by ir to the product prepared by Kpwalski (90), - The overall yield of Q-2 for the three steps was 97,5%. l(H 2 1 -•m-Methox yp hen y le thy 1 )-3, Ii, 4a , 5«, 6, 7, 8 ~ 8a-Octahydro-2, ld-.,ar,., ~,~ --- ws.i: ...... . , . ,........, ov:_,...... _ _ _,.-. • ,......~ _ , • ~a~,8a~-Trimethyl- ~,-Naoht hol ( Q- 9). ~--- .... ... _..,,,.......,..._.,.~ ___,___ Following a modification of the procedure developed by Kowalski (90), a solution of 3,65 g (9.58 mrnoles) of the - cyano a cetate P-Bj mo 95-108°, in 140 ml of dry ether was • placed in a l 1. flask. The atmosphere was replaced with argon and 25 ml (37,5 mmoles) of a l,50 ~ solution of diisobutyl aluminum hydride in benzene ( used as suoplied by Texas Alkyls, Inc.) was introduced all at once; the reaction mixture became slightly warm ini tially. After 155 2.5 hours at rooill temperature the reaction mixture was poured onto 500 ml cf 10% aqueous potassium hydroxide and ice and the aqueous solution was extracted with ether (4x400 ml). The combined organic layers were washed with 2% aqueous potassium hydroxide (lx400 ml) and were dried (~F,SO 4 ). The solution was concentrated and the residue was dissolved in 140 ml of triethylene glycol (previously distilled under vacuum) and the solution was placed in a 300 ml three neck flask which was fitted with a claisen adaptor containing an argon inlet and a thermometer, a magnetic stir bar, a ground glass stopper, and a 14/20 short path still leading to a 65 ml flask. The vacuum adap- tor on the still was plugged with the system u~der argon, 15.5 ml of 99% hydrazine hydrate and 4.6 g of hydrazine dihydrochloride were added, and the internal temperature was raised to 130-135°. After 5 hours the solution was cooled slightly, the plu g was removed, and with a vigorous stream of argon flowing throu gh the system, 30 g of 85 % notassium hydroxide was added in portions over 15 min. The internal tempPrature was then raised to 150-155°, and after 1 hour the plug in the still was replaced. Heating was cont~nued an additional 5 hours under a r e on and the re a ction mixture was allowed to cool overni ~1 t. The resulting white mush was dissolved in 700 ml o f water and the aqueous solution was cxtr·ac ted with ether (4x4G0 ml). The coffibined or gani c layers ~ere washed with 156 water (7x300 ml) and brine (lx300 ml) and were dried (Mgso 4). The solution was concentrated and the residue was chromatographed on 160 g of silica gel; 600 ml of 50% etherpetroleum ether eluted 39 mg of volatile material. Further elution with 1000 ml of the same solvent gave 2.23 g (71%) of the des1.red product whose ir spectra was identical to that of authentic material (90). The rest of the cyanoacetate prepared above was converted to Q-9 in several runs of 1-6 g giving 66-70% yields. '"""""' 3,4,4a,7,8,8a-Hexahydro-l-(2'-m-Methoxyphenylethyl)-2,4ad, ""_,,..__..,_,,., 1q ..,,._ ·---►-- .... ~ 8aP-Trimethyl-5(6H)-Naphthalenone (P-8). ~--~----- ,_..,._.__...... --- ,.., - -=-=--......,.... - .. .,,,...~....... ~ - A solution of 60.5 mg (0.169 mmole) of the alcohol P- 7 in 8 ml of methanol and 2,0 ml of 37-38° hydrochloric acid was refluxed under an argon atmosphere 2 hours. The course of the reaction was followed by tlc (30% ether~petroleum ether); the Spot for the alcohol r.f. 0.3 was quickly replaced by one r.f. 0.7 corresponding to an intermediate ol~fln which formed the product olefin r.f. o.6 over 2 hours. The reaction mixture was diluted to 150 ml with ether and was washed successively with water (lx30 ml), saturated aqueous sodium bic arbonate (2x30 ml) and brine (lx 30 ml). Drying (M gS 0 ), evaporation to d~yne5si and ptlc (30% 4 ether-petroleum ether) afforded 50 - mg (91 %) of a colorless , 2 oil} consisting of a 71:29 mixture oft.:/ a.nd A i;::;omeric olc fins by nmr lnte grati on of the &,ngular metliy l r-0 gi on~ 157 which crystallized on seeding, mp 60-87° [lit(90) 63-98°): ir (CHC1 ) 1700 (C=O), 1600, 1585 (Ph), 1155 (C-0); nmr (CDC1 ) 3 3 c.68l (s, o.85, c-8a-cH 3 ,4~isomer), 0.97~ (s., 2.15, C-8a-cH , 3 1 2 6 -isomer), l.OBJ (s, o.85, C-4a, A -iscmer), l.17J (s, 2.15, C-4a-CH3' A 1 -isomer), l.65l (s, 3, C-2 CH3), 3.Bor (s, 3, , PhOCH ), 6.60-7.40~ (m., 3 4, Ph). _______________ ______________________ 4a,5,6 ,6a.,9, l0 , 10a tl Ob«,ll,12-Dec .__._ ..........,.._____ahydro-2 __,,__,._,..__-Methoxy- 7(8H)-Oxo_.... ---------- -- 4bp,6a~,10ap-Trimethylchrysene (P-9). A. From P-8 with p-Tolulenesulfonic Acid in Tolu lene A 25 ml flask fitted with a Dean-Stark water separator prefil)ed with anhydrous calcium sulfate and dry tolulene was flushed with argon and charged with 67.0 mg (0,205 rnmole) of the mixture of olefins from above and 100 mg of I?_-tolulenesulfonic acid in 5 ml of dry tolulene. The solution was refluxed 1 hour, 100 mg of the acid were added, and reflux was continued for 1 hour. The reaction mixture was cooledt di- lµted with 200 ml of ether., and washed with water (lx20ml) saturated aqueous sodium bicarbonate (lx20 ml) and brine (lx 20 ml). Drying (M gso 4 ) and evaporation to dryness gave a dark brown ojl; ptlc (30 % ether-pe troleum ether) afforded 52.3 mg (78%) of a white solid consisting of a 80:20 mixture of isomer P-9 and the cis, anti, trans isomer P-10 respectively, ~ - _,,_ - •·c w . , _ , . ~ as determined by nrnr inter;ration of the an gu l ar methyl re gi.on. Recrystallization from ether yielded white c rystals mp 141- 148° (vac uum )~ ~rwo further recrystallizcitions f:'om ethe:t~ provided the ~ns, 1 ✓ .. -'cor - 1er mp 150~ ("Vo.--' '"'Cuu·•n) .,_f ,., . ~'...r.. :::·)<> ~~ p tran "'- - .Lu 158 which on admixture with a sample made by the hydrocyanation route (90) mp 150-152° (vacuum) gave mp 150-152° (vacuum) and on admixture of a sample made by the cation cyclization route (92), mp 150-152° (vacuum) gave mp 150-152° (vacuum): ir (CHC1 ) 1700 (C=O), 1605, 1500 (Ph); nmr (CDC13) o.8?.J 3 (s, 3! C-4b-CH3), l.18t, (s, 3, C-lOa-CH3), 1.22! (s:- 3, C-6a-CH ), 3.58~ (s, 3, PhOCH 3 ), 6.57-7.23J 3 (m, 3., Ph). A sample of the trans_..anti-trans_ isomer was recrystallized from ether-heptane, twice from 95% ethanol and finally from ether to give needles mp 153-154° (vacuum) which were submitted for x-ray analysis; The mother liquors from a later experiment were.purified by prepara t ive vpc on a l/4"xl0' 20% SE-30 column heated to 290° with a helium flow of 70 ml/min. The com- pounds with retention times of 16 and 20 min were collect ed by passin g th eqffluent gases through glass tubes packed with alumina. The product with retention time 20 min had a nmr spectrum which was identical with that of the transanti-trans obtained above. _ , ___ _ - · ... - - - 4 · - - - The compound with a retention time of 16 min was freed from SE-30 by ptJ.c (50% ether-petroleum ether) and crystallized on scratchin g mp 125-134~ (vacuum). Recrystallization from Athanol and flash sublimation at. 0, l mm gave the analytical sampl e of the isomer P-10, mp 136-......- 159 I 138° ( •1acuum): ir ( CHC1 ) 1700 ( C=O), 1605·, 1500 (Ph); 3 nmr (CDC1 3 ) 0.35i (s, 3s C-10b-CH 3 ), l.17~ (s, 3, C-4~-CH.) J l.30~ (s, 3, C-12a CH ), 3.75J (s, 3, O-CH ), 6.50~7.~oI 3 3 (m, 3, Ph). B. From alc ohol.._9.:J_:., ,i th tri fluoroaceti c acid. '1.10 an ice cold solut:i.on of 3. 86 g ( 10. 4 mmoles) of the alcohol ....__ Q-9 obtained from two of the above runs in 250 ml of acetone which had been freshly distilled from potassium perman ganate was added 5.0 ml of 8N chromic acid solution (62) over 5 min. After an additional 10 min, 5 ml of iso- propyl alcohol were added and the reaction mixture was poured onto 500 ml of water. The or ganic solution was extracted with ether (4x300 ml) and the combined o:r ganic layers were washed with saturated aqueous sodium bicarbonate (2x300 ml) and brine (lx300 ml) and were dried ( MgS04). Concentration afforded 3,93 g of a crude oil whose ir spectrum was identical with that of authentic material (90). The crude ketone was dissolved ln 115 ml of trifluoroacetic acid fro m a f res hly opened bottle and the resulting dark solution wa s reflux e d und e r an ar gon atmosnhere for 4 hours. On cool 1n g , th e b lack rea c tion rnl xture was dilut e d with 500 ml of benzene and 500 ml cf eth e r and t he s olution was was hed with water (2 x25 0 ml) and satura ted ~que ous sodium • • at e b iearDon r? .:: o m.L .. ) an ct ,3x-__. , was d.r i e ct ( 11g0 ,v C"o ' 4 1. Conc e ntra ti on gave 3. 87 g (1 00 %) of a brow n so l id wh ich .160 was recrystallized from ethanol to give 2.29 g (60%) of the desired ketone mp 145-150° (vacuum). The crystals were better than 99% free of contamination by the cis, anti, trans isomer by glpc. The mother liquors consisted of an approxi- mately equimolar mixture of the els-anti-trans isomer P-10 ----- -- - "---"' and the trans-anti-trans isomer P-9 according to glpc analysis. '-- Two other runs on the rest of the alcohol Q-9 prepared above gave 64 and 67% yields. Attempted Reduction of the ketone P-9 with sodium borohydride. A dry 25 ml flask fitted with an addition funnel was flushed with nitrogen and charged with a solution of 194 mg (0.5911 mmole) of the ketone . P-9 _ in 5 ml of abs ethanol. A solution of 39 mg (1.03 m.~oles) of sodium borohydride 7 ml of ethanol was added rapidly and the reaction mix- in ture was stirred at room temperature for 3 hours. The excess reagent was decomposed by the careful addition of 0.5 ml of glacial acetic acid (gas evolved), and the mixture was concentrated in vacuo. The residue was taken up in 300 ml of benzene and was washed with water (3x50 ml) and brine (2x50 ml), and was dried (M gso 4 ). Evaporation to dryness afforded 186 mg (96%) of recoverect startint:: rnateri2.l. _ ~bj5,6,6a,7 ~8,9,10,10a,l0b~,11,12-Dod ecah ydro-~-Hydroxy-2- .. ~ ~ - - · - _ , , . . . __~--,,,,.-.- - - - - - - .......__-·- - -, -.....,_._,_....__._.... Me tho xy- l~ b ;3 /5 a.:i.: , l Oa~-Tr im(~ th y 1 ch ry s <:: ne (S-1) . . . . . _ _. . . . . ~ • ..... - - __.,,,_......__,.._ _..., . - A - - - • ..._,._,- , _.....-... --- _ _, To a solution of 101.6 mg (0.311 rnmole) of the lce tone .__... P-9 161 in 5 ml of dry tetrahydrofuran under a nitrogen atmosphere was added 53 mg (1.4 mmoles) of lithium aluminum hydride. After 3 ' hours at room temperature the reaction mixture was diluted I 'with 10 ml of ether and the excess hydride was decomposed by the careful addition of 0.2 ml of water. The reaction mix- ture was poured onto 5 ml of water and 3 ml of 5% aqueous hydrochloric acid and the aqueous phase was extracted with ethyl acetate(3x30 ml). The combined organic layers were washed with brine (2x30 ml) and were dried (MgS04). Evaporation and trituration with ether gave 97.0 mg (97 %) of a white crystalline solid mp 121-124° (vacuum). Three crystallizations from ethyl acetate-heptane provided the analytical sample mp 128-130° (vacuum): ir (CHc1 ) 3615 ( 0 -H), 3 1605, 1500 (Ph); nmr (CDC1 ) 0.93J (s, 3, C-12a CH 3 ), J.42J 3 (s, 6, C-4a and C-lOb CH ), 3.43-3.58J (m,l,CHOH), 3.75~ 3 (s, 3, O-CH ), 6,50-7.281 (m, 3, Ph). 3 t.!}~...!. Calcd for C H32 o : C, 80. 4 4; H, 9. 82. 22 2 Found: C, 80,31; H, 9.89. Attempted conversion of the alcohol S-1 to 4b,5,6,6a,7t8,9, '-~.-_-,.__.,,,_.._..,__ 10 ,lOa, lOb~ , l l 312-Dodecahyciro~•7;3-Hy droxy-2-:,1 ethcxy~ 4b53, 6a« ~ ~ . . . _ _ _ _ _ ' - - ~ " ~ ~ ~ - . . . . . . . .... --..., 't • - - - -~~ - lOa~-Trimethylchrysene Methane Sulfonate ....... _....._____ '"" -- (S-2). __,.. ..,__ ~ ~.._.._...._.,,......,.....-"""'...,.,. To an ice cold solution of 36.0 mg (0.109 mmole) of the alcohol ....S-1 .._ in 3 ml of dry pyridine under a n arg on atmosphere was added 0.20 ml of methanesulfonyl chloridec After l hour at 0° the reaction mixture was allowed to warm to r oo~ 162 temperature for 22 hours and was poured onto 15 ml of ethyl acetate. The resulting solution was washed with water (3xl0 ml) and the combined aqueous layers were extracted with ethyl acetate (lx20 ml). The combined organic layers were washed with brine and were dried (Mgso 4). Evaporation to dryness afforded 46 mg of a dark oil which deposited an insoluble brown solid on standing. The nmr spectrum of the oil revealed a complicated mixture of components and attempts at further purification were abandoned. - - 4b,5,6,6a,9sl0,10a , 10b~,lljl2- Decah y dro-7 - Hydroxy - 2-Methox~..._,__ . ,..,.__......,_ 4b~s6a.o(,10af?,-Tri rrethylchrysene Tetramethylphcs phorodiamidate ............. _., ----...........- .. _ ,_ , f":- ______._~,.,. - ('l'-1). A dry 500 ml flask was flushed with argon and char ged with 150 ml of dry ether and 13 ml of a 2.84 M solution of n-butyl lithium in hexane (alpha inor ganics). Next 8.o ml (57 mmoles) of diisopropylamine which had been freshly d istilled from calcium hydride was added over 5 min and af t er another 5 min, a solution of 2.27 g (6.98 rnmoles) of the -- ketone P-9 in 20 ml of dry tetrahy drofuran and 8.0 ml of NiN,N' ,N'-•tetramethylethylene dian:ine which had been freshly distilled from calcium hydride was added over 10 min. The reaction mixtur e was cooled in an ice bath and 15 ml (81 mmoles) of tetramethyldiarn idophospho r ochlorida t e (99) wa s added dropwise. The resultin g yellcw soluti on was al lowed to warm to room temp e rature and a f t e r 1 . 5 hours wr~s po ur e d 163 T'ne onto 400 ml of 10% aqueous hydrochloric acid and ice. aqueous solution was extracted with ether (4x350 ml) and the combined organic layers were washed with water (3x350 ml) and brine (lx350 ml) and were dried (Mgso ). 4 After concentration the crude product was chrcmatographed on 200 g of silica gel. Elution with 800 ml of ethyl acetate gave 156 mg of a mixture of several volatile components; further elution with 600 ml of 5% acetone-ethyl acetate ga ve 530 me of a thin yellow oil whose nmr spectrum correspond ed to that of the starting phosphorochloridate. Finally 1800 ml of 5 - 10% acetone-ethyl acetate eluted 2.81 g (88 %) of a white crystalline solid, mp 108-111° (vacuum). Three recrystallizations of the product from ether-heptane ga ve the analytical sample, mp 108-111°: ir (CHc1 ) 1670 (vin yl), 3 1605, 1500 (Ph), 1305 (P-N), 980 (P-O-C); n mr (CDC13) 1.026 (s, 3, C-l{a CH ), J..22S (s, 6, C-12a, C-l0b CH ), ?..706 (d.t 3 3 12, j:.::l0Hz, N•wCH3), 3,75S (s, 3, OCH3), 5.20~ (m, 1. vinyl). Anal. P, 6.73. Calcd for c 26H 41 o3N2 P: C, 67.80; H, 8.97; N, 6.08; Found: C• 67.96; H, 8.86; N, 6.16; P, 6.64 . -~----....--------- . 4 b, 5, 6 s 6 a , 9, 10 1 102., lO'oc<.., 11 s 12-De cahy dro"' 2- Hydroxy- L\b~ , 6 at>!., 1 Ob~ \..~...........-.......,____~ .......,__ ...,...__ Trimethylchrysene (T-2). ' I r . . ~ ---- In a dry 25 ml fl a::,;,( was placed 135 rng (5.8 mm oles) of 30% lithium disper sior1 (Lithcoa) ~ The atmosphere was replaced with argon and the hydride was washed by decantation with thl'l:e 2 ml portions of hexane and the last tr2.ccs of hexane 164 were removed under reduced pressure. The lithium was sus- pended in 2 ml of dry tetrahydrofuran and 100 mg (0.65 rr.moles) of biphenyl was added. After 30 min at room temperature a - solution of 43 mg (0.094 mmole) of the phosphorodiamidate T-1 in ml of dry tetrahydrofuran was added over the course of 3 15 min. The dark green solution was kept at room tempera- ture for 1 hour and was cooled in an ice bath. The remain- ing reagent was quenched by addition of excess methanol and the reaction mixture was poured onto 40 ml of water. The aqueous solution was made acidic to pH paper with 10% aqueous hydrochloric acid and was extracted with ether (3x 50 ml). The combined orcanic layers were dried (MgSO4) and Ptlc (75% ether-petroleum ether) gave 17 mg evaporated. (62%) of a white crystalline solid mp 137-143°. Ptlc (75% ether-petroleum ether) and three crystallizations from etherheptane gave an analytically pure sample mp 160.5-163°: (CHCJ.3) 3600, (CDC1 ) (On), 1660 w (C=C), 1605, 1500 (Ph); n:nr 3L100 0.93i (s, 3, C-4a CH 3 l.18l (s, 3, ir C-l0b CH 3 ), l.00S (s, ), 3 3, (m, 2, vinyl), 5.501 C-12a CH ), 3 6.53-7.23i ( m, 3, Ph). Antl!_ Calcd for c 21 H o: 28 C, 85.08; H, 9.62. Found: c, 85, 04; H, 9,61. 3 b 5 6'G - 9 10 ' 10 a ' ,._......_..__.10 b 01. ' .l.....,,.,.,.,___... l t 12 ..-__DO de Ca hydro- 2 ( 1 H..., ) - 0. XO - 4 b~ J --.. ~ 1 l; ,!) } 1 t t ;3, t jl \...--.,---...,.___....._....,,-...,-.,.,.,,.-.-..-. - - ---- ----- 6a~,10aJ-Tri me thylchrysene (T-3). '----~......__ _,__....,..._ -- ,__..... 'l'o a solution of 148 mg (21 rnmoles) of lithium wtre in 165 50 ml of NH which had been distilled from sodium was added 3 a solution of 10 l! mg ( 0. 226 mmole) of the tetramethylphosphorodiamidate T-1 in 12 ml of dry tetrahydrofuran over 10 ~ min. After 30 min, 10 ml of ~-butyl alcohol were added and after an additional 45 min, the remaining lithium was destroyed with 5 ml of methanol. The ammonia was evaporated in a stream of argon and the grey residue was partitioned between 150 ml of ether and 30 ml of water. The ether layer was washed with water (lx30 ml) and brine (lx30 ml) and was dried (MgSO ). 4 The solution was concentrated and the residue was dissolved in 12 ml of methanol and 1 ml of water and was treated with 150 ml of oxalic acid. After 2 hours at room tempera- ture the mixture was neutralized with saturated aqueous sodium carbonate and diluted to 150 ml with ether. The ethereal solution was washed with water (2x50 ml) and brine (2x50 ml) and was dried (Mgso 4 ). Evaporation and ptlc (60% ether-petroleum ether) gave a band r.f. 0.7 containing 28 mg (42%) of a clear oil that crystalli~ed on standing mp 94-100° (vacuum). This product was combined with that from a similar experiment and the material was crystallized from aqueous ethanol and sublimed ( 130° /0. 05 mm) (vacuuni)~ to give the analyt1.cal sample mp 109-112° l.r- (CHC1 ) 1715 C==O; nmr (CDC1 ) 0o85i 3 3 (s, 3, c-4b CH3), l.03~ (s, 3, c - 6a CH3), 1.07J (s~ 3, C-J.0a 5.52d (st 2~ vinyJ.). CH3).t 166 Anal. Calcd for c21 H30 o: C, 84.54; H, 10.13. Pound: C, 84.51; H, 10.22. 3,4$4b,5,6,6a,9,10,10a,l0b~,ll,12-Dodecahydro-2(1H)-Oxc-1,l, ----.-_., ~ = e ~ ) . Following the approach described by Wendler et al. (96), a solution of lithium triphenylmethide was prepared by treating a solution of 730 mg (3.0 mmoles) of triphenyl methane in 24 ml of dry tetrahydrofuran with 1.0 ml of a 2.5 M solution of ~_- butyl lithium in hexane (Alpha Inorganics). This solution was added dropwise to a solution of 31.5 m~ (0.106 rnmole) of the ketone ...._. T-3 orepared above in 1 ml of dry tetrahydrofuran under an argon atmosphere until a red color persisted (2.5 ml required). Then 0.2 Ml (3.2 mmoles) of iodomethane which had been distilled from phosphorous pentoxide was added and after 1 hou~ at 0° the solution was diluted to 100 ml with ether and was washed with water (2x 20 ml) and brine (lx20 ml) and was dried (Mgso ). 4 The solution was concentrated and the residue was dissolved in 9 ml of methanol and 4 ml of 10% aqueous hydro·chloric acid and was heated to reflux under argon for 30 min. On coo li n g, the reaction mixture was diluted to 150 ml with ether and washed with water (2x30 ml), and saturated aqueou:.:, sodium bicarbcnate ( lx30 ml) and was dried 167 Evaporation and ptlc (25% methylene chloride-petroleum ether) gave a ba nd r.f. 0.3 containing 23 mg (61 %) of the dialkylated product which was combined with the product from a similar experiment. Ptlc (30 % ether-petroleum ether) and flash distillation at 0.005 mm gave the analytical sample: ir (CHC1 ) 1710 (C=O); nmr (CDC1 ) o.85~ ( s' 3, C-l0a CH ), 3 3 3 1. CJ 3~, l.07cf ( s, 3 each, C-1 CH ), 1.15~ ( s' 3, c-6a cH ), 3 3 1.18~ (s, 3, C-4b CH ), 5.50~ ( s, 2, vinyl). 3 Anal.!_ Calcd for c 23 H3 4O: c, 84.60; H, 10.50. Found: C, 84.63; H, 10.43. 4b, 5, 6, 6a, 9, 10, 10a , l0ba , 11, 12-De ca:iydro - 2-Me th ox y-4 b~ , 6 2.cc , l 0 a~ ~ "'~ - - ----·~ ,__--. Trimethylchrys ene ~.__...~~._...., ....,_,...__, • A solution of -- ~ -__. ____ _, ---= . ~ (S - 3). ~ 37 mg (5.4 mmoles) of lithium wire in 50 ml of ammonia which had been distilled from sodium and 10 ml of dry tetrahydrofuran under an argon atmosphere was s t irred for 30 min and a solution of 209.8 mg (0.45 mmole) of the p h os -phorodiamidate T-1 in 6 ml of dry tetrahydrofuran was added rapidly with a syrin ge. After 1.5 hours the blue color fade d and 37 mg of lithium was added. After a total of 5 hours the excess lithium was quenched by addition of 4oa mg of sodium benzoate followed by 200 mg of solid a mmonium ch loride. The ammonia was eva porated in a s tream of arg on an d th e residue was dissolved in 50 ml of water. The a que ou s s olution was extracted with e th ~r (3x 50 ml) and the c o mb lnc d organic l ay ers were washed wit h 10 % aqueou s sodium hy dr o xide ( 2 x50 ml), water 168 (lx50 ml), and brine (lx50 ml) and were dried (Mgso ). 4 Evaporation afforded 149 mg of a slightly yellow oil; ptlc (30% ether-petroleum ether) gave a single band r.f. 0.7 containing 115 mg (82%) of a colorless oil. Ptlc (30% ether-petroleum ether) and flash distillation (0.1 mm) gave the analytical sample: ir (CHc1 3 ) 1605, 1500 (Ph), nmr (CDC1 ) 0.82! (s, 3, C-l0a CH ), 5,52! (s, 2, vinyl). 3 3 Anal. Calcd for C22H 3 ao: C, 85.11; H, 9.74. Found: C.,84.96; H, 9.64. - ---------------------------------- 4 , 4a«. , 4b , 5 , 6 1 6 a s 9 , 10 , 10 a. ,, 10 b"'-. , 11 , 12--D o..:, e ~ah y d r o ~ 2 ( 3H) - Ox o ~ - 4,_......_---.,__....-~__........._...~ b\, 1 6a«, 10~ -Trimethylchrysene (.......,_.___ u - 1). A. A solution of 370 mg (53 mrnoles) of lithium wire in 550 ml of ammonia which had been distilled from sodium and 140 ml of dry tetrahydrofuran was stirred for 30 min and a solution of 1.53 g (3.32 mmoles) of the tetramethylphosphorodiamidate T-1 in 30 ml of dry tetrahydrofuran was injected with a v--. syringe. After 5 hours 960 mg (139 mmoles) of lithium wire was added followed by 85 ml of dry tert-butyl alcohol. When the reaction had proceeded an additional 2 hours, the excess lithium was decomposed with 20 ml of methanol and the ammonia was allowed to evaporate overnight. The grey residue was partitioned be~ween 500 ml of water and 1000 ml of ether. The aqueous layer was extracted with ether (lx 300 ml) and t h e comblned organic la.yers were washed with wat e r ( l}:300 ml) and brine (lx300 ml) and were dried (Mgso 4). The solution was concentrated and the residue was taken up in 220 ml of ethanol and 130 ml of 5 N aqueous hydrochloric acid and mixture was heated to 65-70° for 40 min under an argon atmosphere. The ccoled mixture was poured onto 500 ml of water and the aqueous phase was extracted with ether ( llx500 ml). The combined ether layers were washed with water (lx500 ml), saturated aqueous sodium bicarbonate (lx 500 ml), and brine (lx500 ml) and were dried (MgSO4). Concentration afforded a dark yellow oil which was chromatographed on 100 g of silica gel; 300 ml of 50% etherpetroleum ether eluted 204 mg of a complicated mixture. Further elution with 300 ml of the same solvent gave 782 mg (79%) of white crystals mp 88-92° whose ir spectrum was identical with that of the analytical sample which was obtained from an earlier experiment starting with 100 mg of the phosphorodiamidate. This experiment was carried out as above except that ter~~-butyl alcohol wa.s present from the start of the reduction. The crude produet following acid hydrolysis was purified by ·ptlc (50% ether-petroleum ether). The less polar band r.f. o.4 contained 26 mg (40%) of the anticipated olefin U-1 .....,.__ mp 87-89°, Recrystallization from ethanol-water and sublimation (120°/0.01 mm) gave the analytical sample mp 94-97°: ir (CHC1 ) J.665 (C"'"O), 1620 (C=C); nmr (CDCl) 0,87i (s, 6, 3 3 170 C-l0a, C-4b CH ) , 1.07b (s, 3 , C-6a CH ) , 5.47$ (s, 2j vinyl), 3 3 5.92t (m, 1, vinyl). Ana,!!_ Calcd for c 21 H30 o: c, 84.54; H, 10.13. Found: C, 84.51; H, 10.22. The less polar band contained 24 mg (35%) of 2(3H), 7 ( 8H )-Dioxo-lt, l!a.,i. , 4b., 5, 6, 6a, 9, 10, 10a, l0bc.l, 11, 12- Dode (!ahydro- - 4~ ,6ao(~l0~-Trimethylchrysene (50) mp 152-154° (vacuum). The product was crystallized from ethyl acetate-heptane and was flash sublimed at 0.01 min to give the analytical sample mp 161-163° (vacuum): ir (CHCl3) 1700 (C=O), 1665 (C=O), 1620 (C=C); nmr (CDC1 3 ) 0.87! (s, 6, C-l0a, C-4b CH 3 ), l. 28~ (s, 3~ C-6a cu 3 ), 5.90& (m, 1, vinyl). Analo C, 80.21; H. 9.62. Found: C, 80.25; H, 9,61. B. Fr·om the olefin S-~3. A solution of 182 mg (0.58 rnmole) of the olefin .....-S-3 in 60 ful of ammonia which had been distilled from sodium, 20 ml of dry tetrahydrofuran, and 10 ml of dry tert -b utyl alcohol under an argon atmosphere was treated with 111 mg (16 mmoles) c,f lithium wi.re. pos ed with After .?. hours the excess lithium was decom- 3 ml of methanol and the ammonia was removed .i n a stream of argon. The grey residue was partitioned between 150 ml of water and 200 ml of ether and the aqueous layer was extracted with ether (lx50 ml). The combined orga nic laye rs 171 were washed with water (lxl00 ml) and brine (lxl00 ml) and were dried (MgSO. ). <! The solution was concentrated and the residue was taken up in 30 ml of ethanol and 20 ml of 5 N aqueous hydrochloric acid and was warmed to 65-70° for 40 min under an argon atmosphere. On cocling, the reaction mixture was poured onto 100 ml of water and the aqueous solution was extracted with ether (3xl00 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2xl00 ml) and brine (lxl00 ml) and were dried (MgSO4). The solution was concentrated and the crude product was chromato gr aphed on 22 g of silica gel; Elution with 55 ml of 5C% ether-petroleum ether gave 26 mg of non-volatile material; continued elution with 120 ml of the same solvent afforded 153 mg (78%) of a white crystalline solid mp 91-94v. 4b., 5, 6, 8a.e<., 9 , l0~IIe xahydro-2-Methoxy-7 ( 8H )-Oxo-4b~ , 8, 8-,•rrimethy 1-------------------------------~ phenanthrene (V-2). '"--------~-- ~- - - - - - - - ~ .......,-_..-. A solution of 582 mg (84.5 mmoles) of lithium w:tre in 500 ml of arnrnonia which had been distilled from sodium and 100 ml of tetra hydrofuran which had been doµbly distilled from lithium 2lu~inum hydride was stirred 15 min. A solution of 9.40 g (36.7 mmoles) of 4b?,,8-dimethylu• 2-me thoxy-7(6H)-oxo (V-l) ..,_ mp 92.5-93.5° [prepared according to th e procedure of Evans (108)] in 100 ml of dry tetrahydrofuran ~n d 0 .66 ml (36.7 n~ol es ) of water was added 172 over the course of 20 min. After 25 min, the remaining lfthium was quenched by addition of a solution of 25 ml of iodomethane, which had been doubljr distilled from phosphorous pentoxide, in 20 ml of tetrahydrofuran. After 45 min the ammonia was evaporated, the grey residue was dissolved in 500 ml of 10% ammonium chloride, and the aqueous solution was extracted with benzene (4x500 ml). The combined organic l a yers were washed with water (2x500 ml) and brine (2x400 ml) and were dried (Mgso 4 ). Concentration gave 10.52 g of a heavy yellow oil which was recrystallized from methanol to give crystilline solid mp 64-67° (vacuum). lizations from methanol gave 7.99 g of a white Three further cry stal- 4.73 g (47.3 %) mp 71 - 72° (vacuum) which was greater than 99% free of unalkylated material (glpc). Stork has prepared this compound and report s mp 56-5 8° ( 12~) ). However, the spectral da,ta ( vide infr2~) were consistent with the assigned structure and in the r.ext reaction it was converted to a known compound V-3 ........... which had the anticipated propert ies, 1500 (Ph); nmr (CDCl?) J Ir (CHCl~) 1700 (C=O), 1610, J 1,131, l.17i (s, 3 each, C- 8 CH 3 ), The cociliined mo t h er li q uo r s were chromatographed on 700 g of silica g2l. Elution with 600 ml of 10 % ether- petro- l e um ether affo r ded o.45 g of a mix tur e of at l east 3 volatile compounds which was d isc ard e d. Fu rther el ution wi t h 200 ml of 173 the same so}.vent provided 4. 36 g of a mixture which contair.ed 73% of the desired product together with two other components by glpc. Recrystallization from methanol gave 2.82 g (28%) mp 64-66°. 2~Methoxy-Llb, 5, 6, 7, 8, 8ac:<, 9, 10-0ctahydro-4~8.!.,8:Tri~t~l_: ~ - --phenanthrene (V-3). In a modification of the Nagata procedure (109), a 1 1. three neck flask was fitted with a football shaped mag- netic stir bar, a Claisen adaptor containing an argon inlet and a thermometer, a ground glass stopper and a 24/40 short path distilling head leading to a 100 ml flask. The vacuum adaptor on the still was closed off leavin g the system under argon and the flask was chn.rged with a solution of 8.48 g (31.0 mmoles) of the ketone V~2 ..._..... mp 71-72° and 15.5 g (148 mmoles) of hydrazine dihydrochloride in 470 ml of diethylene glycol and 53 ml (900 mmoles) of 85% hydrazine hydrate. The reaction mixture was heated to 120-130° (internal tempe rature) and after 17 hours was cooled to 110° while 102 g (1.82 moles) of potassium hydroxide pellets were added over 15 min with a vigorous stream of argon passing through the system. The internal temp erature was rs.i:=:-ed to 160-165° and after 1 .hour the vacuum adaptor was again closed off and heating was continued 4,5 hours. On cooling, the white paste was dis solved in 100 0 ml of wa ter and t he aqueous suspension wa3 extract ed with ether 174 (4xl000 ml). The combined organic layers were washed with water (6xl000 ml) and brine (lxlOOO ml) and were dried (M gS04). Concentration gave 7.95 g of a white solid which was recrystallized from ethanol to give 6.51 g (81.5%) mp 8586.5° (vacuum) in two crops [lit 83-85° (107) and 85-· 86° ( 89 )]. The combined mother liquors were chromato graphed on 100 g of silica gel. Elution with 300 ml of 10% ether-petroleum ether afforded o.68 g which was crystallized from ethanol to give o.49 g (6%) of V-3 mp 78- 81°. ......-- .. Continued elution with 500 ml of 25-100% ether gave 0.58 g (7.2%) of 2- Hydroxy-4b,5,6,7,8, 8a~,9,10-0ctahydro-4b~ , B,8-Trimethylphenanthrene mp 160-161° (vacuum). The phenol was crystallized from ether-hexane and '-tritura ted with ether to provide an analytically pure sample mp 162.5-163,5° (vacuum): ir (CHCL,) 3600 (OH) 1 1610i; j (CDC1 ) o.95~ (s, 6, C-8 cH s), 1.175 (s, 3 1 3 3 C-4b CH ), 6 , 50 - 7.30b (m, 3, Ph)~ 3 Anal.!.. Calcd for c17 H24 o: c, 83.55; H, 9 ; _ 90. Found: 1500 (Fh); n mr C, 83.52; H, 9,96. '-,.-.----·- ------------ ---··------...- - 4,4a~,4b,5 , 6 , 7 , 8 , Ba.,9 , 10 - Decahydro-2(3H)-Oxo-4b~8,8- Trimethy l- phenantllr ene (V~, 4). ~~..........,.. The Birch reduction was c a rried out usin g the procedure ~ described by Church ~_!, ~ ( 107). _ From 5 . 70 g ( 22. 2 r!unoles) of the anisole V..... 3 mp 84- 86° (va c uum) there was ob t a ined 4 .2 g (78 %) of V-...-.4.... mp 89-90.5° [lit (107) 92.5-93.5°]. 175 4, 4ao(, 4b, 5, 6, 7, 8: 8a« i9, 10-Dec~hyclra-2 ( 3H )-Oxo-1 j 4b(3 , 8 1 8-Tetra~~~.....--..-.......,,,,,,--.. methylphenanthrene __,- - ---- ~ ~ (V-6). Employing a modification of the general procedure of Kirk and Petrow (97) a 5 ml pear shaped flask was fitted with a claisen adaptor holding a reflux condenser and a serum cap and was charged with a solution of enone 199 mg (0.81 mmole) of the V-4 from above in 3 ml of abs ethanol and 0.20 ml of thiophenol. The atmosphere was replaced with argon by evac- uating and filling four times and 0.20 ml of triethylamine and 0.26 ml of syringeo 37% aqueous formaldehyde were added via The serum cap was quickly replaced with a ground glass stopper under a vigorous stream of argon and the reaction ~ixture was heated to reflux (bath temperature 95°) for 32 hours. On cooling, the mixture 0as poured onto 50 ml of water and the aqueous solution was extracted with ether (4x50 ~1). The co1~ined organic layers were washed with 10% aqueous sodium hydroxide (2x50 ml)• water (2x50 ml) and brine (lx50 ml) and were dried (Mgso 4 ). Concentration afforded 330 mg of an oil which was chromatographed on 50 g of silica gel. • Elution with 150 ml of 30% ether-pe t roleum ether yielded 22 mg of an unidentified oil. Further elution with 100 ml of the same solvent gave oxo-1-pheny l thj_ o:::.ethy l=•li bfb $ 8, 8-'11 r-lrnethylphens..nthrene 176 as a colorless oil which was used directly in the next step: ir (CHCl3) 1660 (C:::O), 16oor 1580 (Ph); mnr (CDC13) o.72J (s, 3, C-4b CH3), 0,83J, 0.90b (s, 3 each, C-8 CH s), 3.93~ (s, 3 2, C_!:!2S), 7.08~~7.57~ (m, 5, Ph). A suspension of 1 ml of W-2 Raney-nickel was added to an ice cold solution of 169 mg of the thioether from above in 5 ml of abs ethanol under an argon atmosphere. After 30 min the rea~tion mixture was filtered through a pad of celite washing with ethanol (4x20 ml). Concentr a tion afforded 107 mg of yellowish crystals mp 72-80° which were dissolved in ether and centrifuged to remove a flocculent yellow impurity giving after concentration 89 mg (42% from V-4) ,__ of a white crystalline solid mp 78-81°. Recrystallization of the crude product from 95% ethanol and sublimation (0.50 ~~. 80-85°) ir (CHc1 31 1660 (C=O), 1610 (C=C); uv (EtOH) 251 m)J-, C =13, 400; nmr gave the analytical s ample mp 80-81.5° (vacuum): (CDC1 3 ) 0,77i, 0.87S (s, 3 e ac h C-8 CH ), 0.93cf (s, 3, C-4b 3 CH ), 1.88! (s, 1, C-1 CH ). 3 3 Anal ~ Calcd for c1 gH230: C, 83.02; H, 10.84. Found: C, 83.11; H, 10,87, .,..._..~---------------· -3 4 7 8 -. . . . . . - . . . - - - - - ~___.. ..... ~ ( \'1 - 00 1' ~ ~ •nenan t'nrene 8 , 8- T e t r a me th. y .1.p ~~....__,__._..........-..---...- .__.._.._........ 1'h r::: I' ') ;! an d .::.s, ,•ae< 1 '"1,.,, ::>,o, ,________________...., ,_,.,.,,. ------ - j, ~--------------~ 8aQ/. , 9 , lO-Dodec2.hy dr o •• 2C(-Hydroxy- l , L!bp, 8: 8-Te trarr..ethy lp he n an"" ...........,.~--.....~ ._,.,.-._--.,-..-.... ......_.....__...,_.,..,.,____.....--..~ . v-·n. threne ( A. r ed uc tion of V-6 with lithiu m Perh ydr o-9 b-B oraoh e nalvl- By _ _ J,; _ _ _ _ _ , ,_ _ _,. __.. hy dzi d e . - - - - - - -·· , · -- .... ,,.. • • - ·- -·· - - - - ~ - - - - - -- 177 To an ice cold solution of 132 mg (0.508 mmoles) of the enone V-6 .,,._ in 3.5 ml of dry tetrahydrofuran under an argon atmosphere was added 2.0 ml of a o.6 M solution of the boro- - hydride N-1 (87) in tetrahydrofuran. After 30 min at 0° the • excess borane was destroyed by the sequential addition cf' 0.4 ml of 3 ~ sodium hydroxide and 0.4 ml of 30 % hydrogen peroxide. ~he resultin g mixture was poured onto 50 ml of 10% aqueous potassium carbonate and the basic solution was extracted wi t h ether (4x30 ml). The combined organic layers were washed with water (2x30 ml) and brine (lx30 ml) and were dried (MgS04). After concentration, the c r ude product was chro ~a t ographed on 15 g of Florisil; 100 ml of 5% ether- petrol eum ether gave 9 mg of a volatile oil. Continued elution with 80 ml of 10% ether-petroleum ether afforded 50 mg of an oil whlch consisted of mainly the ax:1.al alcohol ~ (vide l 2.1fra) -- contamin a ted with the equatorial alcohol V-7 by tlc (10 % ether-chloroform) analysis. Further elution with 100 ml of the same solvent afforded 49 mg of material consis t ing mainly of the equato r ial alcohol .,__ V- 7 by tlc. Crystalliza t ion fro m hexane gave 34 · ~g (2 6% ) of V.........,....7 mp 119-121°. Recr y stalliza- tion from hex a ne a n d s ubl ima tion (0.05 mm, 12 0 °) gave the analytj.cal sample mp 121-1 23° (va cuum): ir (CHc1 ) 3600, 3 3450 (OP.); 11mr (CDCl3) o. 68 ~ lJ o . 82 ~ (s, 3 e ach, C- 8 CH3), o.87S (s, 3j C- 46 CH ) , 3 l . 75S ( s , 3, C- 1 c H3 ), 3.8o - 4.1 3J 178 (m, 1, CH-OH, width 18 Hz). Anal. ---- Calcd for C18H300: c, 82.38; H, 11.52. Found: c, 82,25; H, 11.43, The mother liquors from above and the material in the ---- fractio11s containing mainly the alcohol V-8 were combined and purified by ptlc (10% ether-chloroform, spectre grade). The less mobile band r.f. 0,4 contained 51 mg (34 %) of material which was identical to the equatorial alcohol by nmr. 'l'he second band r.f. 0.5 contained 26 mg (20%) of the axial alcohol V-8 ............ mp 125-129° (vacuum). Recrystallization from hexane gave the analytical sample as fine needles mp 136.5137.5° (vacuum ): ir (CHCl3) 3600, 3450 (OH), 1660 (C=C); nmr (CDC1 ) 0.73J, 0.83J (s 1 3 each, C-8 CH ), 0.90J" 3 3 3, C-4b CH ), 3. 78-3.95S 3 Anal. (s, (m, 1, C[OH, width l0Hz). B'cund: C, 82.54; H, 11.44, B. _ 1.?Y Lithium Alumi num Hydride reduction of V-6. To a solution of 82 mg (2.2 mmoles) of lithium aluminum hydride in 7 ml of dry ether under an ar g on atmosphere was added a solution of 419 mg (1.61 mmoles) of the enone V-6 ,....._ in 4 ml of dry ether, After two hours at room temperature, the excess hydride was quenched by the sequential add i tion of 0.08 ml of water~ 0.00 ml of 10% sodium hydroxide and 0.24 ml of wate1·. The resulting white suspension was stirred 10 min and was filtered. The ether solution was was hed wit h water 179 (lx25 ml) and brine (lx25 ml) and was dried (Mgso 4) . . Concentration and crystallization from hexane gave 245 -- mg (58%) of the equatorial alcohol V-7 mp 119-120° (vacuum). Ptlc (10% ether-chloroform, spectre grade) of the mother liquors 3ave two bands: r.f. o.4, 110 mg (26%) of the equa- torial alcohol mp 118-120° (vacuum) and r.f. 0.5, 37 mg (9%) --- of the axial alcohol V-8 mp 128~132° (vacuum). !k££dation of .!£l!'~lcohol V-7 to the ketor2_e V..:.?._!.. A solution of chromium trioxide dipyridine complex (74) was prepared in situ (126) by addition of 168 mg (1.68 mmoles) of chromium trioxide to a solution of 0.27 ml (3.34 mmoles) of dry pyridine in 10 ml of dry methylene chloride under an argon atmosphere. After 15 min at room temperature, the character- istic red color had developed and a solution of 110 mg (0.42 mmole) of the alcohol V-7 in ..........was added all at once. 3 ml of dry methylene chloride After an additional 15 min, the r ea c- tion mixture was filtered with suction through a pad of gd III alumina, which was washed with 150 ml of ether. Concentration afforded 106 rng (97%) of the ketone V-6 -' mp 7~-77° (vacuum). 2~-Hydroxy-l~ ,10a- Me t h a no-l,2,3~4,4a~,4b,5,6,7,8s8a~t9jl0 1 lOa~~~ .......... _ . . _ . . . . _ _ ~ ~ r.........~~-..,...,_,.__.__,,,...._.,,,... Tetrade c ahydro-lp.4bp, B,8-Tetramethylph enanthrene (W-1). ' - - ,. - ~ ~ - _ . . . . . . , , , _ _ . . . , , _ , _ _ _ _ _ , , , , , . _ - - - - - - - - - - ~ ~ 1 T 0 a solution o f the S J . r r, m o n : s - S m i t h ( 5 3 ) .......... ~ reagent formed in the usual manner from 1,60 g (23 mmoles) of zinc-copper couple (5 2 ) and 1,9 ml ( 23 rnmoles ) of diiodomethane in 23 ml 180 of dry ether under a~gon was added a solution of 349 mg (1.33 mmoles) of the equatorial alco h ol V-7 in 6 rnl of dry ether. ---- After 2 hours at reflux, the reaction mixture was coole d i n an ice bath and the excess reagent was destroyed by addition of 1 ml of 40% am..1nonium sulfate. The black suspension was poured onto 100 ml of ice and saturated aqueous potassium carbonate and the aqueous layer was extracted with ether (4x 90 ml). The combined ether layers were washed with saturated aqueous potassium carbonate (lxlOO ml), 10% aqueous sodium thiosulfate (lxlOO ml), and brine (lxlOO ml) and were dried (MgS0 4 ). After .2. min of drying, the solution was concentrated and the oil was chromatographed on 100 g of gd III alumi n a . Elution with 200 ml of petroleum ether re moved t h e unreact e d dliodomethane, 200 ml of 25 %-100 % ether afforded 23 mg of a colorless oil which was not investigated, and 100 ml of ether eluted 334 mg (91%) of the desired cyclopropane mp 134-137°. Two recrystallizations of the column product from ether-hexane gave analytically pure needles mp 140.5-141.5 ° : ir (CHC1 3 ) 3600, 3450 (OH), 3020 (cyclopropane); nmr (CDCl3) 0,73J, o.B0J (s, leach, cyclopropane), 0,98J (s, 3, C- 4b CH )i l.02~ (s, 6, C- 8 CH s), l.23~ 3 3 (s, 3, C-1 CH3), 3,77J (t, 1$ j=7Hz, CH - OE). Anal ._ Calcd fo r C19 u3 2o: C$ 82c70; H, 11.47. C, 82. 55; H, 11. 67. Fou.n d: 181 ~--------.... - --- - - 1, 4., 43,o(, l!b, 5, 6, 7, 8, Sac(, 9, 10, lOa-Dodecahyd.ro-lci(, lOa-Methano- --- -----......-- 2(3H)-Oxo-l~,lt~ ,8,8-Tetramethylphenanthrene (W-2). ' - - - ' ~......... ~ ---- -------~---..,....-.. To 2n ice cold solution of 86 mg (0.30 mmole) of the -- equatorial alcohol W-1 in 8 ml of acetone was added 0.15 ml of 8 N chromic acid solution (62). After 5 min the reaction mixture was poured onto 30 ml of water and the aqueous solution was extracted with ether (4x40 ml). The combined ether layers were washed with saturated aqueous sodium bicarbonate (lx40 ml), water (lx40 ml) and brine (lx40 ml) and were dried (MgS04). Evaporation gave 79 mg (93%) mp 122-127° (vacuum) and two re6rystallizations afforded the analytical sample mp 136ir (CHC1 ) 1670 (CmO); nmr (CDCl3) 0.751, 3 138° (vacuum): 0.83S (s, 3 each, C-8 CH s), 0.87~ (s, 3, C-4b CH ), l.33~ 3 3 (s 11 3, C-1 CH ). 3 Anal. Calcd for c19 H30 o: C, 83.15; H, 11.02. Found: C, 83.28; H, 11.00. _______ --- 1,4,4a~,4b,5,6,7,8,8ac<.,9,10,10a-Dodecahydro-2(3H)-Oxo-l,4b~, - - - - - - - - - - - - - - - - - - - - -(W-3) - - -. - - - - - - - - - - - - 8i'8,1oac1..-Pentamethylphenanthrene ............___, To a solution of 41 mg (0.15 mmole) of the cyclopropyl ketone W-2 in 25 ml of ammonia (distilled from sodium) and \,--., 10 ml of dry tetrahydrofuran was added 11 mg (1.6 mmoles) of lithium wire. After 1 hour, the excess lithium was quenched by the sequer1tial addition of ]12 mg dry sodium benzoate and 120 mg of ammoni~m chJori.de. The ammonia was evaporated in 182 a stream of nitrogen. The grey residue was dissolved in 50 ml of water and the aqueous solution was extracted with ether (4x50 ml). The combined ether layers were washed with 10% aqueous potassium hydroxide (2x50 ml) and brine (lx50 ml) and were dried (Mgso ). 4 Concentration afforded 41 mg of an oil which was about 70% starti~g material by infra-red spectroscopy. The crude material was treated with 18 mg (2.6 mrnoles) of lithium wire for 3 hours under exactly the same conditions as before. Following a similar work-up, the crude oil was dissolved in 7 ml of acetone which had been distilled from potassium permanganate. The resulting solution was cooled in an ice ba~h and treated with 0.1 ml of 8 N Jones reagent (62). After 5 min, the reaction mixture was poured onto 40 0 ml of water and was extracted with ether ( 4~40 ml) • The combined ether layers were washed with saturated aqueous sodium bicarbonate (lx40 ml) and brine (lx40 ml) and were dried (MgS0 1~). Evaporation to dryness afforded 37 mg of a colorless oil which was purified by ptlc (5x20 cm plate, 30% ether·petroleum ether). The band r.f. 0.5 contained 15 mg (37%) of the ketone W-3 which gave waxy crystals on standing. ---- The product was further purified by tlc 30% ether-petroleum ether), - recrystallized from hexane-ether and sublimed (85-90°; 0.05 mm) to give the analytical sample mp 85-87°: OO ...1 '/ l\.. ( ...,::::c r ") ) ; 1 .")~1, .... '"'0 .... -lj/~ ..., .. O ( _gem d i1i1e ' • t'ny 1 ) ; nmr ir (CHc1 "'DC __ J ,,· 0. ' 3; 3) 0 ., 7 3 ~~ ' -,,,, 183 3, C-lOa methyl), o.83 -1.00~ (m, 9 C-1 and C-8 methyls). l,15~ (s, 3, C-4b methyl.); 2.87J (q, 1, j=6, C-lH). Anal. Calcd for c19 H32 o: C, 82.55; H, 11.67. Found: C, 82.71; H, 11.62. A second band, r.f. 0.4 contained 8 mg (18%) of a mixture which contained a second saturated ketone by ir which resisted al.l .~fforts at further purification. Attern~~~- equilibration of the ketone W-3. ---- A solutiog ~of 58 mg (0.21 m~ole) of the ketone W-3 (mp 64-68°) and 271 mg of potassium hydroxide in 25 ml of abs. ethanol was heated to reflux for 11 hours under an argon atmosphere. The _cooled solution was diluted to 175 ml with ether and was washed with water (2x30 ml) and brine (lx50 ml) and was dried (Mgso ). 4 Evaporation to dryness and ptlc (10x20 cm plate, 30% ether-petroleum ether) afforded one band, r.f. 0.5, 48 mg (83%) of recovered starting material mp 65-70°. __ 2p~Hydroxy-lp,10a-Methano-l,2,3s4,4ad,4b,5,6,7,8,8ad,9,10,10a-.------------------... - ---,,____,..._......,..._.... _.....___,.____________ . Te trade cahydrov•lc,( , 4bp, 8, 8-bTetramethy J.phenan threne ~ (......--, W-LI) • To a solution of the Simmons-Smith reagent (53) formed in the usual manner from 600 mg (9rnmoles) of zinc-copper couple (52) and 0.70 ml (9 mmoles) of diiodomethane in 10 ml of dry ether contained in a 25 ml fl ask under an argon atmosphere was added c:. solutJon of Jl,8 mg (0.121 mm0les) of the al~ohol V-8 ,.__ in 2.5 ml of dry ether. After 4 hours at reflux, the mix- ture was cooled in an ice bath and the excess reagent was quenched by addition of 1.0 ml of 40% ammonium sulfate. The black suspension was poured onto 40 ml of saturated aqueous potassium carbonate and the resulting solution was extracted with ether (3x50 ml). The combined ether layers were washed with saturated aqueous potassium carbonate (lx50 ml), 10% aqueous sodium thiosulfate (lx50 ml), and brine (lx50 ml) and were dried (MgSO4). After 5 min of drying, the solution was concentrated and the resulting oil was chromatographed on 40 g of gd III alumina: 100 ml of petroleum ether removed unreacted diiodomethane; further elution with 100 ml of 50% ether-petroleum ether gave 6 mg of an oil which was discarded. Finally, 100 ml of ether afforded 21 mg (61%) of the alcohol W-4 _.... mp 1441~8° (vacuum). Two recrystallizations from ether-hexane gave the analytical sample mp 151-153°: ir (CHc1 3 ) 3605 (OH); nmr 0.88i (s, 9, C-4b, C-8 CH s), l.17J 3 (s, 3, C-1 CH 3 ), 3,80-3.9'1~ (m, l, CHOH). li!~lL,, . 4~·' ll C ' R? ~ '-' Calcd for C19H 32 o: C, 82.55; H, 11,67. Found: , 1 ~.4-/, 1 1, 11 ~ 4~, 4b, 5, 6, 7, 8 _ 1 8a..-.: -i 9, 10 , l0a-Dodeea~1ydro-~l(1, 10•-Me thano-2 . ~ ..--._,,.,.,..,,,.,..._.:,,,,,'-~-·- ·- - - - - ~ ~ ~............~~~---~ (3H)-Ox o- 1'<'. ,l! b~ ,8;, 8-l'et:cair,ethylphcmar,threne (W-5). ~ ~ 1---........--...,,..............,,_...,-.. l<t ,,, ... ...,.,,_..._~ ..........- -· - - - - ~....__,...,._~.,... •~ - - ~ To an ice cold solution of 62 mg (0.22 rnmole) of the axial alcohol W-b in 9 ml of acetone which had be e n freshly \o-..-'•...-A 185 distilled from potassium permanganate was added 0.15 ml of 8 ! chromic acid ~elution (62). After 5 min, the reaction mix- ture was poured onto 40 ml of water and the aqueous solution was extracted with ether (3x50 ml). The combined ether layers were washed with saturated aqueous sodium bicarbonate (lx50 ml) and brine (lx50 ml) and were dried (Mgso 4)~ Concentration afforded 60 mg of waxy crystals which were purified by ptlc (10x20 cm plate, 30% ether-petroleum The band r.f. 0.3 contained 54 mg (89%) of the ether). ketone mp 97-103°. Crystallization from hexane gave analy- tically pure cu.bes mp 110-111. 5° (vacuum): (C=O); . nmr (CDC1 ) 0.55J, 3 o.80~ ir ( CHc1 3 ) 1665 0.63S (s, 1 each, cyclopropyl), (s, 6, c-8 cH 3 s), o.85[ (s, 3, c-4b cH 3 ), 1.13! (::,, 3, C-1 CH ). 3 Anal. Calcd for c19 H30 o: C, 83.15; H, 11.02. Found.: C, 82.99; H, 11.03. Trimethylphenanthrene (X-2) and 2,3,4,4ac,4b,5,6,7,8, 8a~ , 9, · ~ 10-Dodecahydro-2oc.-Hydroxy-4b~ i 8, 8-Trimethylphenanthrene (X- 1) . Torin ice cold solution of 2.04 g (8.30 r.-:moles) of' the -- enone V-4 in 30 ml of dry tetrahydrofuran under an argon atmosohere was added 20 ml (18 rnmoles) of a 0.9 M solution of the borohyclride t!.::l- (87). After 30 min at 0° the reagent was decomposed by the sequential addition of 4 ml of 3 ~ sodium hydroxide and 8 ml of 30% hydrogen peroxide. The 186 reaction mixture was immediately poured onto 250 ml of ice cold 20% aqueous potassium carbonate and the solution was extracted with ether (4x250 ml). The combined ether layers were washed with wat~r (2x250 ml) and brine (lx250 ml) and were dried (Mgso 4). The solution was concentrated and the product was chromatographed on 200 g of silica gel eluting with 10% ether-chloroform (spectre grade). mg of a non-polar oil. The first 600 ml gave 106 The next 200 ml eluted 690 mg (34%) of the axial alcohol _,.. X-2 mp 107-109° (vacuum) [lit (107) 109-110°] and the following 200 ml gave 916 mg of a mixture of X-1 and X-2 which was recrystallized from ether-hexane to give 538 mg (26%) of the equatorial alcohol ......._ X-1 mp 122-124° (vacuum) [lit (107) 127.5-128°]. Ptlc (10% ether~chloroform) of the mother liquors gave two bands: r.f. o.4, 73 mg (4%) --- of the equatorial alcohol X-1 mp 116-120° (vacuum) and r.f. - 0.5, 147 mg (7%) of the axial alcohol X- 2 mp 109-111° (vacuum). Finally elution of column with an additional 400 ml of 10% ether-chloroform gave 492 mg (24%) of .__ X-1 mp 120-122° (vacuum) . Reoxidation of the eau a torial alcohol X-1 to the enone V-4. -----~- ---------·------------- - Chromium trioxide dipyridine complex (74) was prepared by the ~n ~ method ( 126). 'l'o a solution of 1. 62 ml ( 20 mmoles) of dry pyridine in 50 ml_ of dry methylene chloride under an argon atmosphere was added 1.0 g (10 mmoles) of chromium trioxide. After 15 min at room temperature a solution 187 of 504 mg (2.03 mmoles) of the equatorial alcohol X-1 mp 118. 122° in 6 ml of dry methylene chloride ~as added all at on ce. After an additional 10 min at room temperature, the dark red reaction mixture was filtered through a pad of gd III alumina with suction. The solution was concentrated to give 480 mg -- (96%) of the ketone V-4 mp 85-88° (vacuum) which was used directly. - - -- -- - - ------ l<i1. s 2 1 3, 4, 4act , 4b , 5 , 6, 7 , 8 , Bacil, 9, 10, 10a-Tetradecahydro- 2p-Hydrox y....__ - l~,10a- Methano-4b, , B, 8- Tri meth y l ph e nant h rene .._.,_, ...---------...__ ,_, ___... ---- (X-3) . To a solution of the Simmons-Smith rea gent (52) pre~ ~ pared in the usual :nanner 5.0 g (71 rnmoles) of zinc-copper couple (53) and 5::.5 ml (69 rnmoles) of diiodomethan e in 60 ml of dry ether under argon was added a sol~tion of 90 3 mg (3.6 4 mmoles) of the axial alcohol X- 2 from above in 15 ml of dry ether. The mixture wa s heated to reflux for 4 hours an1 was cooled in an ice bath. The excess reagent was de composed by addition of 2 ml of 40 % aqueous ammonium sulfate an d th e reaction mixture was poured onto 200 ml of satura t ed aqueous sodium carbona te. The aqueous phase was extracted with ether (4x250 ml) and the combined ether layers wer e washed with saturate d a que o us sodium carbonate (lx250 ml), 10 % aqu e ous sodium thiosulfa te (lx25 0 ml) a n d brine (l x 250 ml) and were dri e d ( M~so 4 ). After .L. lll,~n of dryin g, th e soluti o n was co n centrated and the crud e prodGct wa s chromatographed on 30 0 g of gd I I ! alumina: 500 ml of 0-50 % et h2 r -p2trol eum ether ga ve 3.7 g of 188 recovered diiodomethane. Further elution with 600 ml of ether gave 786 mg (83%) of the alcohol _ X-3, mp 118.5-120.5°. ' The product from a similar experiment was recrystallized twice from hexane to give the analytical sample mp 116-117°: ir (CHC1 ) 3610 (OH); nmr (CDC1 ) 0.17-0.42J (m., 3, cyclo3 3 propane), o.85~ (s, 6, C-8 CH 3s), o.90~ (s, 3, C-4b CH 3 ), 4.13-lJ.1!3~ (m, 1, CHOH, width 22 Hz). Anal. Calcd for c 1 gH3oO: C, 82.38; H, 11.52. Found: C, 82.25; H, 11.47. 1 , 4 , 4 aot , 4 b , 5 , 6 , 7 , 8 , Sa-<. , 9 , 10 , 10 a-Dode c ah yd r o -1@ ~ l O a-~ Me t h::: n 0- ------------------------- 2(3H)-O xo -4b~,8,8-Trimethylphenanthrene .._...---.---- (X-4) . To an ice cold solution of 783 mg (3.10 mmoles) of the alcohol ,____ X-3 from above in 100 ml of acetone (freshly distilled from potassium permanganate) was added 1,5 ml meqv) of 8 ~ chromic acid solution (62) by drops. (6 After 5 min the mixture was poured onto 200 ml of water and th e aqueous solution was extracted with ether (4x200 ml). The combined ether layers were washed with saturated aque ous sodium bicarbonate (lx200 ml), water (lx200 ml), and brine . (lx200 ml) and were dried ( MgS0 4 ). Concentrati on afforded 778 mg of a solid which was recryst allized from ether hexane to give 659 mg (85 %) mp J.33.5-1 3 li.5° (vacuum). '.rhe pr•oduct was rccrystaJ.lized twice from ether-hexane to give the analytical sample mp 133.5- 189 CH3s), o.97S (s,3, c-4b CH3) Anal. Calcd for c 1 gH 2 g0: C, 83.02; H, 10.84. Found: C, 82.94; H, 10.71. ---------------------------------· B, 3,4,4a~g4b,5,6,7,8,8a~,9,10,10a-Dodecahydro-2-Hydroxy-l,4b~ s 8,10~ -Pentamethylph enanthrene Acetate (X-5) ------ A solution of 7 mg (1 mmole) of lithium wire in 10 ml of tetrahydrofuran (doubly distilled from lithium aluminum hydride) and 25 ml of ammonia (distilled from sod .:!.um) was stirred ~nder argon for 15 min and a solution of 60 mg (0.23 - mmole) of the ketone X-4 in 6 ml of dry tetrahydrofuran was added. After 2 hours the blue color faded and one of the ground glass stoppers on the reaction flask was replaced with a dry reflux condenser topped with a drying tube with a hose lead~ng t~ the atmosphere through a mercury bubbler. The ammonia was evaporated in a stream of argon p a ssing through the system and out the bubbler, and when most of the armnonia was gone, the tetrahydrofuran was heated to reflu>-; for 30 min under a gentle stream of argon. The solution of the enola.te was then cooled :ln an ice bath and 2 ml (21 mmoles) of acetic anhydride (purified by double fractional distillation) wa s added. After 30 ffiin, the mixture was poured onto 50 ml of water and was cxt~acted with ether (4x50ml). The combined ether layers wer~ was~cd with sat. aqueous sodium bicarbonate (lx5 □ rul) and brine (lx50ml) and were dried(Mgso 4 ). Evaporation afforde d 72 mg of yellow waxy crystals which were purified by ptlc ( 1W% ether--petroleum ethel'). The 190 band ~.f. 0.7 contained 30 ~g (43%) of the enol acetate X-5 as waxy crystals. Ptlc (40% ether-petroleum e t her) and ----- recrystallization fro m hexane gave the analytical sample mp 67-69° (vacuum): ir (CCl4) 1750 (C=O), 1690 (C=C); nmr (C Cl4) 0.83~ (s, 6, C-8 CH s)s l.02E (s, 3, C-llb CH ), 2.00cf (s, 3, 3 3 acetate CH 3 ), 4.98J' (m, 1 1 vj_nyl). Anal. Calcd for C2aH 32 o: C, 78.90; H, 10.59. Found: Cj 78.78; H, 10.69. A second hand r ~f. 0.5 contained 32 mg (53 %) o;' 3,L!,4a.-< 1 4b,5,6,7,8J8a"- ,9,10 , 10 a -Dodecahydro-2(1H)-Oxo-4b~$8,8,10 a p- - Tetra methyl p henanthrene (59) which was purified by ptlc (40 % ether-petroleum eth e r) and recrystallized from et h er-h exan e ' to give the analytical sampl e mp 155-156°: (C==O); nmr (CCl4) o.85-0.90J ir (CHc1 ) 1700 . 3 (m, 12, an g ular cH 3 s), l.00- 2.43i (m, 18 1 -CH 2-). Anal. Calcd for c18H30 o: C, 82.38; H, 11.52. Found: C, 82.40; H, 11.50. In a later expe r iment starting with 200 mg of ,._-. X- 4 the acetylati o nwa a allowed to proc e ed 7 hours. After ptlc t here ~as obtained r.f. 0.3, 25 mg ( 12,5 %) of recovered starti ng ir.aterial mp 125-127° ( va ,~u;.,tr:1); r.f. 0.5 , 16 m2: ( 8% ) of th e - ketone 59 mp 144- 1 ~8° ( va cuu m) » and r. f . 0.7, 16 9 mg (72 %) o f the encl acetate 1.•;ho:.::e nmr agr e ed p rc d . 8 ely with that o f' the analytj.c a l s amp l e. 191 - Preparation of t h e satura t e d k e t one 5 9 fro m X- 4. ~ A solution of 37 mg (5.4 rnmoles) of lithium wire in 30 ml of tetrahydrofuran (doubly distilled from lithium aluminum hydride under argon) ar.d 75 ml of ammonia whic h had been distilled from sodium was stirred under argon for 25 min and a solution of 284e7 mg (1.10 mrnoles) of the ke t one - X-4, mp 133 - 134°, in 10 ml of dry tetrahydrofuran was added all at once. After 2 hours, the excess lithium was decomposed by the sequential addition of 400 mg of sodium benzoate and 300 mg of ammonium chloride. The ammonia was evaporated in a stream of argon, and the grey residue was d i s s olve d i n 100 ml of water. l.00 ml). The aqueous layer was e xtracted wi t h ether (3x The combined .ethereal layers were was hed wi th 1 0 % aqueous potassium hydro~ide (2x75 ml), water (l x 75 ml), and brine (lx75 ml) and were dried ( MgSO4). Evaporation afforded 286 mg (quant) of g listenin g wh i te crystals of ..__ 59, mp 136-1146°. Rec r ystallizat t on f ro m ether- he xane gave 216 mg (76 %) mp 142-150°. P tlc (30% ether- petroleum ethe r) of the mother liquors gave 18 mg ( 6% ) F.l p 140 - 150° • lf.i, 2 , 3 s l! , l! a«.,. 4b , 5 , 6 ) 7 » 8 8ac< 9 9 , 10 5 10 a-'l'et r a de c ah y d r•o-2~ -Hy d!"'o xyj ~ .-..._~ .,. . . . . . . . . . , ~ - - - . . - - - - - - - ~-~ - - 1~,2-Methano-4b ~ s8,8~10ap-Tetrame t h y l n he nanthre n e ~ A. ------ ..-....__...__~- ~ _,.......__-....,.__..____...___..,__. ----- ( X- 6 ). ~ Fro m the enol aeetate X-5. The enolate was fo r me d us i n g th e method des cr i b ed b y liouse (1 1 4) ahd t he cy clo p r opy l ation was c ar ried ou t by a 192 variation of the method of Whitlock and Overman (115). A solution of the Simmoni-Smith reagent (53) in 10 ml of d~y ether was prepared in the usual manner from 700 mg (10 rr~oles) of zinc copper couple (52) and o.8 ml methane. (10 mmoles) of diiodo- At the same time, a solution of 51 mg (0.17 rr~cles) -- of the enol acetate X-5 in 4 ml of dry dimethoxyethane was treated with 0~25 ml (0.4 mmoles) of a 1.6 M solution of methyl lithium in ether (Alpha Inorganics). After 30 min, the Simmons-Smith reagent was cooled in an ice bath and was transferred~ syringe to the flask containing the enolate. The cyclopropylation was allowed to proceed 2 hours at room temperature and the reaction mixture was cooled in an ice bath and was quenched by addition of o.4 ml of 40% aqueous ammonium sulfate. The resulting grey mixture was poured onto 40 ml of saturated aqueous sodium carbonate and the aqueous suspension was extracted with ether (3x25 ml). The combined ethereal layers were washed with saturated aqueous sodium carbonate (lx25 ml), 10% aqueous sodium thiosulfate ml), and brine (lx25 ml) and were dried (Mgso 4 ). After drying for 5 min tl1e solution was concentrated and chromatographed on 50 g of gd III alumina. Washing with J.50 ml of petroleum ether removad unreacted diiodomethane. Elution with lCO rul cf 25-50% ether-petroleum ether gave 15 mg of an unidentified prcduct and furth er elution with 100 ml of ether afforded 34 ~g (731) of the ~yclopropyl alcohol 193 -- X-6 mp 152-157° (vacuum). The product was recrystallized twice from ether-hexane to give the analytical sample as fine needles mp 171-174° (vacuum): (OH); nmr (CDC1 ) o.80~, o.83c\ Anal. 3 Calcd for ir (CHC1 ) 3600 1 3450 3 (s, 6 each, angular c 19 H32 o: CH 3s). C, 82. 55; H, 11. 67. Pound: C, 82.55; H, 11.71. B. From the ketone X-4. A solution of 11 mg (1.6 mmoles) of lithium wire in 10 ml of dry dimethoxyethane and 60 ml of ammonia (distllled from sodium) was stirred under an argon atmosphere for 50 min ---- and a solution of 93.5 mg (0.359 mmoles) of the ketone X-~ mp 133.5-134.5° (vacuum) in 5 ml of dry dimethoxyethane was introduced all at once. After 4 hours, one of the ground glass stoppers was removed from the reaction flask and was replaced with a dry reflux condenser topped with a drying tube with a hose leading to the atmosphere through a mercury bubbler. The ammonia was removed from the still blue solution in a stream of argon and the residue was heated to reflux for 30 min under a slow stream of argon and then was cooled in an .ice bath. At the same time a solution of the Simmons-Smith reagent (53) was prepared in the usual manner from 1.20 g (17 ~noles) of zinc-copper couple (52) and 1.40 ml (17.4 mmoles) - of diiodomethane in 17 ml of dry ether. .rhe reagent 1 was cooled in an ice bath and was transferred with a syrin ge 194 to the solution of the enolate anion. The resulting grey suspension was stirred at room temperature for 2 hours and was poured onto 50 ml of saturated aqueou3 sodium carbonate. The carbonate solution was extracted with ether (4x50 ml) and the combined organic layers were washed with saturated aqueous sodium carbonate (lx50 ml), 10% aqueous sodium thiosulfate (lx50 ml), and brine (lx50 ml) and were dried (MgS04). After drying for 5 min the solution .was concentrated and was chromatographed on 80 g of gd III alumina: 200 ml of petroleum ether removed unreacted diiodo me thane and 200 ml of 25-50% ether-petroleum ether afford a d 20 mg of a mixture of the starting ketone ____... X-4 and the unalkylat e d ketone 59. ........ Further elution with 200 ml of ether gave - 75 mg (7 61 ) of the alcohol X-6 mp 137-152° (vacuum) which was cont&~inated with a little starting material. Crystallization from e the r- hexane gave 56 mg (57%) in two crops mp 161.5-164.5° (vacuum). .__ _ _ _ _ _,__________________ 1~,~,4a~,4b , 5,6,7,8 , Ba~, 9,10,10a-Dodecah ydr o-2(3H)-Oxo-1Ps4bp , 8, 8" lOap-•Pent amethy lp hen anthrene (W-6). ~-____________.,-~~- ~ To a solution of 43.5 mg (0.159 mmole) of the ketone W-5 in 6 ml. of tetrahydrofur an (doubly distilled from lithium ---- aluminum hydride) and 25 ml of ammonia (distilled from s odium) under· an argon atmosphere was added 19 mg ( 2. 7 mm oles) of li th:t um 1:-rire·~ After 2 hours 1 the exc es s li thi urn was quenched 195 by the sequential addition of 0.3 g of sodium benzoate and 0.3 g of ammonium chloride. The arnnonia was allowed to evaporate in a stream of argon and the residue was dissolved in 40 ml of water. The aqueous solution was extracted with et.her (3x50 ml) and the combined ether layers were washed with 10% aqueous sodium hydroxide (2x50 ml), and brine (2x50 ml) and were dried (MgS04). Evaporation and ptlc (10x20 cm plate, 30% ether-petroleum ether) gave r.f. 0.5, 33.7 mg (78%) of the ketone~ mp 78-82° (vacuum). Recrystallization from hexane gave the analytical sample mp 83-86° (vacuum): ir (CHc1 ) 1700 (C=O); 3 nmr (CDC1 3 ) 0.78J (s, 3, C-l0a CH 3 ), 0.82-0.92, (m, 12, angular Anal, Calcd for c19 H32O: C, 82.55; H, 11.67. Found: C, 82.61; H, 11,52. B. From the cyclonrooanol X-6. To a solution of 32 mg (0.12 mmole) of the cyclopropanol X-6 from above in 10 ml of abs ethanol contained in a 25 ml flask under an argon atmosphere was added 1 ml of concentrated hydrochloric acid and the resulting mixture was heated to 70° for 2,5 hours. The solution was cooled in an ice bath and was poured onto 30 ml of water. The aqueous phase was extracted with ether ~3x25 ml) and the combined ether layers were washed with saturated aqueous sodium bicarbonate (2x25 ml) and brine (lx25 ml) and were dried ( MgSO4). 196 Concentration and ptlc (10x20 cm plate, 30% etherpetroleum ether) gave r.f. 0.5, 28 mg (86%) of the ketone W-6 mp 80~83° (vacuum) which was spectrally identical to that ---obtained above (.:tr, nmr). c. Prom the Alcoh ol x-6 with Iodine. A solution of 12.9 mg (0.0467 mmole) of the alcohol x-6 ...____ and 11 mg (0.087 mmole) of iodine in 10 ml of ether wa,s stirred at roorr. temperature for 24 hours. The solution was diluted with 60 ml of ether and was washed with 10 % aqueous sodium thiosulfate (2xl0 ml) and brine (lxlO n1l) and was Evaporation io dryness gave 14 mg of a y e llow oil which exhibited a carbonyl absorbtion at 1700 crn- 1 and no hydroxyl absorbtion in their. The crude keton e was dis- solved in 10 ml abs ethanol containin g 87 mg of potassium hydroxide and the mixture was stirred 10.5 hours under an argon atmosphere. The reaction mixture was diluted with 50 ml of 1:1 ether- benzene and was washed with water (2xl0 ml) and brine (1 xlO ml). Drying (M gS0 4) and e vapor a tion to dryne ss gave an oil which was purifi e d by ptlc ( 30% et h er- pe t roleum ether) to give 7.c mg (55 %) of th e ketone W- 6 mp 70 - 73° which was spec tr ally ---- identical (irs nmr ) to the material p repared above. 197 The general procedure described by House was employed (114). To a s olution of 55 mg (0.18 mmole) of the enol ace- tate ..____ X-5 in 4 ml of dry dimethoxyethane under an argon atmosphere was added 0.28 ml of a 1.6 M solution of methyl lithium in ether (Alpha Inorganics). ature, After 1.3 hours at room temper- 2.0 ml (32 mmoles) of iodomethane was added all at once to the slightly yellow, cloudy solution. After an additional 5 min the reaction mixture was poured onto 25 ml of brine and ice and the aqueous suspension was extracted with ether (3x25 ml). The combined ether la yers were washed with water (lx25 ml) and brine (lx25 ml) arid were dried (Mgso 4). Concentration afforded 54 mg of a yellow oil which was separated by ptlc (10x20 cm plate, 10% aceton e-pe troleum ther). A broad band r.f. o.4 contain e d 35 mg which did not contain any of the desired product by nmr. The material was equilibrated using a var i ation of the procedure of Ramire z (127), The product was dissolved in 15 ml of abs ethanol containin g 150 mg of potassium hydroxide a nd the resulting mixture was heated to reflux for 6 hours under an argon atmosphere. The reaction mixture was then poured onto 50 ml of dilute aqueous sodium chloride and the aqueous solution was extracted wj_th ether (3x25 ml). The combine: d e ther layers were washed with wat e r (2x25 rnl) and brine (lx25 ml) and were dr·1.ed (MgSO~). Concent ra t io n a n d pt lc (40 % ether-petr o l e um e ther) 198 gave three bands which were identified by nmr: r.f. 0.5, 5 mg (10%) of the unalkylated product 59; r.f. o.6, 10 mg -(20%) of the desired ketone W-6; and r.f. 0.7, 19 mg (40 %) -- of material which by nmr integration of the angular methyl region appeared to be a mixture of polyalkylated products. E. Attem12ted -~educ t i ve Alkylation of___!he Ketone X-4. A solution of 7 mg (1 mmole) of lithium wire in 25 ml of ammonia (distilled from sodium) and 5 ml of tetrahydrofuran (doubly distilled fr om lithium aluminum hydride) was stirred 30 min under an argon atmosphere. A solution of 62 mg (0.25 ---- mmole) of the cyclopropyl ketone X-4 in 6 ml of dr y tetrahydrofuran was added over the course of 6 mj_n and the reaction mixture was stirred for 2 hours before it was quenched by the rapid addition of 2.5 ml (5.7 g, 40 mmole) of methyl iodide (ooubly distilled from phosphorous pentoxlde). After an additional 10 min, 300 mg of solid ammcniu m chloride was added and most of the ammonia was removed in a stream of nitrogen. The resulting grey suspension was dissolved in 50 ml of water and was extracted with ether (3x 50 ml). The combined ethereal layers were washed with water (lx50 ml) and brine (lx50 ml) and were dried (MgSO4). Eva- poration to dryness and ptlc (40% ether-petroleum ether, double elution) gave two bands; r.f. 0.2, 10 mg (10%) , recovered starting material, and r.f. 0.5, 46 mg (74 %) of the ketone 59. '-- 199 2«-Hydrox y- 2p,3 . 4 ,4aA,4b,5,6,6a,9, 10,l0a,10b~,ll,12-Tetra- ,-, ~ -=- ,___ ~---------------~------------------- decahydro-4b\?, ,6&:>t., l 0a.(3-Tr,1methylchrys ene - --------~ ~- (Y-1) and 2$-Hydroxy..._.......__.. --------- ----------------- 2~, 3, l.;, 4a.c , 4b, 5, 6 • 6 a, 9, 10, l0a, l 0br-i., 11, 12-Te trade cahydro~ 4b p, ,_______________ 6aA, l0ap-Trimeth y lchrysene (Y-2). Followin g the general procedure of Brown and Dickason (87), a!1 ice colci solution of 781 mg (2.62 mmoles) of the enone U-1 in 15 ml of dry tetrahydrofuran contained in a 50 ml flask under an argon atmosphere was treated with 6.o ml (5.1 mmoles) of a 0.85 M solution of the triall<ylborohydride N-1 in tetrahydrofuran. .._._ After 30 min the exces s bo rohydr ide was decomposed by the sequential addition of 1.0 ~ l of 3 N aqueous sodium hydroxide and 2.0 ml of 30 % hydrogen pero xide. The reaction mixture was i mmediately poured onto 50 ml of saturated aqueous sodium carbonate and the aqueous solution was extracted with 4:1 ether-benzene (4x50 ml). Th e combined organic layers were washed with saturated aqueous sodium carbonate (lx50 ml), water (lx50 ml) and brine (lx50 ml) and were dried (MgSO4). After 30 min of drying, the solution was concentrated and the crude product was chromatographed on 100 g of florisi l eluting with 50% ether-petroleum ether. eluted The first 300 ml 75 mg of a mixture of non-polar products that was discarded. The next 200 ml afforded 1 83 ml (23 %) of the axial alcohol Y-2. ~~ ?urther elut:i.on with 480 mi of the same solvent gave 316 mg of a mixture of the tw o al cohols whi c h 200 was separated by ptlc [3-20x20 cm plates, 10 % ether-chloroform (spectre grade)] to give: r.f. o.4, 188 mg (24 %) of the - equitorial alcohol Y-1 and r.f. 0.5, 114 mg (15 %) of the axial alcohol Y-2. Finally washing the column with 500 ml of ether gave 206 mg (26%) of the equatorial alcohol mp 119-120° (vacuum). The nmr of the combined axial alC;ohol, 296 mg (38 %), was identical to that of the analytical samp l e mp 131-134° (vacuum) which was prepared from a similar experiment and purified by ptlc followed by recrystallization from ethyl acetate-heptane and ethanol-water: ir (CHC1 3 ) 3600, 3450 (0-H), 1650 (C=C); nmr (CDC1 3 ) 0.85I ( s , 6); 1.051 (s, 3 C-4b, 6a, 10a CH3s), 4.00 - 4.2ot (m, 1 CH~OH), :>.4 8 t (s, 2 vinyl), 5.50 - 5.77~ (m, 1 vinyl). Anal. C, 83.9L1; E, 10.73. Found: C, 83.87; H, 10.78. The nmr of the combined equatorial alcohol, 394 mg (50%), was identical to that of the analytical sample mp 114-115° (vacuum) which was prepared from the same expe r i me nt as the s ample of the axial alcohol and was purified by ptlc and recrystallizat i on from ethyl acetate-he p tane and ethanolwater: ir (CHC1 ) 3605, 3450 (OH), 1655 (C=C ) ; n m!' (C DC1 ) 3 3 0.7n, 0.82S, l.0 5 S (s, 3 each C-~b, 6a, 10a CH3 s ), 3.954.30~ (m, 1 CHOH) , 5.37-5.53~ (m 1 3 vinyl). 201 C, 83.93; H, 10.87. Oxidation of the alcohol Y-1 to the enone U-1. The chromium trioxide dipyridine complex was prepared by the in situ procedure of Ratcliffe and Rodehorst (126). A dry 1000 ml flask fitted with a mechanical stirrer was flushed with argon and charged with a solution of 12.8 g (101 ~~oles) of dry pyridine in 252 ml of dry methylene chloride and 5.0 g (50 mmoles) of anhydrous chromium trioxide. The red solution was stirred for 15 min and a solution of 2.54 g (8.45 mmoles) of the allylic alcohol ..._, Y-1 in 30 ml of dry methylene chloride was added all at once. After 10 min, the dark reaction mixture was filtered through a pad of grade III alumina contained in a 350 ml Buchner funnel washing with 500 ml of ether. Concentration afforded 2.287 g (91 %) of white crystals -- of U-1 mp 98-101° (vacuum) whose ir spectrum was identical to that of the analytical sample. 1«$4j4a~,4b,5 1 6g 6a , 9 ,10 , 10a , 10b~ 9 ll,12 ,12a-Te tradec ahydro- --- ---------- - -)-O - -xo-4bp - - - -~6a~,10a~-Trimethylchrysene - - - - - - - - - - - - - - - -·- --lp,12a-Methano -2(3H '------- ' A solution of the Simmons-Smith reagent (53) was prepared in the usual manner from 4.o g (57 mmoles) of zinc- copper couple (52) and 4.6 ml (57 mmoles) of dii odornethane in 60 ml of dry eth er. A 17 ml portion of the reagent wa s removed for a different reactj.on and a solution of 638 mg -- (2.21 mmoles) cf the axia l alcoho l Y-2 in 10 ml of dry ether 202 was added all at once. The resulting solution was heated at reflux for 4 !:ours before it was cooled and poured onto 100 ml of saturated aqueous sodium carbonate. The aqueous suspension was extracted with 4:1 ether- benzene (4xl00 ml) and the combined organic layers were washed with saturated aqueous sodium carbonate (lxlOO ml), 10% aqueous sodium thiosulfate (lxlOO ml), and brine (lxlOO ml) and were dried (MgSO) for 5 min. 4 The solution was concentrated and chromatographed on 250 g of gd III alumina. Elution with 500 ml of petroleum ether removed unreacted diiodomethane and 300 ml of 3% methanol-ether eluted 512 mg (80%) of 1Cl{ 1 2«,3,4,4a<><.,4b,5,6, 6a,9,10,10a,10b•,ll,12,12a-Hexadecahydro-2p-Hydroxy-l~,l2aMethano-4bp ,6~ ,10•aj3-Trimethylchrysene (Y-3), mp 135-139° .....-. ir (CHc1 ) 3600, 3450 (OH); nmr (CDC1 ) 0.85S, 3 3 0.95J, 1.05i (s, 3 each, C-4b, 6a, 10a CH s) 4.07-4.43J (m, 3 1, C£!,OH) t 5. lt 7$ ( s , 2, viny 1) • . (vacuum): The crude alcohol was oxidized with chromium trioxide dipyridine complex using the in situ procedure of Ratcliffe --- and Rodehorst(l26). A dry 100 ml flask fitted with a mechanical stirrer was flushed with argon and charged with a solution of 1.62 ml (10 mmoles) of dry pyridine in 50 ml of dry methylene chloride followed by 1.00 g (10 mmoles) of anhydrous chromium trioxide. The red solution was stirred 15 min and a solution of 512 mg (1.69 mmoles) of the alcohol --~ Y-1 from above ln 8 ml of dry methylene chloride was added 203 all at once. After 10 min, the dark mixture was filtered through a pad of grade III alumina which was washed with 200 ml of ether. Concentration afforded 490 mg (76.5% from the alcohol) of off-white crystals of the ketone mp 149-152° (vacuum). The analytical sample mp 150-153° (vacuum) was prepared by ptlc (50% ether-petroleum ether) and recrystallization from ir (CHC1 ) 1670 (C=O); nmr (CDc1 ) o.90J , ether-hexane: 3 3 1.02~, l.07<l (s, 3 each C-4b, 6a, 10a CH s), 5.47~ (s, 2, 3 'vinyl). Anal. C, 84.56; H, 10.32. __ ----- Found: -- - ~----------~--------- 2-Hydroxy-3 , 4 , 4a~,4b,5 , 6,6a , 9 , 10,10a,10b«)ll,12,12a-Te t ra d ec a - . . . . ,_.,__,~ ,_ ..,__-- - -- - hydro-4b~ .,6 a..~, J.0 a.~,12a~-Tetrameth y lchrys ene Acet at e ~~________...__. ,,__ - ......... (Y-5). ~_,...,. A dry 200 ml flask fitted with a glass coated stir bar, a dry ice conde nser connected to an argon source, an inlet tube and a serum cap was char ged with a solution of 18 mr; (2.6 mmoles) of lithium in 60 ml of ammonia (freshly distilled from sodium) and 20 ml of tetrahydrofuran (doubl y distilled f r om lithium aluminum h y dride und e r ar gon ) . Af'ter 1 hour, a solution of 202.5 rn g (0.647 mmo le) of the cycl o pro- ---- py l k e tone Y-4 in 5 ml of dry tetrahyGr ofur ~n was added a ll at once. The b lue color faded at the end o f 1.5 hours, an d 18 mg of lith ium wire were added. After a tot a l cf 4 hour s , the inlet tub e wa s r e place d with a dry r e f lux c ond::::nser con ne cted through a drying tube to a mercury bubbler and most of the ammonia was removed :i.n a stream of argon. The residue was heated to reflux for 30 min in a gentle stream of argon as the last traces of ammonia evaporated. The resulting grey suspension was cooled to room temperature, and 5 ml . (53 rnmoles) of acetic anhydride (doubly fractionally distilled, bp 139°) were added. After 6 hours, the reaction mixture was poured onto 70 ml of 10% aqueous potassium hydroxide and ice and the aqueous solution was extracted with 1:1 ether-benzene (4x50 ml). The combined organid layers were washed with 10% aqueous potassium hydroxide (lx50 ml), water (lx50 ml), and brine (lx50 ml) and we re dried (Mgso ). 4 Evaporation to dryness afforded 285 mg of a yellow oil which was chromatographed on 30g of silica gel. Elution with 20% ether-petroleum ether gave succe3sively, 17 mg of a non-volatile oil which was discarded, and 146 mg -- (6~%) of the enol acetate Y-5 mp 119-121° (vacuum). Ptlc (20% ether-petroleum ether) of a portion and recrystallization frbm ether-hexane gave the analytical sample mp 121-123° (vacuum): ir (CHCl) 1755 (C=O), 1690 (C~C), 1220 (C-0); nmr (cc1 ) 4 3 0.78l, o.88J (s, 3 e?.ch) 1 a!1d 1.02J (s, 6, C-4b, c-6a, C-lOa, C-12a CH ::, ) i 2.00J 3 (s, 3$ acetate CH ), 4.97J 3 (s, 1, C-1 !! ) , 5 . l! 0 J ( s 5 2 : C·- 7 , 8 Vin y 1 ) . AnaJ.. C, 81.05; H, 10. 23, .,..c r· c·'2 11'36 H o •• LI C, 80.85; H, 10.1 8 . F ctlnd: 205 Further elution of the colunm with 25 ml of the same solvent gave 37 mg (10 %) of a mixture of approximately equal amounts the enol acetate Y-5 and a second encl acetate 2'--" h~1 droxy-lf3 , 12a-:neth a no-l, 4,. 4&.l, 4b, 5 11 6, 6a, 9, 10, 10a, lOb«, 11 11 12, 12a-tetradecahydro-4bp, 6&1, lCl~ -trimethylcr,rysene acetate (67), as de termined by estimation of the acetate methyl peaks "'""' in the nmr (2.00 and 2.03!)• A second experiment, in which a shorter r e action time was employed starting with 468 mg (1.50 m..Tioles) of the ketone ._._.. Y-4 gave from the column 407 mg (77%) of a 7:3 mixture of the two enol acetates which was purified further by ptlc (3 plates, 20% ether- petroleum ether). The band r.f. 0.5 contained 246 mg (46 %) of the desired enol a cetate Y-5 and the band r.f. 0.4 contained ----129 m~ (24%) of the enol acetate 67 mp 101-106° (vacuum) . ........ Recrystallization from hexane gave a sample mp 110-112°: ir (CC1 4) 1755 (c~o), 1685 (C=C), 1220 (C-0); nmr (CCl4) o.85~, o.98~, l.03~ (s, 3 each, angular CH s), 2.0JJ (s, 3, 3 acetate), 4.80-5.05X (m, 1, vinyl), 5.40S (s, 2, vinyl). Anal. Calcd for c24 H3 40 2 : C, 81.31; H, 9.67. Found: C, 81.46; H, 9.75. Fina lly elution with a further 100 ml of the same uolven t afforded 10 mg (5 %) o f 2(3H)-oxo - l,4,4 a~,~b,5,6 ,6a ,9, --from a simi l a r e x peri me n t mp 140- 15 0° ( va cuum) which wa s me thylchr yse n ~ ( G6) w!",l~h was j_dentica l by nmr to the product 206 purified further by ptlc (40% ether-petroleum ether), recrystallization from hexane-methylene chloride, an d subli ma tion ( 0 . 0 2 5 mm , 16 0-1 7OO ) to give the an a 1 y t i cal ~ a.m. p 1 e rr; p (vacuum): i r (CEc1 ) 1705 (C::O); nmr (CDc1 ) o.82l° 3 3 1 7 2- l 7 6 ° (s, 3). 0.901 (s, 6), 1.06S (a, 3) (C-4b, C-6a, C-lOa, C-12a CH 3s), I 5.48S '· s' 2, viny 1). Anal. Calcd for c2 2H340: C, 84.02; H, 10.90. Found: C, 83.90; H, 10.99, £1£.~irn ge of the Enol Acetate 6 7 to the Ke ton e Y- 4. A solution of 90 mg (0.25 mmole) of the enol acetate 67 and.180 mg (2.7 mmoles) of potassium hydroxide in 15 ml of abs ethanol were stirred at room te mperatur e f or 14 hours under an argon atmosphere. The reaction mixtu'r e was lay ered between 50 ml of water and 50 ml of benzene, and the a qu eous layer was extracted with 1:1 ether-benzene (3x50 ml). The combined organic layers were washed with water (2x50 ml ) and brine (lx50 ml) and were dried (M gS04). The crude product was purified by ptlc (60 % ether- ---- petroleum ether) to give 46 mg (61 %) of the ke t one Y-4 mp 123-126° (vacuum) which was spectrally identical to the material prepared above. ---------------------- l~s2,3,4 , 4a~ i 4b~5 , 6,6 a , 9, 10, 10a j l0b« , ll,12,12a -Hexadec ahy dro - . _ _ _ _ _ _ _ __ - _-----~-----~-------------------~ 2., -Hydrox y -lCI(, 2-Me t hano - 4bp , 6a('{ ., 10af3, 12ap -Tetramet h y lchry'-------------·- ---- sene (Y~6) ...__ .. A. Fr om the En ol Aceta t e Y- 5. 207 A dry 25 ml flask was flushed with argon and charged w:tth 0.7 ml (1.2 mmoles) of a 1.68 M solution of methyl lithium in ether (Alpha Inorganics). The ether was evaporated under reduced pressure and a solution of 153 mg (0,430 mmole) of the enol acetate ............. Y-5 in 5 ml of dry dimethoxyethane was added. The resulting yellow cloudy solution was stirred at room temperature for 30 ~in while a solution of the SimmonsSmith reagent (53) was prepared in the usual manner from 1.20 g (17 mmoles) of zinc-copper couple (52) and 1.40 ml (17 mmoles) of diiodomethane in 17 ml of dry ether. The solution of the Simmon s -Smith rea gent was cooled in an ice bath, and the supernatant was withdrawn wi th a syringe and inj e cted into the flask containing t he enolat e . The cyclopropylation was allowed to proceed 1 hour a nd the reaction mixture was cooled in an ice bath and poured onto 50 ml of saturated aqueous sodium carbonate. The aqueous l ay er was extracted with 1: 1 ether-benzene (J.!x50 ml) and the cc ,r.bined organic layers were washed with saturated aqueous sodium carbonate solution (lx50 ml), 10% aqueous sodium thiosulfate solution (lx50 ml)t and brine (lx50 ml) and were dried ( Mgso 4 ) for 5 min. The solution was concentrated and the p r oduct was applied to 70 g of grade III alumina. Washin g with petroleum ether remove d the unreacte d d iiod ome thane, and elution with 200 ml of ethe r gave 10 0 mg (71 %) of the cyclopropyl alcohol Y-6 mp 161.--165° (va c uum). He c r y st al l ization fro m methyle ne --- 208 ~hloride-hexane gave the analytical sample mp 166-168°: (CHC13) 3600, 3450 (OH), 1180 (C-0); ir nmr (CDC13) o.80~, o.87j, l.02J, l.15S (s, 3 each, C-4b, c-6a, C-lOa, C-·12a CH s), 5.42J (s$ 2, vinyl). 3 Anal. Calcd for c 23 H36o: C, 8~.09; H, 11.04. Found: C, 83.85; H, 11.13. B. From the cyc1opropyl KetonE;_!--4. A dry 300 ml flask fitted with a glass coated magnetic stir bar, a dry ice condenser connected to an argon source, and a reflux conde~ser topped with a drying tube with a stopcock leading to the atmosphere through a mercury bubbler was charged with a solution of 54 mg (7.8 rr~rnoles) of lithium wil·e in 100 ml of ammonia ( freshly distilled from sodium) and 25 ml of dry dimethoxyethane. After 40 min, of 250.9 mg (0.805 mmoles) of the ketone 2. solution in 7 ml of dry dimethoxyethane was introduced dropwise. After 3 hours, the stopcock at the top of the reflux condenser was opened, and most of the amrnonia was removed 1.n a strea.m of argon. The residue was heated to reflux for 30 min in a gentle stream of argon to remove the last traces of arr.monia. The grey solu ti on was cooled to room temperature, a~ d a solution of the Slr'.:r,or1s-,Smith rea gen t (53) whic:h was pre- pared in tl-:e no!"mal r:-ianner froE1 2. 5 g ( 36 riunoles) of zinccopper co uple (52 ) and 2.8 0 ml (35 mrnoles) of diiodomettiane 209 in 35 ml of dry ether while the ammonia was distilling was introduced all at on c e. Afte~ 1 hour, the reaction mix- ture was poured cnto 50 ml of saturat e d aqueous sodium carbonate, the flask was rinGed with 40 ml of 40 % aqueous ammonium sulfate, and the aqueous solution was extracted with 1:1 ether-benzene (4xl 0 0 ml) . The combined organic layers were washed with saturated aqueous sodium carbon ate (lxlOO ml), 10% aqueous sodium thiosulfate (lxlOO ml), and brine (lxlOO ml). After 5 min of drying ( Mgso ), t h e solution was con- 4 centrated and the residue was chromatographed on 160 g grade III alumina: 400 ml of petroleu~ ether r e move d unre a cted diiodomethane; 400 ml of 25-50% ether- petroleum et h e~ afforded 65 mg of a mixture which was purified by ptlc (60 % etherpetroleum ether) to give r.f. 0.5, 22 mg (9%) of the startin g ketone mp 137-142° (vacuum) and r.f. 0.7, 26 mg (10 %) of t h e ketone 66. Further elution of the column with 200 ml of 50% ether-petroleum ether gave an additional 38 mg (15%) of recovered startlng mat·erial. Finally, elut~on with 400 ml of ether gave 138 mg (69 % based on consumed startin g ma terial) of the alcohol ._.._,..,, Y-6 mp 123-125°d whose nmr agreed with that of the crude product from part A, However, there were several extran8ous peaks and cleava ge of the cyclopropane ring gave only 72 % o f the ketone Y-7 in s tead of 98% obt a ined ----- by cleavage o f the material from part A (vide infra). 210 ?~,_, (_)H)-Oxo-1~, 4b~ , 6ao<, lOa~, 12a~ -Pentamethyl-lo(, 4, 4ac<, 4b, 5. 6, 6a, - 9,lO,lOa,lOb~,ll,12,12 a-Tetradecahyd rochrysene - (Y-7). - A solution of 161 mg (0.49 mmoles) of the alcohol Y-6 12 ml of abs ethanol and 1 ml of concentr2.ted hydrochloric acid was heated to reflux for 1 hour under an argon atmospheret The cooled solution was poured on to 50 ml of water, and the aqueous solution was extracted with be~ze~e (3x50 ml). The combined or ganic layers were washed with saturated aqueous sodium bicarbona te solution (lx50 ml) and brine (lx50 ml), and were dried (M gS0 4 ). Evaporation to dryness afforded 157 mg ( 9 8 % ) of th e ---~ ketone Y-7 mp 169-176° (vacuum) which was s u itable for use in the next step. Ptlc (40% ether-petroleum ether) and sublimation (150-155°, 0.7 mm) afforded the analytical sample mp 178-184° (vacuum): ir (CHc1 ) 1705 ( c ~ o ) ; nmr ( C D c 1 3 ) 3 o.73~ (s, 3), o.831 (s, 4.5); 0.95S (s, 4.5), l.05i (s, 3, C-J.., 4b, 6a, lOa, 12a CH s), 5.4n 3 Ana.b_ (s, 2 vinyl). Calcd for c 23 H 6o: C, 8l!. 09; H, 11. 0 4. Fcund: 3 C, 84.16; H, 11.16. ________________ ._ ~,2-Ethylenedi oxo-l,2,3,l!,4a~,4b, 5, 6,6a,9j l0,10a~lOb« 1 lJ. ,l 2, - ~- ~--------------- 12a-Hexade cah ydro- l ,4bp,Ga~,10 ap,12a~-Pentamethy lchr ysene (Y-8). '----..... _______,_____,____ '-" . ~ A dry 100 ml fla sk was fitted with a Dean-Stark water separator and was charged with a -solution of 157,3 mg (0.4 80 mrnol.e) of the ketone .......... Y-7 and 49 mg of £_-tolulenesulfonic acid in 30 ml of dry benzen e and 3 ml of ethylene gly col (bp 100 °, 211 The mixture was heated to reflux for 5 hours with 27 mm). separation of the water formed. On cooling, the reactio~ mixture was washed onto 50 ml of water with 50 ml of benzene. The layers were separated, and the aqueous la y er was extracted with 1:1 ether-benzene (3x50 ml). The combined organic layers were washed with water (lx50 ml), saturated aqueous sodium bicarbonate (lx50 ml) and brine (lx50 ml) and were Evaporation to dryness afforded 191 rag of a yellow solid which was chromatographed on 30 g of silica gel. Elution with 125 ml of 30% ether-petroleum e t l10 r afforded 179 mg (quantitative) of the ketal Y-8 mp 150-155° which ------ was represented. by greater than . 90% one volatile ccmponent ir (CHC1 ) 1650 (C=C), l07o(C-O); nmr ( CDC 1 ) 3 3 0.72J (m, 6), 0.90~ (s, 6), l.02~ (s, 3, C-1, C-4b, C--6a, by glpc: C-l0a, C-12a CH 3s), 3. 75-3.97S ( m, 4, ketal), 5. 45i (s, 2, vinyl). Recrystallization from methylenechlcrid2-hexane gave the analytical sample mp 173.5-175.5° (vacuum). Ana1. Calcd for c 25 H40 o2 ~ c, 80.59; H, 10. 82 . Found: C, 80.58; H, 10.88. P.ttemp_t,ed hydroborat.ion of Y~~8 with ~~isiamylborane . A dry 10 ml pear shaped flask was flushed with argon and charged with 1.0 ml of a 0 ~9 M solution of dibcra.ne in tetrahydrcfuran C12S) and 2 ml of dry tetrahydrofu~~n. The 212 IT1.moles) of 2-methyl-2-butan e was added dropwise. The mixture was allowed to warm to room temperature ~ver two hours and a solution of 17.2 mg (0.046 mmole) of the ketal !::]_ :1,n l ml cf dry tetrahydrofuran was added. After an additional 20 hours at room te mperature the excess borane was decomposed with 2 drops of water and t he reaction products were oxidized by the sequential addition of o.4 ml of 3 N sodium hydroxide solution and hydrogen peroxide solution. o.6 ml of 30 % Following the addi t ion, the bath temperature was raised to 60° for one hour and on cooling the reaction mixture was poured onto 25 ml of satu r~t ed aqueous sodium carbonate solution, and the aqueous solu ti on was extracted with benzene (3 x 25 ml). The combined or ganic layers were washed with saturated sodium carbonate sol ut ion (lx25 nl), water (lx25 ml) and brine (lx25 ml) and were dr i e d (Mgso 4). Evaporation to dryness afforded 19.2 rng of a wh ite crystalline solid which exhibited no 0-H s t retch in their. Ptlc (10x20 cm plate , 25% ether- benzene) gave 11.5 mg (67 %) of recovered startin g material mp 164-168° (vacuum). -~ ____ ~~hyl e nedioxo- l c.;., 2 , 3 , 4,4 ao< , 4b, 5, 5,62.i,7 ~10,10 ,ll 1 1 2... ,._____..,_ a,1 0b~ ,,,.,-....._,,_..._. - -:.... __ -------------~~ 12a-Hex a de c ahydro -8 ( 9H ) -Ox o-l p,4b, , 6a« ,l0 a D 1 12ap -? e ntarnet ~y l- -.....-......----.- - -·- . ------ ch ry3e ne ( Y-9 ) • '--.....__,,,____ ' ......--........ - - - - - - ~,..__-• To a solution o f 117 mg ( o. 460 mmo le) o f tte ole fin ~ in 10 m1 of d r•y t ei:;rar,y c.r0fu:r a. r: un d er a :-1 ar g on atmosp:"te re and cr;_~_~l ed i n a n i c e ba t h wa s ad d P_a' ~ • O r"l .) "-· of Jlbo r a :1e in t e t rahydroturan ( 1 2 2). -~ 0.:. a o • 9 !.:'~1_ s o ....1 :. L,lGD ~ · Afte~ · 5 hours the 213 excess borane was decomposed by the careful, sequential addition of 0.1 ml water, 1.5 ml of 3 N aqueous sodium hydroxide, and 2.0 ml of 30 % hydrogen peroxide solutio n. The resulting mixture was heated to 50 - 60° for 1 h our and ~ a s pour ed into 50 ml of satura ted aqueous sodium carbon ate. The a q ueous solution was extracted wj.th 1:1 ether-me th y l ene chloride (4x50 ml) and the combined organic lay ers were was he d with saturated aqueous sodium carbonate (lx50 ml) , water (lx50 ml) and brine (lx50 ml) and were dried ( Mgso 4 ). Evaporation afforded 180 mg of a white solid which was dissolved in 6 ml of dry methylene chloride in a 25 ml flask under an argon atmosphere and was treated with 3 rnl of a 0.24 M solution of chromium trioxi de di py r idine co mplex (7~) in methylene chloride. Aft e r 10 min, t h e reaction mixture was filtered throu gh 10 g of grade III alumina and the column was washed with ether- methylene chloride. Evaporation gave a white solid which was chro mato gra phe d on 30 g of silica ge l. Elution with 200 ml of 0-10 % e t her- methylene chloride gave 4 mg of a mixture of components a.nd further elution with 250 ml of 20 % ether-methy le ne chloride afforded 165 mg (93 %) of a solid which indicat e d a weak 0-H band in their, 149 mg (84 %) of t h e !-:.etone .........._ Y- 9 mp 24 5-2 5 2° ( v acuu m) whic h wa s represente d by glpc: Repetition of the oxidation gave 9 0 % o f a sin gle vol a ti l e co mponent b y n rnr (2, , 3) (a ngular 214 CH s), 3.73-3.97J (m, 4, ket:il). 3 A sample was purified by ptlc (25% ether-methylene chloride) and recrystallization from methylene chloridehexane to give the analytical sample mp 271-273° (vacuum). An~ Calcd for C, 77.24; H, 10.22. c25 H1I00 3 : C, 77.27; H, 10.38. Found: 215 REFERENCES 1. G. Ourisson, P. Crabbe, and o. R. Redig, "Tetracyclic r1°riterpenes 11 , Holden-Day, Inc., Sc.n Francisco (19611) 2. J. Simonsen and W. C. J. Ross, "The Terpenes", Vol. IV, Cambridge University Pressj Cambridge (1957) p. 287 3. B. 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Smith, J. ~~.L Chem. Soc .• 86, 1347 (1964) Chem., -...... 22t 92 (1957) ~ 76. ~ R. E. Ireland, M. I. Dawson, J. Bordner, and R. E. Dickerson, J. Am. Chem. Soc., 92, 2568 (1970) --- .._ o. Schenck, Angew. Chern., 64, 12(1952); also see ref. 77. G. 78. w. Fenical, D.R. Kearns, and P. Radlick, J. Am, Che~, 78 - -- Soc., 91, 7771 (19 69 ) --........ 79, P. s. Wharton, G. A. Biegel, and R. Chem.s 28, 3217 (1 963 ) - • '---- v. Coo mbs , J. Org. 80. R. W. Murra y and M. L. Kaplq,n, ~Am. Chem. Soc., _9_]-, 5358 (1969) - 81 . A• Ni ck on an cl ,: • F . BG.g 1 i , J . Am . Chem . Soc ,. , 83 , 14 9 8 (1961) 220 82. J. K. Crandall and L. -H. C, Lin, J. Or p; . Cher.i., 33, 2375 83. D. J. Dawson, ?h. D. Thesis, CIT (1971) p. 146 84. B. J. Christensen, R. G. Strachan, N. R. Tr e nner, B. H. Arisen, R, Hirschmann, and J. M. Chernerda, J. Am. Chem. Soc., 82 , 3995 (1 9 60) - -- 85. '-"-" ( 196 8) v...... s. c. Watson and J. F. Eastham, J. Organome~al. Chem . , 9, 165 (1967) ~ 86. J. D. 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Ref. 98, p. 7B 101. J, J . E1 sc h ,. _J , _ Or_ r,;, . .. __ Chemq 28, 707 (1963) _ _ _" V\.,, (1958) c. A. Lipinski, unpublished results (1957) '-"'-' vv s. 221 102. Ref. 98, p. 70-71 10 3. Ref. 9 8, p. 40 104. A. P. Krapcho and A. A. Bothner-By, J. Am . Chem. Soc., 81; 3658 (1959) vv 105. G. w. Kenner and N. R. Williams, J. Chem. Soc., 522 (1955) 106. Ref·. 98, p. 78 107. R. F. Church, R, E. Ireland, and J. A. Marshall, J, Oi:_g!_Chem,, 31, 2526 (1966) . V'V 108, D. A. Evans, Ph.D. Thesis, CIT (1968) p. 76 109. w. Nagata and H. Itazaki, Chem. Ind., 1194 (1964) 110. R. M. Coates and J.E. Shaw, J. Am, Chem, Soc . , 92, 5657 (1970) V\.✓ 111. D, W. Mathieson, "Nuclear Magnetic Reson ance 11 , Press, London, 1968 Academic p. 141 112, T, Tsuyuki, R. Aoy agi, s. Yamada, and T. Takahashi, Tetra hedron Le t t ., 52 6 3 (1968) 113. W,. G. Dauben and R, E, Wolf, J. Org. Chem., J.2_, 2361 (1970) 114, H, 0, House and B. M. Trost, J, Org . Chem, 1 30 , 2502 (1965) '-"'-' 115. H, W. Whitlocl<: and L. E. Overman, J. Org . Chem., ~, 1962 (1969) 116, W. G. Dauben, P. Lau g , and G, H. Berezin, J. Or ~ . Che rn., 31, 3869 (19G6) __....,,. 117, M, Nussim, Y. Mazur, and F. Sondheimer, J. Or g . Chem., 29, 1120 (1964) V'v §)J, 117 (1958) :11.8. R, Kuhn and H. 'I'rishmann, Ann., 119, H. Minlon , ~T. Am. Chem. Soc., 68, 2487 (1948) 120, W, E, B2.c h mann and D. F, Themas,;;. Arn.. Chem. $oc, , 64, 94 ( 1 9 1i 2) -- V"V - · -~ 222 121. D. B. Bigley, J. A, Barltrop and M.A. J. Rogers, J. Chem. Soc., 4613 (19 6 0) 122. H. C. Brown and G. 123. F. Zweifel, Org. Re a ctions,. J.3, 33 (1963) V'- s. Prout, R. J. Hartman, E. P. -Y. Huang, C. J. Korpics, and G, R. Tichelaar, Org. Syn. Coll. Vol. IV, 93 124. I. M. Downie, J. B. Holmes, and J.B. Lee, 9hem. Ind., (London)~ 900 (1966); J.B. Lee, J. Am. Ch em. Soc., 88, '-"' 3440 (1966) 125, G. Stork, A. Meisel s , and J.E. Davies, J. Am. Chem. Soc., -~-' 3419 (1963) 126. R. Ratcliffe and R, Rodehor s t, J. Org . Chem., 35, 4000 (1970) _..., 127. F. Ramirez and s. Stafiej, J. Am. Che m. Soc.) ~., 64 4 (1958) 128. H, C. Brown and A. W. Moerikofer, J. Am. Che m, Soc~ 85, 2063 (1963) V'V 223 Proposit!on 1 It is proposed that the ability of allylic amines and thioalcohols to direct the Simrnons-Srr.ith cyclopropylation reaction be investigated. The Simmons-Srnlth reagent, iodomethylzinc iodide or bis(iodomethyl)zinc zinc iodide (1) , has been developed into a versatile reagent for the stereospecific introduction of methylene into olefins since its discovery 13 years ago. A recent modification has extended the reaction to the synthesis of methyl and phenyl substituted cyclopropanes (2). The discoverers and other groups have investigated the reaction of the S:l. mrnons-Smi th reagent with unacti vate. d aliphatic and alicyclic olefins (3,4,5) and have found that the reagent is electrophilic and subject to steric hinderance. This data fits the generally accepted mechanism shown in eq. 1 rather than the alternatively proposed additionelimination mechanism (6). ----;,· )> + ZnI, 2 Quite early during the development of this reagent, Wlnstein and Sonnenberg (7) discovered that the alcohol 1, ~ X=OH reacted at least an order of ma gnitude faster than the corre s ponding hydrocarbon 1, X=H and moreover, that the on ly ' ~ eq. l 224 product obtained was the cyclopropyl alcohol -> 2 x~oII., resulting from cis attack of the Simmons-Smith reagent. The mechanism - 1 2 ..,_ and generality of the directing and rate enhancing abilities of allylic and homoallylic alcohols have been investigated further by Dauben (8) and Rickborn (9) and the use of alcohols to control the reaction has now seen a p plic at ion in nurr.erous synthetic scheme::;. There ar-J appax·ently no exceptions to the rule that allylic and homoally lj. c alcohols direct the cyclopropylation to the side of the dou~le bond closest to the cxygen (10). It is not clear whether alcoholysis occurs prior to the cyclopropylation or not; Dauben (8) has presented evidence that it does not in the case of l-hydoxycyclohex-2-e ne , but Ginsig and Cross (11) found it to be a necessary step in the cyclopropylation of estr-5(10)-ene-3, 17-diol. However, the latter case may be anomalous since the reaction was extremely slow. Thus it appears that ionization of the alcohol is not an essential part of the reaction mechanism. During the ensuing years, the effect of nei gh boring esters, ethers 5 and acetate on the stereochemical course of the re ::,ct1on ha·,,e been stud1ed. Win.stein (12) · and.Sims (13) 225 ha.Ve demonstrated that() ,i -unsaturated esters d:1.rect the reagent, presumably through coordination of the zinc with the ester carbonyl. The ester ._3,._ is a typical exampl.e (13b)t giving t~e cyclopropyl esterj 1 on treatment with the Simmons-Smith reagen~which was carried on to the angularly methylated 5 3 "" olefin """"" ·5 via __.,_ decarboxylation of the correspondin g acid. Sawada ~- aL,_ (14) have analyzed the hydrolyzed pro duct s obtained fr-om the reaction with botho( ,p- and p ,.{-unsaturated (-)-menthyl esters for optical activity. In the former series optical yield s of 2 . 5- 9.0% we re achieved while an Q ,1 -unsaturated ester gave a 1.4% yield. These results offer further evidence that association with the ester occurs in the transition state. Allyli c ethers appear to direct the reagent also (8 ,9),. although the only well documented cas e is that of l-methoxycyclohex-2-ene. In view of the recently demon s trated utllity of met hyl ethers as bloc king gro ups for alcohols (15), further study of this point seems Harranted. 'l'he cd'fect of allylic acetate seems t0 be varia.bl 8 t Gape and ccworke1•;:i (16) report that in the c a:,e of 1-hyd:rux;/ r::lclohept~, 226 2-ene acetate, the Simmons-Smith reagent a pproaches from the least hindered side trans to the acetate. Th i s result has been confirmed by Dauben (8) who also obtained the product of cis addition from reaction with the correspondin g alcohol. On the other hand Sawada et al. (14) report that l-hydroxycyclohex-2-ene acetate reacts to give cis cyclopropylation and Winstein (7) indicates a similar result for ......... 1, X=OAc. It is possible that acetate is not favorably oriented to coo r din a te with the rea gent in seven membered rings leading to the anomalous result; Wlnstein's results lend eome credence to this hypothesls. From th e above results, it seems cle ar t ha t the SimmonsSmith rea gent i s directed by functionality p ossessing a nonbonded pair of electrons which can coordinate with the zinc atom. It thus ap p ears reasonable that amino and sulfhydry l groups~ appropriately located with respect to the double bond , would also direct and. enhan ce the rate of the Si mmo n sSmith reaction. Such results are particularly pertinent in view of the numerous natural products which contain nitroge n or sulfur ato ms and of the increasin g use of these hetero atoms, especially nitro gen~ a s maskin g groups in syn t hesis (17), Experiment 8 to determine the affects o f a ll y lic sulfur arid nitro ge n on the c o urse of the reaction c a n most conveniently be carried out on steroi d a l substr a tes s in ce the s t arti ng mat e rials have a l l b een p repare d a nd chara ct e ri zed . Also th e 227 products of the Simmons-Smith reaction on the corresponding steroidal alcohols are well known. Chart A outlines the proposed reactions the allylic amines. Suitable substrates are readily avaolable from 3-oxo- ~-cholestenonei (A-1), through lithium aluminum hydride ..___.._ reduction of the derived oxime A-2 (18). ------ Treatment of the separated equatorial and axial amines,~ and~ respectively, with the Simmons-Smith reagent should then result in formation of the cyclopropyl derivatives A-7 and A-8. If indeed cyclopropylated products are obtained, it should be possible -- to convert them to the ketones A-9 and A-10 resoectively ------ • using the method recently developed by Corey and Achiwa (17). The reaction condtions, 3,5-di-t-butyl-1,2-benzoquinone in methanol at room temperature followed by acidification to pH 2-4 for a few hours, are sufficiently mild that no reactions of the cyclopropane ring are anticipated during the transformation, --- ---- The ketones A-9 and A-10 have been prepared pre- viously by Dauben and co-workers (19) so that the stereochemistry of the addition can be readily determined. The prepa~ation of the necessary thioalcohols is shown in chart B. Bou:cdon ( 20) has synthesized the 3p --thioalcohol B-2 by lithium aluminum hydride reduction of the corresponding ----thioketone B-1 which in turn was obtained by treat ment of the ketone ....A-1 with hydro ge n sulfide .-at 5°. i11 acidic ethanol-benzene The stere ochem~.st ry of the proposed cyclopropylation 228 Chart A 0 - A-1 A-2 ..,.,.......,..,_ H N ,, 2 A-3 '----- l I H l ,T ♦ 21' A-6 i ~ 0 - A-8 229 of ........._ B-2 should be indicated by raney nickel desulfurization to B-¼ and comoarison with the product of Wolff-Kishner reduction ............... . - of the cyclcpropyl ketone A-7. -- Bourdon has also achieved a synthesis of the 3~-thioalcohol B-7 (21). 'l'reatment of the tosyl alcohol B-5 with thiourea ..........,_ ' gives a thLouronlum salt via an sn2 substitution Hhich on base hydrolysis and acetylation gives the alcohol .._._._ B-6. Dehydra- tion with thionyl chloride and deacetylation then leads to the desired ---... B-7, From this point one can proceed in a manner exac tly parallel to the 3~ -case, comparing the desulfurized S1mmons-Smith product ._..._,_ B-9 with the Wolff-Kishner product of A-8 . ~ Should these preliminary investigations prove successful~ nume rous further experiments suggest themselves. It would obvious ly be desirable to extend the results to an appropriate oeries of hornoallylic compounds. It would also be of intere st to look at the effect of N and S alkyl substituents on the rate of the reaction. This can conveniently be done through the use of competition experiments (9). Finally, it would be instructive to determine the relative rates of the Sirnrnons-Smith reaction on a series of 3-substi tutect-.c/1•- cholestenes including the hydroxy, methoxy (22) , carbomethoxy (23) , and acetate as well as the amino and sul f hydryl derivatives. Such a comparison of several directing groups has n e ver been carried out before on a single substrate mak:tng compci.risons of reactivities difficult. 230 Chart B - 0 - A-1 HS -- B-1 ..__ B-2 - HS B-3 -- B-4 OH OH B-5 .......__ B-6 Tso A·-7 -- B-7 0 H B-8 .......-.. B-9 ._ A- 8 .............. 231 References 1. H. E. Simmons and R. D. Smith, J. Am. (1958); ibid. 1 Bl, 4256(1959) ---· • 2. ~ Chem. Soc~, 5323 J. Furukawa, N~ Kawabata , and J. Nishimura, Tetrahedron !:~..!.' 3495(1968); ,J. Nishimura, N. Kawabatai and J.Fu:.~ukawa, 1:etr9,hed_ ! .£!2,Q, 2647(1969) 3. ~.11 -- . E. P. Blanchard and H. E. Simmons, J. Am. Chem. Soc. , ~§, 1337(1961t); H. E. Simmons 1 E. P. Bla.nchard;and Smith , ?:_b :t d . , ill? , 13 4 7 ( 19 6 4 ) H775. E 3576(1967) 4. B. Rickborn and J, H. H. Chan, J. Org. Chem., 5. J. Furuka·..ra, N. Kawabata, and J. Nishimur•a, Tet~dro!:..,_ 2 11 , 5 3 ( 19 6 8 ) ....... 6. H. Hobergp Ann., 656, 1. 15(1962). 7. S. Winstein and J. Sonnenberg s J. Am, Chem. Soc., 81 8~ W. G. Dauben and G. H. Berezint J. Am. Ch ern . Soc., BS 4 6 8 ( 19 6 3 ) • ---- · - - - - - - - - · 9. J. H. H. Chan and B. Rickborn, J. 10. R, Ginsig and A. D. Cross, J. Am. Chem. Soc~, 87~ 4629 11. c. D. Poulter~ E. C. Friedrich, ands. Winstein, J. Am. -- ............... 6523 ( 1959); ib:i.d....!.,, ~; 3235 ( 196I''f____ ,._____ ___ (1968) ( 1965) ..___ '"" Am.~~• _Sof!., 22, 6406 ---- . • -· .._ Ch em. Soc., 91~ 6892(1969) ....,..:,:_, _ 12. _ _ "¥•-:.-rr.• . . r - - ~ T. Han afu aaJ L. Dirladeanu, ands. Winstein, J._Am. Ch em. -Soc.~ 87 , 351C(l965) '-' 13+ a. ~ b. Sims, J. -_Am._ Ch em. __~S'Jc,? §_J , 3511(1965) J. J. Sims, and L. H. Selman, Tetrahedron ----- ,.. ~.,~ Lett., ,.- ---T &.:6 1 U$ 561(1969) J.4. s. Sawada~ K. 'rakehana~ z.nd Y. Inouye, ,I..!.-.9_!'..J5.. CJ~_._, 2 1 15. E. J. Corey, N. M. J. Am. Che m. Sec,, r 1767(19 68 ) ...· --~ - : , . , - - r , - , . . _ . , 232 16. A. c. Cope & S. Moon, and P. E. Peterson., J. A~ Chem. _Soc., ~' 1935(1962) 17. E. J. Corey and K. Achiwa, J. Am. Chem. Soc., 91, 1429(1969) 18. _.._ C. W. Shoppee, D. Evans~ H. C. Richards, and G. H. R. Summers,~ C_b,~~~-Soc.s 1649(1956) w. a. Da.uben, P. Laug, and G. H. Berezin, J. __ Org. ...,nem. , I" ' - 31, 3869(1966) 20. R. Bourdonl Bull. Soc.,_Chim. Fr., 722(1958) 21. R. Bourdon, Bull. Soc. Chim. Fr ., 1977(1960); ibi'!.!_, 844, ( 19 6 2) 22. C. R. Na:cayanan and K. N. Iyer, 1734(1965) 23. G. Roberts, C. W. Shoppee, and R. J. Stephenson, J. Chem. £CC., 2705 (1954) ~~ Cfie.E1.!,_ ~ ~s 233 Proposition 2 Feeding expariments designed to establish the biosynthetic pathway leading to abscisic acid -.,. 1 are proposed. In 1965 Addicott and his coworkers correctly deduced the structure of abscisic acid (ABA) ....-. 1 (1), a plant growth regulating hormone that had defied isolation and characteri- zation for a number of years. The structural assignment was verified and experimental quantities were made available by Cornforth 1 s synthesis of 1 within the year (2). Since "'"""' then ABA has been found to be widely distributed among the higher plants and to be a potent growth inhibitor, occurlng mainly in senescent or aborting organs (3). ABA is effective at low concentrations and is nontoxic to the plant; moreover its effects are antagonized by various growth promoting hormones such as the gibberellins and cytokinins (4). Recent results obtained by Pearson and Wareing have indicated that ABA acts in conju~ction with another cytoplasmic factor to inhibit RNA synthesi s (5), although its exact mode of action is far from well understood. The Qbviously important role of ABA in regulating plant growth cycles and the posaibilities of commercial applications in facilitating crop harvests by controlling absqission 1iave combined to sustain a high level of interest in the chemistry of this compound. 234 Considerable speculation about the biosynthesis of ABA has arisen because of its unusual sesquiterpenoid structure. Its terpenoid origin was confirmed by the work of Noddle and Robinson who demonstrated that 14 c-labeled mevalonic acid was incorporated into ABA when fed to whole tomatoes, strawberries and avocados (6), In another set of experlments Robinson and Ryback (7) fed doubly labeled [(4-R)-4-3H] and [(4-S)-4 - 3H] 3 -2- 14 c mevalcnate and measured the H/14c ratio of the isolated ABA~ From the . 4-R precursor they found, after base treatment to equilibrate the labile ring protons, a ratio. of 1/3 while from the 4-S precursor the ratio r was 0/3, Since it has been shown in a wide variety of systems that the enzymatic coupling of a dimethylallylpyrophosphate '-" 2 with isopropenylpyrophosphate 3 results in the loss of the """' 4-R-3H if the newly formed double bond is cis and the 4..... c:• 31-1 if the bond is trans_, it would appear that the 6,.2 \..)- 3 4 OP 1 P1 235 double bond of ABA is initially formed in the trans configuration and later undergoes isomesization to the active cis form. In one further experiment, Milborrow and Noddle (8) were able to show that the epoxide 5 labeled on either oxygen '-""' or carbon was incorporated into ABA by whole tomatoes and - wheat shoots implicating 5 as a natural precursor of ABA. Furthermore the l',2'-diol epoxide was not active. -6 obtained by hydrolysis of the The selection of the epoxide ...... 5 for CO 2 H 6 5 testing was based on the results of Tamura and Nagao (9) who screened a number of related compounds and found that 5 was almost as active as ABA itself. With the above results in hand detailed ~iozynthetic schemes can be proposed and te3ted. There are no known sesquiterpenes which have structures related to that of ABA 11 but there are a number of degraded '{ 236 carotenes such as vitamin A (7) which do have similar structures. This leads one to suspect that ABA may also be derived from a carotene. Chart A outlines possible biosynthetic routes to ----- ABA starting from either farnesylpyrophosphate (A-1) or ~ -carotene (A-7)~ w-. Protonation of farnesylpyrophosphate (A-1) ............,.. and cyclization through the carbonium ions -- ~ and .~.::} to g1ve the diene A-4 is similar to the scheme proposed for the formation of the cyclic carotenes (10). Enzymatic oxidations such as that - required to convertA-4 into the conjugated olefin A-5 are well .........,... known in carotene chemistry (11) and selective epoxidations such - as that indicated in the conversion of A-5 into the epoxide 5 -.-..;... a.re als·o known ( 12). It seems prob ab le that the 6.2-!.!:§~: · - • cis isomerization would occur at the triene stage since this conjugated system can most readily absorb energy. The type of epo~ide cleavage required for conversion of 5 into the allylic alcohol ..._.___ A-6 has recently been carried out in the laboratory (13) and it certainly would seem feasible that an enzyme system could carry out the same reaction. afford ABA~ Allylic oxidation would then This proposed scheme differs sl1ght1y from that . proposed by Milborrow and Noddle (8) who favor hydroxylization of 5 at C-4' followed by oxidation to th~ corresponding ketone and base catalyzed cleavage of the epoxide. However, their scheme does not account for the high ABA activity of the allylic alcohol A-6 in the screening test employed by Tamura and Nagao (14). '-'""- 237 Chart A OPiPl. • ~ D P1 P1 _ ~A-1 A-2 -- OP P 1 1 OH • -A-4 - ~ co 2H l i ~ ~1 C0 H 2 r ABA __, 238 Alternatively, the conjugated triene acid formed by oxidative cleavage of unspecified series of steps. ~ -carotene &:5- could be !::::J.. in an Numerous other possibilities exist, of course, such as partial completion of the ring transformations at the carotenoid stageprior to degradation. However, it seems appropriate to explore the most probable possibilities first, and if the experiments prove negative, to search for more obscure routes. It would appear most logical to initiate the feeding experiments with compounds close to ABA and to work toward the starting materials. In this way one should be able to minimize the effort expended on incorrect pathways. Further- more, it should be possible to carry out feeding experiments in a manner similar to that employed by Milborrow and Noddle (8), who injected whole fruits with a solution of the substance to be tested and, following an incubation period, macerated and extracted the plants. The extracts then were separated by chromatography for counting. The first compound which should be investigated in this way is the allylic alcohol ,.....__,.__ A-6. Labeled derivatives of this substrate should be available using a variation of the synthesis employed by Tamura and Nagao starting from p-ionone (14). The label could be conveniently introduced at the laet step which involves a Witti g reaction using carbomethoxymethylenetriphenylphosphorane. Efficient incorporation of this compound would 239 imply that the final two steps of the proposed scheme are correct. Secondly, the fate of the cis and trans isomers of the triene acid !J::::3.. should be determined to see if' these compounds are converted through the epoxide 5 to ABA and "" if so, whether the t?-trans-ci~ isomerization occurs at this stage. These compounds are easily obta.ined by treatment of ~ -ionone with carbomethoxymethylenetriphenylphosphorane (9). If the results of these experiments are positive, one could then attempt to determine the source of the triene A-5, while if not, it would be necessary to devise new ............... experiments to determine the actual precursor cf ABA. There are a number of experiments one could perform to as6ertain th~ source of the triene -- A-5 or the other precurs or. One approach would be to feed various labeled carotenes, particula1•ly ~ -carotene and lycopene and possible sesqu:tter-penoid precursors such as the acid fate of the label. -- A-4 9 and to determine the Unfortunately, large hydrocarbon compounds such as the carotenes cannot be administered using the techniques deDcribed above due to solubility problems. However, in recent years methods have been developed for feeding these compounds employing cell free extracts and surfacants to keep everything in solution (15)e In order to apply this technique here, it would first be necessary to demonstrate de novo ABA synthesii in a cell free extract. This should not present a major obstacle since ABA synthesis 240 occurs in the isolated fruits and leaves of a number of plants. Wheat leaves might be a good choice because ABA synthesis can be induced to occur very rapidly (16). It is anti~ipated that a wheat leaf homo genate, puri fied from debris by centrifugatio~would support ABA synthesis. This could be verified by administering labeled mavalonic acid to the extract and looking for incorp~ration of the label in ABA. Then, by measuring the amount of label incorporated (17), one could determine the optimum conditions for ABA synthesis. Should the ABA fail to aquire label from any of the carotenes, it would appear likely that the compound origina t es from farnesylpyrophosphate. This could be further tested by attempting to demonstrate ABA synthesis in a sy s t em where carotene biosynthesis is blocked. This could be achieved usin g either mutants or by taking advantage of the temperature sensitivity of carotene biosynthesis (18). If labeled mevalonic acid is incorporated using such a system , it would provide firm evidence that ABA is not derived by de gradation of the carot e nes. The experiments proposed above should provide insight into the ABA biosynthet ic pathway. Clea~ ly, addit i onal feeding experiments could be de s igned based on the init i al results. Finally, when th es e e xperiments indicate a particu l ar pathway, one could attempt to obtain p roof of its importance in viv<2, 241 by isolation of the proposed intermediates synthesized by the plant from labeled mevalonic acid. References 1. K. Ohkuma, F, T. Addicott, O. E. Smith, and W. E. Thiessen, Tetrahedron Lett . , 2529(1965) 2. J. w. Cornforth, B. V. Milborrow, and G. Ryback, Nature,~, 715(1965) 3. F. T. Addicott, K. Ohkuma, O. E. Smith, and W. E. Thiessen in "Natural Pest Control Agents", R. F. Gould, ed. , A.c . s. Publications , Washington, D. C. (1966) p. 97 4. P. F. Wareing and G. Ryback, Endeavour , 29, 84(1970) 5. J. A. Pearson and P. F. Wareing, Nature, 221 , 672(1969) 6. R. c. Noddle and D. R. Robinson, Biochem . J. , 11211 547(1969) 7 D. R. Robinson and G. Ryback, Biochem . J., 113, 895 (1969) --- 8. B. V. Milborrow and R. (1970) ---- ---- c. Noddle, Biochem . J . - 119, 727 fl s. Tamura and M. Nagao , Planta , 85, 209(1969); Agr. Biol . Ch e ra., 34,1393(1970) 'wW- 10. ·--- ~ T. W. Goodwi.n, Pure and _!\,E_E,lied Chern., ~, 483 ( 1969) s. Liaaen-Jensen, Experirnentia, ~ , 697(1970) 12. H. Y$ Yamamoto , c. o. Chichester , and T. o. M. Nakayama, 11. Arch. Biochem . Bio2hl s ., 96, 645(1962) --- 13. J. K. Crandall and L. H. Chang , J. Or~ . Chern ~, 32, 435(1967) 14. s. 'l'amura and s. Nagao, ~£.!_ Bio! • Chem., 33 , 1357(1969) ---s. c. Kushwaha , c. Subbarayan , D. A. Beeler, and J. W. 15. Porter, ~ J.- -Biol . Chem .~ 244 , 3635(1969) ---·..,,.,-· > ~ --- • __ 16. s. ·r . c. Wright and R. w. P. Hiron, Natu r e , 21~4 , 719(1969) 17. B. v. Mllbarrow, ...Plant a , . ......... 76, 93(1967) - -... 18. J. - E,t~r e and Appl i ed ~t~em.!J.. ~ , 449(1969) w. Port er ,, ----- 246 Proposition 3 A synthesis of 11-desoxyprostaglandin F 1 , via a new, generally useful, conjugate addition of alkynes to°" /1, -unsaturated ketones is proposed. The intense physiological activity of the prostaglandins such as 1 and the difficulty attendant with ...... their isolation from natural sources (1) has evoked a catholic interest in the development of synthetic routes to these elusive molecules. Although a number of suc- cessful schemes have been reported (2), only the most recent approach employed by Corey~ al. (3) gives preparatively useful amounts of the prostaglandins. X I K~C02H ~,,,,,,o ,, OH OH PGE 1o(,, X=---OH PGF 1 X= =O 1 "" Most of the syntheses suffer from low yields at one or more steps and a lack of stereospecificity, particularly during the generation of the C-15 alcohol (4). In view of the potential utility of derivatives of this class of compounds, new synthetic methods for their construction are required. One possible approach, aimed at the 247 efficient introduction of the C-12 side chain is proposed below. The diethylalkynyl alane 2 (5) is isoelectronic with "" the well known diethylalum1num cyanide which has been used by Nagata et al. in the stereospecific cleavage of epoxidcs (6) and in the stereoselective conjugate addition of HCN to a large number of o<. ,~-~unsaturated ketones ( 7). (CH cH 2 ) AlC C~HC H 5 11 3 2 It thus X = H, OBz, CTHP 0 X 2 ...... seems possible that the alane ......,. 2 might undergo some of the same reactions as the later reagent and provide a useful method for the insertion of substituted acetylenes into organic compounds. In support of this theory, Fried and his coworkers (8) have shown that 2 closely resembles "' dicthylaluminum cyanide in its behavior toward epoxides. This epoxide cleavage reaction has been used by Fried in his synthesis of 7- oxaprostaglandin derivatives (Sb). It therefore appears reasonable that the alane ....._2 might also parallel the reactivity of diethylaluminum cyanide toward ~~-unsaturated ketones and transfer acetylene derivatives to the (3 -carbon of thls system. Since this reaction, if successful, would be valuable as a general synthetic tool, the reactions of the alane 2, '-" X=H with a number of' r e adily available unsaturated ketones 248 such as 3-6 should be attempted to obtain a measure of the '-"'~ scope of the reaction. Of particular interest would be the stereochemistry of the addition to the bicyclic enone '"" 6. . This could most easily be determined by reduction of the triple bond and ketone of the addition product 7 with ---- lithium in ammonia (9) and cleavage of the acetate derivative of the resulting olefinic alcohol to the aldehyde ........ 8 with osmium tetraoxide and periodic acid (10) . Finally, Wolff-Kishner reduction (11) of the aldehyde and oxidation of the C-3 alcohol, which would be liberated from ,0 0 OR R = H co Me 2 6 = (CH ) 3 "" 2 0 0 0 4 5 ........ 6 ...... its acetate under the Wolff-Kishner conditions, should give the oc talone 9. ........ - The cis isomer of 9 has been prepared by ...... Marshall et al. (12) and, if necessary, the trans isomer could be obtained by the stereospecific Simmons-Smith cyclopropylation-Birch cleavage method employed in this thesis (13) . Comparison of the octalones prepared by the various routes should reveal the stereochemistry of the addition. Upon successful completion of the first phase of this work, the results should be extended to the known ( Ba) 0 0 AcO CHO 7 """ 8 9 v,. tetrahydropyranyl ether or benzyloxy-substituted alanes ---2, X=OTHP or OBz. Treatment of the cyclopentenone 3, ....... R=carbomethoxyheptyl (14) with this reagent might t h en lead to the cyclopentenone 10. ---- Deesterification and protection of the ketone as the ketal derivative followed by treatment with lithium in ammonia should lead, on deketalization, to the physiologically active (14, 15) cyclopentanone 11. ---- If allylic cleavage of the OH group of 10 competes with reduction of the triple bond, ----- protecting group could be removed and the alcohol ionized prior to the reduction (16). The side chains can isomerize about C-8 to form the more stable trans isomer regardless of the stereochemistry of the initial addition. There are a number of possible modifications to the proposed synthesis which might make it more efficient. For instance, one may be abl_e to trap the intermediate enol aluminate formed in the 1,4 addition to ....... 3, R=H and then regenerate the enolate anion to introduce the C-8 side 250 0 0 CO H 2 3 10 v-- 0 OK 11 ---chain via alkylation. Also the opportunity exists to utilize an optically pure alkyne in the formation of the alane 1 so that the side chain could be introduced in its natural configuration. Should the proposed reaction prove facile, the above work would provide an indication of its utility. Clearly further investigation would be warranted, especially on the stereochemistry of the addition and on the steric and electronic requirements of the reaction~ 251 References 1. S. Berg:s torm, Scienc~, 62], 382 ( 196 7); S. Bergstrom, L.A. Carlson, and J. R. Weeks, fharm. Rev., g_Q, 1(1968) 2. for leading references see: E. J. Corey, u. Koelliker, and J, Neuffer, J. Arn. Chem. Soc., 93, 1489(1971) -- E. J. Corey, N. M. Weinshenker, T. K. Schaaft and W. Huber, J. Am. Chem. Soc., 91 , 5675(1969); E. J. Corey, T. K. Schaaf,W. Huber'";"'u. Koelliker, and N, M. Weinshenker, ibid., .21, 397(1970); E. J. Corey, H. Shirahama, H. Yamamoto, s. Terashima, A. Venkateswarlu, and T. K. Schaaf, ibid., 93, 1490 (1971) --- 4. for a partial solution to this problem see: E. J. Corey, s. M. Albonico , U. Koelliker, T. K. Schaaf, and R. K. Varma, J. Am. Chem. Soc,, 93, 1491(1971) - -- --- - G, Wilke and H. Muller, Ann., 629, 222(1960) -- 6. W. Nagata, M. Yoshioka, and T. Okumura, Tetrahedron Lett., 847(1966); J. Chem. Soc., 2365(19;10) W, Nagata, M. Yoshioka , ands. Hirai, Tetrahedron I -----·Lett,, 461,1962); W, Nagata and M. Yoshioka, ibid., 19I3[1966) 8. a. J. Fried, c. H. Lin, ands. H. Ford, Tetrahedron Lett., 1379(1969) b, J. Fried, s. Heim, s. J. Etheredge, P. s. Plassmann, T. s. Santhanakrishnan, J. Himizu, and c. H. Lin, Chem. Comm., 634(1968); J. Fried, M~ M. M e h r a ~ ~ . and c. H. Lin, Tetrah~on Leth, 2695(1970) 9. N. A, Dobson and R. A. Raphael, J. Chem. Soc., 3558 ( 19 5 5) 10. R. Pappa, D. s. Allen, R. u. Lemieux, and W. Johnson, J. Org. Chem., ~ s 478(1956) 11. W. Reusch in "Reduction", Marcel Dekker, New York, (1968), R. L. Augustine ed., pp. 171 s. 252 12. J. A. Marshall, w. I. Fanta, and H. Roebke, J. Org. Chem. , ~ , 1016(1966) 13. This Thesis, pp. 1~. J. F. Bagli, T. Borgi, and R. Deghenghi, Tetrahedron Le t t . , 4 6 5 ( 19 6 6 ) 15. J. F. Bagli and T. Borgi, Tetrahedron Lett., 1639 16. A. S. Hallsworth, H.B. Henbest, and T. I. Wrigley, J. Chem . §_o c ,, 1969(1957) (1969) - • 253 Proposition 4 Experiments directed toward the interconversion of tri~erpene systems~ backbone rearrangements are proposed. It is now well established that the basic steroid and triterpene ring systems arise biosynthetically from a suitable cationic cyclization of squalene oxide followed by a series of Wagner-Meerwein shifts and loss of a proton. · ( 1) One result of their common biosynthetic ancestry is that many of the major triterpene ring systems are simply interrelated by the appropriate number of 1,2-methyl and hydrogen s hifts. In view of the complexity of these systems and the difficulties involved with the total synthesis of even one, laboratory methods for their interconversion would be highly desirable. Two experiments directed toward achieving such interconversions are proposed below. One experiment involves conversion of the tetracylic epoxide 1, possessing the cis-anti~trans backbone --- --- --- "" characteristic of the curcurbitacins 2 (2), to the enone 3 ""' '-" which has the substitution pattern of lanosterol 4. A '"" similar rearrangement of the epoxide 5 could lead to the «,?-unsaturated ketone i• "' This represents a conversion of a potential key intermediate in the synthesis of shionone J or alnusenone in the pentacyclic series to a potential intermediate in the synthesis of the the dammarenediols -8 (2) and the related pentacyclic triterpenes. OAc H 2 ..... OAc 3 "" 4 6 5 ..,... 6 HO 7 8 .____ '-" Rearrangements of steroidal epoxides have been widely studied, particularly by D. N. Kirk and his co-workers (3). Whereas some backbone rearranged product was obtained from most of the acid catalyzed reactions, in cases where steric or electronic effects limited the competin g r eactions the yields were quite good. The rearrangement of 9 offers an example of a \,A, 9 ...,. tetrasubstituted epoxide where accumulation of positive charg e on C- 4 i s res t ric ~e rl by the inductive effect of the nei g h~o r in g acetate. Treatme nt of 9 with borcntri ,.,.. 256 fluoride etherate in benzene afforded a single backbone rearranged product in 90% yield. (4) ApSimon and Rosenfeld (5) and Whitlock and Olson {6) have studied rearrangements in related systems. Whitlock found evidence that there is a rapid equilibrium between all the possible tertiary carbonium ions during backbone rearrangements and that product formation occurs through the most stable ions. In light of these results, it is anticipated that acid catalyzed cleavage of ........ l will lead to the carbonium ion .............. A-1. Cleavage toward C-10 should be favored by both inductive and stereoelectronic effects, and to the extent that methyl migration is concerted, by the relief of the steric strain associated with the B/C cis ring fusion . The possible fates of A-1 are fourfold: The angular methyl '"-- group could shift back to C-9, although this could provide More likely, a proton could no special stabilization. be lost from either C-8 or C-11 to give, after quenching, the mixture of olefins ----. A-2. However, this elimination must involve accumulation of considerable positive charge on C-9 since there are no protons which are tr~-diaxial to the migrating methyl. This opens the fourth possibility that a 1,2-shift of the C-8 hydrogen could occur initiating further rearrangements which, if they proceeded into the D ring, would give a molecule with the elusive fusidic acid skelton. (7) Unfortunately, such a rearrangement 257 CHART A OAc Co OH A-1 ......... .,.,. l "" OAc 0 l OAc OH A-2 .........,... 2 --- seems unlikely due to the strain associated with the ~-backbone of fusidic acid. The anticipated products, the mixture of olefins ............... A-2 should yield the unsaturated ketone ......2 via deketalization, which should proceed with concomitant dehydration, and acid catalized equilibrium of the olefin mixture into the more stable A 8-isomer. This equilibrium is similar to that employed by Woodward and Barton in their partial synthesis of lanostercl. (8) Rearrangement of the double bond into the 8(14) position should not compete so effectively here since there is a six rather than a fiv~ membered D ring. The ketone 2 has th e lanosterol --- skelton an d the appropriate functionality in the A and 258 D rings to serve as a key intermediate in a total synthesis. Similar considerations lead one to expect that the epoxide 5 would give the ketone B-1. "" ............,, CHAR'l1 B 0 5 \.,,, OH I B-1 ............... B-2 ............... In th::l.s case all the migrating groups are t r ~-diaxial and the reaction should proceed to the oxy gen stabilized C-18 carb onium ion and give the ketone B-1 on quenchin g -------- with water. Such extensive rearran gements in vitr~ a r e well p r ecedented : most dr a ma tically by the rearrangement of frei.d e l e n e ,._,._~ 10 into a mix ture of A12 and 1,. 13 (lB) oleanene s l.L ( 9) He du e ti.on of the C-18 ketone of ...,.._,.__ B-1 259 and deketalization should then give the enone B-2 ~ which again is well suited for further synthetic elaboration. 11 ..._.._ The almost paralle l preparations of the substra tes 1 and 5 are outlined in chart c. The starting ketone s C-2 and C-3 were obtained in 15 and 80% yields re s p e ctively from the trifluoroacetic acid catalyzed cycliza tion of the tricyclic C- 1 ~ (10) Birch reduction of the aroma tic ~ rings should result in the simultaneous reduction of the C-18 ketones to the more stable equatorial alcohols. (11) Mild acid hydrolysis of the intermediate dihydroanisols should proceed without migr ation of the double bond to provide the~ ~--£-uns aturated ketones ~ c ~ 4 and C-5. (12) \ ............,...._ Ketaliz a tion cf .............. C- 5 and the 18- ac e tate of '--"-'"" c- ~ should l e ad to the keta l s .........,__ C- 7 and ..__,,_ C- 6 r es p e ctively. Jeger and cowor kers have succe s sfull y ket a li zed e s tr- 5(10) - ene-3$17 - dionc without affectin g the dou ble bond ( 1 3) demonstratin g the 260 Chart C 0 CH 0 3 C-3 C-2 .........,..._ C-1 ....,,....... T 0 l OH OAc 0 \_ 0 C-7 OAc 1 ...,... 5 ...... L OH 261 feasibility of the proposed step. Molecular models indicate that the ketals and the .__ C-9 angular methyls of both .......__ C-6 and £-7 shleld the (3 ~face of the A rings so peracid epoxidation is expected to take place from the less hindered c1... -side to give the desired epoxides ..,.. 1 and V'. 5. Succezsful completion of these rearrangement experiments would extend the utility of the existing synthesis of the tetracyclic ketone~ and could stimulate efforts toward a direct synthesis of the cis fused tetracyclic C-2. ~ 262 References 1. T. G. Halsall and R. T. Aplin, Forsch. Chem. Or ~. Nat·urstoffe , 22, 153(19611); R. B. Clayton, Quart-:• ~-ev:~J:.2,-J.68';201(1965); J. W. Cornforth, Ang_ew. Chem. In terw Eng. Ed., '-""' 7, 903(1968) 2. G. Ourisson, P. Crabbe, and o. R. Redig, Tetracyclic Tr;~nes..t. Holden•·•Day, Inc. ( 1964) --- 3. J. W. Blunt, M. P. Hartshorn, and D. N. Kirk, !~.!!:_ahedro~6.?, 3195(1966) and references contained therein. 4. J.M. Coxon, M. P. Hartshorn, and D. N. Kirk, 20, 2531(1964) Tetrahedron, - 5. • .4.JbJJLbJ ::,.. • . t - ............ J. W. ApSimon and J. M. Rosenfeld, Chem. Comm . _ _, 1271(1970) 6. H. W. Whitlock and A. H. Olson, ~!...-~!!l•~c~t 92, 5383(1970) ""'"' 7. W. o. Godfreds on, w. von Daehne , s. Van gedal 1 A. D. Arigoni, and A. Melera, ~tr?-h~d1... on~ 3505(1965) .Mai-•quet, y, 8. R. B. Woodard , A. A. Patchett, D. H. R. Barton , D. A$ J. Ives , and R. B. Kelly, J. Am. Ch em. Soc., 76, 2852(1954); J. Chem. Soc. , 1 1 3 ~- - - ...... 9. J. L. Courtney , R. M. Gascoigne, and A. z. Szumers J. Chem. Soc ., 881(1958); R~ M. Coates 9 Tetrahedron Lc~t f~;-iITTm9 6 7) ; H. W~ !E.i:1.~, 821<1968 > Whit lock and M. --c-.Smf t h , 10, This Thesis, pp. 88 11. w. F. Johns, J. Or~. Chem., 28, 1856(1962) 12. D. Burn and V. Petrow, J. Chem.__§_.£.9,..:_, 3614(1962) 13. J~ Hill, H. Iriarte~ K. Schn a ffner , and o. Je ger, He 1 v • Ch:i.m -. ACTA, 119 ,- 292 ( 1966) __,_........--~ --· - ----~ - -6 - - - - - ........ Proposition 5 A total synthesis cf cyclopiazonic acid, v,. 1, is proposed. Cyclopiazonic acid ....... 1 has recently been isolated from the mold Penicillium Cyclopium Westling which occurs widely on stored grains and cereal products. (1) It is the prin- cipal toxic metabolite of the mold 9 showing acute toxicity toward rats and ducklings. A structure for 1 has been """ proposed on the basis of chemical degradation of the E ring and on NMR and mass spectral data. More recently, the 2 1 ......... related compound '-2 has been isolated from the same source (2) linking cyclopiazonic acid biogenetically to the medicinally important ergot alkaloids. (3) An unambiguous synthesis of 1 would be of value both to confirm the "" structural ass i gnment and to make derivatives available which ma y b e biologically active. 264 Previous synthetic efforts toward the ergot alkaloids have suffered from the high reactivity of the indole ring. (4) Thus it seems wise to delay introduction of this functionality as long as possible. Furthermore., while most synthetic routes to indoles involve cyclization of aniline derivatives . (5)., the use of such derivatives in the synthesis of __... 1 would require either relatively inaccessible starting materials containing a suitably placed and masked nitrogen atom or an electrophillic nitration step on some intermediate which would lead to mixtures of nitro isomers. Consequently, it is proposed that the A, c, D ring system be constructed initially, followed by generation of the indole functionality via an intramolecular attack of the aromatic A ring onto an electron deficient nitrogen species. The E ring is left to last since the tricarbonyl system ls prone to cleavage. The first key intermediate in the proposed synthesis is the amino ketone A-3 containing the A and C rings. '--""-""'- A fairly direct synthesis of '---"' A- 3 is possible starting with the keto-ester ....A-1. (6) ~ Protection of the ketone as the corresponding ethylene or dimethyl ketal and tre a tment with methyl lithium should give the tertiary alcohol A-2. ~ A Ritter reaction in sulfuric acid containing acet onitrile should proceed with concomitant deketa lization leadin g directly to the protected amine A- 3, R=Ac. (7) ------- Although this is a potentially efficient route to A-3, the yi elds ~ 265 in the Ritter reaction are variable and the effect of the neighboring ketone may be detrimental so that it seems prudent to have a reasonable backup route available. An alternative starting material is the diacid A~4 (8) ------ which can be cyclized quantitatively in sulfuric acid and esterified to give the keto ester .._____,__ A-5. (9) ketone must be protected as the ketal. Once again the Although it is difficult to avoid claisen condensation during the alkalation of esters, a recent report by Rathke and Lindert (10) indicates that it can be carried out even in simple cases by forming the enolate at low temperatures using a very strong base. Thus it should be possible to obtain the dialkylated e s t e r ~ ' X=OEt. yia dialky1ation wlth methyliodide. The amine A-3 should then be available ------- through a Curtius rearrangement (11) of the acyl azide ~ • X=N 3 which in turn should result from the action of sodium azide on the acid chloride or by reaction of the ester itself with hydrazine followed by nitrous acid. Deketalization would probably occur during the hydrolysis of the rearrangement product, but could be carried out as a separate step before the rearrangement if necessary. Formylation of the free amine A-3t R=H with ethyl \...--. formate and sodium ethoxide (12) should lead to the introduction of ano<. ~formyl group which, it is anticipated, will condense with the amine either under the reaction conditions or· upon sultable workup to give the~ ,p-unsa.turated ketone 266 Chart A 0 oJ 1 ----A-3 ....,.._ A-3 A- 7 ----- A-8 267 -- A-7. (13) Condensation of the amine with the ketone is not expected to compete since generation of an sp3 center adjacent to the aromatic ring would result in loss of resonance energy and dehydration of this intermediate . would put a double bond at the bridgehead of a (3.2.1) system which would be unfavorable. (14) In view of the propensity for 5 membered rings to contain an SP 2 center, -- it is possible that the imine form of A-7 will predominate, but this will make no difference in the next step. Treatment of either A-7 isomer with cyanide should ------ lead 1.!_~ a micheal addition or a 1,2-addition at the carbon bearing nitrogen to the cyanide~ in a variation of the well known Strecker ~-amino acid synthesis. (15) Inspection of molecular models indicates that the flexible cis C/D ring fusion is favored over the trans fusion which requires a 1,3-methyl hydrogen diaxial interaction. Thus under equilibrating conditions, the desired cis form of A-8 is anticipated to predominate although it ------- should still be available from an unfavorable mixture by separation and requilibration of the ~r~ns_ fused compound. Alternatively, it should be possible to formylate the N-acetyl derivative ............... A-3, R~Ac and isolate the ~-formyl ketone prior tc the condensation step~ It seems reasonable that the cyano function will be stable through the next few steps, but it could be hydrolyzed to the corresponding acid or ester at this point if necessary. 268 The next transformation involves construction of the indole ring yi~ attack of the benzene ring on an electron deficient nitrogen species followed by loss of a proton or rearrangement. There are a number of reports in the literature of indole syntheses through pyrolysis of 2-phenylethyl oximes (16) or p-styryl azides (17) and by treatment of~ -nitrostyrenes with triethyl phosphite. (18) All of these are thought to involve similar but undefined mechanisms and in all cases the yields are fair to good (50-85%) under reasonably mild conditions, Pyrolysis of the oxime B-3 is the most attractive ~ method for the present synthesis since it should be readily available from the aldehyde B-2. ~ There are two ---- convenient approaches to the conversion of A-8 to the --- homologous aldehyde B-2, both involving the use of ylide reagents. Prior protection of the amine as the acetyl derivative should avoid complications caused by this functionality, E. J, Corey has determined that dimethyl- oxosulfonium methyli~ewill react with ketones selectively in the presence of esters or amides (19) to give the corresponding oxi:r.anes. (19b) Rearrangement of the oxirane ln the presence of mild lewis acids should then proceed in the direction of the more stable benzyl carbonium ion to give the desired aldehyde ..___ B-2. (20) More conveniently 1 rea,c ti.on wl th methoxymethy J.enetripheny lphosphorane should Chart B CN / / B-1 ---- ,,,,, .- -NAc CN r B-4 B-3 '--"-"'- N-ro NH l CO Et 2 NH B-5 '-- U Hvv OH 0 270 also proceed by selective attack of the ketone to give a methyl vinyl ether which would give the desired aldehyde on hydrolysis. (21) The yields using the latter method are inconsistent but good in favorable cases and the former may prove the more efficient. Formation of the oxime should present no problem and the pyrolysis then can be carried out. A possible side reaction during the oxime pyrolysis is dehydration to form a cyanide similar to that observed during the attempted Beckmann rearrangement of aldoximes. (22) However, it is also noteworthy that normal Beckmann rearranged products can be obtained from aldoximes when the reaction is carried out under non-acidic conditions. Alternatively it should be possible to form the indole by pyrolysis of the appropriate styryl azide which should be available from the action of sodium azide on the epoxide ~ followed by dehydration according to the procedure of Smolinsky and Pryde. (17b) With the tetracyclic indole B-4 in hand, it should be ~ a simple matter to hydrolyze the cyanide under basic conditions to the corresponding acid. The reaction conditions should also cause claava ge of the N- acetyl group to give, after esterification, the amino ester ...__....._ B-5 . A reaction slmilar to that requ1.red to convert e:::2 to cyclopiazonjc acid has been described by R. L. Lacey (23) who trea.ted a series of 01,, -am1no esters 3 with ketene dimer, and then cyclized the resultin g acetoacetamides with sodium 271 ethoxide in benzene-ethanol to give derivatives of o<.-acety 1 tetramic acid 4 in 70-85% yields. "' R NH • R'CH-CO Et R-~ R = H' (.'J R'• CH 3 , H 0 OH 4 .....3 "' A suitable modification of this procedure appears promising 2 for the synthesis of cyclopiazonic acid also. Selective acylation of the amine nitrogen of .....,.,_,,.._ B-5 seems feasible in view of the low nucleophilicity of indole nitrogen. (24) For example, Johns and Crosby report no difficulty in the selective acylation of several 5-aminoindoles with benzoyl chloride (25) and cyclopiazonic acid itself reacts with acetic anhydride in pyridine only once to give an encl acetate. (1) Cyclization of the acetoacetamide using Laceyts conditions should then give cyclopiazonic 1 as ""' desired. 272 References 1. 2. c. W. Holzapfel, Tetrahed~, 24, 2101(1968) c. W. Holzapfel, R. D. Hutchison, and D. C. Wilkins, T&~rahed~on, 26, 5239(1970) 3. A. Stolland, A. Hoffmann, "The Alkaloids", R.H. R. Manske, ed., Academic Press (1965) 4. E. 5. R. J. Sundberg , "The Che mis try - of Indoles", Academic c. Kornfeld, E. J. Fornefeld, a. B. Kline, M. J. Mann, D. E. Morrisonl R. G. Jones, and R. B. Woodward, J, Am. Chem. Soc., 7~ , 3087(1956) Press (1970) , pp. 142-213 6. E. c. Horning and G. N. Walker, J. 7 4, 5147(1952) Arn. Chern . Soc., J. J. Ritter and P. P, Minieti, J. Am. Che!'!l. Soc., 70 4045(1948) 8. D. Vorlander and E. Strunck, ~ ' 345, 233(1906) A. Stevenson and J. F .• Thorpe, J. Chem . Soc ~, 1717(1922) 10. M. W. Rathke and A. Lindert, J. Am. Chem. Soc,, 93 2319(1971) 11. P. A, 12. P. J. Palmer, J . Chem. Soc., 3901(1963) 13. A. J. Birch and R. Robinson, J, Chem. Soc ., 501(1944) 14. G. w. Wheland, "Advanced Organic Chemistry", Wiley & Sons (1960) pp . 491-492 15. a. A. Strecker, Ann .. , 75, 27(1850) b. R. Graudry, ~an . J..!,_~~a~ch, 24, 301(1946) a. H. Loffler and D. Ginsburg, !le_tur~, 172, 820(1953) 16. s. Smith, "Organic Reactions", 3, 337 (1946) 273 17. a. b. 18. K. Isomura, s. Kobayashi, and H. Taniguchi, • 'Tetrahe d r.:~1h, 3 499 ( 196 8) G. Smolinsky and 33, 2411(1968) c. A. Pryde, J. Or~. Che~., J. I. a. Cadogan, ~- c. Cameron-Wood. R. K. Mackie, and R. J. G. Searle, J. Chem. Soc., 4831(1965) - - - ·· 19. a. E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. , 86, 16lJ0(l964) b. E. J' . Corey and M. Chaykovsky, ibid., 87, 1353(1965) 20, E. L. Eliel, and D. W. Delmonte, J. Am. Chem. Soc., 80, 1744(1958) 21. a. s. G. Levine, J, Am. Chem. Soc~, Bo, 6150(1958) b, G. R. Pettit, B. Green, B. L. Dunn, and P. S. Plassmann, J. Org. Chem~ 35, 1385(1970) a. P. DeMayo, "Molecular Rearrangereents'', Interscience (1963) pp. 504 b, 1. G. Donaruma and 22. 11, 41 (1960) w. z. Heldt, "Organic React:tons", 23. R, N. Lacey, ,Je Ch~. Soc.P 850(1954) 24. ref. 5, pp. 412-417 25. H. E. Johnson and D. C. Crosby, J. Org. Che~., 28, 2794(1963)