Synthesis of A-23187 and Related Model Compounds

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Sacks, Clifford Eugene (1980) Synthesis of A-23187 and Related Model Compounds. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/ca7z-w903. https://resolver.caltech.edu/CaltechTHESIS:10312025-213425765

Abstract

A-23187 is a calcium specific ionophore isolated from Streptomyces chartreusis. Syntheses of model systems containing the 1, 7-dioxaspiro[5.5]undecane ring system and the total synthesis are discussed. Based on results from the total synthesis the absolute configuration of A-23187 is assigned.

A new ionophore, X-14547A, was recently discovered which, like A-23187, contains a pyrrole ketone subunit. Kew methodology designed to introduce the pyrrole unit via an N-protected 2-pyrrylcuprate is presented.

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[6S*-{6α(2S*,3S*),8β(R*),9β,11α}]-5-(Methylamino)-2-[{3,9,11-trimethyl-8- |l-methyl-2-oxo-2-(1H-pyrrol-2-yl)-ethyl |-1,7-dioxaspiro[5.5]undec-2-yl}methyl]-4-benzoxazole-carboxylic acid.

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):	Evans, David A.
Thesis Committee:	Unknown, Unknown
Defense Date:	17 September 1979
Record Number:	CaltechTHESIS:10312025-213425765
Persistent URL:	https://resolver.caltech.edu/CaltechTHESIS:10312025-213425765
DOI:	10.7907/ca7z-w903
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ID Code:	17744
Collection:	CaltechTHESIS
Deposited By:	Benjamin Perez
Deposited On:	05 Nov 2025 17:14
Last Modified:	05 Nov 2025 17:14

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SYNTHESIS OF A-23187 AND RELATED MODEL COMPOUNDS Thesis by Clifford Eugene Sacks In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1980 (Submitted September 17, 1979) ii To Cheryl and To i\lv Mother and the Menw-ry of My Father "A candle loses nothing by lighting another." Anonymous iii ACKNOWLEDGMENTS I would like to thank Dave Evans for his guidance and interest during my tenure at Caltech. He has an excite- ment and enthusiasm which makes anything seem possible. I ~ould also like to thank Neil and Gretchen Mandel for doing our X-ray structure determinations, and also for taking the time to show me ho~ they did them. During the last four years I have benefited greatly from my interactions ~ith the other members of the Evans' Group. Without the help of my coworkers, Ralph Whitney, Terry Taber and Bill Kleschick, the completion of this work would no~ have been possible. I would also like to thank Ken Hurst, Ed Thomas and Dave Baillargeon who helped me maintain my sanity by their stimulating conversations of life, sports and politics. Also, thank you Cheryl for being there when I needed you. I wish to thank the California Institute of Technology and Dave Evans for financial assistance. Finally, a special word of thanks is extended to Dot Lloyd whose superb typing and patience made this thesis possible. iv ABSTRACT A-23187 is a calcium specific ionophore isolated from Streptomyces chartreusis. Syntheses of model systems containing the 1, 7-dioxaspiro[S.S]undecane ring system and the total synthesis are discussed. Based on results from the total synthesis the absolute configuration of A-23187 is assigned. A new ionophore, X-14547A, was recently discovered which, like A-2318 7 , contains a pyrrole ketone subunit. Ke w methodology designed to introduce the pyrrole unit via an N-protected 2-pyrrylcuprate is presented. A-23187 [6~*-{6a(2~*,3~*),8 B(~*),98,lla}J-S-(Methylamino)-2[{3,9,ll-trimethyl-8- \l-methyl-2-oxo-2-(1~-pyrrol-2-yl)ethyl \-1,7-dioxaspiro[S.S]undec-2-yl}methyl]-4-benzoxazolecarboxylic acid. V TABLE OF CONTENTS PAGE LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi LI ST OF F I GU RE S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi i CHAPTER I. Chemistry and Biology of A-23187 .. ... 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Chemistry and Structure 3 Biological Significance 5 References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . CHAPTER II. 12 Synthesis of Model Compounds .. . . .. .. 16 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . 37 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 l-Methoxy-4-methyl-1,4-cyclohexadiene (9b) 38 (Z)-3-Methyl-3-hexen-1,6-diol (10b) .... .. 38 (Z)-3-Methyl-1,6-bis(phenylmethoxy)-3hexene (llb) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 (3R*,4R*)-4-Methyl-l,6-bis(phenylmethoxy)3-hexanol (!~£) . . . . . . . . . . . . . . . . . . . . . . . . . . 40 (3R*)-3-[(4R*)-2,2-Dimethyl-l,3-dioxacyclohex-4-yl]-butanol (!~~) ..... ... ..... 41 (3R*)-1-Bromo-3-[(4R*)-2,2-dimethyl-l,3dioxacyclohex-4-yl]outane (!~~) . . . . . . . . . . 42 (2R*,8R*)-2,8-Bis[(4R*)-2,2-dimethyl-l,3dioxacyclohex-4-yl]-l-(methylthio)-4-nonene (16b) and (2R*,8S*)-2-[(4R*)-2,2-dimethyl1;3:dioxacyclohex-4-yl]-8~[(4S*)-2,2dimethyl-1,3-dioxacyclohex-4-yl]-5-(methylthio)-4-nonene C!Z~) ... ... ............... 44 - --- (2R*,3R*,8R*,9R*)-2,8-Bis(2-hydroxyethyl) 3,~-dirnethyl-1~7-dioxaspiro[S.S)undecane (5) .................. ............... ..... 45 vi TABLE OF CONTENTS (continued) PAGE (f)-3-Hexen-1,6-diol (10a) 46 (Z)-1,6-Bis(phenylmethoxy)-3-hexene (lla) 4-Methyl-1,6-Bis(phenylmethoxy)-3-hexanol (12a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . --- 46 46 3-(2,2-Dimethyl-l,3-doixacyclohex-4-yl)propanol (!~~) . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 l-Bromo-3-(2,2-dimethyl-l,3-dioxacyclohex4-yl)propane (~~':) .. .. . . . . . . . . . . . . . . . . . . . 47 l,7-Bis[(4R*)-2,2-dimethyl-l,3-dioxacyclohex-4-yl]-l-methylthio-3-heptene (16a) and 1- [4R*)-2 2-dimethvl-l 3-dioxacvclohex4-ylJ-7-[4S*)-2,2-dimethyl-l,3-dioxacyclohex-4-yl]-l-methylthio-3-heptene (17a) ... 48 (2R*,8R*)-2,8-Bis-(2-hydroxyethyl)-l,7dioxaspiro[S.S]undecane (4) and (2R*,8S*)2,8-Bis-(2-h ydroxyethyl)-1,7-dioxaspiro[S.S]undecane (18) ....................... 49 (2R*),8R*)-2,8-Bis-[(4R*)-2,2-dimethyll,j-dioxacyclohex-4-ylJ-5-nonanone (~~) and (2R*,8S*)-2-[(4R*)-2,2-dimethyl-l,3dioxacfcloliex-4-yl]~8-[(4S*)-2,2-dimethyll,3-dioxacyclohex-4-yl]-S~nonanone .. .. . .. SO (2R*)-l-Bromo-2-[(rR*)-2,2-dimethyl-l,3dioxacyclopent-4-ylJpropane (~£~) . . . . . . . . 51 (2R*,3R*,SR*,6S*,8R*,9R*)-2,8-Bis(hydroxymeihylJ-3,~,9-lrimithyI-1,7-dioxaspiro[ S . S] un de cane ( ~ ~ ~) . . . . . . . . . . . . . . . . . . . . . . S2 Irnine 2 2a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Methylated imine 22b ..................... 54 Spiroketal 23a ........................... 54 Equilibration studies on spiroketal 23a .. 55 (5~)-5-Carboxy-oxacyclopentan-2-one (27) 56 ' "' ' ,I vii TABLE OF CONTE~TS (continued) PAGE 3- [(4~)-2,2-dirnethyl-1,3-dioxacyclohex4-yl]propanol (~~) .. . . . . . . . . . . . . . . . . . . . . . 56 1-Brorno-2-[(4S)-2,2-dirnethyl-1,3-dioxacyclohex-4-ylJpropane (~~) . . ..... ...... .. 57 1,7-Bis-[(4S)-2,2-dirnethyl-1,3-dioxacyclohex-4-yl]-5-:-(rnethylthio)-4-nonene (~Q) .. . 58 (2S,8S)-2,8-Bis(hydroxymethyl)-1,7-dioxaspiroT5.5]undecane (31) .. . .. ...... ... ... . 59 Optic a 1 purity of s pi r o k et a 1 ( ~ ! ) .... ... . 60 References and :-:otes ........ -~................ 62 CHAPTER III. Synthesis of A-23187 . . . . . . . . . . . . . . . 68 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 ..Discussion of Alkylation Approach............ 71 Discussion of Aldol Approach . . . . . . . . . . . . . . . . . 86 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . 100 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2-(Methoxycarbonyl)-4-thiacyclohexan-lone (6a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4-Thiacyclohexan-1-one (~~) .......... .... 102 l-Pyrrolidin-l-yl-4-thia-l-cyclohexene (7) 103 Methyl 3-(1-thia-4-cyclohexen-3-yl)propionate (~) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Hydrolysis of ester~ .................... 105 Methyl 2-(trans-1,8a-cis-6,8-oxa-3-thiaperhydronaphth-l-y1Tpropanoate C!!~) ..... 106 (3R*)-Methyl-3-[(4S*,5R*)-5-methyl-1,3dioxacyclohex-4-y1Tpentanoate (12b) ...... 108 viii TABLE OF CONTENTS (continued) PAGE (3R*)-3-[(4S*,SR*)-5-Methyl-l,3-dioxacyclohex-4-yl]pentanoic acid (12a) ....... 109 [3(R*,S*),SR*]-3-Methyl-[(4S*,SR*)-5methyl~l,3-aioxacyclohex-4-yl]hexan-2on e ( 13) .......................... , . . . . . . 1 O9 (S)-(+)-3-t-Butyldiphenylsiloxy-2-methylpiopionic icid (15) . . . .. . . . . .. .. ...... .. . 111 ~- (+)-3-_!-Butyldiphenylsiloxy-2-methylpropan-1-ol (16) . .. .. .. . . .. .. .. . .. . . .. .. . 112 ~-(+)-2-t-Butyldiphenylsiloxy-l-methylpropionaTdeh yde (17) . . . . . . . . . ... ...... ... 113 (2S)- 1-t-Butyldiphenylsiloxy-2-methyl4-Tl-oxi-3-azainden-2-yl)-3-butanol · .. · ... ·....................... 114 (2S,3S)-2-Methyl-4-(1-oxa-3-azainden-2ylJ-1~3-butandiol (19b) . . . .. . . ..... ... ... 116 (2S,3R)-2-Methyl-4-(l-oxa-3-azainden-2y1Jbuian-l,3-diol (18b) . . . .. .... ...... ... 116 (2S,3R)-2-Methyl-4-(l-oxa-2-azainden-2ylT-l-=-E_-toluenesulfonyloxybutan-3-ol (23a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 (2S,3R)-3- (Oxacyclohex-2-yloxy)-2-methyl4-Tl-oxa-2-azainden-2-yl)-l-E_-toluenesulfonyloxybutane (23b) . .. ....... ... ..... 117 (2S,3R)-4-Iodo-3-methyl-l- (l-oxa-2aziinoen-2-yl)-2-butanol (23d) .. .. .. .. . . . 118 1- (l-t-Butyloxycarbonyl-l-azacyclopenta2,4-dien-2-yl)-l-propanone (~~) .......... 119 l-(l-Phenylmethoxymethyl-l-azacyclopenta2,4-dien~2-yl)-l-propanone C~Z) .......... 120 Pyrrole ketone enolate. General procedure for aldols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 (!~~' !~~) lX TABLE OF CONTENTS (continued) PAGE Aldol condensation of ketone 37 with benzaldehyde ................ -:--:- . . . . . . . . . . . 121 Aldol condensation of ketone 38 with benzaldehyde ................ -:--:- . . . . . . . . . . . 122 Aldol condensation of ketone 38 with methyl 3-methyl-4-oxopentanoate (39) 122 Aldol condensation of ketone 37 with methyl-3-methyl-4-oxopentanoat~ (39) 124 Methyl-5- (methylamino)-2- 1{(SR)-2- [ (2R)l-hydroxy-2-methylpent-4-yl]-~-methyl 7 oxacyc lohex- 2- en- 6-yl }methyl \- 4- benzoxa zol e carboxylate (43a, 44a) ·:· ... . .. ....... ... 124 Methyl-5- (rnethylarnino)-2- \{(SR)-2-methyl1-oxopent-4-yl]-5-methyloxacy~lohex-2-en6-yl }methyl \- 4- ben zoxa zol eca rboxyl ate (43b, 44b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 (2S)-Methyl-5-(rnethylamino)-2- \{(3R,6R, 8S~9R,11R)-3,9,11-trimethyl-8- [(lST-1~ methyl-2 7 oxo-2-(1H-pyrrol-2-yl)etnyl]1, 7-dioxaspiro[S.S]undec-2-yl}methyl \-4benzoxazolecarboxylate (!~) . . . . . . . . . . . . . . 126 (2S)-5-(Methylamino)-2- \{(3R,6R,8S,9R,11R)3,9,ll-trimethyl-8-[(1S)-1-metnyl~2-oxo-2-(lH-pyrrol-2-yl)ethyI]-1,7-dioxaspiro[ 5. 5Jundec-2-yl }methyl \-4-benzoxazolecarboxylic acid (!~) ..... .... ..... .. ... .. 128 References and Notes . .. . . . . . . . .. . . .. . . . . . . . . . 130 CKAPTER IV. Studies on Pyrroles ... .. .... .. . ... .. 137 Experimental Section .................... ..... 143 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 1-[(2-Methoxyethoxy)methyl]azacyclopenta2,4-diene CZ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Lithiation of pyrrole 7 145 X TABLE OF CONTENTS (continued) PAGE Reactions with p y ryllithiurn 8 . . . . . . . . . . . . 145 1-Bromohexane . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 But anal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 .r_-By trolactone . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 1- { [(2-Metho x yethoxy)methyl] azacyclopenta2,4-dien-2-yl}-1-propanone (~~) .. . . .. . .. . 147 References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . 149 APPE KDIX I. Thermochemical Estimates of 1,7Dioxaspiro[5.5]undecane Ring Systems ... . . . ... 150 13 AP PE:\DIX II. c- N~IR Spectral Catalog for Chapter II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 13 APPE NDIX III. C-l\MR Spectral Catalog for Chapter I I I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 APPE!\DIX IV. IR and 1 H- N!'-IR Spectral Catalog for Chapter I I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 1 APPE NDIX V. IR and H-~~1R Spectral Catalog for Chapter III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 1 APPE ~DIX VI. IR and H-NMR Spectral Catalog for Chapter IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 PROPOSITIO)';S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 xi LIST OF TABLES PAGE CHAPTER III Table 1. Table 2. Table 3. Table 4. Ta b le 5. CHAPTER Chemical Shift Analysis of 2 0 and 21 . . . . . . . . . . . . . . . . . . . . . . . . 82 Coupling Constant Data of 2 0 and 21 . . . . . . . . . . . . . . . . . . . . . . . . 82 Aldol Studies of Threo vs Ervthro Selectivity ... -:-:- ........ . 90 Aldol Studies of Cram vs AntiCram Selectivity .... . ........... . 94 Comparison of Data for Authentic and Synthetic A-23187 . . . . . . . . . . . . 98 Metalation of z and Quenching h'ith CH 0D ...................... . 141 n· Table 1. 3 APPE:-:DIX I Table 1. Table 2. Table 3. Fiee Energ y Estimates for Spirane ! (R = H) . . . . . . . . . . . . . . . . . . . . . . . . ·Free Energy Estimates for Spirane ! ( R = CH ) ..................... . 3 Free Energy Estimates for Spirane 156 156 5 .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Outline Characteristics of Three Common Forms of Aphasia ......... . 289 PROPOSITIO~ II Table 1. xii LIST OF FIGURES PAGE CHAPTER I Figure 1. ++ Octahedral Ca Complex of A-23187 ......................... . 3 Divalent Ion Binding Selectivity 4 Fi gure 1. Divalent Ion Binding Selectivit y 19 Fi gure 2. Computer Generated ORTEP Drawings of Spiranes 4, ~~and~~~ ....... . 13 c-\1'1R Chemica1 ·· Shifts of Spiroketals ..................... . 35 Comparison of Spirane Diols With Cram's Binaphthyls .............. . 36 9 0 ~1Hz Proton Spectra of 11 b and 12b ................ ..... -:-:-: ..... . 76 Expansion of the Methylene and Methine Regions of the 90 MHz 1 H-NMR for 20 and 21 .... , < , • • • • • • 83 Figure 2. CHAPTER II Fi gure 3. Figure 4. 28 CHAPTER III Fi gure 1. Figure 2. -1- CHAPTER I Chemistry and Biology of A-23187 -2- Introduction In the past ten years a large number of biologically interesting mold metabolites have been isolated. 1 ' 2 Among these metabolites is a large and growing class known as the polyether antibiotics. 3 The ability of some of these to form lipid soluble complexes with cations and provide a vehicle to transport the cations across 4 lipid barriers led to their being named ionophores. Several reviews have appeared on the topic of . 1onophores. 5- 9 Recently, Westley published a review of the carboxylic acid ionophores in which he classifies them on the basis of structure. 2 The four classes are: monovalent polyethers, monovalent glycoside polyethers, divalent polyethers and divalent pyrrole ethers. A-23187 (1) is the only known member of the last class. 1 - 3- Chemistry_and_Structure Although A-23187 was isolated in 1972, 10 the structure was not determined until 1974. Proton and carbon-13 nuclear magnetic resonance and infrared spectroscopy indicate the presence of the pyrrole • d b enzoxazo 1 e s1"d e c h a1ns. • ll,l 2 k-etone an d su b st1tute X-ray crystallography shows that the backbone is a 1,7-dioxaspiro[S.S]undecane ring system. 11 ' 13 This makes A-23187 one of a small class of molecules to contain such a ring system, others beini: Oscillotoxin A, 14 . . 15 Sa 1 1nomyc1n, . . 16 ,Naras1n . 17 A nt1.b 1ot1c .. A p 1ys1atox1n, B-41, 18 Milbemycin, 19 Oligomycin B, 20 and Rutamycin. 21 X-ray studies of the calcium salt indicate that only 22 four bonds have any rotational freedom and that the Figure 1 -4- Divalent 101 B ind ing Select ivity 0 -;:_ .6-23187 0 \ \ \ \-z- X-537.6 - I \ \ \ \ • &.: 0 \ 4 -_-2\/0 - 0 \ 0 \ 0 z . ., - 2 2 .5 .7 .9 I.I Ionic Radius (A) Figure 2 1.3 1.5 - 5- complex contains two molecules of A-23187 in an octahedral • f'1gurat1on · . . 13 ' 22 NMR con surroun d.1ng one ca 1 c1um 10n. studies in solution (proton and carbon-13) also indicate the 2:1 octahedral complex with complexation occurrin g at the carboxylate, benzoxazole nitrogen and pyrrole carbony1 22 (see Figure 1 and starred positions in structure 1). Bindin g affinities re v eal another unique feature which makes A-2318 7 especially useful for biochemical 23 24 research. ' A- 23 18 7 is ver y selective for divalent cations in the presence of mono valent cations. More sp e cificall y , it selects for calcium ov er other divalent species (see Figure 2). 25 Rigidity of the backbone structure is probabl y responsible for this by maintaining a cavit y si ze which cannot var y over a large range of . 22 sizes. Biolo gical Si gnificance - -~~~~~~~ ~ ~~~~~~ ~ ~~~~ ~~ Amon g the di v alent cations involved in physiological processes, calcium ion is perhaps the most ubiquitous in location and diverse in function. For example, alteration of cellular calcium levels is an important component of cellular control mechanisms. Especially sensitive are • h on d ria. • 26 energize d structures in cells sue h as m1toc Calcium ion flow down concentration gradients is important -6- . muse l e action. . 27 in Steady-state structures of cell membranes and walls, cell-cell conglomerates and structural units inside cells are also controlled by calcium mediated processes. 27 Evidence also exists that calcium is an important control mechanism in the synaptic transmission of nerve impulses, perhaps by mediating sodium and potassium gates. 28 Clearly, any agent that influences the binding of membrane-bound or protein-bound calcium, or that alters the rate of transport of calciu~ across membranes would be a valuable biochemical probe. The ion specificity of A-23187, and its fluorescence (allowing for easy detection and analysis of its environment) make A-23187 a very potent probe into calcium mediated cell functions. As a consequence A-23187 is increasingly being used to study complex physiological processes such as secretion . 30 mem b rane permea b.i 1 ity, . 24,31 p h enomena, 29 part h enogenesis, . 32 sperm moti·1·ity, 33 1 ymp h ocyte trans f ormation, . g 1 ucogenesis, . meta b o 1 ism. 34 and platelet function, structure and 35 Although nothing specific is known about the exact mechanism of calcium complexation and transport, several studies have shown that each calcium ion transported into 25 the cell corresponds to an outward flux of two protons. 36 One mechanism to account for this is shown in Scheme 1. -7- Scheme I H+ H+ f inner cell M2+ I i I-M-I I meDbrane The 2 : 1 stoichiometr y of the complex has recently been questioned . Hunt and his coworkers have evidence 37 38 of an active transport species in a 1:1 ratio. , His results are based on NMR studies of the transport of praeseod ymium ions across artificial lipid membranes. Most indications, ho wever, are that, at least in vivo, the active transport species is a 2:1 complex. 12 , 25 , 39 - 8- OH Os: :i: otox in CH 3 .. ,C CH 3 H3C I I I OH - OHO = 0 0 O H 3 H3CN OHO Aplysiotoxin -9- H~,~ OH H3C \ 0 = 0 HO CH3 OH H = CH CH3 3 H3C '" H•'' 0 ,..::' ,,, OH ., CH3 / CH3 So l1no myc 1n H 3 c'' OH H ' H3C Ori ~C0 2 H ,, : H CH3 CH3 No rosin -10- Mi lbe:-nyc in Antibiotic B-41 -11- H C H C CH 3 H HO H 0 Oligomycin Rutamycin B -12- References and Notes !~, 246 (1975). 1. J. W. Westley, Annu. Rep. Med. Chem., 2. J. W. Westley, Adv. App. Microbial., 3. C. Moore and B. C. Pressman, Biochem. Biophys. Res. Commun., 4. ~~' 177 (1977). !~, 562 (1964). B. C. Pressman, E. J. Harris, W. S. Jagge~ and J. H. Johnson, Proc. Natl. Acad. Sci. U.S.A., 58, 1949 (1967). 5. K . 0. Hodgson, Intra . -Sci. Chem. Rep., ~' 27 (1974). 6. S. McGlocklin and M. Eisenb~rg, Annu. Rev. Bioeng., 4, 335 (1975). 7. M. R. Truter, Philos. Trans. R. Soc. London, Ser. B., 272, 29 (1975). 8. B. C. Pressman, Annu . Rev. Biochem., 45, 501 (1976). 9. R. M. Izatt and J. J. Christensen, Eds., "Progress 1n Macrocyclic Chemistry, Vol. I," John Wiley and Sons, New York, 1979, p. 79. 10. R. L. Hamill, M. German, R. M. Gale, C. E. Higgins, and M. M. Hoehn, Abstracts, "12th Interscience Conference on Antimicrobial Agents and Chemotherapy," Atlantic City, New Jersey, September 26-29, 1972, p. 65. 11. M. 0. Chaney, P. V. Demarco, N. D. Jones, and J. L. Occolowitz, J. Am. Chem. Soc., 96, 1932 (1974). 12. C. M. Deber and D. R. Pfeiffer, Biochemistry, 15, -13- 132 (1976). 13. M. 0. Chaney, N. D. Jones, and M. Debono, J. Antibiot., 29, 424 (1976). 14. J. S. Mynderse and R. E. Moore, J. 0rg. Chem., ~~' 2301 (1978). 15. Y. Kato and P. J. Scheuer, Pure Appl. Chem., 48, 29 (1976). 16. H. Kinashi, N. Otake, and H. Yonehara, Tetrahedron Lett., 4955 (197&). 17. D. E. Dorman, J. W. Paschal, W. M. Nakatsukasa, L. L. Huckstep and N. Neuss, Helv. Chim. Acta, 59, 2625 18. (1976). J. S. Glasby, "Encyclopedia of Antibiotics," John Kiley and Sons, New York, 1976, p. 47. 19. H. Mishima, M. Kurabayashi, C. Tamura, S. Sato, H. Km\·ano, and A. Saito, Tetrahedron Lett., 711 (1975). 20. M. von Glehn, R. Norrestam, P. Kierkegaard, and L. Ernster, Fed. Eur. Biochem. Soc., 20, 267 (1972). 21. B. Arnoux, M. C. Garcia-Alvarez, C. Marazano, B. C. Das, C. Pascard, C. Merienne, and T. Staron, J. Chem. Soc., Chem. Commun., 318 (1978). 22. G. D. Smith and W. L. Daux, J. Am. Chem. Soc., 98, 1578 (1976). 23. D. R. Pfeiffer, P. W. Reed, and H. A. Lardy, Biochemistry, 13, 4007 (1974). -14- 24. A. H. Caswell and B. C. Pressman, Biochem. Biophys. Res. Commun., 49,292 (1972) . 25. D. R. Pfeiffer and H. A. Lardy, Biochemistry, 15, 935 (1976). !!~, 129 (1970). 26. A. L. Lehninger, Biochemistry , 27 . R. J. P. Williams, Biochem. Soc . Symp., ~~' 133 (1974). 28. J. R. Cooper, F. E. Bloom, and R. H. Roth, "The Biochemical Basis of Neuropharmacology," 3rd Ed., Oxford Uni v ersity Press, NeK York, - 1978. 29 . (a) :t\ . B. Thoa, J. L. Costa, J. Moss, and I. J. Kapin, Life Sci., 14, 1705 (1974); (b) J.C. Foreman, J. L. Manga~ and B. D. Gomperts, Nature, 245, 249 (1973); (c) C. B. Wollheim, B. Blondel, P.A. Truehart, A. E. Renold, andG. W. G. Sharp, J. Biol. Chem., 30. ~~2, 1354 (1975). (a) R. A. Steinhardt and D. Epel, Proc. Natl. Acad. Sci . U.S.A . , 71, 1915 (1974); (b) R. A. Steinhardt, D. Epel, E. J. Carrol, and R. Yanagamachi, Nature, 252, 41 (1974). 31. D. T. Wang, J. R. Wilkenson, R. L. Hamill, and J.-S. Horng, Arch. Biochem. Biophys., 156, 578 (1973). 32. V. C. Maino, N. M. Green, andM. J. Crumpton, Nature, ~~I, 324 (1974). 33. P. W. Reed and H. A. Lardy, "Proceedings of the -15- Second Annual New England Bioengineering Conference,'' R. A. Peura, et al., Ed., Vermont University Press, Burlington, Vermont, 1975, pp. 73-80. 34. R. N. Zahl ten, F. W. Stratman, andH. A. Lardy, Proc. Natl. Acad. Sci. U.S.A., 35. D. R. Holland, M. ZQ, I. Steinberg, and W. McD. Armstrong, Proc. Soc. Exp. Biol. Med., 36. !~~' 1141 (1975). G.D. Case, J.M. Vanderkool, and A. Scarper, Arch. Biocher.i. Biophys., 37. 3213 (1973). !~~' 174 (1974). G. R. A. Hunt, L. R... H. Tipping, and M. R. Belmont, Biophys. Chem., ~' 341 (1978). 38. G. R. A. Hunt, FEBS Letters, ~~' 194 (1975). 39. M. J. 0. Anteunis, Biorg. Chem., 6, 1 (1977). -16- CHAPTER II Syn thesis of Model Compounds -17- Since their isolation, the polyether antibiotics have aroused much interest in the chemical and biochemical communities because of their interesting, highly complex structures and their ability to complex and transport a ' wide variety of cations across lipid barriers. The latter characteristic led to their being named ionophores. 1 Several reviews of the antibiotic ionophores are currently 2 available. Historically, three of the most important 3 for clinical stud y have been A-23187 (1), Lasalocid 4 acid (2) and ~lonensin (3). 5 Monensin has successfully been used as a poultry and livestock feed additive, greatly increasing weight gains, 6 while Lasalocid acid and A-23187 have proven useful in biochemical studies due to their ability to transport mono- and divalent 7 8 ions, potent biological cations, across lipid membranes. ' 01/ ~ 0 I N ,. *o ~ NHCH 3 COOH I H 1 (Calcimycin) -18- 2 HO CH, H .H • _..CH, 0 HOCH l ' H HO : 3 CH, Since, as shown in Figure 1, 8 A-23187 is much more selective for calcium ions in the presence of other monoand divalent cations than is Lasalocid acid, and since its fluorescence allows for easy detection and analysis, A-23187 has become a key biochemical tool for investigating calcium-mediated cellular phenomena. 9 As a result of this interest in A-23187, we felt that the synthesis of structurally related bidentate analogs would prove useful. Also, although the structure and relative stereochemistry have been firmly established by proton- and carbon-NMR . 3 10-13 and by X-ray analysis, ' total synthesis would allow assignment of the absolute configuration of A-23187. -19- Divalent Ion Binding Selectivity 12 0 10 o, ... ... 0 ... 8 ... ... 'o - \ 0 \ \ \ \-z... X-537A - \ I \ \ \ 4 \ 0 2 .5 .7 .9 I.I Ionic Radius (A) Figure 1 1.3 1.5 -20- Our retrosynthetic planning for the total synthesis centered on the formation of the 1,7-dioxaspiro[S.S]undecane ring system. This rare structural feature affords a high degree of structural rigidity to A-23187 and is probably largely responsible for the observed complexation selectivity. The spirane system is also interest- ing since only a few other molecules contain it, most of them also ionophores isolated from mold metabolites: . . 14 • lS M"lb • 16 Ant1.b 1ot1c • • B- 41 , 17 Sa 1 1nomyc1n, Naras1n, 1 emyc1n, . . Bl 8 an d Rutamyc1n. • 19 01 1gomyc1n Two ot h ers, Ap 1 ys1atox1n • . 20 and Oscillotoxin, 21 have recently been isolated from marine sources. The retrosynthetic plan as detailed 1n Scheme I immediately poses two problems. First, would internal ketalization occur to give the proper configuration at the spiro-carbon (c 14 ) and second, would the methyl group at c equilibrate to the equatorial configuration, thus 15 allowing its introduction in a non-stereospecific reaction? An investigation of these concepts in models was deemed important,since not only would the results be applicable to the total synthesis of A-23187, but they could also be applied to the construction of bidentate analogs of narrowly defined cavity size,perhaps useful in ion-selective electrodes. Chiral synthesis could also afford ligands useful in asymmetric reductions. -21- Scheme I OJ) . I 5 s CH 3 Y "\ 0 ':, ~ ~ NHCH 3 H H •o 1cOOH • I 19 CH 3 N.,.... H I 1 3 CH 3 'l, ♦ 1 l ~H3 --- N H OH 8 0 OH I l:v~ ¢ ~ N l I 5 0 1 NHCH3 C02H C2 Hoping to utilize the latent c2 -axis of symmetry revealed in Scheme I, we chose spiranes ~ and 5 as our initial synthetic goals to test the spirane closure. -22- H 0 H H 4 As de p icted in Sche me II, closure of an acyclic ketone dial can giv e not onl y t~o confi gurational isomers, 6= 7 but also t,,·o conformational isomers, ~ ~ ~- In determining which isomer would predominate, two considerations are of major i mportance. First are the steric interactions 22 • 1 su b stituents • • a eye 1 oh exane ring. • cause d b y axia in Second is the ano meric effect which favors the axial . . 23 orientation of a polar group at c2 of a pyran ring 22 Using standard A values and a value of 0.6 kcal/mole 24 for the anomeric effect, we calculated that the diaxial oxygen configuration (~) should be favored by at least 2.3 kcal/mole over the next most stable configuration, CZ). Correspondingly, conformation 6 is also at least 2.3 kcal more stable than conformation 8 (see Appendix I for a more complete discussion). -23- Scheme II Stereochemical Considerations R R~R OH O R OH R•H t.G•+2.3 kcol/mol. t.G • + 5.3 kcol/mol. Rt~H ~ R R• H t.G•+2.3 kcol/mol. R• CH 3 t.G•+6.8 kcal/mo!. The synthesis of spiranes 4 and 5, to test the above hypothesis, followed the previously published route as 25 26 depicted in Scheme III. , Thus, treatment of dihydroanisoles 9a and 9b with ozone and in situ reduction with lithium aluminum hydride gave the diols 10a and lOb. 27 Even though the reaction was carefully monitored by GLC, over-oxidation was still a major problem. Attempts to overcome this by using lower temperatures were moderately successful. By operating at -78°C and using high concentrations so that the intermediate ozonide precipitated -24- from solution, yields could be maximized at 50%. Protection of the diols by benzylation gave high yields of ethers lla and llb. 28 Hydroboration then gave alcohols 12a and 12b. 29 In series b, this reaction also served to cleanly establish the relative stereochemistry of the hydroxyl and methyl groups. only one diastereomer. Carbon-13 analysis indicated By using a chiral hydroborating • bl y cou ld pro d uce c h.1ra 1 1nterme • d.1ates. 3 o agen t we conce1va Direct conversion of alcohols!~~!~ to the corresponding acetonide alcohols 13a and 13b was easily accomplished in ~~~ --~ high yield by hydrogenolysis in acetone over a palladium/ carbon catalyst. 31 The bromides 14a and 14b were then formed by the method of Servis 32 in a 63% overall yield from diols 10a and 10b. To assemble the backbone, we required an acyl anion 33 Investigation of Collman' s reagent [Na 2Fe (CO) 4 ] or Masuyamo's reagent [NCCH 2SC(S)N(CJI 3 ) 2 ] 34 proved un35 successful. Although l,3-dithiane gave acceptable yields, equivalent. the anion of methyl methylthiomethyl sulfoxide proved superior in both yield and operational simplicity. 36 Treatment of Ogura's reagent with two equivalents of racemic bromide 14a or 14b and excess potassium hydride gave rise to racernic vinyl sulfides!~~!~ and !Z~!~· Isolation of these unexpected products was probably due to the presence of excess potassium hydride. Deprotonation of -25- Scheme III a, b, R = CH 3 R = H; BZ = CH 2 Ph R R ¢ R (LOBZ (LOH OCH 3 OH OBZ 9 ~ 10 11 R CH H0, ,, 0 CH R R ~ :',,,n 3 CH3 0 ~n ',,, 3 CH3 0 Br OH OBZ OBZ 13 12 14 0 ' CH -S ' 3 ) CH 3-S 15 SCH 3 ~CH 3 CH 3 16 R R - R - R + xo CH 3 CH 3 17 -26- the initial bisalkylated product to!~ which could undergo subsequent intramolecular elimination to give the observed products and methylsulfenic acid is one reasonable explanation. Eliminations of this kind have recently been observed by Biellmann. 37 We were now ready to test the intramolecular ketalization. Treatment of the 1:1 mixture of 16 and 17 with mercuric chloride in aqueous acetonitrile 38 could • • • g ive rise to f our possi"bl e d.iastereomers 39 ass h own in Scheme IV. ~and~- In the a series two compounds were isolated, Since only one of the four, namely 4a, has a c 2 -axis of symmetry, then the seven-line carbon spectrum of the white crystalline~ implies it has the structure as shown for 18. An X-ray analysis (Figure 2) confirmed . 40 thi s . B, an oil, had a carbon spectrum consistent with a mixture of 18 and epi-18. The b series gave similar results, that is a white crystalline solid with an eight40 line spectrum consistent with ~' confirmed by X-ray (Figure 2), and an oil as a mixture of 19 and epi-19. We therefore concluded that, given the proper relative stereochemistry at the alcohol bearing centers, spirane closure would occur in a stereospecific manner. Next we investigated the equilibration of the methyl group at c 15 . Although closure with the methyl group -27- Scheme IV 16 + 1 7 I CH2CH20H R H H CH 2 CH 2 0H R 4' R = H 5 ' R = CH 3 epi-~ e p i-5 16 R H CH2CH20H + I 17 CH2CH20H ' H epi-!~ 18, R = H epi-!~ !~, R = CH 3 -28- 4 5 22a Figure 2. Computer generated ORTEP drawings of spiranes ~' 5 and 22a. -29- axial would lea~ to a severe 1,3-diaxial methyl-methyl interaction, we had no estimate for the offsetting A-1,2 strain due to an equatorial methyl. Based upon literature precedent 41 we believed that, even if closure should occur with the c15 methyl axial, acid-catalyzed equilibration could occur via a dihydropyran (eq 1). Testing the equilibration of duction of a methyl group at c15 c15 . required introRepeated attempts to hydrolyze vinyl sulfides under acidic or neutral con42 ditions led only to isolation of spiranes presumably due to anchimeric-assisted hydrolysis (eq 2). In an (1) spiranes (2) attempt to affect hydrolysis without proceeding through a !Z carbocation, we treated!~ and with lithium diphenylphosphide, 43 but recovered only starting material. To circumvent this problem we sought an alternate synthesis of ketone 25. Conversion of bromide 14b to the corre- - 3 0- spending lithium reagent 44 and quenching the reaction with carbon dioxide gave good yields of ketone~~ (eq 3). Attempts to monomethylate either the ketone or 45 its corresponding dimethyl hydrazone, however, were unsuccessful. (3) 1\'e next turned our attention to the route outlined in Schem e ¥. Conversion of known alcohol 20a to the bromide was accomplished as described previously. 32 The sequential bisalk)·lation and methy lation of acetone imine 21 was conveniently carried . out in a one-pot procedure. Alk y lation of acetone cyclohexylimine (21) with two equi valents of bromide 20b in the presence of two equiva46 lents of lithium diethylamide gave the bisalkylated imine 22a. The imine could be isolated or deprotonated in situ by addition of another equivalent of base and then alk y lated with methyl iodide. Acidic workup then yielded a crystalline spirane (48%) identified as 23a and an oil (23b) which carbon-13 analysis indicated to be a mixture of at least two different spiroketals (32%). X-ray analysis of the crystalline spirane con- -\0 23 b CH 3 '-../H CH 3 b, R = Br CH 20H 21 ~~ 20a, R = OH y 0 R + 0 NC 6 H 11 0~ ~H3 Scheme V 3v CH 3 CH / ~ 24 ~1 sY R CH 3 CH 0H 2 h, R = Cl! 22n, R = II ~ H _.. z~ .. l O' H3~ 3 D+ l ~ 1 ~H3 CH 3 "'O 23a CH 3 H ~H 20H + Mesa. CH 20H I I-' t,.J -32firmed its assignment as structure 23a. 40 Treatment of 23a with DCl in deuterium oxide (see experimental) gave a single crystalline spirane in 80% yield. Carbon-13 and 1H-NMR as well as mass spectral analysis indicated an average of 1.5 deuterium per molecule with complete incorporation at c15 . Ke therefore c15 had convincing evidence that equilibration of the methyl was possible. Further, whatever the magnitude of the A-1,2 strain (very obviously present from the deformations detectable in the X-ray structure), it is less than the 1,3-diaxial methyl interaction. Having satisfied ourselves that the configuration at the spiro-center cc 14 ) could be controlled by the hydroxy- bearing stereocenters, and that the configuration of the methyl at c15 could be controlled by equilibration, we turned our attention to a chiral model synthesis. 26 We felt such ligands should be particularly successful as ligands for chiral reducing agents because: 1) they would have a c -axis of symmetry, 2) they would have 2 7 high conformational rigidity~ Also, the chiral spiranes could be incorporated into crown ethers similar to 48 Cram's chiral binaphthyls (Figure 4). The required chiral bromide (~~) was prepared as shown in Scheme VI. Diazotization of ~-glutamic acid ~Z· 49 (26) gave lactone Reduction to the triol with diborane 50 and ketalization with acetone and mineral acid -33- Schem e VI 0 0 ~ c1 60% OH ,NH 2 ~ OH 01/ 51% OH 0 26 27 Br OH 92% 28 29 0 ' CH-S 3 ) CH-S 3 KH 2 RBr 60% 30 50% OH 31 -34- gave alcohol 28 in 40% yield from the amino acid. Careful control of the diazotization of glutamic acid was crucial in obtaining high optical yields of 28. The best optical yields were realized if lactone 27 was used without distillation (see experimental). Conversion to the 32 bromide (29) followed standard procedures. Alkylation 36 of Ogura's reagent with 29 gave vinyl sulfide ~Q which was • h mercuric • c hl ori"d e 38 to give • h y d ro 1yze d wit a mercury complex of spirane 31. X-ray analysis showed that mercur y (as HgC1 2 ) had formed a linear complex with two molecules of 40 31. Treatment with gaseous hydrogen sulfide sufficed to re move the mercury giving spirane 31 in 85 % ee (see experimental). Alternatively the vinyl sulfide could be hyd ro51 l yze d with trifluoroacetic acid. Carbon-13 and 1 H- NMR confirmed the symmetrical nature of 31. Studies are cur- rently in progress to determine the utility of this chiral 52 bidentate ligand for asymmetric hydrogenation catalysts. In conclusion, we have shown that the facile construction of spiroketals is possible by internal ketalization. Control of the stereochemistry of the hydroxyl-bear- ing centers allows complete control of the configuration of c15 can be equilibrated to give the proper configuration at c15 . the spiro-carbon. Finally, a methyl group at The application of these studies to the total synthesis 53 of A-23187 will be reported s hortly. -35- OH OH CH 3 11. 1 31 5 64 . 4 12, 2 CH 3 OH 5 9. 4 19. 0 3 1, 1 H CH 3 11 · 4 4 Figure 3. 22a 13 c-NMR chemical shifts of spiroketals. - 36- OH I d l OH ~H ,,,,, 0 OH R 0 ¢ = 80-85°; d = 3.4 A Figure 4. ¢ = 85°; H Comparison of spirane diols with Cram's binaphthyls. 0 d = 3.2-7.5 A -37- General. Diethyl ether, 1,2-dimethoxyethane (DME) and tetrahydrofuran (THF) were dried by distillation from benzophenone ketyl. diethylamine Triethylamine, diisopropylamine and were distilled from calcium hydride under nitrogen just prior to use . Dichloromethane was filtered through activity I alumina. Oil dispersions of potassium hydride (24 %), sodium hydrid e (5 0% ) and lithium 2% sodium (50%) were washed free of oil ~ith ether or pentane and dried under vacuum prior to use. All Grignard and alkyllithium reagents were standardized by the procedure of Watson and Eastham~ 4 Unless otherKise specified all reactions were run under an inert atmosphere of nitrogen. Melting points were determined Kith a Biichi SMP-20 meltin g point apparatus and are uncorrected. Infrared spectra were recorded on a Beckman IR-4210 spectrophoto. meter and are reported 1n cm -1 Proton nuclear magnetic resonance spectra were recorded on a Varian Associates Model T-60, A-60, or EM-390 spectrometer. Chemical shifts are reported in parts per million on the 6 scale relative to tetramethylsilane internal standard. as follows: Data are reported chemical shift, multiplicity (s d = doublet, t = singlet, = triplet, q = quartet, m = multiplet), -38- integration, coupling constants (Hz), and interpretation. Carbon-13 nuclear magnetic resonance spectra were recorded on a Varian Associates XL-100 (25.2 MHz) or T-60 (15.1 MHz) spectrometer and are reported in parts per million on the o scale relative to tetramethylsilane internal standard. Mass spectra were recorded on a DuPont MS 21-492B mass spectrometer at 75 eV. Mass spectral analyses as well as combustion analyses were performed by Dr. Susan Rottschaeffer, Mrs. Jan Mitchell and Ms. Sally Muir of the California Institute of Technology Microanalytical Laboratory. Analytical gas chromatographic analyses were performed on a Varian-Aerograph Model 1440 gas chromatograph equipped with a flame ionization detector using 2 m by 3.18 mm stainless steel columns of 10% Carbowax 20 M, or 10% SE-30 on 80-100 mesh DMCS Chromosorb W support. 1-Methoxy-4-methyl-1L4-cyclohexadiene_(9b). The title compound was prepared by Birch reduction of 4methylanisole according to the procedure of Pappas et al.,55 in a 70% yield: bp 83-85°C (36 mm); IR (neat) 2820, 1690, 1663, 1450, 1385, 1217, 1172, 1010, 936, 775 cm- 1 ; 1 HNMR (CDC1 ) o 5.30 (m, lH vinyl), 4.49 (m, lH, enol ether), 3 3.45 (s, 3H, -OCH 3), 2.62 (d, 4H, J = 1.5 Hz, allylic -CH 2 ), 1. 65 (s, 3H, vinyl -CH 3 ). (i)-3-Methyl-3-hexen-1,6-diol (10b). A solution of ----------------------------------- - 3 9- 12.5 g (0.1 mol) of l-methoxy-4-methyl-1,4-cyclohexadiene in ether (250 mL) was cooled to -78°C. Ozone (0.82 mmol/ min) was bubbled through the stirred solution for 2 h. The course of the reaction was monitored by GLC (5% carbowax). After complete consumption of starting material, lithium aluminum hydride (5 g, 150 mmol) was added and stirring continued at -78°C for 2 h followed by warming to 25°C. After 3 h water (5 mL), 15 % sodium hydroxide (5 mL) and then water (15 ml) were carefully added and the precipitate removed by filtration. Removal of solvent in vacuo gave a colorless oil which was distilled bulb-to-bulb at 120°( (0.01 mm) to yield 7.1 g (54%) of a clear, colorless oil: IR (CHC1 3 ) 3619, 3380, 2962, 1445, 1374, 1050, 877 cm-l 1H-~~IR (CDCl~)o 5.65 (t, lH, J = 8 Hz, .) vinyl), 3.68 (t, 2H, J = 6 Hz, -OCH 2 -), 3.60 (t, 2H, J = 6 H:, -OCH -), 2.67 (t, 4H, J = 6 Hz, allylic -CH 2 ), 1.75 2 (s, 3H, allylic CH 3 ); 13 C-NMR (CDC1 3 ) o 134.5, 124.1, 62.0, 60.1, 35.0, 31.4, 23.4. An a 1 . ca 1 c d. for C7H14 0 2 : Found: C, 64.61; C, 64 . 58 ; H, 1 0 . 8 4 . H, 10.65. (l)-3-Methyl-1,6-bis(phenylmethoxy)-3-hexene_(llb). To 6.0 g (0.25 mol) of oil-free sodium hydride suspended in THF (250 mL) at 0°C was added 14.7 g (0.113 mol) of diol 10b in THF (60 mL) with stirring. After gas evolution -40- ceased, 31.6 mL (0.25 mol) of benzyl chloride (filtered through alumina) in THF (60 mL) was added dropwise over 20 min . Following complete addition, a reflux condenser was attached and the suspension was heated at reflux for 12 h. Water (30 mL) was carefully added followed by removal of THF in vacuo. The residue was diluted with 150 ml hexane and the organic layer was washed successively with water and brine, and dried (Na 2so 4 ). Filtration and solvent removal in vacuo afforded a yellow oil which was distilled bulb-to-bulb at 150°C (0.003 mm) to yield 27.7 g (79 ~o) of a colorless oil: IR (CC1 4 ) 3064, 3030, 2860, 1 H- NMR 1491, 1450, 1360, 1203, 1100, 1028, 728, 698 cm-l (CDCl-) o 7.23 (s, l0H, Ar), 5.27 (t, lH, J .) 4.4 2 (s, 4H, -OCH2Ar), 3.54 (t, 2H, J 3.43 (t, 2H, J = = 6 Hz, vinyl), 7.5 Hz, -OCH2-), 7.5 Hz, -OCH 2 -), 2.35 (t, 4H, J = 7.5 Hz, 13 vin y l -CH ), 1.74 (d, 3H, J = 1.2 Hz, vinyl -CH 3 ); C-NMR 2 (CDC1 ) o 138.4, 133.9, 128 . 2, 127.5, 127.3, 122.8, 72.8, 3 70.1, 68.7, 32.4, 28.6, 23.9. = An a 1 . ca 1 c d . f o r C H2 0 2 : 21 6 Found: C, 81.20; H, 8.49. C , 81 . 2 5 ; H, 8 . 4 4 . (3R*,4R*)-4-Methyl-l,6-bis(phenylmethoxy)-3-hexanol (12b). To a solution of alkene llb (27.7 g, 89 mmol) in THF (250 mL) at 0°C was added diborane in THF (90 mL, 96 mmol) over a 10 min period. After an additional 30 min the reaction was warmed to 25°C and stirred for 18 h, -41- then cooled in ice before careful addition of 3N sodium hydroxide (120 mL) and 30% hydrogen peroxide (60 mL). The reaction was warmed to 25°C and stirred 6 h then the product was isolated by partitioning between ether and water. The ether layer was washed with water and dried (Na 2so 4 ). Filtration and solvent removal in vacuo gave a crude product which could be used directly or purified by silica gel chromatography (30% ether/hexane) to give 22 g (75 %) of colorless oil: IR (CC1 4 ) 3527, 3064, 3035, 2 8 6 0, 14 91 , 14 5 0, 13 6 0 , 12 0 3, 10 9 5 , 10 2 8 , 7 28 , 6 9 5 cm - 1 ; 1 HN~1R (CDCI 3 ) o 7.31 (s, l0H, Ar), 4.50 (s, 4H, Ar-CH 2 -O), 3.63 (t, 4H, J = 6 Hz, -OCH2-), 3.40-3.80 (m, lH, -OCH-), 2.90 (d, lH, J 3 Hz, -OH), 1.45 - 1.92 (m, SH, -CH 2 - and -C!j_CH 3 ), 0.88 (d, 3H, J = 7 Hz, -CH 3 ); 13 c-NMR (CDCI ) o 138.5, 3 128.3, 127.5, 73.2, 73.0, 69.3, 68.7, 36.1, 33.9, 33.3, = 14.0. An a 1 . c a 1 c d . for C21 H280 3 : Found: 76.63; H, 8.46. C, 7 6 . 7 9 ; H, 8 . 5 9 . i~~~2=~=Ji~~~2:3r3:~~~=!~t!:!r~:~!~~~~r~!~~=~:~:r!1: butanol (13b). A solution of 10 g (30 mmol) of dibenzyl - - - - - ~- - - - - -~ ether 12b in acetone (200 mL) containing 10% palladium on charcoal (1.0 g) was hydrogenolyzed at 25-30 psi for 12 hon a Parr low-pressure hydrogenator. Catalyst -42- filtration and removal of solvent in vacuo gave a clear oil which was dissolved in a solution of acetone (20 mL) and benzene (30 mL) containing one crystal of p-toluenesulfonic acid and stirred for 5 h. Following addition of K2co 3 , filtration and removal of solvent in vacuo, the residue was distilled bulb-to-bulb at 80°C (.005 mm) to yield 4.4 g (77%) of a colorless oil: IR (CC1 4 ) 3450, 2990, 2960, 2935, 2870, 1375, 1267, 1194, 1 1095, 966 cm-l H-NMR (CC1 4 )o 3.41-3.98 (m, SH, -OCH - and 2 -OCH-), 2.34 (broad s,lH,-OH), 1.00-1.91 (m,5H,-CH 2 -, -C!::!_CH 3 ), 1. 37 (s, 3H, acetonide CH 3 ), 1. 28 (s, 3H, acetonide CH 3 ) , 0 . 9 8 ( d , 3H, J = 7 Hz , - CH 3 ) ; l 3C- NM R (CD C1 3 ) o 98.4, 72.6, 60.7, 60.0, 35.4, 35.1, 29.8, 24.5, 19.8, 15.1. Anal. calcd. for Found: C, 64.02; c10 H20 o3 : C, 63.80; H, 10.71. H, 10.34. i~t~2:!:~:~~~:~:1i~t~2:~t~:~!~:!~r!:!t~:~!~~~~r~!~~:~= 4-yl]butane (14b). Acetonide alcohol 13b (1. 7 g, 9.1 mmol) ---~~ ------------ --- was dissolved in methylene chloride (30 mL) and cooled in an ice bath. Next, with stirring, triethylamine (1.62 mL, 10.6 mmol) was added, followed by dropwise addition of methanesulfonyl addition (ca. chloride. After complete 5 min), the reaction was stirred for 1 h at 0°C during which time triethylamine hydrochloride precipitated. Dilution with dichloromethane (20 mL) followed by washing with water, drying (Na 2so 4 ), -4 3- filtration, and removal of solvent in vacuo at 25°C gave the straw colored mesylate: IR (neat) 2990, 2963, 2868, 1453, 1365, 1193, 1168, 1097, 970, 940 cm-l; 1 H-NMR (CC1 4 ) 6 Hz, MsOCH -), 3.80 (dd, 2H, 2 J = 3, 6.5 Hz, -OCH 2 -), 3.65 (m, lH, -OCH-), 2.95 (s, 3H, -sO2CH3), 1.49-2.05 (m, SH, -CH2-' -CH-), 1.38 (s, 3H, cS 4.25 (t, 2H, J = acetonideCH 3 ), 1.28 (s,3H,acetonide CH 3 ), 0.93 (d,3H, J = 6 Hz). The mesylate was dissolved in acetone (15 mL) and 2,2-dimethoxypropane (15 mL) and anhydrous lithium bromide (4.S g, 54 mmol) ~ere added and the resultant mixture heated at reflux for Sh. The crude bromide was isolated by removing excess solvent in vacuo, dissolution of the residue in ether-hexane (1:1) and partitioning with water. The or ganic layer was dried (~a 2 so 4 ) filtered and solvent re moved to give a yellowish oil which on distillation at 60°C (.03 mm) gave 1.65 g (78 %) of an unstable colorless bromide: IR (CC1 4 ) 2960, 1502, 1375, 1265, 1215, 1195, 1168, 1100, 1063, 1000, 968 cm- 1 ; 1 H-NMR (CDC1 )o 4.00 3 (t, lH,J = 3.5 Hz, -OCH2-)' 3.83 (d, lH,J = 3 Hz, -OCH2-), 3.52-3.80 (m, lH, -OCH-), 3.50 (t, 2H, J 7.5 Hz, BrCH 2 -), 1.08-2.10 (m, SH, -CH- and -CH 2 -), 1.42 (s, 3H, acetonide CH ), 1.35 (s, 3H, acetonide CH 3 ), 0.90 (d, 3H, J = 6 Hz, 3 -CH ); 13 C-NMR (CDC1 ) cS 98.2, 71.9, 60.0, 37.2, 36.4, 3 3 32.4, 31.3, 29.8, 28.4, 14 . 1. = -44- Exact mass (75 eV) ~/~, calcd. for 235.033. Found: c10 H19 o2 Br, M-CH 3 : 235.031. (2R*,8R*)-2,8-Bis- [(4B*)-2,2-dimethyl-1,3-dioxacyclohex- ~~~~~~~~~~~~~--~~~~~~~~~~~~~~~~~~~-~~~~~~~~~~~~~~~~~~~~ ~ 4-yl]-5-(methylthio)-4~nonene (16b) and (2B*,8~*)-2-[(4B*)- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2,2-dimethyl-l,3-dioxacyclohex-4-yl]-8-[(4~*)-2,2-dimethyl- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1,3-dioxacyclohex-4-yl]-5-(methylthio)-4-nonene (17b). ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ To a dr y, three-neck, 100-mL, round-bottomed flask equipped with a reflux condenser, nitrogen inlet, rubber septum and magnetic stirring bar was added potassium hydride (24 % in oil, 2. 2 g, 56 mmol). The oil was removed by several washings with ether then THF (37 mL) was added. To the ice-cooled stirred suspension was added methyl methylsulfinylmethyl sulfide (0.86 mL, 6.9 mmol) dropwise over a 5 min period. After stirring 15 min, bromoacetonide 14b (3.5 g, 14 mmol) was added and stirring continued for 0.5 hat 0°C, 1 hat 25°C and 1 hat 45-55°C (oil bath). Excess hydride was quenched with moist ether and the crude product was isolated by ether extraction. Purification by chromatography (alumina activity III, hexane to 70 % ether/hexane) gave pure vinyl sulfide (1.1 g, 75 %) as a mixture of olefin isomers: IR (CCI ) 2990, 2960, 2865, 1620, 1455, 1377, 1366, 1270, 4 -1 1 1240, 1195, 1097, 970, 850 cm ; H-NMR (CCI 4 ) 6 5.55 (t, 0.4H, J = 7 Hz, E-vinyl), 5.05 (t, 0.6H, J 3.89 (t, 2H, J = = 7 Hz, Z-vinyl), 3 Hz, -OCH 2 -), 3.75 (d, 2H, J = 3 Hz, -45- -OCH 2 -), 3.18-3.64 (m, 2H, -OCH-), 2.13 (s, 3H, -SCH ), 3 1.1-1.8 (m, l0H, CH 3 -CH-, -CH -, allylic CH -), 1.37 (s, 2 2 6H, acetonide CH), 1.28 (s, 6H, acetonide CH 3 ), 0.89 (d, 6H, J = 6 Hz, CH 3 ). Exact mass (75 eV) ~/~, calcd. for c 22 H40 o4 s: Found : 4 0 0 . 2 6 2 . 400.264. (2B*,3R*,8B*,9B*)-2,8-Bis-(2-hydroxyethyl)-3,9-dimethyll,7-dioxaspiro[5.5]undecane (5). To a solution of vinyl sulfide 16b and 17b (1.70 g, 4.25 mmol) in 75% aqueous acetonitrile (40 mL) ~as added mercuric chloride (2.8 g, 8 . 8 mmo 1) a t 25 oc. had formed. Within minutes a white precipitate The resultant suspension was stirred for 10 h, benzen e (10 0 mL) was added and water was removed by azeotropic distillation (Dean Stark). removal gave a colorless oil. Filtration and solvent Chromatography on Silica Gel (1:1 ethyl acetate/hexane) gave an oil (0.33 g, 30 %) which solidified on triturationwithhexane, mp. 86-88°C (hexane): IR (CHCl_) 3600, 3410, 2965, 2935, 1462, 1383, .) 13 6 8 , 12 2 7 , 112 0, 107 7 , 10 3 5 , 9 8 2 , 9 5 0 , 8 8 4 cm - l l H- NMR (CDCl3) o 3.01-4.35 (m, 6H, -OCH2-, -OCH-), 2.72 (s, 2H, -OH), 1.07-2.26 (m, 14H, -CH- and -CH 2 -), 0.94 (d, 6H, J = 6.8 Hz, -CH 3 ); 13 c-NMR (CDC1 3 ) o 95.9, 67.1, 59.1, 36.2, 30.8, 30.0, 26.6, 11.1. Anal. calcd. for Found: C, 66.92; c15 H28 o4 : H, 10.23. C, 67.10; H, 10.36. -46- (I)-3-Hexen-1,6-diol (10a). The title compound was prepared according to the procedure described for diol 10b. Ozonolysis and reduction of dihydroanisole (11 g, 0.10 mol) gave diol 10a (4.6 g, 40%), bp. 80°C (0.1-0.05 mm) : cm I R (CH C1 3 ) 3 61 9 , 3 3 8 0 , 2 9 6 2 , 14 4 7 , 13 7 0 , 1 0 5 0 , 8 7 0 -1 1 H-NMR (CDC1 3 ) 6 5.56 (t, 2H, J = 4.5 Hz, vinyl), 4.06 (broads, 2H, -OH), 3.51 (t, 4H, J = 6.5 Hz, -CH 20-), 2.33 (t, 4H, J eV) ~/~ 6 Hz, allylic CH -); mass spectrum (7S 2 (rel intensity) 98 (13), 68 (100), 67 (48), SS = ( 3 9) . (;)-1,6-Bis(phenylmethoxy)-3-hexene (lla). ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~--~-~~~ The title compound was prepared according to the procedure described for diether llb. gave diether Benzylation of diol 10a (11.6 g, 0.10 mol) !!~ (27.1 g, 92 %), bp. 140°C (0.002 mm): IR (CC1 4 ) 3030, 2860, 1490, 1448, 1360, 1202, 1100, 102S, 1 H-NMR (CC1 ) 6 7.17 (s, l0H, Ar), 5.44 723, 69S cm-l 4 ( t ' 2H, J = 4. 5 Hz, vinyl), 4. 2S ( s' 4H, Ar-CH 20-) ' 3.35 = 5 . 5 ' 6. S 6.5 Hz, -OCH-) 2 ' 2.30 (d, t' 4H, J 13 c-NMR (CDC1 ) 128.29, 127.56, Hz, allylic CH 2 - ) ; 3 6 7 2. 9, 7 0. 0, 2 8. 2. (t, 4H, J = Exact mass (75 eV) ~/~, calcd. for c 20 H24 o2 , P-C 7H7 : 205.123. Found: 205.122. i:~~!bt!:!l~:~!~iP~:~r!~:!~~~r2:~:~~~~~~~-i!~~2· title compound was prepared according to the procedure for alcohol 12b. Hydroboration of olefin lla (27.1 g, The -47- 0.092 mol) gave alcohol~~~ (31.0 g, 100%): IR (CC1 ) 4 3535, 2920, 2860, 1448, 1360, 1201, 1094, 1026, 725, 1H-NMR (CC1 ) 6 7.21 (s, l0H, Ar), 4.47 (s, 693 cm-l 4 4H, -OCH 2Ar), 3.63 (t, 4H, J = 6.3 Hz, -OCH 2 -), 3.32-3.54 (m, lH, -OCH-), 3.10 (broads, lH, -OH), 1.34-1.92 (m, 6H, 13 -CH 2 -); C-NMR (CDC1 3 ) 6 128.3, 127.6, 73.2, 72.9, 70.5, 68.8, 36.9, 34.5, 26.l; mass spectrum (75 eV) ~/~ (rel intensit y) 208 (5), 108 (62), 107 (81), 91 (100), 79 (57), 77 (33) . 3-(2,2-Dimethyl-l,3-dioxacyclohex-4-yl)propanol (13a). ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-~~~~~-~~~~~~~~~~~~~~~~~ The title compound was prepared from alcohol 12a according to the procedure for acetonide 13b. Hydrogenation of alcohol!~~ (9.4 g, 30 mmol) gave acetonide 13a (3.68 g, 7 2 %) , b p . 7 5 ° C ( 0 . 0 2 5 mm) : I R (CC 1 4 ) 3 3 6 0 , 2 9 4 0 , 2 8 6 0 , -1 1 H-NMR (CDC1 3 ) o 3. 35-4 .10 (m, 6H, -OH, - OCH 2 -, -OCH-), 1.4-1. 9 (m, 6H, -CH 2 -), 1.41 (s, 3H, acetonide CH ), 1.35 (s, 3H, aceto3 13 nide CH 3 ); C-NMR (CDC1 3 ) 6 98.9, 69.6, 62.7, 60.5, 1373, 1360, 1210, 1192, 1048, 963 cm ; 33.8, 32.2, 30.4, 29.1, 19.6. l-Bromo-3-(2,2-dimethyl-l,3-dioxacyclohex-4-yl)- ~~ ~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ propane_(l4a). The title compound was prepared according to the procedure for bromide 14b. Reaction of alcohol 13 a ( 3 . 6 8 g , 21 . 6 mm o 1 ) gave bromide 14 a ( 3 . 7 3 g , 7 0 %) , bp. 50°C (0.03 mm). ~~~r!~E~= IR ccc1 4 ) 2980, 2940, 2855, 1360, 1337, -481240, 1192, 1170, 1095, 963, 935, 855 cm -1 1H-NMR (CC1 ) 4 0 4.16 ( t' 2H, J = 6 Hz, -so cH -), 3.82 (dd, 2H, J = 4. 5, 3 2 8 Hz, -OCH-) 2 , 3.52-3.87 (m, lH, -OCH-), 2.90 ( s, 3H, CH 3 so 3 -), 1.19-2.18 (m, 6H, -CH -), 1.35 (s, 3H, acetonide 2 CH 3 ), 1.25 (s, 3H, acetonide CH 3 ). Bromide was distilled bulb-to-bulb at 50°C (.03 mm) to give a colorless oil: IR (CC1 4 ) 2990, 2945, 2863, 1435, 1375, 1365, 1265, 12 4 0, 1195, 1110, 1050, 967, 858 1 H-N~!R (CC1 ) = 4 , 9.5 Hz, -OCH-) cm -1 2 ' 4 6 3.78 (dd, 2H, J 3.55-3.95 ( m, lH, -OCH-), 3.33 ( t , 2H, J = 6.5 Hz, BrCH2-)' 1.18-2.33 (m, 6H, -CH 2 -), 1.33 (s, 3H, acetonide CH 3 ), 1. 23 (s, 3H, acetonide CH 3 ); 13 c-NMR (d 6 -acetone) o 99.0, 68.9, 60.3, 35.8, 34.5, 32.2, 30.4, 29.5, 19.6. Anal. calcd. for Found: C, 45.35; c9H1 7 BrO 2 : C, 45.58; H, 7.23. H, 6.94. 1, 7-Bis- [(4B*)-2,2-dimethyl-l,3-dioxacyclohex-4-yl]- ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4-methy lthio-3-heptene (16a) and l-[(4B*)-2,2-dimethyl- ~~~~~~~~~~~~~~~~~~~~~~~~ ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ l,3-dioxacyclohex-4-yl]-7-[(4§*)-2,2-dimethyl-1,3-dioxa- ~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-~~~~~~~~ cyclohex-4-yl]-4-methylthio-3-heptene (17a). ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title compounds were prepared from bromide 14a according to the procedure for vinyl sulfides 16b and 17b. Alkylation of Ogura's reagent 36 (0.47 g, 3.8 mmol) with bromide 14a (1.9 g, 8.0 mmol) gave vinyl sulfides 16a and 17a. Purification by column chromatography on alumina (neutral, activity III, gradient from hexane to 70% ether/hexane) -49- gave a colorless oil (1.07 g, 76%): IR (CC1 ) 2995, 2950, 4 2870, 1455, 1430, 1375, 1365, 1270, 1197, 1162, 1097, -1 1 9 6 7 , 8 7 0 , 8 5 0 cm ; H- NM R (CC 1 ) o 5 . 5 3 ( t , 0 . 5H , J = 4 6.5 Hz, (E)-vinyl), 5.09 (t, 0.5H, J = 7 Hz, (Z)-vinyl), 3.50-4.14 (m, 6H, -OCH- and -OCH-) 2 ' 1.90-2.40 (m, 4H, allylic CH -), 1.40-1.85 (m, l0H, -CH -), 2 2 1.42 (s, 6H, acetonide CH ), 1.35 (m, l0H, -CH -), 1.42 2 3 13 (s, 6H, acetonide CH ), 1.35 (s, 6H, acetonide CH ): c3 3 ?\~IR (CDC1 3 ) o 129.8, 122.2, 97.8, 68.5, 68.2, 67.8, 59.7, 36.6, 36.0, 35.7, 31.3, 29.9, 24.7, 24.2, 23.9, 19.2, 14.7. Exact mass (75 e\' ) ~/~, calcd. for Found: c 20 H36 o4 s: 372.233. 372.235. (2R*,8R*)-2,8-Bis-(2-hydroxyethyl)-l,7-dioxaspiro[5.5]- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-~-~ undecane (4) and (2R*,8~*)-2,8-Bis-(2-hydroxyethyl)-l,7- ~~~~~~~~-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ dioxaspiro[5.5)undecane_(l8). The title compounds were prepared from vinyl sulfides 16a and 17a as for the preparation of spirane 5. and Hydrolysis of vinyl sulfides 16a !Z~ (1.07 g, 2.88 mmol) and purification by chromatog- raphy on alumina (neutral, activity III, gradient elution from ether to 3 % methanol/ether) gave (2R*,8R*), spirane 4 (0.317 g, 44.5%), mp. 97-98°C (hexane): IR (CC1 ) 4 3600-3100, 2930, 2860, 1430, 1275, 1195, 1140, 1110, -1 1 1085, 1075, 1050, 1030, 970, 900 cm ; H-NMR (CDC1 3 ) o 3.80-4.20 (m, 6H, -OCH - and -OCH-), 3.17 (broads, 2H, 2 13 -OH), 1.31-2.00 (m, 12H, -CH2-); c-NMR (CDCl3) o 96.0, - 5 0- 66.8, 59.4, 38.4, 35.1, 31.1, 19.0. (2R*,8S*) Spiroketal 18 (20%) as an oil: IR (CHC1 ) 3 3610, 3600-3200, 2000, 2940, 2870, 1440, 1375, 1080, 1055, 1 1 900 cm- ; H-NMR (d 6 -DMSO)o 3.80-4.20 (m, 4H, -OCH-, -OH), 3.60 (t, 2H, J = 7 Hz, -OCH2-), 3.45 (t, 2, J = 7 Hz,OCH2), 1. 0 0 - 2 . 0 0 (m , 1 H, - CH 2 - ) ; l 3C- NM R (CD C1 ) o 9 7 . 8 , 7 2 . 5 , 7 0 . 3 , 3 60.8, 60.6, 38.0, 36.0, 30.9, 30.7, 28.3, 19.5, 16.3 Anal. calcd. for c13 H24 o4 : C, 64.1 ; H. 9 .6. , C, 63.9; H, 9.9. Found: (2R*, 8R*)-2, 8-Bis- [ ( 4B*)- 2, 2-dimethyl-l, 3- dioxacyclo- ~~ ~~ ~~~~~~~~~~~~~~~~ ~~ ~~~~ ~ ~~~~~ ~ ~~~~~ ~ ~~~~ ~ ~~~~~~~ ~ hex-4-yl]-5-nonanone (25) and (2B*,8~*)-2-[(4R*)-2,2 - ~~ ~ ~ ~ ~~ ~ ~ ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~!~r!:!t~:~~~~~~r~!~0~~:i:r!l:~:Il~~~2:~t~:~~~~!~r!: 1,3-dioxacyclohex-4-yl]-5-nonanone. A 50 % oil dispersion of lithium powder containing 2% sodium as an amalgam was placed in a three-neck, 50-mL, round-bottomed flask under an argon atmosphere and oil removed by washing with ether (4 x 20 mL). The powder (0.33 g, 47.5 mrnol) was suspended in ether (10 mL), cooled to -10°C and bromide !i~ (2.3 g, 9.1 mmol) was added in ether (10 mL) over 0.5 h. Stirring was continued for 2 h (analysis by GLC, 5% SE-30). The purple colored sus- pension was cooled to -20°C and carbon dioxide gas was passed through the reaction for 2 min (ca. 50 mL/min). The reaction was quenched by slowly adding it to -51- vigorously stirred ice-cold water (50 mL). Extraction with ether (80 mL), drying (Na so ), 2 4 filtration and removal of solvent gave a yellow oil. Bulb-to-bulb distillation at 180°C (.03 mm) gave 1.01 g (60 %) of a colorless oil: IR (CC1 ) 2995, 2975, 2870, 4 1712, 1456, 1378, 1368, 1270, 1240, 1197, 1098, 970, 804 cm -1 1 H- NMR (CCl4)6 3.87 (t, 2H, J (d, 2H, J = 3.2 Hz, 2.37 (t, 4H, J = 3 Hz, -OCH2-), 3.72 -OCH2-)' 3.34-3.72 (m, 4H, -OCH-), = 6.5 Hz, -COCH -), 1.1-1.91 (m, l0H, 2 -CH- and -CH -), 1.36 (s, 6H, ac·etonide CH ), 1.26 (s, 6H, 3 2 13 acetonide CH ), 0.86 (d, 6H, J = 5.5 Hz, -CH ); c- NMR 3 3 (d -acetone) 6 6 221.7, 98.3, 72.7, 60.2, 40.6, 38.1, 30.2, 28.9, 27.0, 19.5, 14.8. Exact mass (75 eV) !!!_/~, calcd. for c 22 H o , M-CH : 10 5 3 369. 264. Found: 369. 264. Treatment with 10% hydrochloric acid/THF at 25°C gave spiroketal ~' as characterized above. £~~:l:!:~~~~~:~:I£±E~l:~t~:~!~~!~t!:lt~:~~~~~~t~l~r~~!~ 4-yl]propane (20b). --~~~~~~ ~ ~~~~~~~~~ method of Servis. 32 The title compound was prepared by the Reaction of alcohol ~2~ (5.9 g, 36.8 mmol) gave bromide~~~ (7.06 g, 86%), bp. 54°C (4.0 mm). ~~Ell~!~= IR (neat) 2980, 2956, 1455, 1350, 1212, 1 1170, 1057, 958, 850 cm- ; 1 H-NMR (CDC1 ) 6 4.10 (d, 2H, 3 J = 6 Hz, MSOCH 2 -), 3.87-4.18 (m, 2H, -OCH -), 3.452 3.84 (m, lH, -OCH-), 2.99 (s, 3H, -sO2CH3), 1.67-2.28 -52(m, lH, -CH-), 1.37 (s, 3H, acetonide CH ), 1.30 (s, 3H, 3 acetonide CH 3 ), 1.01 (d, 3H, J = 7.5 Hz, -CH ); 13 c-NMR 3 (CDC1 3 ) 6 108.5, 75.6, 71.4, 66.7, 37.0, 35.9, 26.3, 25.0, 11.4. Exact mass (75 eV) ~/~, calcd. for C9H o s: 18 5 Found: 2 3 8 . 0 8 7 . Bromide: Distillation at 73°C (.04 mm); 238.089. IR (neat) 2980, 2935, 2875, 1450, 1375, 1365, 1254, 1210, 1150, 1060, 1 1000, 850 cm-l; H-NMR (CDC1 )o 4.06 (A B pattern, 2H, 3 2 -OCH 2 -), 3.54-3.78 (m, lH, -OCH- ), 3.00-3.52 (A B pattern, 2 -CH2Br), 1. 90 (m' lH, - CH-) , 1. 40 (s, 3H, acetonide CH ) , 3 1. 33 ( s ' 3H, acetonide CH ), 1. 07 (d, 3H, J = 6.9 Hz, 3 - CH ) ; 13 C- NMR (CDC1 ) 6 108.8, 7 7. 3, 66.9, 38. 6, 36.4, 3 3 26.3, 25.2, 14.4. Anal. calcd. for C H15 BrO 2 : 8 Found: C, 42.85; H, 6.76. C, 43.07; H, 6.8. (ZR* 3R* SR* 6~* 8R* 9R*)-2,8-Bis(hydroxymethyl)- ~~~~t~~~l---t~--t---t~~---~-----------~~-~~--~--- ~t~t~:!Et~~!~t!:!tZ:~t~~~~EtE~l~:~!~~~~~~~~-1~~~2• A THF (20 mL) solution of diethylamine (5.36 mL, 51.8 mrnol) in a three-neck, 100-mL round-bottomed flask (flask 1) equipped with a thermometer, septum, magnetic stirring bar, and nitrogen inlet was cooled to -20°C (internal temperature) and ~-butyllithium in hexane (20.5 mL, 49.8 mmol) was added. After 0.5h, hexamethylphosphoric acid triamide (1 mL) was added followed by the addition of acetone -53- cyclohexylimine (21) 56 (3.31 g, 23.8 mmol) at -20°C. The reaction was warmed to -5°C, stirred for 3 h then cooled to -60°C and bromide 20b (11.0 g, 47.3 mmol) in THF ~~~ (12 mL) was added. Stirring was continued at -60°C for 1 h followed by warming to 25°C for 12 h. To a separate three-neck, 250-mL round-bottomed flask (flask 2) equipped with a septum, magnetic stirring bar, thermometer and nitrogen inlet cooled to -20°C were added 1) diethy~amine (2.69 mL, 26 rnmol) in THF (20 mL) and 2) ~-butyllithium in hexane (10.3 mL, 25.1 mmol). After 0.Sh, the solution was cooled to -50°C (internal). The alkylated imine (flask 1) was cooled to -50°C and transferred into flask 2 by cannula. Flask 1 was rinsed with TP.F (10 mL) which was also transferred to flask 2. The solution in flask 2 was stirred for 1 hat -50°C; then warmed to -5°C for 2 h followed by recooling to -50°C and methyl iodide (1.9 mL, 30.0 mmol) was added. After 1 h the reaction was warmed to 25°C and stirred for 12 h. Hydrolysis of imine 22b was accomplished by the addition of excess concentrated aqueous hydrochloric acid (20 mL) to the cooled reaction mixture followed by heating at reflux for 4 h. The desired spiranes were isolated by ether extraction (4 x 50 mL), drying (Na 2so 4 ), filtration, and removal of solvent in vacuo to afford a yellow oil. Purification by column chromatography on - 54- alumina (neutral, activity III, gradient from ether to 5% methanol/ether) gave two components. The less polar mate- rial (1.0 g, 48%) solidified by trituration with hexane mp. 75-77°C (hexane), was determined to be spiroketal ~~~ by 13 c-NMR analysis and later by X-ray crystallography. The minor component (0.62 g, 30%) was present as a more polar component which was presumed to be spiroketal 23b as a mixture of ketal isomers. fJE~~~-~£~: IR (CC1 4 ) 2980, 2930, 2875, 1650, 1445, .• -1 1 1375, 1365, 1245, 1210, 1158, 1060, 860, 690 cm ; H-N;-lR (CCl4) o 3.45-4.08 (m, 7H, -CHO-, -CH2O-, -CHN-), 2.012.33 (m, 4H, -cH 2 -, alpha to imine carbon), 1.13-1.95 (m, 16H, -CH 2 - and -CH-), 1.32 (s, 6H, acetonide CH ), 3 1.25 (s, 6H, acetonide CH 3 ), 0.93 (d, 6H, J = 6 Hz, -CH 3 ). ~:!~rI~!:~-i~i~~-~~~: IR ccc1 4 ) 2970, 2925, 2830, 1647, 1442, 1370, 1362, 1243, 1205, 1155, 1060, 853 cm -1 ; 1 H-N~lR (CCl4) o 3.32-4.05 (m, 7H, -CHO-, -CH2O-, -CHN-), 1.902.42 (m, 3H, -CH 2 - and -CH- alpha to imine carbon), 1.10-1.90 (m, 16H, -cH 2 - and -CH-), 1.28 (s, 6H, acetonide CH ), 1.23 (s, 6H, acetonide CH 3 ), 0.97 (d, 3H, J = 6.5 3 Hz, -CH ), 0.92 (d, 3H, J = 6 Hz, -CH 3 ), 0.90 (d, 3H, J = 3 6 Hz, -CH 3 ). Exact mass (75 eV) ~/~, calcd. for c26 H47 No 4 : Found: 437.352. 437. 354. ~P!!~~~!!!_~~~: IR (CHC1 3 ) 3600, 3400, 2965, 2925, -55- 1460, 1382, 1368, 1225, 1110, 1075, 1035, 980, 950 cm-l 1 H- NMR (CDC1 ) cS 3.78-4.02 (pi, 2H, -OCH-), 3.40-3.78 (m, 4H, 3 -OCH 2 -), 2.87 (broads, 2H, -OH), 1.05-2.21 (m, 9H, -CH 2 - and -CH-), 0.88 (broad d, 9H, J = 6.5 Hz, -CH ); 3 13 c-r,rMR (CDC1 ) cS 98.0, 71.6, 71.2, 64.4 (two carbons), 3 35.5, 32.8, 29.4, 28.0, 26.5, 26.0, 16.2, 12.2, 11.4. An a 1 . ca 1 c d . for C H 0 : 14 2 6 4 Found : C, 6 4 . 76 ; C, 6 5 . 0 9 ; H , 1 0 . 14 . H, 9 . 9 5 . Mass spectrum (75 eV) ~/~ (rel intensity): 258 (5), 244 (5), 227 (24), 213 (56), 195 (22), 184 (81), 145 (100). Spiroketals ~~~ were isolated as an oil: IR (CHC1 3 ) 3590, 3420, 3000, 2960, 2935, 2875, 1450, 1375, 1210, 1110, 1070, 1015, 980, 945, 900, 720 cm cS -1 ; 1 H- NMR (CDC1 3 ) 3.31-4.33 (m, 8H, -OCH-, -OCH OH), 1.11-2.48 (m, 9H, 2 -CH-,-CH -),0.88 (d, 6H, J= 6.5Hz, -CH ), 0.78 (d, 3H, 2 3 13 J = 6.5 Hz, -CH alpha to spirocenter); c-NMR (CDC1 ) 3 3 cS 110.2, 108.1, 96.0 (indicates three different spiroketal carbons). Equilibration studies on spiroketal 23a. To a solution -----------------------~--~~----------~ of spiroketal ~~~ (0.22 g, 8.4 mmol) in THF (6 mL) was added deuterium chloride in deuterium oxide (2 mL, 38% solution). The mixture was heated at reflux for 18 h. Spiroketal was isolated as -previously described for spirane 23a, to yield a ~~~ white crystalline solid (80%) mp. 75-77°C (hexane): IR (CHC1 ) 3600, 3400, 2230, 2160, 1455, 1380, 1360, 1225, 3 -56- 1125, 1100, 1075, 1030, 980, 915 cm -1 3.42-4.10 (m, 6H, -CH 20-, -CHO-), 3.33 (broads, 2H, -OH), 1.17-2.33 (m, 7-8H, -CH 2 -, -CH-), 0.84 (broad d, 9H, J = 6.5 Hz, -CH 3 ); 13 C-NMR (CDC1 ) o 97.8, 71.5, 71.2, 64.55, 3 64.47, 35.4, 32.6 (triplet), 29.3, 28.0, 26.3, 26.1, 16.1 (broadened), 12.2, 11.4. (5~)-5-Carboxy-oxacyclopentan-2-one (27). To (2S)-- -- ~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~ ~~~ glutamic acid (100 g, 0.68 mol) in water (250 mL) was added concentrated hydrochloric acid (38 %, 96 mL, 1 mol) and the resultant solution cooled to 0-5°C with an icesalt bath. A solution of sodium nitrite (71 g, 1.03 mol) in water (150 mL) was added dropwise during 5 hat such a rate that the temperature did not exceed 5°C. After complete addition, the reaction mixture was warmed to 25°C and stirred 12 h. Concentration under reduced presiure at 40°C gave an oily residue that was dissolved in hot acetone and filtered to remove inorganic salts. Purification gave lactone 27 (65.7 g, 74 %) bp. 155-160°C (0.1-0.2 mm, lit. 150-155°C at 0.2 mm); [a ]D = +12.5° (C = 3.25, ethanol). 3-[(4~-2,2-dimethyl-1,3-dioxacyclohex-4-yl]propanol ~~~~------------------------------------------------ (28). A solution of lactone ~~ (48.3 g, 0.37 mol) in THF (100 mL) was added to a 2-liter, 3-neck,round-bottomed flask equipped with a septum, overhead mechanical stirrer, nitrogen inlet and reflux condenser and cooled to 0°C in an ice-salt bath. Diborane (1000 mL of a 1 M solution - 5 7- in THF) was added slowly. After 50% addition (hydrogen evolution ceases~ the rate of addition was increased. The reaction was heated to reflux for 20 h. Cooling was followed by destruction of excess borane with methanol (300 mL). After a further 5 h reflux, the reaction was con- centrated by atmospheric distillation of THF, methanol and trimethylborate. The residue was redissolved in methanol (300 mL) and evaporated to dryness in vacuo; then benzene (300 mL), acetone [300 mL) and sulfuric acid (1 mL) were added. Stirring was continued for 12 h at which time potassium carbonate (30 g) was added to neutralize the acid. Filtration and removal of solvent in vacuo gave an oil which was distilled at 80-87°C (1 mm) to give 30 g (51%) of a clear colorless oil: IR (CC1 ) 4 3600-3200, 2980, 2940, 2870, 1470, 1450, 1375, 1365, 1245, 1210, 1155, 1050, 848 cm -1 ; 1 H- Ni\!R (CC1 4 )o 3.90-4.30 (m, 2H, -C!i 2OH), 3. 35-3.90 (m, 4H, -OCH 2 -, -OCH-, -OH), 1. 551.90 (m, 4H, -CH 2 -), 1.34 (s, 3H, acetonide CH 3 ), 1.28 13 (s, 3H, acetonide CH 3 ); C-NMR (CDC1 3 ) 6 108.6, 75.9, 69.3, 61.9, 30.3, 29.2, 27.0, 25.7; 1.747, CC1 4 ). Ana 1. ca 1 c d. for C8 H1 60 3 : Found : C, 6 0 . 01 ; 9 . 9 2 . [a]D = +7.1° (C = C, 5 9 . 9 8 ; H, 1 0 . 0 7 . !:~E~~~=~:1£~§2:~r~:~!~:!~r!:!t~:~!~~~~r~!~~~~=~:r!l: -58- EE~P!~~-£~~2- The title compound was prepared by the 32 method of Servis. Reaction of alcohol 28 (12.3 g, 77 rnrnol) gave bromide ~~ (12.12 g, 70%). NMR (CC1 4 ) 6 4. 25 (t, 2H, J = 6. 5 Hz, -S03CH2-), 3.85-4.32 (A2B, 2H, -OCH2-), 3.3-3.6 (m, lH, !jf~Y!e!~: -OCH-), 3.00 (s, 3H, -S03CH3), 1.43-2.20 (m, 4H, -CH2-), 1.37 (s, 3H, acetonide CH 3 ), 1.32 (s, 3H, acetonide CH ). 3 Bromide was distilled at 56°C (0.07 mm) to give a colorless oil (70%): IR (CC1 ) 2_9 80, 2935, 2870, 1455, 4 1430, 1245, 1205, 1150, 1100, 1060, 968, 852 cm- 1 ; 1 H- N!'IR (CCl4) o 3.78-4.18 (A2B, 2H, -OCH2), 2.90-3.61 (m, lH, -OCH-), 3.44 (t, 2H, J = 6.5 Hz, -S03CH2-), 1.34-2.20 (m, 4H, -CH 2 -), 1.33 (s, 3H, acetonide CH 3 ), 1.27 (s, 3H, a c e ton i de CH 3 ) ; l 3C- NM R (CD C1 ) o 1 0 8 . 7 , 7 5 . 1 , 6 9 . 2 , 3 2 . 8 , 3 32.3, 29.3, 27.0, 25.6; [a]D = -1° (C = 1.03, benzene). Exact mass (75 eV) ~/~, calcd. for 207.003, 209.001. Found: c7H12 Bro 2 , M-CH 3 : 207.002, 209.002. 1,7-Bis-[(4~)-2,2-dimethyl-l,3-dioxacyclohex-4-yl]-5~~~~~~~~~---~~ --------~~~~~~~--------------~-------(methylthio)-4-nonene_(30). The title compound was prepared from bromide 29 according to the procedure for vinyl sulfides 16b and 17b. Alkylation of Ogura's reagent 36 (12.6 g, 0.102 mol) with bromide 3~ (45.5 g, 0.204 mol) gave vinyl sulfide 30. Purification (neutral alumina, activity-III, gradient from hexane to 50% ether/hexane) ~£forded a 57% yield of an oil: IR (CC1 4 ) - 5 9- 2980, 2935, 2870, 1450, 1375, 1365, 1245, 1210, 1150, 1130, 1100, 1062, 855 cm -1 1 ; H-NMR (CC1 ) cS 6.35 (t, 0.5H, 4 J = 7.5 Hz, E-vinyl), 5.02 (t, 0.5H, J = 7.0 Hz, Zvinyl), 3.78-4.17 (A 2 B, 4H, -OCH 2 -), 3.38 (apparent t, 2H, J = 9.0 Hz, -OCH-), 2.03-2.48 (m, 4H, allylic CH -), 2 2.15 (s, 3H, -SCH 3 ), 1.30-1.78 (m, 6H, -CH -), 1.32 (s, 2 6H, acetonide CH 3 ), 1.27 (s, 6H, acetonide CH ). 3 Anal. calcd. for c18 H32 o4 : C, 62.75; H, 9.35. Found: C, 63.02; H, 9.20. (2S,8S)-2,8-Bis(hydroxymeth ~l)-l,7-dioxaspiro[S.5]- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~-1~!2· Vinyl sulfide 30 (300 mg, 0.87 mmol) was dissolved in trifluoroacetic acid (2 mL) and water (2 mL); then stirred overnight at 25°C. Benzene (30 mL) was added and water removed by azeotropic distillation. Dilution Kith ether, drying (MgSO 4 ), filtration and solvent removal in vacuo gave 368 mg of crude product. -1 IR (CC1 4 ) 1780 cm . Dissolution in 75% aqueous methanol (10 mL) containing potassium carbonate, refluxing for 3 h; then dilution with water and ether-methylene chloride (1:1) gave, after drying (MgSO 4 ), filtration and evaporation to dryness, 186 mg of an oil. Chromatography (neutral alumina, activity III, gradient from dichloromethane to 5% methanol/dichloromethane) mp. 96.0-96.5°C (ether): IR (CHC1 3 ) 3590, 3600-3200, 3000, 2940, 2870, 1450, 1430, 1380, 1370, 1280, 1220, - 6 0- 1 H- NMR (CDC1 ) 6 3 3.80 (broads, 2H, -OH), 3.20-3.59 (m, 6H, -0CH 2 -, -OCH-), 0.91-2.05 (m, 12H, -CH2-); 13 C-NMR (CDCl3) 6 95.9, 69.7, 1200, 1155, 1080, 1040, 1010, 980 cm-l 66.1, 35.2, 26.4, 18.2; [a]D = +60.5 (C = 0.81, chloro- form). Anal. calcd. for Found: C, 60.75; c11 H22 o4 : C, 61.09; H, 9.32. H, 8.95. Qp!JS~!_P~E!!l_~f-~E!E~~~!~!-!~!2· (+)-a-Methoxy- a trifluoromethyl phenylacetic acid 57 ( 250 mg, 1.05 mmol) in thion y l chloride (2 mL) i,.;as refluxed for two days . Excess thionyl chloride was removed in vacuo and the residue was distilled bulb-to-bulb (125°C, 20 mm) to give the acid chloride: -1 IR (CC1 4 ) 1785 cm . A solution of spiroketal ~! (43 mg, 0.2 mmol) 1n pyridine (1 mL) Kas reacted Kith the acid chloride (132 mg , 0.52 .mmol) in carbon tetrachloride (1 mL). After stirring 12 hat 25°C the reaction mixture was diluted with ether (3 mL) and filtered through alumina (neutral, activity III) to give the diester: IR (CC1 4 ) 2950, 1751, 1450, 1270, 1243, 1187, 1172, 1125, 1022, 9 9 0 , 7 2 0 , 6 9 5 cm - l ; l H- NJ\ IR ( CC 1 4 ) 6 7 . 1 7 - 7 . 6 7 ( m, 1 0H, Ar ) , 4.16 (d, 4H, J 3.66-4.16 (m, 2H, -OCH-), 19 3.52 (s, 6H, -OCH 3 ), 1.16-1.80 (m, 12H, -CH 2 -); F-NMR (207 MHz) gave two singlets separated by 9 Hz in a ratio of 9:1. [aJ; 2 of spiroketal used was +55.6° (C = 0.1 g/ = 5 Hz, -OCH 2 -), -61- mL, CHC1 3 ). spiroketal. Therefore [a]D22 = +69.5° for optically pure -62- References and Notes 1. C. Moore and B. C. Pressman, Biochem. Biophys. Res. Co mm u n . , 1 5 , S 6 2 (19 6 4 ) . 2. K. 0. Hodgson, Intra-Sci. Chem. Rep., ~' 27 (1974); M. R. Truter, Philos. Trans. R. Soc. London, Ser. B, • 272, 29 (1975); J. W. Westley, Adv. Appl. Microbial., 22, 177 (1977). 3. M. 0. Chaney, P. Y. Demarco, N. D. Jones, and J. C. Occolohitz, J. Am. 4. Chem. So.c., 96, 1932 (1974). J. K. Westley, R. H. Evans, W. T. Williams, and A. Stempel, J. Chem. Soc., Chem. Commun., 71 (1970). 5. A. Agtarap, J. W. Chamberlain, M. Pinkerton, and L . Ste in r au f , J . Am . Chem . Soc . , 8 9 , S 7 3 7 (19 6 7 ) . 6. A. T. Phillipson, Ed., "Physiology of Digestion and Metabolism in the Ruminant," Oriel Press, Boston, 19 70 , pp. 408-410. 7. (a) B. C. Pressman, Role Membr. Metab. Regul. Proc. Symp., 149 (1972); (b) B. C. Pressman, Fed. Proc. Fed. Amer. Soc. Exp. Biol., 32, 1698 (1973); (c) A. H. Caswell and B. C. Pressman, Biochem. Biophys. Res. Commun., 49, 292 (1972); (d) A. Scarpa and G. Inesi, FEBS Lett., 22, 272 (1972). 8. D. R. Pfeiffer and H. A. Lardy, Biochemistry, 15, 935 (1976). - 6 3- 9. (a) A. L. Lehninger, Biochemistry, ~~~' 129 (1970); (b) R. J. P. Williams, Biochem. Soc. Symp., (1974); ~~' 133 (c) N. B. Thoa, T. L. Costa, J. Mass, and I. J. Kapin, Life Sci., ~~' 1705 (1974); (d) R. A. Steinhardt and D. Epel, Proc. Natl. Acad. Sci., U.S.A., I! , 1 91 5 (19 74 ) ; ( e ) D. T . \fang , J . R. Wi 1 kens on , R. L. Hamill, and J.-S. Horng, Arch. Biochem. Biophys., 156, 578 (1973); (f) V. C. Maino, N. M. Green, and ~I. J. Crumpton, Nature, 251, 324 (1974); (g) R. N. Zahlten, F. W. Stratman, and H. A. Lardy, Proc. Natl. Acad. Sci., U.S.A., 70, 3213 (1973); (h) D. R. Holland,~!. I. Steinberg, and W. McD. Armstrong, Proc. Soc. Exp. Biol. Med., 10. ~~~' 1141 (1975). R. L. Hamill, M. German, R. M. Gale, C. E. Higgins, and ~1. M. Hoehn, Abstracts, "12th Interscience Conference on Antimicrobial Agents and Chemotherapy," Atlantic City, September 26-29, 1972, p. 65. 11. C. M. Deber and D. R. Pfeiffer, Biochemistry, 15, 132 (1976). 12. M. O. Chaney, N. D. Jones, and M. Debona, J. Antibiot., ~~' 13. 424 (1976). G. D. Smith and W. L. Baux, J. Am. Chem. Soc., 98, 1578 (1976). 14. H. Kinashi, N. Otake, and H. Yonehara, Tetrahedron Lett., 4955 (1978). -64- 15. D. E. Donnan, J. W. Parchal, W. M. Nakatsukasa, L. L. Huckstep, and N. Neuse, Helv. Chim. Acta, ~~' 2625 (1976). 16. H. Mishima, M. Kurabayashi, C. Tamura, S. Sato, H. Kuwano, and A. Saito, Tetrahedron Lett., 711 (1975). 17. J. S. Glasby, "Encyclopedia of Antibiotics," John Wiley and Sons, New York, 1976, p. 47. 18. M. von Glehn, R. Norrestam, P. Kierkegaard, and L. Ernster, Fed. Eur. 19. Biochem. Soc., 20, 267 (1972). B. Annoux, ~l. C. Garcia-Alvarez, C. ~1arazano, B. C. Das, C. Pascard, C. Merienne, and T. Staran, J. Chern. So c . , Chern . Co mm u n . , 31 8 (1 9 78 ) . 20. Y. Kato and P. J. Scheuer, Pure Appl. Chern., 48, 29 (1976). 21. J. S. Mynderse and R. E. Moore, J. Org. Chern., 43, 2301 (1978). 22. E. L. Eliel, "Stereochernistry of Carbon Compounds," McGraw-Hill Book Co., Inc., New York, 1962. 23. (a) E. L. Eliel and C. A. Giza, J. Org. Chem., 33, 3 7 5 4 (19 6 8) ; Effect: ( b) W. A. Szarek, Ed. , "An om er i c Origin and Consequences," American Chemical Society, Washington, D. C., 1979. 24. M. Gelin, Bahurel, and G. Descotes, Bull. Soc. Chim. France, 3723 (1970). 25. D. A. Evans, C. E. Sacks, R. A. Whitney, and N. S. - 6 5- Mandel, Tetrahedron Lett., 727 (1978). 26. The syntheses of 4 and 31 were carried out by Dr. R. A. Whitney. 27. E. J. Corey, J. A. Katzenellenbogen, N. W. Gilman, S. A. Roman, and B. W. Erickson, J. Am. Chem. Soc., ~~' 5618 (1968); J. Org. Chem., 28. J. A. Sousa and A. L. Bluhm, ~~' 108 (1960). J. S. Brimacombe, D. Portsmouth, and M. Stacey, J. Chem. Soc., 5614 (1964). 29. H. C. Brown, "Organic Synthesis Via Boranes," John Wiley and Sons, New York, 1975. 30. H. C. Brown and N. M. Yoon, J. Am. Chem. Soc., 99, 5516 (1977). 31. C. M. MacCloskey, Adv. Carbohydrate Chem., 12, 137 (1957). 32. R. V. Crossland and K. L. Servis, J. Org. Chem . , 35, 3195 (1970). 33. J. P. Collman, S. R. Winter, and D. R. Clark, J. Am. Ch em . Soc . , 9 4 , 1 78 8 ( 19 7 2 ) . 34. Y. Masuyamo, Y. Ueno, and M. Okawara, Tetrahedron Lett., 2967 (1976). 35. D. Seebach, N. R. Jones, and E. J. Corey, J. Org. Chem., 36. 22, 300 (1968). K. Ogura, M. Yamashita, M. Suzuki, and G. Tsuchihashi, Tetrahedron Lett., 3653 (1974); G. Schill and P. R. -66- Jones, Synthesis, 117 (1974). 37. J.-F. Biellmann, H. d'Orchymont, and J. L. Schmitt, J. Am . Chem. Soc., 101, 3283 (1979). 38. E. J. Corey and J. I . Schulman, J. Org . Chem., 35, 777 (1970). 39. For other examples of 1,7-dioxaspiro[5.5]-undecane formation see: J. C. Chabala and J. E. Vincent, Tetrahedron Lett., 937 (1978); T. M. Cresp, C. L. Probert, and F. Sondheimer, ibid., 3955 (1978). 40. The structure was solved by direct methods using Multan 74 and refined by full-matrix least squares to a final R value of 0.065. N. S. Mandel and G. S. Mandel, manuscript in preparation. 41. W. E. Gore, G. T. Pearce, and R. M. Silverstein, J. Org. Chem., 42. ~2, 1705 (1975). E. J. Corey and J. I. Schulman, J. Org. Chem., 35, 777 (1970); T. Mukaiyama, K. Kamio, S. Kobayashi, and H. Takei, Bull. Chem. Soc., Japan, 45, 3723 (1972). 43. R. E. Ireland, P. Bey, K.-F. Cheng, R. J. Czarny, J.-F. Moser, and R. I. Trust, J. Org. Chem., 40, 1000 (1975). 44. H. Gilman, F. W. Moore, and 0. Baine, J. Am. Chem. Soc., ~~' 2479 (1941); !~, 1 (1970). M. J. Jorgenson, Org. Reactions, -67- 45. E. J. Corey and D. Enders, Tetrahedron Lett., 3 (1976). 46. T. Cuvigny, M. Larcheveque, and H. Normant, Justus Liebigs Ann. Chern., 719 (1975). 47. H. B. Kagan and T.-P. Dang, J. Am. Chern. Soc., 94, 6429 (1972); ~~~' 48. F. D. Fryzuk and B. Bosnich, ibid., 5491 (1978). S. C. Peacock and D. J. Cram, J. Chern. Soc., Chern. Commun., 282 (1976). 49. H. Plieninger, 0. Ege, R. Fischer, and W. Hoffman, ~~' Chem. Ber., 2106 (196l) f C. Eguchi and A. Kakuta, Bull. Chern. Soc., Japan, 47 , 1704 (19 74). SO. C. F. Lane, Aidrichirnica Acta, 8, 20 (1975); S. Krishnamurthy and K. L. Thompson, J. Chern. Educ., 54, 778 (1977). 51. D. Seebach, ~I. Braum, and N. DuPreez, Tetrahedron Lett., 3509 (1973). 52. R. Grubbs, studies in progress. 53. Manuscript accepted for publication, J. Am. Chern. Soc. 54. S. C. Watson and J. F. Eastham, J. Organomet. Chern., ~' 165 (1967). 55. J. J. Pappas and W. P. Keaveney, Tetrahedron Lett., 4273 (1966). 56. E. P. Kyba, Org. Prep. Proc., ~' 149 (1970). 57. J. A. Dale, D. L. Dull, and H. S. Mosher, J. Org. Chem., ~~' 2543 (1969). -68- CHAPTER III Synthesis of A-23187 -69- Introduction Having confirmed in models that control of the stereochemistry of c10 and c18 of diol ~ would ensure closure to the correct c14 spirane configuration for A-23187 (la) and further, that the configuration of the methyl at c15 could be equilibrated during the acid-catalyzed closure of diol ~' we planned to utilize these results for the total synthesis of A-23187. Since we desired both a conver gent and an asymmetric synthesis (so that the absolute configuration of A-2318 7 could be assigned 1 ) we initially investigated the synthesis of diol ketone 3 and heterocycle 4 resulting from disconnection of the c12 -c 13 bond as depicted in Scheme I. Subunit 4 was a likel y candidate for chiral synthesis from chiral hydroxy2 butyric acid 14 (detailed in a later section). Resolution of la could then be accomplished by separation of diastereomers without requiring further chemical modification. The synthesis of 3 posed an interesting problem being confronted increasingly more often in organic synthesis, • an acyc 1·1c unit. • 3 name 1 y, contra 1 o f asymmetry 1n 0 ur strategy was to use a ring to control stereochemistry and then to free the desired acyclic piece. chose diol 5 as our immediate target. Accordingly, we Desulfurization would then yield acyclic~ (R 1 = R2 = H). -70- Schem~_! --~-- lo, R=H -lb, R = CH3 l 3 S CH 3 , , X! /CH3 HO H OH H , 5 - 71- Discussion of Alkylation Approach ~~~-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Starting from the known thiacyclohexanone 6b, 4 the enamine 7 was formed by standard methods. 5 Conversion to the olefin~ was conveniently done in one pot, without isolation of intermediates, by treatment ·of enamine 7 5 with methyl acrylate followed by hydroboration of enamine 6 8. Acid-catalyzed elimination 6 of the intermediate a-amino alkyl borane gave olefin 9 in a 64% overall yield 7 from 6b. Saponification quantitatively gave the desired acid 10. Scheme II summarizes the above sequence. We now faced the problem of introducing the elements -CH 2OH and -OH across the double bond in a regio- and stereospecific fashion. Our initial plan was to utilize the acid side chain to direct attack 8 by an incoming electrophile as in equation 1. The lactone could then 0 HO~Hz I H 'b 0 (1) 5 0 9 0 " b, R = H ~~ . OCH 3 6a, R = C02Me c)R Scheme II 7 6 ► Q 10 ~OH 0 ► ► 8 Oo ~ S b, R = CH lla, R = H 0 JillY o.._..o s OCH3 . 3 OR I -..J N - 7 3- be methylated and treated with methyllithium 9 to give diol 5. Unfortunately, reaction of several electrophiles 12 (POC1 3/DMF,lO CH 3 COC1/A1C1 3 , 11 or Br 2 ) with the acid 12, or the derived amide or ester, failed to y ield any lactonic material. Likewise, attempted 1,3-dipolar 13 Th e • • f ai• 1 e d to give • • eye 1 oa dd itions any reaction. explanation for these ne gative results may be that the sulfur in 10 complexed with electrophiles to form 10', in which the olefin was sufficiently deactivated to prevent an y further reaction. This is partiall y sub- stantiated by the failure of attempts to cyclopropanate 14 similar systems with dichlorocarbene. Gaining some OH 0 (2) encouragement from a literature report that the Prins reaction in aqueous media was successful for a system similar to ours 15 (eq 2), we attempted to apply it to 10. -74- Treatment of 10 under standard Prins conditions 16 led to the isolation of small amounts of a crystalline material which we identified as lla. After many attempts, we optimized the yield of lla at approximately 25% by use of very carefully controlled conditions. Temperature and concentration as well as the scale of the reaction were found to be crucial factors in controlling the yield (see experimental). Esterification of the acid gave an oil, llb, which could be purified by careful chromatography on a Waters' Prep 500. The formation of the dioxane, rather than a diol, probably arises from the high concentration of formaldehyde used giving formaldehyde dimer 17 as the active electrophile rather than free monomer. Regio- and stereochemical assignments for llb were made by proton and 13 c-NMR analysis of llb and the desulfurized ester (12b). 18 13 c-NMR spectra indicated that both llb and 12b were diastereomerically homogeneous. The proton spectrum 19 of!!~ (Figure 1) revealed a proton (3.85 6) which was coupled to only two other protons (H 17 and H19 ). From the chemical shift and integration, this signal was determined to be a methine proton with an ~-oxygen. This confirmed the regiochemistry as that shown in llb since in the other regioisomer the corresponding proton would be coupled to three protons. Also, desulfurization did not effect the chemical shift -75- Scheme III (~'l,,, ~ I 0.,_,,6 ~OR 0 lla, R = H b, R = CH 3 12a, R = H b, R = CH 3 CH3 ~H3 CH 3 0 ~CH3 o....__......6 o 13 of this proton (Figure 1), consistent with structure !!~ (one might expect a shift in the regioisomer since desulfurization would correspond to the loss of a S-sulfur atom). The stereochemistry was assigned by analysis of the coupling constants of H18 to H17 and H19 and 12b. in~~~ In llb, the coupling constants are 2.7 and 11.1 Hz, consistent with one trans-diaxial coupling and one cis-coupling (or trans-diequatorial). Removal of sulfur yields a compound which retains the diaxial coupling Figure 1. 0'-./0 ~H3 9 0 MI-I z Proton Spec tr a of 11 b and 1 2 b . 5.0 6 A Ji OCH3 llb 14 OCH3 I I °' ---i - 77- constant virtually unchanged (11.4 Hz) indicating it is probably present in the dioxane ring. The other coupling constant increases to 4.8 Hz from 2.7 Hz, consistent with a coupling between a ring proton and an acyclic proton. All these data, plus the fact that the Prins reaction is known to proceed with high trans selectiv16 ity, b,l 7 , 20 is consistent with the structure shown for llb. Three steps remained to convert 12b to 3: of the methyl group at introduction c15 , conversion of the ester to a methyl ketone and hydrolysis of the dioxane. The hydrolysis could be accomplished in quantitative yield by the method of Ness 21 but was postponed since the methylene acetal protecting group was useful to mask the dial function during subsequent transformations. Introduction of the two required methyl groups was readily accomplished in one pot from acid 12a. Hydrolysis of ester 12b by treatment with potassium hydroxide in methanol was • • Th en, 1n • one pot, t h e d 1an1on • • 22 was quant1tat1ve. generated, quenched with one equivalent of methyl iodide and treated with methyllithium 23 to give methyl ketone 13 (Scheme III) in a 59% overall yield from ester 12b (a net yield ·from the known ketone 6 to 13 of 10%). 13 Proton and C-NMR spectral analysis of!~ revealed it to be a 1:1 mixture of diastereomers due to the newly intro- - 7 8- duced asymmetric center at c15 . With the piece corresponding to ketone 3 in hand, we investigated the synthesis of heterocycle ~- Since the required aromatic acid was not available at the time, we chose instead to utilize 2-methylbenzoxazole as a model. 24 From literature precedent, we felt that an aldol reaction of 2-lithiomethylbenzoxazole with aldehyde 17 should give the desired Cram product (!~~). To test this hypothesis, the synthesis of aldehyde 17 was undertaken ( Scheme IV) . Scheme IV ~H3 - (Y OH OH 0 ► ~H3 = rY OR OH fl OR 0 15 14 16 .. 17 R = _!-Bu(Ph)zSi OH -79- Protection of the known chiral hydroxy-isobutyric 2 acid 14 was accomplished by silylation 25 to give the monoprotected acid 15. Reduction with borane-methyl26 sulfide quantitatively afforded the alcohol 16. • Oxidation with Collins Reagent 64% overall yield from 14. 27 gave aldehyde 17 in a Proton NMR examination of alcohol!~ and aldehyde!~ in the presence of tris-(3(heptafluoropropylhydroxymeth y lene)-i-camphorato], 28 europium rrr revealed them both to be enantiomerically pure (Appendix V). Then we investigated the generation of 2-lithiomethylbenzoxazole and its application in the aldol reaction. Surprisingly, little precedent for this kind 29 • • d 1n • t h e 1 1terature. • o f anion ex1ste Af ter some experimentation, we found that the success of the aldol depended on maintaining the anion at temperatures belo~ -60°C, otherwise it degraded. Meyers has observed 30 similar degradation with simple lithiooxazolines, but only at higher temperatures. Disappointingly, the aldol reaction (Scheme V) was non-selective, giving an 85% yield of a 1:1 mixture of the Cram (19a) and anti-Cram (18a) products. Ster_e ochemical assign- ments were made by converting the separated alcohols, high Rf and low Rf, into two conformationally locked acetonides, A and B respectively, via desilylation with - 8 0- fluoride 31 and ketalization of the dials with acetone in the presence of E-toluenesulfonic acid. Application of the results from proton Nr-IR studies of similar 19b 32 systems ' and proton NMR analysis of A and B (Figure ~ ~ 2) allowed us to assign the anti - Cram aldol product (!~~) as the high Rf component and the Cram product (19a) as the low Rf component. Specifically, the ~ c11 -methyl resonance for was upfield (closer to TMS) from the corresponding resonance for~ implying that the methyl was equatorial i· n A and axi·a1 i·n B. 19 b s·irni·1 ar 1 y, t h e met h"ine proton, H11 , in~ was downfield from H11 in~ indicating that H11 • 1 in • A b ut equatoria • 1 in • B , l 9b consistent • · h was axia wit the observations for the methyl resonances. Further, the methine proton H10 of acetonide ~ appeared as the X part of an ABMX pattern with a value for J 10 , 11 of 12.6 Hz (by computer analysis), consistent with a trans-diaxial coupling. The corresponding value in~ was 7.2 Hz, con- • • h an axial-equator1a • • 1 coup 1·1ng. l 9 a sistent wit Ana 1 ys1s • of the chemical shifts and coupling constants for the axial and equatorial protons at c12 was also consistent with the structural assignments of A as anti-Cram derived acetonide 20 and Bas Cram derived acetonide 21. All of these observations are summarized in Tables 1 and 2. Next, we briefly explored methods to increase the yield of 19a. Changes of counter-ion from lithium to -81- Scheme V 17 + 0 LiCH2---{ N~ 'rry l + ~H3 12 11 ~ : : r g o I OR 18a, R = !-BuPh 2Si ~ OH I N 0 19a, R = !-BuPh 2Si b, R = H b, R = H I H + CH3tot\' H 0~1 1CH 20 21 3 -82- Table 1. Chemical Shift Analysis of 20 and 21. Proton Methyl at c11 Conclusion A B 0.80 1.13 equatorial methyl in A axial methyl in B 1. 77 1. s s axial in A equatorial in B !rn ppm relative to tetramethylsilane internal standard, CDC1 3 soln, 90 :-lH:. field strength. Table 2. Coupling Constant Data of 20 and 21. Potons Coupled A B a (Hz)- J Conclusion HlO-Hll 12. 6 trans-diaxial Hll-H12 eq 6. 0 axial-equatorial H11 ·-H12 ax 10. 2 trans-diaxial HlO-Hll 2. 6 axial-equatorial Hll-Hl2 eq 2. 7 equatorial-equatorial Hll-H12 ax 1.5 axial-equatorial !By computer modeling. -84- zinc as well as variation in temperature and solvent 24 , 32 33 gave no improvement in the ratio of!~~ to !~~. Dispensing with attempts at optimization, we turned our attention to the formation of the c12 -c 13 bond. Encouraged by 'studies done by Stork 34 and Normant, 35 we believed that alkylation of the imine anion derived from 13 would afford the best yields of the desired mono-alkylation product corresponding to 2. Accordingly, 19b was converted to Scheme VI c;H3 + 22 = ,oJCJ--...:: N x~ ,..-; OR 23a, X = OTs, R = H b, X = OTs, R = C H 0 5 9 = X = I , R C H C' 5 90 ~' X = I , R = H l ~H3 ~~)) OH 24 25 - 8 5- 36 and the secondary hydroxyl was protected 37 • as a THP et h er to give tosy 1 ate 2 3b . In order to study tosylate ~~~ the alkylation reaction, imine 22 was used as a model. 35 Reaction of the imine anion derived by reaction of 22 38 and LDA with either tosylate 23b or iodide 23c led only to the elimination product 24 (Scheme VI). Reasoning that if OTHP were converted to a poorer leaving group the elimination reaction might be prevented, we converted iodide 23d (from 23a 38 ) to an alkoxide with sodium hydride. Unfortunately, after treatment with the anion of 22 only alcohol 25 and a small amount of diene 24 were isolated. Alcohol~~ probably arises by initial formation of oxetane 26 followed by proton transfer and elimination. 25 26 At this point, faced with a poor ratio in the aldol reaction and a low yield in the Prins reaction as well as difficulties with the final alkylation we decided to abandon further investigation of this approach to A-23187. -86- Rather, we turned our efforts toward the aldol approach outlined in Scheme VII. Discussion of Aldol Approach ~~~~~~~~~~~~--~~~~~~~~~~~~~~ As in our previous approach, we again visualized that closure of dial~ would give A-23187. Retrosynthetic aldol disconnection between c9 -c 10 and c18 -c 19 gave heterocyclic subunits~~ (R 1 = Hf and~~ (R 4 = H) and the ketone 27 which possessed a c 2 -axis of symmetry with respect to skeletal carbons c10 -c 12 and c16 -c 18 (Scheme VII). We felt that a chiral synthesis of 27 from chiral subunits 29 and 30 should be straightforward (Scheme VIII). 39 , 40 Also, literature precedent indicated that the aldol of the benzoxazole anion derived 24 32 from 28 should favor the Cram product. ' (The ratio 40 was found to be 4:1, Cram/anti-Cram. ) Therefore, the success of the synthetic sequence seemed to hinge on whether an aldol reaction would establish the correct configurations of c18 and Cl9 relative to each other and 41,42 To this end, we decided to pursue relative to C17· model studies designed to answer that question. In the model studies we needed to investigate two problems: could the relative configurations of -87- la, R=H lb, R = CH3 1 1 ~ H 0 26 JJ_ 28 -88- Scheme VIII ~H3 ~I CH 3 .l._ - .;,CH n PhS.,, R3Si O 3 - 29 NNMez -- 31 32c, b, X = SPh )( = H H X R 3 Si0 - 27 a, OCH 2 Ph x = NNMez ~• _£, X =0 £, X = C(Me) 2(CH 2 0) 2 - b, 0 0 R 3 Si0 X OH I~ /2 N X'"H,OH X =0 NMe(COCF3) C0 2 Me 34 l R 3 Si0 R 3 Si0 CH 3 1-...;:: (CF 3CO)MeN 0 ~ C0 2Me N - 35 (CF 3CO)MeN ~ C02Me y - N - 36 H3 - 8 9- c18 -c 19 (threo vs erythro, threo desired) be controlled and could the relative configurations of c17 -c 18 (Cram vs anti-Cram, Cram desired) also be established. Initially, we studied the threo-erythro problem by using benzaldehyde as a model. We hoped that the known pyrrole 26 could be used, thereby avoiding the necessity of incorporating and later removing a protecting group . 42 Usin g as an analogy the studies done by House (in which he used the zinc enolate to_ obtain the thermodynamically favored threo product), we examined the zinc enolate of 26 (R = Zn) as shown in equation 3. As can be seen from Table 3, this was not a satisfactory solution since the ervthro product predominated. ~\Y3 R OZnCl 26 (R = H) CH 3 PhCHO Ph 0 erythro OH Ph 0 --OH (3) threo The ratio of threo/erythro was independent of counterion (Zn vs Li) and was constant with time and temperature implying that the dianion probably forms a kinetic product 44 (enriched in erythro) which cannot equilibrate to the thermodynamically more stable threo product. In -90- Table 3. Aldol Studies of Threo vs Erythro Selectivity. PhCHO Temp Pyrrole R (°C) 1. 26 Zn -78 2. 26 Zn 4 3. 26 Zn 4. 26 5. ZnC12 (equiv) Ph a Solvent- Threo/ErythroE. A 1:3.0 0. 5 B 1:3.1 4 0.5 C 1:3.2 Zn 4 1.0 C 1: 1. 8 37 C BzO- 4 1.0 C 1: 1. 6 6. 37 BzO 4 1.0 D 1:1 7. 37 BzO 4 2. 0 D 1: 1 8. 38 d t-BOC- -78 B 1: 3 9. 38 t-BOC 4 1.0 B 1: 1 10. 38 t-BOC 4 1.0 C 3:1 11. 38 t-BOC 4 1.0 D 3:1 ~A= THF, B = ether, C = ether/dimethoxyethane (1:1), D = ether/dimethoxyethane (1:2). -OCH- doublets. E.By NMR integration of the C -Benzyloxyrnethyl. d -!-Butoxycarbonyl. -91- an attempt to solve the problem of non-equilibration of the dianion, we decided to investigate N-protected pyrroles. Since the ketalization step to close diol 2 would be acid catalyzed, we wanted to use a protecting group which would be removed under acidic conditions but stable to the conditions necessary for the aldol reaction. 45 Pyrrole ketones 37 and 38 (readily available from 26 ) were chosen to fulfill these conditions. Initial experiments with benz~ldehyde indicated that 38 gave the best threo/erythro ratio (ca. 3:1). WCH3 l b 0 4 ~\T3 H 0 To ~\T3 t-BuO Ao 0 ~Ph 37 26 38 determine the effect of an asymmetric center next to the aldehyde (ie. Cram vs anti-Cram), we chose aldehyde 39 44 b, 46 as a model. Condensation of 39 with pyrrole ketone~~ gave the four lactonic products~~~' ~~~' ~~: and ~Q~, in order of elution on analytical HPLC (Scheme IX). Separation of the isomers, analysis of the proton NMR spectra and comparison with analogs of the Prelog- -92- Scheme IX CH 3 HhOCH3 + 38 39 CH 3 ~H3 -- p CH 3 ~H3 p 0 40a 0 40b 0 pry 40c 0 40d p = (¼ t-BuO ~0 O -93- • • 1 actone an d one o f its . . 44b ( 41 an d 42 DJerassi isomers respectively) allowed assignment of 40a as erythroanti-Cram and 40b as threo-Cram. Several reactions were run to optimize the yield of 40b~ the results are tabulated in Table 4. From the results summarized in the ~H3 ~H3 - HO - HOry 41 0 42 0 table, we chose the conditions of experiment 3. Before applying these results to the total synthesis, we investigated the stability of A-23187 to conditions necessary for the removal of the pyrrole protecting Treatment of an authentic sample of A-23187 47 with ion-exchange resin 48 (H+ form) in refluxing toluene 49 group. convinced us of its stability to the conditions necessary for deprotection of the pyrrole. The final steps for the total synthesis are outlined in Schemes X and XI. Treatment of a 4:1 mixture of pyrans 35 and 36 with fluoride ion effected not only silicon ether cleavage but also the removal of the trifluoroacetyl group in approximately 60% yield. Because the deprotected aromatic nitrogen might interfere with the oxidation -94- Table 4. Aldol Studies of Cram vs Anti-Cram Selectivity. CH 3 W R 0 + 0 0 Pyrrole b Solvent- 40a 40b 40c 40d£ 1. 38 A 21 44 21 14 2. 38 B 26 32 19 23 3. 38 C 27 42 19 12 4. R = -t-Bu-OCH 2 - D 24 36 21 20 5. 37 D 20 32 25 23 ~l equivalent. QA= ether/dimethoxyethane (2:1), B = ether/ dimethoxyethane (1:2), C = ether/dimethoxyethane (1:1), D = dimethoxyethane. C -By HPLC. - 9 5- Scheme X R 3 Si0 '7 0 i ""' I,: (CF 3CO)MeN ~oy 0 N {CF 3CO)MeN~N ·• C0 2 Me C0 2 Me 36 35 j H H + X 1/ (CH ) HN 3 r7l(OY I ~ N C0 Me 2 43a, X = H, OH ~' X = 0 (CH 3 ) H N ~ N C0 Me 2 44a, X = H, OH ~' X = 0 -96- Scheme XI 43b 44b + i~~ CH 3 Py CH 3 Py + 0 1/ (CH ) HN 3 fl(OY I : : :. ,_ OH N (CH 3 ) H N ~ N COile Py = H C 3 C0 Me 2 0- cH 3 ~oAo CH 3 ¥ ~0:::-----1 . H CO R 0 H la, R = H b, R = CH 3 2 NHCH 3 -97- of alcohols!~~ and~~~' we first investigated the stability (~ = H) (obtained from~~' R3 = COCF 3 , by fluoride treatment) to conditions of a Collins . 27 Since 28 (R = H) was found to be stable, oxi. d ation. 3 we proceeded to oxidize the mixture of 43a and 44a (4:1) of benzoxazole ~~ to give aldehydes i~~ and i~~- Condensation of the aldehydes with pyrrole ketone~~ gave an aldol mixture containing all eight possible diastereomers. The crude . h ion-exc . h ange resin . 48 to give . pro d uct was treate d wit a mixture of eight spiroketals now lacking the pyrrole protecting group. Isolation of the major component (ca. 50 50% of the total) afforded a material (18%, overall yield from aldehydes 43b and 44b) identical (IR, 1 H-NMR, 51 MS, [a] 0 , HPLC) with an authentic sample of lb. Cleavage of the methyl ester by treatment with lithio-~52 propylmercaptide gave a crystalline acid in quantitative 1 yield. Synthetic!~, mp 184.5-186°C (lit mp 181-182), a [a] 24 -56° (C = 1.0 g/mL, CHC1 ) 53 was identical in all 0 3 1 13 respects (IR, UV, MS, H-NMR, C-NMR, [a] 0 , mixed mp) to an authentic sample of A-23187 (Table 5). This total synthesis firmly established the absolute configuration of A-23187 as that depicted in structure la. - 98- Table 5. Comparison of Data for Authentic and Synthetic A-23187. . 1, 53 Aut h ent1c 1640 cm UV (ethanol) mass spec (~/~) mp -1 Synthetic 1640 cm -1 1690 1690 204 mµ 208 mµ 224 226 278 279 284-288 (sh) 284-288 (sh) 379 377 523 523 318 318 206 206 123 123 94 94 185-186 184.5-186 -56° -56° - 99- In this chapter, two routes to A-23187 were discussed. The first route was unsuccessful due to low stereoselectivity in an aldol reaction and failure of a key alkylation step. This route was noteworthy, however, in that if the chirality of c were inverted and a methyl group were 18 added to c15 , then acid 13 could be converted to the Prelog-Djerassi lactone i~, 54 a key intermediate in the • o f •1 •• 54a synt h es1s ivet h ym1c1n. HO 0 45 I 111 CH 3 0 The second route, based on two key aldol reactions, was successfully accomplished to afford synthetic A-23187. Since this route started from chiral precursors of known configuration, the completion of the synthesis allowed assignment of the previously unknown absolute configuration of A-23187 as that depicted for!~· Improvement of the second aldol should be investigated to increase the stereoselectivity of that step. -100- General. Diethyl ether, tetrahydrofuran (THF) and 1,2-dimethoxyethane (DME) were dried by distillation from benzophenone ketyl under nitrogen. propylamine Triethylamine diiso- and pyrrole were dried by distillation under nitrogen from calcium hydride. Hexamethylphosphoric acid triamide was distilled from sodium metal and stored over 13X molecular sieves. Dichloromethane was filtered through activity I alumina prior to use. Ion-exchange 48 resin was washed with methanol and methanol removed by azeotropic distillation with toluene immediately prior to use. Methyl acrylate was distilled just prior to use. All commercial alkyllithium reagents were titrated 55 by the procedure of Watson and Eastham. Unless otherwise specified, all reactions were run under an inert atmosphere of nitrogen. Melting points were determined with a Bilchi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded on a Beckman IR-4210 spectrophotometer and are reported in cm -1 . Proton nuclear magnetic resonance spectra were recorded on a Varian Associates EM-390 or T-60 spectrophotometer. Chemical shifts are reported in parts per million on the o scale relative to tetramethylsilane internal standard. follows: Proton data are reported as chemical shift, multiplicity (s = singlet, d = -101- doublet, t = triplet, q = quartet, m = multiplet), inte- gration, coupling constants (Hz) and interpretation. Carbon- 13 nuclear magnetic resonance spectra were recorded on a Varian Associates XL-100 (25.2 MHz) spectrometer and are reported in parts per million on the o scale relative to tetramethylsilane internal standard. Mass spectra were recorded on a DuPont MS 21-492B mass spectrometer at 75 eV. Mass spectral analyses as well as combustion analyses were performed by the California Institute of Technology Microanalytical Laboratory. Analytical gas chromatographic analyses were performed on a Varian-Aerograph Model 1440 gas chromatograph equipped with a flame ionization detector using 2 ~ by 3.18 mm stainless steel columns of 10% Carbowax 20 Mor 10 % SE-30 on 80-100 mesh DMCS Chromsorb W support. Analytical HPLC was performed on a Water's Associates high pressure liquid chromatograph equipped with ultraviolet and refractive index detectors using a 35 mm by 6 mm ~-porasil column. Optical rotations were recorded on a Perkin Elmer 141 polarimeter at the sodium D line. 4 2-(Methoxycarbonyl)-4-thiacyclohexan-l-one (6a). ----------- - ----------~-~--~----~-~~~~~~~~ - ---Commercial reagent grade sodium methoxide (54.2 g, 1 mol) was suspended in reagent grade THF (400 mL) in a threeneck, 500-mL, round-bottomed flask equipped with a mechanical -102- stirrer, nitrogen inlet, reflux condenser and 150-mL constant-volume addition funnel and heated to reflux. Dimethyl-3,3'-thiodipropionate (100 g, 0.49 mmol) in THF (100 mL) was added over 1 h. by GLC (10% SE-30). The reaction was monitored After an additional 0.5 hat reflux the reaction mixture was cooled and THF removed in vacuo. The residue was added to acetic acid (130 mL) in icewater (400 mL). Extraction with ether (4 x 200 mL), washing of the combined organics _with water and saturated sodium bicarbonate (to remove acetic acid), drying (Na 2 filtration and removal of solvent in vacuo gave an oil. so 4 ), Distillation gave a 2.2 g forerun (70-98°C, 1 mm) and a major fraction (98-102°C), 48.5 g (58 %): IR (neat) 2995, 2950, 2900, 2830, 1735, 1650, 1603, 1435, 1350, 1304, 12 5 0 , 12 2 0 , 119 3 , 1104 , 10 6 0 , 8 3 0 , 6 9 0 , 6 7 0 cm -1 1 H- NMR (CDC1 3 ) o 12.16 (s, 0.5H, enolic form) 3.73 (s, 3H, -OCH 3 ), 2.48-3.68 (m, 6.5H); 13 c- NMR (CDC1 3 ) o 203.3, 172.2, 97.2, 58.6, 52.4, 51.7, 43.5, 32.4, 30.7, 30.3, 24.6, 23.4. ~=!~!~~f~!~~~~~~:!:~~~-i~~2· Keto-ester 6a (45.5 g, 0.26 mol) was added to a 500-mL round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser. 10 % Sulfuric acid in water (400 mL) was added and the heterogeneous mixture heated to reflux until carbon dioxide evolution ceased (ca. 3 h). caused formation of a white precipitate. Cooling The mixture was -103 - extracted with ether (4 x 100 mL); then organics were combined, washed with water and dried (Na 2so 4 ). Filtration and removal of solvent in vacuo gave a yellow solid which was sublimed at 85°C (30 mm) to give 23.8 g (80%) of a white solid, mp 62-63°C: IR (CHC1 ) 3025, 2980, 2930, 3 1718, 1430, 1378, 1300, 1299, 1275, 1228, 1130, 980, 655 cm-l 1 H-NMR (CDC1 3 ) o 2.81 (A B pattern); 13 c- NM R (CDC1 ) 2 2 3 o 207.6, 43.9, 30.0. !:~IEE~!!~!~:!:r!:~:!~!~:!:~r~!~~~~~~~~l!~~· Ketone 6b (30.0 g, 0.26 mol) was dissolved in benzene (300 mL) and pyrrolidine (38.7 g, 0.54 mol) was added. The mixture was heated to reflux with azeotropic removal of water. After 5 h (GLC, 10% SE-30) benzene was removed by distillation. The residue was distilled 98-102°C (0.2 mm) to give 39.1 g (90 %) of a colorless air and moisture sensitive liquid: IR (CHC1 ) 2980, 2920, 2870, 2815, 1630, 3 -1 1 1410, 1385, 1345, 1300, 1285, 1165, 1138, 885 cm ; HNMR (CDC1 ) o 4.41 (t, lH, J = 4. 5 Hz, vinyl), 3. 24 (d, 3 2H, J = 4.5 Hz, -SCH 2 - vinyl), 3.00 (t, 4H, J = 7.3 Hz, -NCH -), 2.61 (A B2 , 4H, SCH 2 CH 2 - vinyl), 2.68-2.00 (m, 2 2 4H, -CH2CH2-). Methyl 3-(1-thia-4-cyclohexen-3-yl)propionate (9 ). -~~~~~-~~~~~~~~~~~ ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~ Enamine 7 (32 g, 0.19 mol) in E_-dioxane 56 (200 mL) in a three-neck 1000 mL round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, nitrogen inlet -104- and 150-mL constant-volume addition funnel was heated to reflux. Freshly distilled methyl acrylate (22 mL, 0.25 mol) in £-dioxane (30 mL) was added during 2 h. Reflux was continued an additional 14 h (GLC, · 10% SE-30) followed by cooling to 25°C. Borane-methylsulfide (25 mL, 0.25 mol) in £-dioxane (SO mL) was added (mild exotherm) over 1 h with stirring. After stirring an additional 2 h, the mixture was cooled in an ice bath and propionic acid (56 mL, 0.75 mol) was slowly added (vigorous hydrogen gas evolution at beginning). When the initial reaction subsided, the cooling bath was removed and the mixture was heated to reflux for 9 h (GLC, 10% SE-30). Solvent was then removed in vacuo, the residue taken up in hexane (200 mL), washed with water and brine and dried (Na 2so 4 ). Filtration, removal of solvent in vacuo and distillation at 75-80°C (0.05 mm) gave 25.4 g (72%) of a colorless oil: IR (CC1 4 ) 3015, 2955, 2920, 2880, 1735, 1434, 1320, -1 1 1245, 1210, 1193, 1160, 1020, 690, 680 cm ; H-NMR (CC1 4 ) 6 5.45-5.86 (m, 2H, vinyl), 3.61 (s, 3H, -OCH 3 ), 3.03 (broad d, 2H, J 3 Hz, -SCH 2 vinyl), 2.50-2.78 (m, lH, vinyl CH-), 2.14-2.42 (m, 4H, -SCH 2 -, -CH 2co 2Me), 1.73 13 (t, 2H, J = 6 Hz, -CHC~2CH2); c-NMR (CDCl3) 6 173.4, = 131.2, 124.1, 51.4, 33.9, 31.2, 30.0, 29.6, 25.3. Anal. calcd. for c 9H14 o 2s: Found: C, 58.15; H, 7.70. C, 58.03; H, 7.58. -105Enamine 8: IR (CC1 4 ) 2960, 2880, 2820, 1725 1625, 1434, 1300, 1240-1180, 1170 cm- 1 ; 1H-NMR (CDC1 3 ) 8 4.32 (t, lH, J = 4 Hz, vinyl), 3.66 (s, 3H, -OCH 3 ), 1. 50-3.11 (m, 22H). Anal. (performed on a sample of 8 that had been calcd. for c H o s: 9 14 3 C, 53.20; H, 6.76. hydrolyzed to ketone) H, 6.98. Found: C, 53.44; IR (CHC1 3 ) 2950, 2910, 1725, 1700, 1430, 1365, 131 0 , 1 2 6 5 , 119 0 , 116 5 , 111 0 , 1 01 5 , 9 7 5 , 8 2 5 , 7 3 0 cm - 1 1 H- NMR (CDC1 3 ) 8 3.63 (s, 3H, -OCH 3 ), 2.20-3.01 (m, lH); 13 c-NMR (CDC1 3 ) 8 209.3, 178.8, 52.0, 44.1, 36.0, 31.3, 31.0, 24.5. ~r~E~~l':~~~-~~-:~!:E~~~. Ester 9 (29 .1 g, 0 .16 mol) was dissolved in THF (70 mL) and sodium hydroxide (6.8 g, 0.17 mol) in water (100 mL) was added. The resulting biphasic mixture was stirred 1 h during which time the mixture became homogeneous. TLC (silica gel, 50% ethyl acetate/45% hexane/5% acetic acid) indicated consumption of ester (Rf= 0.55 ). After cooling the reaction in ice it was acidified with concentrated hydrochloric acid to pH 1. The acid was isolated by extraction into chloroform (4 x 100 mL), drying (Na 2so 4 ), filtration and removal of solvent in vacuo to give 18.2 g (100%) of a waxy solid mp. 42-44°C: IR (CHC1 3 ) 3400-2400, 2990, 2910, -1 1 1720, 1700, 1432, 1405, 1270 cm ; H-NMR (CDC1 3 )8 ll.65 -106- (s, lH, -co 2H), 5.42-5.97 (m, 2H, vinyl), 3.00 (broad d, 2H, J = 3 Hz, -SCH 2 - vinyl), 2. 70 (t, lH, J = 8 Hz, -CH-), 2.13-2.52 (m, 4H, -SCH 2 - and -CH 2co 2 -), 1.50-1.95 (m, 2H, 13 -CHCJi2CH2-); c-NMR (CDCl3) 6 179.6, 131.2, 124.4 , 33.8, 31.3, 29.7, 29.6, 25.3. An a 1 . ca 1 c d . f o r C8H1 20 2S : Found: C, 56.25; H, 7.16. C, S 5 . 8 2 ; H, 7 . 0 2 . Methyl 2-(trans-1,8~-cis-6,8-oxa-3-thiaperhydronaphth~~~~~~~~~ - - ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ;~r;2e~~e~~~~!~~l!!~). In each of. two 50-mL round-bottomed flasks was placed paraformaldehyde (9.0 g, 0.30 mol). To each was added H20 (19 mL) followed by concentrated sulfuric acid (7 mL). The resulting mixtures were heated to 100°C and maintained at that temperature for 2 h during which time the formaldehyde depolymerized to give homogeneous solutions. acid 10 After cooling to 70°C, olefinic (5.0 g, 29 mmol) was added to each flask (ie . , total of 10 g of acid). The reactions were maintained at 70°C until consumption of acid was complete (ca. 1625 h) as indicated by TLC (silica gel, 50% ethyl acetate/ 45% hexane/5% acetic acid; product: Rf= 0.56). olefinic acid: Rf= 0.66; The two reactions were cooled, combined, diluted with water (SO mL) and extracted with Drying, (Na 2so 4 ), filtering, and removing solvent gave a crude waxy material which could ether (5 x 40 mL). be purified by medium-pressure chromatography (silica -107- gel, ether) to give a solid acid (ca. 25%), mp 128.5- 120°C (chloroform/hexane): IR (CHC1 3 ) 3400-2400, 3000, 2850, 1704, 1421, 1368, 1280, 1180, 1125, 1085, 1075, 1038, 1025, 933 cm -1 ; 1 H-NMR (CDC1 ) o 9.80 (broad s, lH, 3 -co 2H), 5.00 (d, lH, J = 7 Hz, part of AB quartet, H eq -OCH 2O- ), 4.62 (d, lH, J = 7 Hz, part of AB quartet, H , ax -OCH 2O-), 3.88 (dd, lH, J 2.7, 11.1 Hz, -OCH-), 2.903 . 50 ( m, 2H, - 0 CH 2 - ) , 1 . 6 5 - 2 . 8 5 ( m, 1 0H) ; l 3C- NM R = (CDC1 3 ) o 179.1, 93.9, 82.8, 70.3, 37.3, 35.6, 32.3, 32.2, 28.5, 20 . 6. Anal. calcd. for c 10 H16 o 4 s: Found : C, 51 . 3 7 ; H, 6 . 6 3 . C, 51.70; H, 6.94. A better purification procedure consisted of dissolving the crude acid!!~ in methanol (50 mL) and £-toluenesulfonic acid (monohydrate) (0.1 g), heating to reflux for 1 h, removal of solvent in vacuo and chromatography on a Waters' Prep 500 (silica gel , 30 % ethyl acetate/70 % hexane) with recycle to give 3.3 g (23%) of ester llb: IR (CHC1 ) 3000, 2950, 2905, 2845, 1720, 1430, 1365, 1270, 3 -1 1 12 2 3 , 116 7 , 112 3 , 1 08 5 , 1 0 7 0 , 1 0 2 7 , 9 3 2 , 9 0 5 cm ; H- NMR (CDC1 ) o 4.99 (broad d, lH, J = 7 Hz, part of AB quartet, 3 Heq' -OCH 2O-), 4.62 (d, lH, J = 7 Hz, part of AB quartet, Hax' -OCH 2O-), 3 . 86 (dd, lH, J = 11.0, 2.5 Hz, -OCH-), 3.64 (s, 3H, -OCH 3 ), 3.13-3.40 (ABX, 2H, -OCH 2 -), 2.0013 3.00 (m, l0H, -CH2-' -CH-); c-NMR (CDCl3) o 173.4, -108- 93.8, 82.7, 70.3, 51 .4, 37.4, 35.6, 32.4, 32.0, 28.4, 20. 7. Anal. calcd. for Found: C, 54. 0 4; c11 H18 o4 s: C, 53.65; H, 7.37. H, 7. 5 0. (3B.*) -Methyl- 3- [ ( 4~*, SB_*) - 5-methyl- l, 3-dioxacyclohex- -~~~ ~~~~~~~~~~~~~~ ~~~ ~~~~~~~~~ ~~ ~~~ ~ ~~ ~~~~~~ ~~ ~~~~ ~~~ 4-yl]pentanoate (12b). The ester llb (2.9 g, 11.7 mmol) ~~~~~~~~~~~~~~~~~~~~~ in ethanol (70 mL) was treated with Raney-nickel (11 g) prepared from 1: 1 nickel-aluminum alloy (22 g) by the method of Fieser and Fieser~ 8 The mixture was heated to reflux and monitored by GLC (10% SE-30). After 5 h filtration through a celite pad, washing the filter cake with dichloromethane (3 x 20 mL), removal of solvent in vacuo and bulb-to-bulb distillation at 130°C (0.005 mm) gave 2.2 g (85%) of a colorless oil: IR (CHC1 3 ) 2970, 2940, 2850, 1725, 1455, 1435, 1380, 1260, 1240, 1175, -1 l H- NM R ( CDC 1 ) o 5 . 0 1 1085, 1030, 925 cm (d, lH, J = 3 ' 11 Hz, part of AB quartet, Heq' -OCH 20-) ' 4.48 (d, lH, J = 11 Hz, part of AB quartet, Hax' -OCH 20-) ' 3.91 (dd, lH, J = 1 2 . 0 , 4. 8 Hz, - OCH-) , 3.64 (s, 3H, -OCH 3 ), 3.16 (t, 2H, J = 10.8 Hz, -OCH 2 -), 2.31 ( t' 2H, J = 6. 9 Hz, -CH2COz-), 1. 68 (dt, 2H, J = 1. 3' 5.4 Hz, -C!:!2CH2COz-)' 0.9 (broad d, 3H, J = 6.3 Hz, acyclic CH 3 ), 0.63 (d, 3H, 13 J = 6.6 Hz, cyclic CH ); C-NMR (CDC1 3 ) o 173.8, 93.8, 3 84.6, 72.6, 51.4, 32.6, 31.9, 31.3, 29.0, 12.6, 12.2. Anal. calcd. for c11 H20 o4 : C, 61.09; H, 9.32. -109- Found: C, 60.93; H, 9.17. £~E-~2:~::.I£~~~!.~E-~2:~=-~~!~r!::.!t~=-~~<::?5~~r~!<::~~?5::.~::.r!l::. pentanoic acid (12a). To ester 12b (1.1 g, 4.9 mmol) in -------------------- a 25-mL round-bottomed flask with reflux condenser was added potassium hydroxide in methanol (10 mL solution, 8.2 mmol). 1 hand cooled. of a 0.82 M The solution was heated to 50°C for Ethanol was removed in vacuo and the residue redissolved in water (10 mL). Aqueous concentrated hydrochloric acid was added to rH l; then the acid was extracted into dichloromethane (4 x 20 mL). Drying (Na 2so 4 ), filtration, removal of solvent in vacuo and distillation at 160°C (0.006 mm) gave 0.97 g (97%) of a colorless oil: IR (CHC1 3 ) 3340-2400, 2960, 2850, 1705, 1455, 1400, 1380, 1275, 1175, 1150, 1085, 1030, 960, 1 920 crn-1; H- NMR (CDC1 3 ) o 8.98 (broads, lH, -co 2 H), 4.89 (broad d, lH, J = 6 Hz, part of AB quartet, Heq , -OCH 20-), 4.54 (d, lH, J 6 Hz, part of AB quartet, Hax , -OCH 2O-), 3.80 (dd, lH, J = 4.8, 11.4 Hz, -OCH-), 3.14 (apparent = t, 2H, J = 10 Hz, -OCH 2 -), 2.33 (t, 2H, J = 7.3 Hz, -CHzCO2-), 1.41-2.19 (rn, 4H, -CH- and -C!i2CH2CO2-), 0.94 (d, 3H, J = 7.2 Hz, ring CH 3), 0.67 (d, 3H, J = 6.9 Hz, acyclic CH 3 ). Anal. calcd for Found: C, 59.21; c10 H18 o4 : C, 59.39; H, 8.97. H, 8.90. [3(B*,~*),5B*]-3-Methyl-[(4~*,SB*)-5-rnethyl-l,3~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -110- dioxacyclohex-4-yl]hexan-2-one (13). ~---------------------------------- To diisopropylamine (1.76 mL, 12 mmol) in THF (5 mL) at -10°C was added methyllithium (5.6 mL, 10 mmol) in ether. After stirring for 10 min acid!~~ (0.894 g, 4.4 mmol) in THF (7 mL) was added over 0.5 hat -10°C, stirred for an additional 0.5 h and cooled to -30°C. Methyl iodide (0.67 mL, 11 mmol) was added (exotherm) with stirring over 5 min at -30°C then warmed to 25°C and stirred 1 h. The reaction flask was connnected to a vacuum pump and solvent removed in vacuo. The residue was redissolved in THF (6 mL) and cooled in an ice bath; methyllithium (2.6 mL, 4.4 mmol) in ether was added and the reaction warmed to 25°C. After 1 h (TLC, silica gel, 20 % ethyl acetate/hexane, Rf= 0.34) the reaction was slowly added to vigorously stirred ice water. Extraction with ether (4 x 30 mL), so ), filtration and removal of solvent gave 2 4 a pale yellow oil which was purified by column chroma- drying (Na tography (silica gel, 15 % ethyl acetate/hexane) giving 13, 0.55 g (59%): . IR (CHC1 ) 2970, 2930, 2850, 1705, 1455, 3 -1 1 1380, 1230, 1175, 1090, 1070, 1030, 965, 925 cm H-NMR (CDC1 3 ) o 5.00 (dd, lH, J = 11, 1.2 Hz, part of AB quartet, Heq' -OCH 2O-), 4.56 (dd, lH, J = 11, 1.9 Hz, part of AB quartet, Hax' -OCH 2O-), 3.80 (dd, lH, J = 11, 5 Hz, -OCH-), 3.24 (d, lH, J 3.07 (d, lH, J = 11 Hz, Heq , -OCH 2 -), 7 Hz, Hax' -OCH 2 -), 2.53 (m, lH, -C~CH 3 , = -111- in ring), 2.10 (s, 3H, CH 3 CO-), 1.1-2.0 (m, SH, -CH- and -CHz-), 1.05 (d, l.SH, J = 7.5 Hz, c~3CHCO-), 1.03 (d, l.SH, J = 7 . 2 Hz, C~ 3 CHCO-), 0.90 (d, 3H, J = 6 . 8 Hz, rin g CH 3 ), 0.66 (d, J = 6.8 Hz, acyclic CH ); 13 C-NMR 3 (CDC1 3 ) cS 212.0, 93.7 (84.7, 84.6), 72.S (44.6, 44.4), (36.8, 36.6), 31.3, 30.8 (2 7.7, 27.6), (16.9, 16.4), (13.1, 12.8), 12.1. Anal. calcd. for c 12 H22 o 3 : Found: 67. 16; H, 10.2. C, 67.26; H, 10.4. (~)-(+)-3-t-But y ldipheny lsiloxy-2-methylpropionic ~~~~~~ ~~~ - ~~~ ~~~~ ~~~~~~~~ ~~~~~~~~~~~ ~~~~~~~~~~~ acid (15). ~-(+)-hydroxyisobutyric acid 2 (5.0 g, 48 mmol) was dissolved in dry dimethylformamide (SO mL). Imidazole (10.1 g, 150 mmol) and !-butyldiphenylchlorosilane (14.6 g, 53 mmol) were added. After 16 h (TLC, silica gel, 30 % ethyl acetate/hexane, Rf= 0.39), the reaction mixture was cooled in an ice bath and sodium hydroxide (5.0 g, 0.12 mol) in water (SO mL) was added. The aqueous layer was washed with ether (3 x 30 mL) then recooled, acidified with concentrated hy drochloric acid, and extracted with ether (4 x SO mL). Drying (Na 2so 4 ), filtration and removal of solvent in vacuo gave an oil (12.3 g, 75%) which crystallized on storage at -10°C, mp 52.5-53.5°C: IR (CHC1 ) 3400-2400, 3070, 2950, 2930, 2860, 1705, 1585, 3 1465, 1455, 1385, 1110, 820, 800, 695 cm- 1 ; 1H-NMR (CDC1 ) 3 cS 9.21 (broads, lH, -co 2H), 7.54 (m, 4H, aromatic), -112- 7.36 (m, 6H, aromatic), 3.76 (d, lH, J 7.5 Hz, -0CH -), 2 3.74 (d, lH, J = 6.0 Hz, -OCH -), 3.67 (hextet, lH, J = 2 6.7 Hz, -CH -), 1.13 (d, 3H, J = 7.0 Hz, -CH 3 ), 1.03 (s, 9 H, .!. - but y 1 me thy 1 s ) ; l 3t - mlR (CD C1 ) o 1 8 0 . 8 , 1 3 5 . 4 , 3 133.1, 129 .6, 127.5, 65.5, 42.2, 26.7, 19.2, 13.3; [a]D = +10.37° (C = 1.09, CHC1 ). 3 An a 1 . ca 1 c d . for C2 H 0 Si : 0 26 3 Found: C, 69.73; H, 7.70. = C, 7 0 . 13 ; H, 7 . 6 5 . R-(+)-3-t-Butyldiphenylsiloxy-2-methylpropan-1-ol ~~~~~-~ - ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (16 ) . Ac id ~ ~ ( 6 . 1 3 g , 1 7 . 9 mm 6 l ) wa s d i s s o 1 v e d in ether (20 mL) and borane-dimethylsulfide (2 mL, 20 mmol) in ether (10 rnL) was added dropwise at 0°C. After the initial reaction the borane was added faster. At the end of 3 h (TLC, silica gel, 30% ethyl acetate/hexane, Rf= 0.48) the reaction was added to ice water and extracted with ether (4 x 20 mL). The combined organics were washed with 4 N sodium hydroxide (aqueous), water and brine, dried (Na 2 so 4 ) and filtered. Removal of solvent in vacuo gave 5.54 g (94%) of a colorless oil: IR (CHC1 ) 3500, 3060, 3000, 2950, 2930, 2860, 1580, 3 14 6 0 , 14 2 0 , 13 8 5 , 1100 , 10 8 0 , 10 2 0 , 9 2 0 , 6 9 5 cm - l ; l H- NMR (CDC1 3 ) 0 7.45 (rn' 4H, aromatic), 7.16 (m, 6H, aromatic), 3.61 (d, 2H, J = 5. 0 Hz, -C!j_ 20H), 3.60 (d, 2H, J = 6.0 Hz, -OCH-) 2 , 2.40 (broad s, lH, -OH), 1. 91 (octet, lH, J = . 6-. 0 Hz, -CH-), 1.06 ( s' 9H, .!_-butyl methyls), 0.83 (d, -1133H, J = 6.3 Hz, C!j_ 3CH-); 13 C-NMR (CDC1 3 ) cS 135.4, 133.0, 129.6, 127.6, 68.5, 67.4, 37.3, 26.8, 19.2, 13.2; [a]D = +7.43° (C = 1.09, CHC1 3 ), optically pure by 1H-NMR/chiral shift rea gent (tris[3-(heptafluoropropylhydroxymethylene)i-camphorato], europium (III) derivative) analysis of methy l doublet. 28 S-(+)-2-t-Butyldiphenylsiloxy-1-methylpropionaldeh yde ~~~~~~~ - ~~~~~~~~~~~~~~~~~~~~~-~~~~~~~~~~~~~~~~~~~~~ (17). To an ice-cold solution of pyridine (39 mL, 0.48 mol) in dichloromethane (600 mL) was added chromium trioxide (24 g, 0.24 mmol). The orange solution was stirred 15 min then warmed to 25°C and stirred 0.5 h. Alcohol 16 (12.9 g, 39.4 mmol) in dichloromethane (10 mL) Kas added in one portion to the deep red solution. black precipitate formed immediately. A After 15 min the solution was decanted and solvent removed in vacuo. The residue was taken up in ether and filtered through florisil, eluting with ether. After removal of solvent in vacuo the residue was dissolved in toluene (20 mL) and solvent removed (to azeotropically remove pyridine). The toluene procedure was repeated again and after complete removal of solvent a white solid (10.46 g, 91%) was obtained, mp. 60-62.5°C: IR (CHCI ) 3070, 2950, 2930, 2860, 1720, 3 1580, 1460, 1450, 1420, 1380, 1360, 1105, 1030, 1005, 995, 820, 695 cm- 1 ; 1 H-NMR (CDC1 3 )o 9. 76 (d, lH, J = 2.1 Hz, -COH), 7.64 (m, 4H, aromatic), 7.36 (m, 6H, aromatic), -1143.8 0 (d, 2H, J = 5.4 Hz , -OCH 2 -), 2.51 (m, lH, -CH-), 1. 07 (d, 3H, J = 6. 3 Hz, -CH ), 1. 04 (s, 9H, !_-butyl 3 13 meth y ls); C-NMR (CDC1 ) 6 203.9, 135.4, 132.9, 129.6, 3 127.5, 64.0, 48.7, 26.7, 19.2, 10.2; [a]D = +25.93° (C = 1.08, CHCl,). Optically pure by 1H-NMR/chiral shift .) rea gent anal y sis of meth y l doublet. 28 An a 1 . ca 1 c d . for C2 0H2 6 0 2Si : Found: C, 73.65; H, 7.85. C, 7 3 . 5 7 ; H, 8 . 0 3 . (2~) -l-t-But y ldiphenylsiloxy-2-methy l-4-(1-oxa-3~~~ ~~~~~ ~~~~~~~~ ~~~~~~~~~~~ ~~~~~~~ ~~~~~~ ~~ ~~ ~~ - ~~~~~~~~=-~:r!2:_~:,~1:!!~~~!~i!~~!~!·~~2- To a dry, three-necked 100-mL round-botto m flask equipped with a septum ma gnetic stirrin g bar, thermometer, nitrogen inlet and con s tant-volume addition funnel were added THF (20 mL) and diisopropylamine (5.3 mL, 3 mmol). The solution v.'as cooled to -20°C and meth y llithium (19.5 mL, 35 mmol) in ether was added over 20 min. After 15 min the colorless solution was cooled to -78°C (internal) and 2-methylbenzoxazole (4.15 mL, 35 mmol) in THF (10 mL) was added dropwise over 15 min while maintaining an internal temperature below -70°C. Stirring was continued an additional 1 h during which time a yellow precipitate formed; then aldehyde 17 (9.67 g, 30.0 mmol) in THF (7 mL) was added over 5 min. The mixture was sti r red 5 min followed by quenching with saturated ammonium chloride. The reaction was partitioned between water -115- (60 mL) and ether (4 x 50 mL). Combination of organics, washin g with water and brine, dr y ing ( Na so ), filtration 2 4 and removal of solvent gave 13 g of a crude product . Purification on a Waters' Prep 500 (10% ethyl acetate/ hexane) gave 3S alcohol!~~ (5.9 7 g, 43.4 %): IR (CHC1 ) 3470, 3 3060, 3000, 2950, 2920, 2850, 1605, 1560, 1460, 1445, 1420 1 3 8 5 , 1 2 3 5 , 11 0 0 , 1 0 1 0 , 9 9 5 , 9 0 0 , 8 1 5 , 6 9 0 cm - l ; l H - NMR (CDC1 ) 6 7. 64 (m, SH, aromatic), 7. 36 (m, 9H, aromatic), 3 4.40 (m, lH, -C!:iOH), 3.68 (d, 2H, J = 5.4 Hz, 3.5 8 (broads, lH, -OH), 3.05 (d, lH, J -CHzO-) , = 2.2 Hz, -CH 2 ben z oxa::ole), 3.00 (s, lH, -CH - ben z oxazole), 1.65-2.00 2 (m, lH, -CH-), 1.06 (s, 9H, !_-butyl methyls), 0.96 (d, 3H, J 13 = 6. 2 Hz, -cH 3 ); c-NMR (CDC1 ) 3 o 165.6, 150.4, 14 0 .8, 135.4, 132.7, 129.6, 127.6, 124.3, 124.0, 119.4, 110.4, 71.0, 6 7 .4, 39.6, 33.7, 26.9, 19.2, 11.0; -3.8 7 ° (C = 1.27, CHC1 3 ); eth y l acetate/hexane): Anal. calcd. for c N, 3.05. Found: k 22 [a]D = HPLC (1 foot .E_-porasil, 10 % = 3.5 H No si: 28 33 3 C, 73.47; C, 73.16; H, 7.42; 3R alcohol!~~ (4.95 g, 35%): H, 7.24; N, 2.91. IR same as!~~; 1 H-NMR (CDC1 ) o 7.55 (m, SH, aromatic), 7.34 (m, 9H, aromatic), 3 4.21 (q, lH, J = 5.3 Hz, -OCH-), 4.04 (broads, lH, -OH), 3.73 (d, lH, J = 5.3 Hz, -OCH -), 3.72 (d, lH, J 2 = 6.0 Hz, -0CH -), 3.10 (s, lH, -CH - benzoxazole), 3.03 (d, 2 2 lH, J = 2.2 Hz, -CH 2 - benzoxazole), 1.90 (heptet, lH, -116- J = 6.0 Hz, - CH-) , 1. 07 (s, 9H, !_-butyl CH 3 ), 0.97 (d, 3H, J = 6. 6 Hz, -CH ) ; 3 13 C-KMR (CDC1 ) 0 165.2, 146.0, 3 140. 7, 135.4, 132.8, 129.6, 127.5, 124.3, 123.9, 119.4, 110. 2, 7 2 . 4 , 6 7 . 2 , 4 0 . 1 , 3 3. 9 , 2 6 . 8 , 19. 2, 13 . 4 ; k HPLC : = 3.1. An a 1 . ca 1 c d . f o r C H NO S i : 28 33 3 K , 3.05. Found: C, 73.47; C, 73 . 1 6 ; H, 7.42; H, 7 . 24 ; ~, 2.91. (2~,3~)-2-Methyl-4- (l-oxa-3-azainden-2-yl)-1,3- ~~~~~~~~~~~~~~~ ~ ~~~~~~~~~~~~~~~~~~~~-~~~~~~~~~~ butandiol (19 b) . To alcohol 19a (2.1 g, 4.6 mmol) in ~~~ ~ ~~~~~~~~~~~ ~~~ THF (4 mL) ~as added tetra-~-butylammonium fluoride (8 rnL, 8 mmol) in THF. After 0.5 h solvent was removed in vacuo and the residue chromatographed on silica gel (ethyl acetate) to give an off-white solid (0.953 g, 94%), mp 102-104°C (1:1 ethyl acetate/hexane): IR (CHC1 ) 3 3600, 3450, 3000, 2970, 1610, 1570, 1455, 1345, 1160, 1145, 1100, 1030, 1005, 840 cm- 1 ; 1 H-NMR (CDC1 )o 7.16-7.72 3 (m, 4H, aromatic), 4.30-4.59 (m, lH, -OCH-), 4.01 (broad s, lH, -OH), 3.80 (broad d, 2H, J = 5.4 Hz, -OCH -), 2 2.78-3.19 (m, 3H, -OH, -CH - benzoxazole), 1.73-2.16 (m, 2 13 lH, -CH-), 1.00 (d, 3H, J = 7.2 Hz, -CH ); C-NMR (CDC1 ) 3 3 o 165.3, 150.3, 140.5, 124.6, 124.2, 119.3, 110.2, 71.1, 66.0, 39.2, 33.2, 10.7; Anal. calcd. for N, 6.33. Found: [a]D = -24.22° c12 H15 No 3 : C, 65.11; (C C, 65.14; H, 7.02; = 1.09, CHC1 3 ). H, 6.83; N, 6.27. i~~!~~2:~:~:!~rI:~:S!:~~~=~=~~~~~~:~:~:r~2~~!~~=~!~= -117- ~~~!_i1~22· Prepared as for diol 0.95 g (94%): IR (see 1g9); !~~- !~~ (2.1 g) gave 1 H-NMR (CDC1 ) cS 7.16-7.72 3 (m, 4H, aromatic), 4.20 (q, lH, J = 4.2 Hz, -OCH-), 3.58- 3. 76 (m, 3H, -CH 2OH), 3. 08 (broad s, 2H, -OH and -CH 2 benzoxazole), 3.02 (d, lH, J = 4.8 Hz, -CH - benzoxazole), 2 1.80-1.89 (m, lH, -CH-), 0.93 (d, 3H, J = 7.5 Hz, CH ). 3 £~~r~~2:~:~~!~r!:~:£!:~~~:~:~~~~~~~~:~:r!2:!-E!~!~:~:~~!!~~r!~~r£~!~~=~:~~-i~l~2· Diol!~~ (0.284 g, 1.28 mmol) was dissolved in pyridine (20 mL), cooled to 0°C and E-toluenesulfonylchlorid~ (0.266 g, 1.4 mmol) was added. After 40 h (TLC, silica gel, 50% ethyl acetate/hexane, Rf= 0.30) the reaction (deep purple) was added to ice water (60 mL) and extracted with ether (4 x 30 rnL). The combined organics were washed with 10 % hydrochloric acid, water, brine and dried (Na 2 s □ 4 ). Filtration and removal of solvent gave a yellow oil (0.373 g, 78%): IR (CHC1 ) 3640-3200, 3000, 2930, 1610, 3 1595, 1565, 1450, 1355, 1240, 1185, 1170, 1090, 965, 1 935, 905, 830, 810, 655 cm-l H-NMR (CDCl)cS 7.07-7.82 (m, 8H, aromatic), 4.09 (d, 2H, J = 4.5 Hz, -OCH 2 -), 3. 78-4. 08 (m, 2H, -CHOH), 2. 98 (s, lH, -CH 2 - benzoxazole), 2.91 (d, lH, J = 4.5 Hz, -CH 2 - benzoxazole), 2.30 (s, 3H, CH 3 - aromatic), 1.74-2.03 (m, lH, -CH-), 0.97 (d, 3H, J = 7.5 Hz, -CH 3 ). (2£,3R)-3-(Oxacyclohex-2-yloxy)-2-methyl-4-(l-oxa- -------------------------------------------------- -118- 2-azainden-2-yl)-1-£-toluenesulfonyloxybutane (23b). The -~- ~~-~~~--~~ ~~~~~ -~-~-~-~~~~~~~~--~-~~~-------crude tosylate 3~~ (0 . 341 g, 0. 92 mmol) was dissolved in dichloromethane (2 mL), cooled to 0°C and dihydropyran (0.2 mL, 2.22 mmol) added. After addition of one crystal of E-toluenesulfonic acid the reaction was stirred 1 h (TLC, silica gel, 40% ethyl acetate/hexane, Rf= 0.27). The reaction was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate then dried (~a 2 so 4 ). Filtration and removal of solvent gave 1 0.41 5 g (9 2%) of a yellow oil: IR no -OH; H-NMR (CDC1 3 ) 6 7.10-7. 78 (m, SH, aromatic), 4.50 (broads, lH, -OCHO-), 3.8 9-4.20 (m, 2H, -CH -oso 2 -), 3.17-3.81 (m, 3H, -OCH-, 2 -OCH of THP group), 3.17 and 3.03 (d, 2H, J = 5.4 Hz, 2 -CH - benzoxazole), 2.37 (s, 3H, CH 3 - aromatic), 1.122 2 . 28 (m, 7H, -CH- and -CH 2 - of THP), 1.03 and 1.00 (d, J = 7. S Hz, - CH 3 ) . (2S,3R)-4-Iodo-3-meth y l-1-(1-oxa-2-azainden-2-yl)2 - but an o 1 ( 2 3d ) . To s y 1 at e 2 3a ( 0 . 9 7 7 g , 2 . 6 mm o 1 ) was ~~~~-~~~~~~~~- ~ ~~ ~ dissolved in acetone (10 mL) and sodium iodide (1.51 g, 10 mmol) added. The mixture was stirred at 25°C for 17 h (TLC, silica gel, 50% ethyl acetate/hexane, Rf= 0.37). The iodide was isolated by filtration, rinsing the filter cake with ether and removal of solvent. The oil was redissolved in ether, washed with 10% sodium sulfite, dried (Na so ), filtered and ether removed to yield a 2 4 -119pale yellow oil (0.570 g, 67%): 1 H-NMR (CDC1 )o 7.07-7.68 3 (m, 4H, aromatic), 4.14 (broads, lH, -OH), 3.95 (doublet of triplets, lH, J = 3.9, 7.8 Hz, -OCH-), 3.23-3.50 (m, 2H, -cH 2 I), 2.66-3.10 (m, 2H, -CH 2 - benzoxazole), 1.321. 73 (m, lH, -CH-), 1. 02 (d, 3H, J = 6. 9 Hz). 1- (1-t-Butyloxycarbonyl-l-azacyclopenta-2,4-dien~~~~ - ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-yl)-1-propanone (38). ~~~~~~~~~~~~~~~~~~~~~~ To a three-neck 100-mL round- bottomed flask with a septum, nitrogen inlet, mechanical stirrer and constant-volume addition funnel were added potassium !_-butoxide (2. 58 g, 22· mmol) and THF (20 mL). The suspension was stirred with cooling to 0°C and 43 pyrrole ketone 26 (2.46 g, 20 mmol) in THF (10 mL) was added over 10 min. After warming to 25°C and stirring for 1 h !_-butyloxycarbonyl anhydride (5.1 mL, 22 mmol) in THF (30 mL) was added over 0.5 h (exotherm). The heterogeneous mixture was stirred an additional 2 h (TLC, silica gel, 40 % ethyl acetate/hexane, Rf= 0.60); then water (50 mL) was added and the mixture partitioned Drying (Na 2so 4 ), filtration and removal of solvent gave an oil which was between water and ether (4 x 50 mL). purified on a Waters' Prep 500 on silica gel eluting with 6% ethyl acetate/hexane to give 0.20 g of starting ketone and 3.51 g (85% based on recovered ketone 26) of a solid mp. 57.5-58.5°C: IR (CHC1 3 ) 2880, 1740, 1670, 1440, 1410, 1390, 1370, 1315, 1250, 1150, 1100, 1080, -120- 1 -1 H-NMR (CDC1 ) o 6.96 (dd, lH, J = 1.4, 3 3.1 Hz, pyrrole C-5H), 6.70 (dd, lH, J = 1.4, 3.7 Hz, 1030, 925, 845 cm pyrrole C-3H), 6.10 (dd, lH, J = 7.5 Hz, -CH2-)' 1.56 (s, 9H, C-4H), 2.73 (q, 2H, J !-butyl CH 3 ), 1.17 (t, 3H, J (CDC1 3 ) = 3.1, 3.7 Hz, pyrrole = 7.5 Hz, -CH 3 ); 13 C-NMR o 191.9, 148.7, 133.8, 127.3, 119.9, 109.7, 84.6, 33.6, 27.5, 8.8. Anal. calcd for Found: C, 64.51; c12 H17 No 3 : C, 64.55; H, 7.68. H, 7.68. l-(l-Phenylmethoxymethyl-l-iiacyclopenta-2,4-dien- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-yl)-l-propanone_(37). The title compound was prepared according to the procedure for ketone~~- To ketone 26 ( 2. 4 6 g, 2 0 mmol) ,\·ere added commercial potassium !- butox i d e ( 2 . 5 0 g , 2 2 mm o 1 ) and ch 1 or om e thy 1 be n z y 1 ether ( 3 . 4 4 g , 22 mmol) to yield ketone 37. Purification by distillation at 120°C (0.006 mm) gave a colorless oil (4.90 g, 100%): IR (CHC1 ) 3000, 2960, 2900, 1665, 1550, 1480, 1430, 1310, 3 1 1250, 1220, 1100, 1040, 950, 755, 710 cm- 1 ; H-NMR (CDC1 3 ) o 7.32 (s, SH, phenyl), 6.97-7.14 (m, 2H, pyrrole), 6.20 (dd, lH, J = 3, 4.5 Hz, pyrrole), 5.81 (s, 2H, -NCH O-), 4.50 (s, 2H, ArCH 2 O-), 2.83 (q, 2H, J = 6.9 Hz, 2 13 CH2CO-), 1.17 (t, 3H, J = 6.9 Hz); c-NMR (CDCl3) o 191.9, 137.3, 130.2, 129.6, 128.2, 127.6, 119.8, 108.8, 77.0, 70.4, 32.3, 8.9. Anal. calcd. for c15 H17 No 2 : C. 74.05; H, 7.04; -121- N, 5.76. Found: C, 74.20; Pyrrole ketone enolate. H, 7.20; N, 5.76. General procedure for ---------------------------------------------aldols. In a two-neck round-bottomed flask equipped with a magnetic stirring bar, septum and nitrogen inlet is placed diisopropylamine (1.2 equiv) and ether (2 mL/ equiv of amine). The solution is cooled to 0°C and ~-butyllithium (1.1 equiv) in hexane is added. 15 min the solvent is removed in vacuo. After The white powder is redissolved in ether (1 mL/equiv), cooled to -98°C and pyrrole ketone (1 equiv) in ether (2 mL/equiv) is added ·over 2 min. After 0.5 h, zinc chloride (1 equiv, freshly fused) in ether (2 mL/equiv) is added and the reaction warmed to 10°C to give a yellow solution. Dimethoxyethane (5 mL/equiv) is then added. Aldehyde (0.8 equiv) is added in dimethoxyethane (1 mL), the reaction is stirred 5 min and saturated ammonium chloride (1 mL/equiv) is added. diluting with ether; The reaction is worked-up by washing 1 x water, 1 x 10% hydrochloric acid, 1 x sodium bicarbonate; (Na drying so ); filtration and removal of solvent in vacuo. 2 4 Aldol condensation of ketone 37 with benzaldehyde. ~~~~~~~~----------------------------------------- According to the general procedure, ketone 37 (0.249 g, 1.02 mmol) was added to benzaldehyde (0.1 mL, 1.0 mmol) to give 0.359 g (90%) of an aldol product. The crude product was purified by flash chromatography on silica -122- gel (25% ethyl acetate/hexane) TLC [silica gel, 25% ethyl acetate/hexane, Rf= 2.8 (threo), 2.6 (erythro)]: IR (CHC1 ) 3460, 3050, 3000, 2960, 2900, 1645, 1540, 3 1510, 1460, 1425, 1300, 1240, 1210, 1090, 1040, 970, 920, -1 1 740, 710 cm ; H-NMR (CDC1 )o 7.41 (s, l0H, phenyl), 3 6.96-7.15 (m, 2H, pyrrole), 6.20 (dd, lH, J = 2.1, 4.5 Hz, pyrrole), 5.76 (s, 0.6H, -NCH O-), 5.74 (s, 1.4H, -NCH O-), 2 2 5.13 (d, 0.3H, J = 3.5 Hz, erythro, -OCH-), 4.93 (d, 0.7H, J = 6.6 Hz, threo, -OCH-), 4.58 (s, 0.6H, -OCH 2 -Ar), 4.36 (s, 1.4H, -OCH -Ar), 3.93 (broads, lH, -OH), 3.43 (dt, 2 0.7H, J = 3.6, 7.5 Hz, -CHCO-), 2.74 (dt, 0.3H, J = 2.4, 5.4 Hz), 1.22 (d, lH, J = 7.5 Hz, CH 3 -), 1.13 (d, 2H, J = 6.0 Hz, CH--). ::J Aldol condensation of ketone 38 with benzaldehyde. ~~ ~ ~~~~~--~~~~~~~ ~ ~~~~~~~~~~~~~~~~~-------------.According to the general procedure, ketone ~~ (0. 22 2 g, 1. 0 . mmol) was added to benzaldehyde (0.1 mL, 1.0 mmol) to give 0.263 g (85 %) of an aldol product. 1 H-NMR ( CDC1 3 ) o 7.33 (broads, SH, phenyl), 6.78-7.00 (m, 2H, pyrrole), 6.14 (t, lH, J = 3 Hz, pyrrole), 5.23 (d, 0.25H, J Hz, -OCH-), 4.90 (d, 0. 75, J (pentet, lH, J = 7.5 Hz, = 7.8 Hz , = 1.5 -OCH-), 3.43 -CH-), 3.06 (broads, lH, -OH), 1.60 (s, 9H, !-butyl CH ), 1.03 (d, 3H, J 3 = 6.9 Hz, -CH 3 ); HPLC (10% ethyl acetate/hexane, 1 foot ~-porasil) kthreo 4 • 2 , kerythro = = 6 •1 • ~!~~!-~~~~~~~~!!~~-~~-~~!~~~-~~-~i!t_~~ttrl_~:~~tlrr.l:~: -12 3- ~~~E~~!~~~~!~-i~~2· According to the general procedure, ketone~~ (0.305 g, 1.37 mmol) was added to aldehyde 39 to give four lactones (0.267 g, 80%). HPLC (1 foot ~-porasil, 25% ethyl acetate/hexane) kA = 2.46, kB= 3.54, kc= 4.30, kD = 4.74). Isomers A and B were separated pure by chromatography on a Waters' Prep 500 (silica gel, 25% ethyl acetate/hexane). C and D were isolated as a mixture enriched in C. 40a: IR (CHC1 ) 3000, 2960, 2920, 1725, 1690, 1665, 3 1445, 1430, 1405, 1360, 1305, 1Z40, 1140, 1065, 1030, 945, -1 1 900, 840 cm ; H-NMR (CDC1 3 )c5 7.43 (dd, lH, J = 1.5, 3.1 Hz, pyrrole), 6.96 (dd, lH, J 6.22 (t, lH, J = 1.5, 3.6 Hz, pyrrole), = 3.4 Hz, pyrrole), 4.41 (dd, lH, J = 2.2, 10.2 Hz, -OCH-), 3.20-3.88 (m, 2H, -C~CH ), 2.48 (t, 2H, 3 J = 6.0 Hz, -CH2CO), 1.83-2.49 (m, 2H, CH2), 1.56 (s, 9H, .!_-butyl CH ), 1.48 (d, 3H, J = 6.6 Hz, acyclic -CH ), 0.92 3 3 (d, 3H, J = 6.6 Hz, cyclic -CH 3 ). 1 40b: H-NMR (CDC1-)c5 7.43 (dd, lH, J = 1.5, 3.1 Hz, ~~~ ~ pyrrole), 6.96 (dd, lH, J = 1.5, 3.6 Hz, pyrrole), 6.22 (t, lH, J = 3.4 Hz, pyrrole), 4.48 (dd, lH, J = 5.1, 8.3 Hz, -OCH-), 3.15-3.49 (m, 2H, -C~CH 3 ), 2.46-2.60 (m, 2H, -CH CO), 1.58-2.03 (m, 2H, -CH 2 -), 1.59 (s, 9H, .!_-butyl 2 CH ), 1.27 (d, 3H, J = 6.9 Hz, acyclic -CH 3 ), 1.04 (d, 3 3H, J = 6.3 Hz, cyclic -CH 3 ). 4 0 c : l H- NM R ( CDC 1 3 ) c5 4 . 6 6 ( d d , 1 H , J = 1. 5 , 1 0 . 5 Hz , -124- -OCH-). 1 H-NMR (CDC1 ) 6 4.26 (dd, lH, J = 4.5, 8.4, 3 40d: -OCH-). Aldol condensation of ketone 37 with methyl-3-methyl-4- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ oxopentanoate~(39). According to the general procedure ketone 37 (0.240 g, 0.99 mmol) was added to aldehyde 39 to give four lactones (0.311 g, 80%). Analysis of the four lactones was performed by HPLC analysis (1 foot ~-porasil, 25% ethyl acetate/hexane): k 0 = 7. 50. kA = 4.43, kB= 6.07, kc= 7.00, By analogy; A was as·signed as erythro/anti- Crarn, and B was assigned as threo/Crarn. ~1ethyl-5- (rnethrlarnino)-2- !{(SB)-2-[(2.B)-l-htdroxy-2rnethylpent-4-yl]-5-rnethyloxacyclohex-2-en-6-yl}methyl \- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4-benzoxazole carboxvlate (43a, 44a). Silyl ethers 35 and ~~~~~~~~-~~~~~~~~---~---~~~~~~~~~~~~ ~~ ~~ (0.368 g, 0.49 mmol) were dissolved in THF (1 mL). Tetra- ~-butylarnmonium fluoride (5 mL, 1 ~' 5 mrnol) in THF was added. TLC (silica gel, ethyl acetate, Rf= 0.72) showed a new spot which fluoresced, indicating removal of the trifluoroacetyl group. After 10 h three new components were present (Rf= 0.69, 0.64, 0.46). The hi-Rf spots were spiroketals. The lower Rf component was isolated by flash chromatography (silica gel, 50% ethyl acetate/49% hexane/1% triethylamine) • 57 of an unstable oil: IR (CHC1 3 ) to yield 75.8 mg (37%) 3660, 3370, 3000, 2960, 2930, 1730, 1665, 1565, 1555, 1525, 1425, 1410, 1250, 1205, 1160, 1110, 1040, 925, -125- 665 cm 1 -1 (d, lH, J H-NMR (CDCl 3 ) 6 7. 86 (broad s = 9 Hz, Ar), 6.68 (d, lH, J 1 H , NH) , 7 . 5 4 = 9 Hz, Ar), 5.52 (broad s, lH, OH) , 4. 11- 4. 2 8 (m, lH, vinyl) , 3. 9 6 ( s, 3H, -OCH 3 ), 3.45-3.65 (m, lH, -OCH-), 3.32 (d, 2H, J -OCH 2 -), 3.05 (d, 3H, J = 6.9 Hz, = 3 Hz, -NCH 3 ), 2.91 (d, 2H, J = 6 Hz, -CH - benzoxazole), 0.71-1.89 (m, 16H). 2 Exact mass (75 e\') Found: ~/~ calcd. for c23 H32 N2 o6 : 432.226. 432.229. Meth y 1 - 5 - (met h y 1 amino) - 2 - J { ( 5 B) - 2 - [ ( 2.B) - 2 - met h y 1 - 1 - ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ oxopent-4-yl]-5-methyloxacyclohex-2-en-6-yl}methylJ-4- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ben:oxazolecarboxylate (43b, 44b). Pyridine (0.18 mL, 2.16 ~~~~~~~~~~~~~~~~~~~~~~-~~~~~~~~~~ mmol) in dichloromethane (9 mL) was cooled to 0°C and chromium trioxide (0.108 g, 1.08 mmol) was added. After 10 min the orange solution was warmed to 25°C and stirred for 15 min. Alcohols 43a, 44a (0.0758 g, 0.18 mmol) in dichloro- --- --- methane (1 mL) were added to the burgundy-colored solution. After 15 min the reaction was worked-up as for aldehyde 17 to give 49.9 mg (66%) of a colorless oil: IR (CHC1 ) 3 3350, 2990, 2950, 2930, 1730, 1720; 1670, 1560, 1520, 1430, 1410, 1250, 1160, 1130, 1085, 1040, 800 cm-l; (CDC1 ) 3 1 H-NMR o 9.68 (d, lH, J = 1.5 Hz, -CHO), 7.75 (broads, lH, NH), 7.54 (d, lH, J = 9 Hz, Ar), 6.68 (d, lH, J = 9 Hz, Ar), 4.11-4.28 (m, lH, vinyl), 3.96 (s, 3H, OCH ), 3.453 3.65 (m, lH, -OCH-), 3.09 (d, 3H, J (d, 2H, J = 3 Hz, -NCH ), 2.91 3 = 6 Hz, -CH 2 - benzoxazole), 0.69-2.00 (m, 16H). -126- Exact mass (75 eV) !!!_/~, calcd. for c 23 H30 N2 o6 : Found: 4 3 0. 2 0 9. 430.210. (2S)-Methyl-5- (methylamino)-2- I { (3R,6R,8S,9R,11R)- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~--~--~--~---~-- 3,9,11-trimethyl-8-[(l~)-1-methyl-2-oxo-2-(lH-pyrrol-2- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~--~-~~~~~~~ yl)ethyl]-l,7-dioxaspiro[5.5]undec-2-yl}methyll-4- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-~~~~~~~~~~~~~~~~ benzoxazolecarboxylate (lb). In a two-neck 25-mL round~~~~~~~~~~~~~~~~~~~~~~~~~~~ bottomed flask, connected to a three-way valve and equipped with a septum and magnetic stirring bar, were placed diisopropylamine (0.15 mL, 1.1 mmol) and ether (2 mL). The solution Kas cooled to 0°(, . ~-butyllithium (0.69 mL, 1.0 mmol) in hexane ~as added and stirring continued for 15 min. After solvent removal in vacuo the residual Khite powder Kas dissolved in ether (2 mL), cooled to - 9 8 ° C and k e t on e 3 8 ( 0 . 2 2 3 g , 1. 0 mm o 1 ) in e the r ( 2 mL) was added over 5 min. The yelloK solution was stirred 0.5 hand zinc chloride (0.14 g, 1.0 mmol, freshly fused) 1n ether (2 mL) was added. Warming to 10°C was followed by dilution with dimethoxyethane (5 mL). Aldehydes 43 and 44 (0.050 g, 0.12 mmol) in dimethoxyethane (2 mL) were added, the reaction was stirred 5 min and saturated ammonium chloride (2 mL) was added. as in the general procedure. The crude product was dis- solved in toluene (2 mL), Dowex resin + H Workup was the same 48 (2 g, sulfonic acid form) was added and the mixture was heated to 100°C for 8 h. The mixture was purified to isolate the major -127- component (flash chromatography, silica gel, gradient fro m 10 % ethyl acetate/hexane to 50% ethyl acetate/ hexane, TLC silica gel, 40% ethyl acetate/hexane, Rf= 0.1 7) as a yellow oil (11.2 mg, 18% 50 based on aldehyde) identified as A-23187 methyl ester by comparison with an authentic sample: IR (CHC1 ) 3440, 3360, 3000, 2960, 3 293 0 , 2870, 1710, 1670 , 1635, 1555, 1520, 1450, 1430, 1415, 1405, 1305, 1250, 1160, 1130, 1070, 1000, 985, 890 , -1 800 cm ; 1 • H- NMR (CDC1 3 ) o 10.2 (broad s, lH, p y rrole - NH) , 7 .84 (broads, lH, -NH), 7.62 (d, lH, J = 9.0 Hz, ben:ox azole aromatic), 6 . 89 (apparent triplet, 2H, J = 1.9 Hz, py rrole), 6.65 (d, lH, J = 9.0 Hz, benzoxazole aro matic), 6.13-6.2 7 (m, lH, pyrrole), 4.10-4.21 (m, lH, -OCH-), 3.9 7 (s, 3H, -OCH 3 ), 3.60 (dd, lH, J = 2.1, 10.7 Hz, -OCH on pyrrole side), 2.61-3.40 (m, 3H, -CH 2 benzoxazole and -CHCO-), 2.92 (d, 3H, J = 3.6 Hz, -NCH ), 3 23 0.78-2.09 (m, 21H); [o:]D = -10.0° (C = 0.011 g/rnL, CHC1 ). 3 Anal.:_ calcd. for c30 H39 N3o6 : C, 67.02; H, 7.31; N, 7.82. Found: C, 67.11; H, 7.53; N, 8.04. Exact mass (75 eV) ~/~, calcd. for Found: c30 H39 N3o6 : 537.284. 53 7 .286. The authentic sample was prepared by treating A-23187 with 20 equivalents of dimethylformamide dimethylacetal in toluene at 110°C for 10 h. Isolation was by chromatog- raphy on silica gel (ether). IR and NMR were identical. -128- [aJi 3 = -10.4° (C = 0.009 g/mL, CHC1 3 ). ( 2~) - 5 - (Me thy 1 amino ) - 2 - I { ( 3R , 6R , 8.S., 9R , 11 R) - 3 , 9 , 11 - ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~----~~--~~ trimethyl-8- [(1.S.)-1-methyl-2-oxo-2-(lH-pyrrol-2-yl)- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ethyl]-l,7-dioxaspiro[5.5]undec-2-yl}methyll-4-benz- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ oxazolecarboxylic_acid_(la). A-23187 methyl ester!~ (5.1 mg, 9.5 µ mole) was dissolved in hexamethylphosphoric triamide (1 ml) and lithio-~-propylmercaptide (0.12 ml, 0.038 mmol) in the same solvent was added at 25°C. After 3 h ether (10 mL) and ice cold Kater were added. The ether so ), 2 4 filtered and solvent removed. Trituration with hexane gave layer Kas washed several times with water, dried (Na a solid. Recrystallization from hexane/acetone gave 4.8 mg (95 %) as a cream colored solid, mp. 184.5-186°C (lit. 181182°(): la IR (CHC1 ) 3500-2600, 3440, 3350, 3000, 2960, 2940 3 1695, 1635, 1595, 1560, 1530, 1450, 1420, 1405, 1255, 11 6 0 , 1 0 8 0 , 1 0 6 0 , 1 0 0 0 , 9 8 5 cm - l ; l H- NM R (CD C1 ) o 1 3 . 2 3 12. 0 (broads, lH, -co 2H), 10.81 (broads, lH, pyrrole NH), 8.06 (broads, lH, NH), 7.59 (d, HI, J = 9.3 Hz, benzoxazole aromatic), 7.06 (m, lH, pyrrole), 6.94 (m, lH, pyrrole), 6.73 (cl, lH, J = 9.3 Hz), 6.30 (m, lH, pyrrole), 4.26 (dt, lH, J = 3.1, 7.2 Hz, -OCH- benzoxazole side), 3.70 (dd, lH, J = 2.1, 10.2 Hz, -OCH- pyrrole side), 2.73-3.45 (m, 3H, -CHCO- and -CH 2 - benzoxazole), 2.96 (s, 3H, NCH 3 ), 1.00-2.00 (m, 9H), 0.71-1.03 (m, 12H, CH 3 ) ; 13 c-NMR (CDC1 ) o 193.8, 168.0, 165.9, 150.6, 141.5, 140.5, 3 -129133.0, 124.4, 116.7, 116.25, 110.0, 108.2, 98.4, 97.6, 72.6, 68.3, 43.4, 35.0, 32.4, 32.2, 29.9, 28.6, 28.2, 25.7, 25.4, 16.1, 13.1, 11.35, 10.75; 184); [a]D = -55° (C C = 0.01 g/mL, CHC1 ); 3 mixed mp. = 0.007 g/mL, CHC1 3 ) (lit. (182.5-56°c, mass spectrum (75 eV) m/e: 523.270 (calcd. 523.268), 479, 318, 274, 123. An a 1 . ca 1 c d . f o r C ~, 8.02. Found: H N 0 : 29 37 3 6 C, 66.61; C, 6 6 . 51 ; H, 6.96; H, 7 . 1 3 ; N, 7.78. 53 -130- References and Notes 1. For papers on the structural determination of A-23187 see: (a) ivl. 0. Chaney, N. D. Jones, and J. L. 0ccolo~itz, J. Am. Chem. Soc., ~~' 1932 (1974); (b) C. M. Deber and D. R. Pfeiffer, Biochemistry, 15, 132 (1976); ~l. 2. (c) M. 0. Chaney, N. D. Jones, and Debono, J. Antibiot., ~~' 424 (1976). We are indebted to Dr. Noal Cohen of Hoffrnan-LaRoche, Inc. for a generous gift of hydroxy acid 14. C. T. Goodhue and J. R. Schaeffer, Biotechnol. Bioeng., 13, 302 (1971). 3. For example, see: Act a, 4. A. S. Masamune, Aldrichchimica ! ! , 2 3 (19 7 8) . E. A. Fehnel and M. Carmack, J. Am. Chern. Soc., 70, 1813 (1948). 5. G. Stork, A. Brizzolara, H. Landesman, J. Szrnuszkovicz and R. Terrell, J. Am. Chem. Soc., 85, 207 (1963). 6. J. W. Lewis and A. A. Pearce, J. Chem. Soc., B, 863 (1969). 7. S. Danishefsky, P. F. Schuda, T. Kithara, and S. S. Etheredge, J. Arn. Chern. Soc., 99, 6066 (1977). 8. (a) M. F. Ansell and M. H. Palmer, Q. Rev. Chern. Soc., ~~' 211 (1964); (b) V. I. Staninets and E. A. Shilov, Russian Chem. Rev. Engl. Transl., 40, 272 (1971); -131- (c) E. Demole and P. Enggist, Helv. Chim, Acta, 456 (1971); ~~' (d) E. J. Corey, M. Shibasaki, and J. Knolle, Tetrahedron Lett., 1625 (1977). 9. H. Hauptmann and M. Mader, Svnthesis, 307 (1978). 10. J. White and M. McGillivray, J. Org. Chem., 4348 (1978); ~~' R. M. Silverstein, E. E. Ryskiewicz, C. \\.i 11 a rd , and R. C. Koe h 1 er , i b id . , 2 0 , 6 6 8 (19 SS) . 11. K. Sato, S. Inoue, and K . Kondo, J. Org. Chem., 2077 (1 97 1); ~~' R. E. Christ and R. C. Fuson, J. Am. Che m. Soc., 59, 893 (19 77 ). 12. K. E. Barnett and K. H. Sohn, Tetrahedron Lett., 17 77 (1 97 2); H. Wang, J. Chapuis, and I. Monkovic, J. Org. Che m., 39 , 104 2 (1974). 13. P. Caramella and G. Cellerino, Tetrahedron Lett., 229 (1974); G. R. Delpierre and M. Lamchen, J. Chem. Soc., 4693 (1963). 14. W. E. Parham, L. Christensen, S. H. Groen, and R. ~!. Dodson, J. Org. Chem., 29, 2211 (1964); W. E. Parham and S. H. Groen, ibid., 29, 2214 (1964). 15. E. E. Smissman, R. A. Schnettler, and P. S. Portoghese J. Org. Chem., ~Q, 797 (1965). 16. (a) E. Arundale and L. A. Mikeska, Chem. Rev., SOS (1952); (b) D. R. Adams and S. P. Bhatnagar, Synthesis, 661 (1977). 17. E. E. Smissman, J. Org. Chem., 797 (1965). -132- 18. L. Fieser and L. Fieser, "Reagents for Organic Synthesis," Vol. 1, John Kile y and Sons, New York, 1967, p. 729. 19 . For relevant di s cussion of similar systems see: H. Booth, Tetrahedron Lett., 411 (1965); (a) (b) J. B. Lambe rt and J. E. Goldstein, J. Am. Chem. Soc., 9 9 , 5 689 (19 78 ) 20. E. E. Smis s man and D. T. Kitiak, J. Org. Chem., 25, 47 1 (1 960) ; A. T. Blo om quist and J. Wolinsk y , J. Am . Chem. Soc., 7 9 , 6025 (1957). 21. A. T. !'\ e s s, R. H. Han n , and C. S. Hudson, J. Am. Chem. Soc. , 66, 6 6 5 (1 9 4 4) . 22. P. E. Pfeff e r, L. S. Gilbert, and J. N. Chirinko, J. Or g . Ch em ., 3 7 , 4 51 (19 72 ). 23. N. J. Jor ge nson, Or g . React.,~~' 1 (1970). 24. N. T. Anh and 0. Eisenstein, Naur. J. Chem., 1, 61 (1 977 ). 25. S. Hanessian and P. Lavalle, Can. J. Chem., 53, 2975 (1 97 5 ) . 26. C. F. Lane, Aldrichimica Acta, 8, 20 (1975); S. Krishnamurthy and K. L. Thompson, J. Chem. Educ., ~~' 27. 778 (19 7 7). R. R. Ratcliffe and R. Rodehurst, J. Org. Chem., 35, 4000 (1970). 28. M. Kainosho, K. Ajisaka, W. H. Pukle, and S. D. Beare, -133- J. Am. Ch em. Soc . , 29. ~ ':., V. Dryanska and C. Ivanov, Dakl. Bolg. Akad. Nauk . , 23, 1227 (1970); W. Borsche and W. Doeller, Justus Liebigs Ann. Chem., 30. 5 9 24 ( 19 7 2) . ~~~' 53 (1939). A. J. Meyers, D. L. Temple, R. L. Nolen, and D. Mihelich, J . Org. Chem., 39, 27 78 (1974). 31. E. J. Core y and A. Venkateswarlu, J. Am. Chem. Soc., 94, 6190 (1972). 32. For a review see J. D. Morrison and H. S. Mosher, 11 As ym met r i c Organ i c Re a c t i on s , 11 Prent i c e - Ha 11 , Inc . , Washin gton, D. C., 1976, pp. 81-132. 33 . A similar condensation using the O-!-butyl ether of !Z was reported to give a 9:1 ratio of Cram/anti-Cram product; 34. W. C. Stille, private communication. G. A. Stork and S. R. Dowd, J. Am. Chem. Soc., 85, 2178 (1963). 35. Th. Cuvigny, M. Larcheveque, and H. Norrnant, Justus Liebigs Ann. Chem., 719 (1975) . 36. W. S. Johnson, J. C. Collin, Jr., R. Pappa, M. B. Rubin, P. J. Kropp, W. F. Jones, J. E. Pike, and W. Bartmann, J. Am. Chem. Soc., 85, 1409 (1963). 37. W. E. Parham and~- L. Anderson, J. Am. Chem. Soc., 70, 4187 (1948). 38. K. Kato, Y. Hirata, and S. Yamamura, Tetrahedron, 27, 5987 (1971). -134- 39. The construction of the benzoxazole 28 was carried out by Mr. Terry Taber. 58 40. The synthesis of ketone 27 and the aldol to form 34 were carried out by Dr. William A. Kleschick. 58 41. For a relevant example see: T. Nakata, G. Schmid, B. Vranesic, M. Okigawa, T. Smith-Palmer, and Y. Kishi, J. Am. Chem. Soc., 42. H. 0. House, D. !22, 2933 (1978). s. Crumrine, A. Y. Teranishi, and H. D. Olmstead, J. Am. Chem. Soc. , 95, 3310 (1973). 43. G. N. Dorofeenko, A. P. Kucherenko and N. V. Prokofeva, Zh . 0 ks ch . Khim . , 3 3 , S8 6 ( 1 9 6 3) . 44. (a) W. A. Kleschick, C. T. Buse, and C. H. Heathcock, J. Am. Chem. Soc., 99, 247 (1977); (b) C. T. Buse and C. H. Heathcock, ibid., 99, 8109 (1977). 45. H. J. Anderson and S. J. Griffiths, Can. J. Chem., ~~' 46. 2227 (1967). The unstable aldehyde~~ was always distilled immediately prior to use. For its preparation see: W. H. Pirkle and W. V. Turner, J. Org. Chem., 40, 1617 (1975). 47. We are indebted to Dr. Manuel Debono of the Eli Lilly Company for a generous sample of A-23187. 48. + Bio-Rad AG SOW-XS 20-50 mesh sulfonic acid H form resin was used after washing with methanol and azeotropic removal of residual solvent with toluene. -135- 49. G. S. Fanken and W. S. Johnson, J. Am. Chem. Soc., 74, 831 (1952). 50. The yield was 23% based on aldehyde 38b being 80% of the mixture of aldehydes used. 51. An authentic sample of lb was prepared from la by the method of Eschenmoser: H. Brechbiihler, H. Blichi, E. Hatz, J. Schreiber, and A. Eschenrnoser, Helv. Chim. Acta, 52. ~~' 1746 (1965). P. A. Bartlett and W. S. Johnson, Tetrahedron Lett., 4459 (1970). 53. It should be noted that the optical rotation reported la for la is incorrect. The correct rotation (M. Debona, Eli Lilly) is [a]~ 5 -56° (C = 1, CHC1 3 ). We have 22 • • • [ a ] D, k dl y h t h e optical rotation, is mare f oun d tat concentration dependent (CHC1 3 ): C = 2.76 (-58.6°), C = 1.38 (-58.3°), C = 1.00 (-56.0°), C = 0.69 (-54.8°), C = 0.53 (-53.4°), C = 0.27 (-45.1°), C = 0.133 (-36.1°). 54. For other syntheses of the Prelog-Djerassi lactones see: (a) S. Masarnune, C. U. Kim, K. E. Wilson, G. 0. Spessard, P. E. Georghiou, and G. S. Bates, J. Am. Chem. Soc., 97, 3512 (1975); ibid., 101, 1315 (1979); Fukuyama, ibid., (b) G. Stork and V. Nair, (c) J. D. White and Y. !~!, 226 (1979). Note: Structure ! of the Stork paper is inverted at c3 relative to the Prelog-Djerassi lactones. -136- 55. S. C. Watson and J. F. Eastham, J. Organomet. Chem., ~' 165 (1967). 56. £-Dioxane was distilled from sodium-benzophenone ketyl. 57. In subsequent studies this yield could be improved to 60% by adding 0.1 equivalent of triethylamine to the reaction. 58. D. A. Evans, C. E. Sacks, W. A. Kleschick, and T. Taber, J. Am. Chem. Soc., accepted for publication. -137- CHAPTER IV Studies on Pyrroles -138- Besides A-23187, ~' only one other pyrrole containing ionophore is known, X-14547A (2) . 1 Isolated by Westley and coworkers, its structure has been solved by X-ray anal1 ysis. As investigations for new antibiotics possessing 10n transporting qualities continue, new pyrrole containing molecules will undoubtedly be found. For this reason, general me thodology for the introduction of a pyrrole unit is desirable. 01/ 5 e H 0- I 0 N 1 COOH NHCH l 3 A i• Me 3 JO ,,,,Me (o-i , H 0 ' , ':,...,-- '''.I , = I H CO H ( u· l l} Et ll I! " ~Et 26 / 1 H 2 1 In general, pyrryllithium 3a alkylates on nitrogen 2 and carbon. Addition of esters or acid chlorides to 3a or 3b gives both C-2 and C-3 acylated products. To be useful, complete control of the regiochemistry (ie, alkylation or acylation at C-2) is important. Specifically, for both A-23187 and X-14547A, control of the acylation reaction is necessary. An initial investigation of the pyrrylcuprate ~' as shown is Scheme I, was less than satis- -139- factory. Although cuprates are known to give ketones by reaction with thioesters or acid chlorides, 3 cuprate 4 gave only poor yields of the desired pyrrole ketone 6. Scheme I 3 0 2 Ot CuLi-Me 2 s + ~ 0 2 I 4 ~l R ~~' R = Cl b ' R = SCH-.) 3a, M = Li b, M = Mg 6 We therefore considered blocking the nitrogen and generating the 2-pyrryllithium with a strong base. Such a blocking group, in order to be compatible with sensitive functionality generated during a synthesis, should be easily removed under mild conditions. A search -140- of the literature revealed that the only N-blocked pyrryllithium known was the N-methyl pyrrole. 4 the meth yl was not removable . by Sundberg 5 and Levy 6 Unfortunately, However, based on studies with N-blocked indole systems, we chose to investigate the methox yethoxymethyl (MEM) blocking group . 7 . 8 wit .h T reatment o f pyrro 1 e potassium ~1EM-Cl gav e the protected pyrrole 7 as shown in Schem e I I. Reaction of Z with !-but yllithium under carefully controlled 9 condition s then gave good yields of the lithiated pyrrole 8 ( s ee Ta b le 1). Treatment of pyrryllithium 8, under con- Schem e II Q I CH 2 'o I cw__.,, OCH 3 CH 2 7 2 8 ditions which gave 65% lithiation (experiment 2), with electrophiles proceeded well as shown in Scheme III. -141- Table 1. -- - -·~--- Metalation of 7 and Quenching With CH 3OD. ~ Experiment Base (equiv) T % Mass Solvent Recovery ether a 80 68 65 1. t-BuLi (1. 1) 4-25 2. t-BuLi (1. 7) -10-25 THF 60 3. n-BuLi ( 1. 2) -30 THF C 4. t-BuLi (1. 1) -30 5. t-BuLi ( 2. 0) -30 ether a ' d ether a ' e a 8 1• s 1• n s o 1 u b 1 e . LM+ 1) + . of THF. 9 Sc ( o C) Conv;rsionb 85 75 80 100 b By ma s s - s p e c t r a 1- an a 1y s 1• s o f ('!) + an d i' c~-Butyl incorporated into molecule. d0.5 equiv el . O equiv of THF. 9 Conversion to the cuprate ~ was affected by treatment • h cuprous b rom1" d e- d"1methy • 1 su lf 1" d e. 4 b ' lO wit React1on • • h wit !-butyl thiopropionate then gave a high conversion to pyrrole ketone 10 as shown in Scheme IV. Unfortunately, attempts to remove the MEM blocking group from any of the pyrroles under standard conditions was unsuccessful. 7 These studies demonstrate the feasibility of generating an N-blocked pyrryllithium or pyrrylcuprate and using it to introduce a pyrrole ring. Studies should be continued to develop a protecting group which can be easily and selectively removed. -142- Scheme III ------~--- py~CH 3 8 r;>=o, 25% OH (3B) OH PY~ a -Based on 65 g,o maximum PY= 0 (4 I MDI Scheme IV ~-~~~~~~ s (\cuLi·S(CH) I 2 CH 2, 3 2 CH 3 OCH CH 0/ 2 2 9 10 + -143- Experimental_Section General. Diethyl ether and tetrahydrofuran (THF) were dried by distillation from benzophenone ketyl under nitrogen. Pyrrole was dried by distillation under nitrogen from calcium hydride. All commercial alkyllithium reagents were titrated by the procedure of Watson and Eastham. 11 Unless otherwise specified all reactions were run under an inert atmosphere of nitrogen. Melting points were determined with a Btichi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded on a Beckman IR-4210 or Perkin El mer 727B spectrophotometer and are reported in cm -1 . Proton spectra were recorded on a Varian Associates EM-39 0 or T-60 spectrophotometer. Chemical shifts are reported in parts per million on the 6 scale relative to tetramethylsilane internal standard. reported as follows: Proton data are chemical shift, multiplicity (s singlet, d = doublet, t = = triplet, q = quartet, m = multiplet), integration, coupling constants (Hz) and interpretation. Carbon-13 nuclear magnetic spectra were recorded on a Varian Associates XL-100 (25.2 MHz) spectrometer and are reported in parts per million on the 6 scale relative to tetramethylsilane internal standard. -144- Mass spectra were recorded on a DuPont MS 21-492B or a Kratos MS 25 (equipped with a DS SOS data system) mass spectrometer. Mass spectral analyses as well as combustion analyses were performed by the California Institute of Technology Microanalytical Laboratory. 1- [ (2-Methoxyethoxy)methyl]azacyclopenta-2,4-diene( 7). ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ In a three-neck, 100 mL, round-bottomed flask with a magnetic stirring bar, nitrogen inlet, reflux condenser and constantvolume addition funnelwereplaced potassium metal (3.8 g, 0.0 98 mol) and THF (30 mL). The mixture was heated to reflux and freshl y distilled pyrrole (6.7 mL, 0.097 mol) in THF (20 mL) was added over 10 min. be gan to form and hydrogen ,,;as evolved. A white precipitate Refluxing was continued until all the potassiumKas consumed (ca. 3 h). The suspension was cooled in an ice bath and MEM-chloride (1 0 . 3 mL, 0. 09 mol), in THF (20 mL) was added over 20 min (mi 1 d exotherm) . The cooling bath was removed and the reaction brought to 25°C. After 1 h the reaction (pumpkin colored) was filtered to remove salts. The THF was removed in vacuo and the residue dissolved in ether (100 mL). After washing the organics with water (2 x 20 mL), drying (MgSO 4 ), filtering and removing solvent in vacuo the oil was distilled to give a colorless oil, bp. 85-86°C (4 mm), 4.01 g (35%): IR (neat) 3100, 2930, 2810, 1490, 1450, 1365, 1270, 1100, 1080, 1070, 850, -145- -1 NMR (CDC1 3 ) o 6.79 (t, 2H, J = 1.1, pyrrole C-2H), 6.18 (t, 2H, J = 1.1, pyrrole C-3H), 5.23 (s, 2H, 730 cm -NCH2O-), 3.47 (s, 4H, -OCH2CH2O-), 3.29 (s, 3H, -OCH3). Lithiation of pyrrole 7. In a dry two-neck round~~~~~~~~~~~~~~~~~~~~~~~~ bottomed flask with a magnetic stirring bar, nitrogen inlet and septum ~ere placed pyrrole Z (1 equiv), ether (2 mL) and THF (1.1 equiv). The solution was cooled to -78°C and !-butyllithium (2.2 equiv, 1.30 ~ in pentane) was added. After stirring for 10 min the reaction was warmed to -30°C for 0.5 h, then cooled to -78°C. Quenching with CH 3OD indicated 99.7% metallation with 78 % recovery of material. Reactions with pyryllithium 8. All reactions were ~~-~~~~~~-~~~~~~~~~~~~~~~~~~~~ run with pyrryllithium generated in pure THF which gives only ca. 60 % metallation. Yields should be higher utilizing the above lithiation procedure. 1-Bromohexane. 1-Bromohexane (0.13 mL, 0.9 mmol) was added to pyrryllithium in THF (3 mL) at -78°C, then warmed to 25°C for 8 h. Product isolation by ether dilution wash- so ), filtr at ion removal of 2 4 solvent, and flash chromatography (silica gel, 17% ethyl ing with water, drying (Na acetate/hexane; TLC, Rf= 0.31) gave a colorless oil (120 mg, 56%): IR (CHC1 3 ) 3030, 2940, 2870, 1490, 1480, 1380, 1290, 114 0 , 11 0 0 , 1 0 6 0 , 8 7 0 cm - l ; l H- NMR (CD C1 3 ) o 6 . 6 4 ( d d , 1 H, J = 2.4, 1.5 Hz, pyrrole), 6.06 (t, lH, J = 3 Hz, -146- pyrrole), 5.81-6.04 (m, lH, pyrrole), 5.19 (s, 2H, -NCH 2O-), 3.47 (s, 4H, -OCH 2 CH O-), 3.34 (s, 3H, -OCH ), 2 3 2.57 (t, 2H, J = 8.1 Hz, pyrrole -cH 2 -), 1.49-~l.78 (m, 6H), 1.10-1.42 (m, 6H), 0.87 (t, 3H, J = 6 Hz, CH ). 3 Anal. calcd. for c 14 H25 No 2 : C, 70.25; H, 10.53; N, 5.85 . . Found: Butanal. C, 70.55; H, 10.26; N, 5.97. Butanal (0.09 mL, 1.0 mmol) was added at -78°C, stirred 10 min and saturated ammonium chloride was added. The product was isolated as above. (silica gel, 80% ether/hexane; Flash chromatography TLC, Rf= 0.29) gave a col- orless oil (92.1 mg, 50%): IR (CHC1 3 ) 3500, 3030, 2990, 2960, 2900, 1495, 1470, 1410, 1380, 1290, 1100, 1060, 760 cm- 1 ; 1 H-NMR (CDC1 ) 6 6.70 (dd, lH, J = 2.4, 1.3 Hz, pyrrole), 3 6.20 (m, lH, pyrrole), 6.10 (m, lH, pyrrole), 5.36 (AB quartet, 2H, J = 10.5 Hz, -NCH 2O-), 4.70 (t, lH, J = 6.0 Hz, pyrrole -CH-), 3.43 (s, 4H, -OCH 2CH 2O-), 3.26 (s, 3H, -OCH ), 3.0 (broads, lH, -OH), 1.70-2.05 (m, 2H, -OCHC£!. 2 -), 3 1.19-1.67 (m, 2H, -CH 2 -), 0.95 (t, 3H, J = 7.2 Hz, -CH 3 ). Anal. calcd. for N, 6.16. Found: c12 H21 NO 3 : C, 63.84; y-B_y__:t_y_r__,o)_a_c_t_o_p._e C, 63.41; H, 9.14; H, 9.31; N, 6.25. y-Butyrolactone (0.07 mL, 0.9 mmo~ was added at -78°C, stirred 10 min and quenched. Isolation as above and flash chromatography (silica gel, ethyl acetate; TLC, Rf= 0.25) gave a colorless oil ~8.5 mg, 22%): IR (CHC1 ) 3640, 3450, 3010, 2940, 2890, 1730, 1650, 3 -1471540, 1480, 1420, 1300, 1220, 1090, 1050, 860 cm-l; 1 H-~MR (CDC1 3 ) o 7.00-7.15 (m, 2H, pyrrole), 6.22 (dd, lH, J = 3.0, 3.6 Hz), 5.74 (s, 2H, -NCH 2O- ), 3.35-3.75 (m, 4H, OCHzCHzO and -C!::!_z-OH), 3. 32 (s, 3H, -OCH3), 2. 92 (t, 2H, J = 6.6 Hz, -COCH 2 -), 2.48 (broa~ s, lH, -OH), 1.95 (pentet, 2H, J 6.6 Hz, -f_H -cH OH). 2 2 Anal. calcd. for c H No : C, 59. 72; H, 7 . 93; 12 19 4 N, 5.8 0 . Found: C, 59.83; H, 7.60; N, 5.91. = 1- { [(2-Methoxyethoxy)methy l] azacyclopenta-2,4-dien~-~~~~ ~~~~~ ~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~ 2-yl}-1-propanone_(l0) . The pyrryllithium (0.54 mmol) was formed as in the general procedure. It was added to a solution of CuBr·l'-le 2 s (0.052 g, 0.27 rnrnol) in ether (2 mL) and dimethylsulfide (1 rnL) via cannula. After 10 min the reaction was warmed to 0°C for 0.5 h (greenish solution). !-Butylthiopropionate (0.09 mL, 0.57 mmol) was added. After 2 h the brown heterogeneous reaction was quenched with saturated ammonium chloride and product isolated by extraction with ether (3 x 30 mL). The organics were washed with 1:1 ammonia/saturated ammonium chloride (2 x 30 mL), water (1 x 30 mL), dried (Na 2 so 4 ) and filtered. Removal of solvent gave an oil which was purified by flash chromatography (silica gel, 30% ethyl IR (CHC1 3 ) 3010, 2 94 0, 2880, 2820, 1650, 1525, 1460, 1410, 1375, 1295, 1 -1 tt-NMR (CDC1 ) o 7.09 1220, 1130, 1085, 1050, 930 cm . 3 ' acetate/hexane) to give 0.039 g (69%): -148- (t, lH, J = 3 Hz, pyrrole), 6.99 (dd, lH, pyrrole), 6.16 (dd, lH, J J = 4.5, 1.5 Hz, = 4.5, 3 Hz), 5.79 (s, 2H, -NCH 0-) 2 ' 2.78 (q, 2H, J J = 7.2 Hz, = 7.2 Hz, pyrrole -CH 2 CO-), 1.14 3H, H, 8 . 11 ; N -CH 2 c~ 3 ). An a 1 . . ca 1 c d. for Cl l Hl 7 NO : 3 6.63. (t, Found: C, 62.48; C, 6 2 . 54 ; H, 8.12; N, 6.27. ' -149- References and Notes 1. J. W. Westley, R. H. Evans, Jr., C.-M. Liu, T. Hermann, and J. F. Blount, J. Am. Chern. Soc., 100, 6784 (1978). 2. R. A. Jones and G. P. Bean, "The Chemistry of Pyrroles," Academic Press, Ne~ York, 1977, pp. 173-187. 3. G. H. Posner, Organic Reactions, 22, 253 (1975); R. S. Anderson, C. A. Henrick, and L. D. Rosenblum, J . Am . Chem . So c . , 9 6 , 3 6 5 4 ( 1 9 74 ) . 4. (a) D. J. ChadKick and C. Kilke, J. Chem. Soc., Perkin Trans. 1, 88 7 (19 77 ); (b) N. Gjos and S. Grono~itz, Acta Chern. Scand., 25, 2596 (1971). 5. R. J. Sundberg and H. F. Russell, J. Org. Chern., 38, 3324 (19 73). 6. A. B. Levy, J. Org. Chern., 43, 4684 (1978). 7. E. J. Corey, J.-L. Gras, and P. Ulrich, Tetrahedron Lett., 809 (1976). 8. E. P. Papadopouka and K. I. Y. Tabello, J. Org. Chern., 33, 1299 (1968). 9. R. K. Beeckman, Jr. and K. J. Bruza, Tetrahedron Lett., 4187 (1977). 10. For p rep a rat i on o f Cu Br • ( CH 3 ) 2S ,s e e H. 0 . Hou s e , C. - Y. Chu, J.M. Wilkins, and M. J. Urnen, J. Org. Chern., 40, 1460 (1975). 11. S. C. Watson and J. F. Eastham, J. Organornet. Chern., 9, 165 (1967). -150- APPENDIX I Thermochemical Estimates of 1,7-Dioxaxpiro[S.S]undecane Ring Systems -151- Thermochemical esti~ates for the relative stability of the spirane configurations and conformations are based on standard A-values for cyclohexanes. 1 Where necessary 2 corrections have been applied for the anomeric effect. ' 3 These values come from the investigation of Gelin and coKorkers on 2-alkoxy pyrans. 4 All numerical values 1n this section are free energy terms and are expressed 1n kcal/mol. ScheJile I - H R configuration :_;-O~ H 0 OH ? ~ 1 • I R 1l jlconformat ion H CH 3 R OH • 0 0 2 H ~E~:~ R H OH OH -152- In the general case, spirane 1, R =His a suitable example (Scheme I). If 1 is arbitrarily chosen as the ground state (zero level) then the relative stability of epi-1, ~' and epi-~ can be computed by tabulating changes usin g positive values for destabilizing and negative values for stabilizing effects relative to!· For example, comparison of epi-! (change of configuration at C-6) with 1 reveals t~o interactions not present in 1. C-8 ther~ i s no~ an axial substituent. of +3.0, Namely, at This costs a net +0 .8 for one 1,3-diaxial carbon-hydrogen interaction (gauche butane) and +2.2 1 for one 1,3-diaxial C-O Also, examination of C-6 and use of 3 and 4 as mod e l s gives another +2.3 4 destabilizing effect (0.6 interaction. OCH 3 c+CH3 --t:,G = +2.3 q O C H3 3 d: CH 3 0 40CH3 t:,G = +O. 6 -153- for the anomeric effect, 1.7 for an axial methyl) for a net of +5.3. This is summarized in Table 1. For~ going to 2 (conformational change in ring A) there is a change at C-2 and C-3. At C-2 there is now an axial methyl group 1,3-diaxial to a methylene. This 1 (some estimates are lS destabilizing by at least +4.5 as high as 5. 5) . Also, at C-6 there is again the anomeric 4 effect of 0. 6 + 1. 7 or 2. 3. This gives a net destabiliza- tion of at least 6.8 as summarized in Table 1. The rest of the calculations are summarized in Tables 1, 2 and 3. Some of these values deserve a somewhat expanded explanation. For example, for spirane ! (R = CH 3 ) going to epi-! a stabilizing interaction of 1.3 is realized by the change at C-9. Normally an axial-methyl to equatorial-methyl is worth 1.7 in stabilization, however, here only one gauche interaction is being relieved, worth 0.8. Also, using 7 and 4 as models - tiG H 7 we H = +1.9 H calculate that for a methyl 1,3-diaxial to an oxygen lone pair there is 1.9-0.6-0.8 or 0.5 worth of strain energy. -154- This gives a net of -0.8 + (-0.5) or -1.3 stabilization. For C-5 in the transformation of 5 to epi-5 (Scheme II) ~ there is a stabilization of 0.5. ~ This is because in 5 Scheme I I ~-~~-~- ~~ CH 3 - H CH 3 configuration OH 11 '_/ OH CH 5 H OH 3 H CH 3 HO OH 3 :E~:~ )j jl conformation CH 3 CH H CH 3 . OH H H H H OH :P~:~ 6 there is a trans-1,2 diequatorial methyl-methyl interaction (destablizing ~ by 0.8), but in epi-~ there is a trans-1,2 diequatorial methyl-oxygen interaction. Using 8 as a model and allowing 1.3 for the axial methyl to equatorial methyl -155- H .. t:iG = -0.4 as Kell as 0.6 for the anomeric effect (as explained above) Ke get a net destabilization due to the methyl oxygen gauche interaction of -0.4- (-1.3 + 0.6) or 0.3. Thus, this interaction stabilizes epi-~ over 5 by 0.8-0.3 for a net of 0.5. Although the application of these models to such a rigid system as 5 is not without risk, the fact that we are not using absolute numbers but rather differences should tend to cancel most of the errors inherent in applying a conformationally mobile model to a conformationally locked system such as~Since we are using only relative numbers, no intersystem comparison is possible [ie., epi-! (R = CH 3 ) is not necessarily more stable than epi-! (R = H)]. However in all three systems the desired isomer (1 and 5) is always favored by a substantial margin. -156- Table 1. (R = H) --~~~-- Carbon No. 1 epi-1 2 epi-2 0 0 0 0 0 2.3 3.0 +5.3 4. 5 2. 3 0 +6.8 0 2. 3 Carbon No. 1 epi-1 2 epi-2 2 0 0 0 0 0 0 0 0 2. 3 3.0 -1. 3 +4.0 4. 5 -1. 3 2.3 0 0 +5.5 0 0 ... X 2. 3 0 0 +4.6 5 epi-5 6 epi-6 0 0 0 0 0 0 -0 0 0 -0. 5 2.3 3.0 -1. 3 +3.3 4.5 -1. 3 -0.5 2.3 0 0 0 2 X 2.3 0 0 +4.6 2 6 8 Net (relative to 1) Table 2. (R = ~~~~~~- 2 X 0 +4.6 CH 3 ) 3 6 8 9 Net (relative to 1) ') Table 3. ~-~~~~- Carbon No. 2 3 5 6 8 9 Net (relative to 5) 0 0 +5.0 -157- References and Notes 1. E. L. Eliel, "Stereochemistry of Carbon Compounds," McGraw-Hill Book Co. Inc., New York, 1962. 2. (a) E. L. Eliel and C. A. Giza, J. Org. Chem., 3754 (1968); ibid., 3. ~~' ~~' (b) G. 0. Pierson and 0. A. Runquist, 2572 (1968). h' . A. Szarek, Ed., "Anomeric Effect: Origin and Consequences," American Chemical Society, Washington, D. C., 1979. 4. ii. Gelin, Y. Bahurel and G. Descotes, Bull. Soc. Chim. France, 3723 (1970). -158- APPENDIX II 13 c-NMR Spectral Catalog for Chapter II -159- Discussion In general, assignments were made based on offresonance decoupling experiments and chemical shift data of models available in the literature. 1 For 10 and 11 ambiguities in assignment were resolved by calculation based on a hydrocarbon substitution system utilizing equation 1 2 for the saturated carbons and the method of (1) RobertsJ for the unsaturated carbons. The results are tabulated in Table 1. Assignments for!~ and 14 as well as for 20a and 20b were made by intersystem comparisons. The assignments for spiroketals were based on intersystem comparisons, 4 related methyl cyclohexane systems, multistriatin models, 5 heteroatom substituted cyclohexanes 6 and deuterium incorporation studies. 7 All numerical values in this section are reported in parts per million on the 6 scale relative to tetramethylsilane internal standard, and are reported as chemical shift and multiplicity. -160- X X 3 2 4 1 o ex 8 Carbon No. Cale. 1 62.1 6 2. 0, t 7 0. 1, t 2 32.S 31. 4, t 28.6, t .) 121.4 124. 1, d 1 22 . 7 , d 4 139.9 134. S, s 133.9, s s 42.2 35.0, t 3 2. 4, t 6 59.9 60. 1, t 68. 7, t 7 20.4 23.4, q 2 3. 9, q 8 aromatic a -Ipso aromatic. = OH) 11 (X = OCH Ph) 2 72.8, t a 138.9, s ,127.3, d, 127.5, d, 128.2 -161- 7 12@,~HzO 11 ~H3 l 0 3 6 2 l+ 5 - OH oCHr--@ 12 o· Carbon No. 1' 6 68.7, t 2' 5 33.3, t· 3 6 9. 3, d 4 36.1, d 7 14.01, q 8 7 2. 3, t· 9 138.5, s 10, 1 1 , 12 128.3, d· 127.3, d ' ' ' 33.9, t 7 3. 0, t 127.5, d· ' -162- ~,y r3,; l 0 4 ~6 l( oxo 8 Carbon i\ 0. 9 R ( 6) 13 OH 14 Br 1 59. 4, t· 2 35. 3, t 3 7. 2, t .) 72 . 2 , d 71 . 9 , d 4 30. 0, d 29.8, d 5 2 7. 9, t 2 8. 4, t 6 59.4, t· ' 98. 1, s 59.6, t 34.5, q; 19. 3, q ' 7 8 9 10 J 14. 7, q 5 9. 6, t 60.0, t 5 9. 4, t 98. 2, s 13.4, q; 14. 1, q 18.4, q -163- R 20a -OH ( 0) 9 OSO CH 2 3 20b Br 1 108.2, s 108.5, s 108.8, s 2 7 7. 2, d 7 5. 6, d 7 7. 3, d .) 6 7. 0, t 66. 7, t 66.9, t 4 65. 2, t 71. 4, t 3 6. 4, t 5 3 7. 9, d 3 5. 9, d 38. 6, d 6 26.4, q 2 6. 3, q 26.3 7 2 5. 2, q 2 5. 1, q 2 5. 2, q 8 12. 1, q 11. 4, q 14. 4, q Carbon 9 ;\Q. 3 7. 0, q ' q -164- H 4 Rl 5 CH (13) 3 CH 2OH (12) H ~ 31 H OH H 22a CH (13) 3 OH CH (14) 3 Carbon '!'Jo. Rl' H R2, CH 2OH ( 12) R3' H 1 96. 0, s 95.9, s 9 5. 8, s 98.0, s 2 66. 8, d 61.1, d 6 9. 7, d 71.6, 71. 2, d 3 31. 1, t~ 30.8, d 2 6. 5, t~ 28.0, 29.4, d 4 19.0, t~ 30.0, t 18. 2, t~ 3 5. 5, 5 3 5. 1, 26.6, t 35.1, tQ 3 2. 8, aQ 6 66.8 67.1 69.7 71. 6, 71. 2, d 7 31. 1 30.8 26.5 2 8. 0, 29.4, d 8 19.0 30.0 18.2 26. 5, t 9 35.1 26.6 35.1 2 6. 0, tQ 10 3 8. 4, t 36.2, t 66.1, t 64. 4, t 11 38.4 36.2 66.1 64. 4, t 12 5 9. 4, t 59.1, t 13 14 tQ 11.1, q t C 12.2, 11. 4, q- b 16. 2, q- 2 bB d a • • - y euter1at1on -By analogy to methyl cyclohexanes. studies. £Resonance at 11. 4 is on the dimethyl ring. 2 -165- References and Notes 1. G. C. Levy and G. L. Nelson, "Carbon-13 Nuclear Magnetic Resonance for Organic Chemists," John Wiley and Sons, New York, 1972. 2. L. P. Linderman and J. Q. Adams, Anal. Chem., ~~' 1245 (1971). 3. D. E. Dorman, M. Jautelat, and J. D. Roberts, J. Org. Chern., 4. ~~' 2757 (1971). D. Doddrell, C. Charrier, B. L. Hawkins, W. 0. Crain, Jr., L. Harris, and J. D. Roberts, Proc. Natl. Acad. Sci., ~z, 1588 (19 70); D. K. Dalling and D. M. Grant, J. Am. Chem. Soc., 89, 6612 (1967). 5. G. T. Pearce, W. E. Gore, and R. M. Silverstein, J. Mag. Res., 6. ~2, 497 (1977). J. R. Dernember, R. B. Greenwald, and D. H. Evans, J. Org. Chem . , ~?, 3518 (1977); E. Havinga, ibid., 7. ~~' J. A. Hirsch and 455 (1976). The spiroketals ~~~and~! were refluxed with DCl/D 20 to give the C-5, C-9 deuteriated spiranes. -166- APPE;--;DIX III 13 c-N:'-1R Spectral Catalog for Chapter II I -167- Discussion Most assignments are based on chemical shift data, 1 off-resonance decoupling experiments and internal consistency ~ithin a sequence of transformation. For the sulfur containing molecules, reference ~as made to studies 2 by Demember and Hirsch. 3 Assignments for metadioxanes also utilized examples in the literature. 4 All numerical values in this section are reported in parts per million on the 8 scale relative to tetramethylsilane internal standard and are reported as chemical shift and multiplicity. -168- lylS 5 2 3 4 R 0 6 7 8 9 Carbon No. R = H R = CH2CH2CO2CH3 1 30. 0, t 31. 0, t 2 43.9, t 36. 0, t 3 207.6, s 209.3, s 4 43.9 31. 3, s s 30.0 31.0, t 6 24. S, t 7 36. 0, t 8 178.9, s 9 52.0, q -169- 0 Carbon Ko. a R = CH 3 ( 9) R = 1-l 31.3, t 1 31. 2, t 2 131.2, d· l 2 4 . 1 , d 131.2, d·, 124.4, d 3 131.2, d· 124.1, d 131.2, d· 124.4, d 4 33.9, d 33. 8, d s 2 9. 6, t~ 2 9. 6, t~ 6 2 S. 3, t 2 S. 3, t 7 30.0, t 2 9 . 7 , t~ 8 173.4, s 179.6, s 9 S1. 4, q ) ' -By comparison of R = CH 3 vs R = H. ' -170- 10 R 0 Carbon :\ 0. R = H R = CH 3 2. 4, t· ' 3 7. 4, d 2 32. 2, t· ' 3 7. 3, d 3 8 2. 8, d 8 2. 7, d 4 35 . 6, d 35.6, d 5 6 32. 2, t . ' 20.6, t 7 28. 5, t 28 . 4 , t 8 179.1, s 173.4, s 1 3 2. 3, t 3 2. 3, t 3 2. 4, d· ' 2 0. 7, t 51.4, q 9 10 70.3, t 7 0. 3, t 11 9 3. 9, t 93.8, t 3 (9) 32.0, t 32.0, d -171- l 0 o.........._,... 6 0 11 Carbon No. Rl R2 OCH 3 (9) = H = Rl = CH 3 (12) R2 = CH 3 (13) 1 a 1 2 . 2 , q- 12.1 2 32.6, d 30.8 3 8 4 . 6, d 84. 7, 84.6Q 4 31. 3, d 31. 3 5 1 2 . 7 , q-a 13. 0, 12. sE. 6 2 9. 0, t 36.8, 36.6Q 7 31 . 9, t 44.6, 44. 4E. 8 1 73.7 , s 9 51.4, q 10 72 . 6 , t 7 2. 5 11 9 3. 8, t 93. 7 212.0 12 2 7. 7, 27.6E. 13 16. 9, 16. 4E. aThese assignments were made by comparison of the diastereomers (R = R2 = CH 3 ) with the ester (R 1 = OCH , R = H) and 1 3 2 assuming the farther a center was from the diastereomer center (C 7 ) ~he smaller the effect. QThe multiplicity of resonances is due to the diastereomers caused by the introduction of the methyl at c7 . -172- 8 X = 0 = OH H, OH H H 1 180. 7, s 68.5, t~ 203.9, s 2 4 2. 2, d 3 7. 3, d 48.7, d 3 6 5 . 5, t 6 7 . 4 , t~ 64. 0, t 4 19. 2, s 19.2, s 19. 2, s 5 133.1, s 133 . 0, s 132.9, s 135.4 129.6 127.6 135 . 4 129.6 127.5 Carbon No. 6' 7 ' 8 y 135.4 129.6 ( 127.5 0 CH 3 (2) 2 6. 7, q 26.8, q 26.7, q CH_ ( 4) J 13. 3, q 13.2, q 10.3, q a -By comparison with aldol adducts 18a and 19a of Chapter 3. -173- ~H3 _ CH 3 Ph 4 I 3 16 9 "o ~ ~ 0 ,s CH 3- - - S i - - O OH N 14 12 13 5 6 7 8 Alcohol Configuration At C-1 a: s 1 7 2. 4, d 71 . 0 , d 2 4 0. 1, d 3 9. 6, d 3 67 . 2 , t 6 7. 4, 4 19. 2, s 19. 2, s 5 132.8, s 132.7, s Carbon Ko. 6' 7 ' 8 135. 4 129.6 ( 127.5 t 135.4 129.6 127.6 9 33. 9, t 33. 7, 10 165.2, s 165.6, s 11, 12 146. 0, s ( 14 0. 7, s 150.4, s 140.8, s 13, 14, 15, 16 124.3 123.9 { 119.4 110.2 124.3 124.0 119.4 110.2 t 26.8, q 26. 9, q 13.4, q 11.0, q -174- ~H3 3 16 1 I~ - ~~II 1 1 / 1s OH OH N 12 ~ l 14 l 3 Carbon ifo. 1 71.1, d 2 39. 2, d 3 66. 0, t 9 33. 2, d 10 165.4, s 11, 12 150.4, s; 13, 14, 15, 16 124.6, 124.2, 119.3, 110.2 CH-.) ( 2) 10. 7, q 140.6, s -175- 8.8 12 7. 3 11 9 . 9 l O 9. 7 3 3.6 0 12 7. 6 11 9. 8 l O 8. 8 8.9 1 3 2. 3 N 7 7. O lo 0 7 0- 4 13 0. 2 12 9. 6 12 8. 2 -176- References and Notes 1. G. C. Levy and G. L. Nelson, "Carbon-13 Nuclear Magnetic Resonance for Crganic Chemists," John Wiley and Sons, New York, 1972. 2. J. R. Demember, R. B. Greenwald, and D. H. Evans, J. Org. Chem., 3. ~~' 3518 (1977). J. A. Hirsch and E. Havinga, J. Org. Chem., ~~' 455 (1976). 4. A. J. Jones, E. L. Eliel, D. M. Grant, M. C. Knoeber, and W. F. Bailey, J. Am. Chem. Soc., ~~' 4772 (1971); F. G. Riddel, J. Chem. Soc. (B), 331 (1970); N. K. Wilson and J. B. Stothers, Topics in Stereochem., 8, 1 (1974). -177- APPEKDIX IV IR and 1 H-:t\':\lR Spectral Catalog for Chapter II -178- Page 38 9b ... :LO + ,. t I ,:o •.o I I I ... ,.o I I ... ,.o I I 11> I ,,' T I. :I j ·1 . ! ' ; , , • I -, I ~. I I- -I I I " I iI r •I - .' i +- ' I i : l !. I :.l l· '' I 1£ I ... , • I ,; 11P ·, !. .0 )l f W . t . ~ l 1'1,,M, 1 ·,-,-~----,,,=--------10 II \l I) I) 16 -179- Page 3 8 OH HO 10b 1.0 1.0 , .o 1'. o _, 7.0 6.0 ,.• , .o 2.0 1.0 ,. i t J •. ,b -180- Page 39 Bz BzO llb s:o ,.o s.c 1.0 , , . . . ! .,. ... i i 7.0 ,.,II I "T' t ,b , .o 1 .0 I I i I I I I I ,, ,__ .. h: -. I ' J I :, I 1 .0 ll • : ,: i: i•' ,. 'i°: >I 1.0 l.O t..o • WA.'t'IUHGJk.- , f IO 11 t, la U • -181- Page 40 OH OBz ~ BzO 12b ,. 2.0 .. .. s:C, u ""' T l 7.0 .,, .. ... tb I T t I' I I I ·. . ! . i ..., l J i ... 7.0 ) S WA'IBJHGft,,,., 6 I _, 11 11 11 tS • -182- Page 41 13b , .o io 7.0 , .o lb I ,I .... "i j -1 I II ! i ' ! i .I I • I II i j: I l • ' I I I I I ' ! : J.. I 1 ! I -1 I· I lI I Ii ; j I i I I I i • I I.O 7.0 i' i 6-0 11 - I 1.0 1.D 0 JI 111 :11 . ii! !'. •l ::: '. !It,: ~I 1 '''Ill ' ''I I' I, _:,11 , . '! l ii ·: 'I 1 '1 ir, .1; ii. , _ _ ,_ ,~. ·1 1,;. .- . 1;• I I : I. 11; I r f,- .. I: I, ; 'I · : 111 .1 1; ' 'j !I • •1;1 ''ii ,1 •~,,~.r.+__r-H ; ,'!>-,+:~,i+.- :+i--+-+;-+r+.,,+-!lf---+--4-+-4+-l..:;+.;;..i-+-+-_~_~ ,.+ ~:!H',Hl-l-+-'-h-r-,t,....+-+-+-+-+-4'-4,-+-+--H+.1-1--++-+-_~;1 i, I I 'I , ,..1 " • .,.. --.;:Hf+-•t:.-.r-:;;;"'_ r-r-t-+-""t-:::t'."'1;;:::i----4.-,.p;;;j.;;:;c.::t::t::!?~.~-, nr·r .:~,,,---r-n--t-t-t-t-t--t--tHlvtt-+n 1,H, 1-:. :' j '\-t-,--t,,-'!rr+-V-,-+-i-h-+-+-+.-+.-.-.,.,+-+++++++-+-+..+-+H-~--lio,l,rfl-l---+-+-+--4-+-.-.J-+-+-+41<1,....,'"'--l 1 1 "ltt"'r'~•r··_!r h'~~•+v_••t',-'+·-:-t-•~ · +'-~1 +"7' ~!--+~ :~~t+-'*i+'➔·~P+1 ·i+++-H+1r~•~·~'·H1-·r·~•·r·~'·+•~~r-~tt--++ttt-+-+:~,++fut+--+-+++++~ .. .! .: : ... • ,,, ,:, , !'/: . 1. l ' ,;- ' ! 1 Iv § Ii , . i: I . :;, .: I . I • ~ i i I. ; ,:· :; '\, I ,, .. .:; :, ::1 , :--i 11. .J,, 1J , I.·,·· :i: :,, :, .. " •i . 'l ~ i .. , . ,. · '''i. ''Vd r ,.. ,, ,,1 ,, . .., .,, :'' ,. q- 11 • ,, 1:· · rr '"'-- .....-+..,-. -,:...· _.,._,_,_,_,.......,.....,--, •t,,--t-,-r-Hl1 1.:• "\ .; _,, • ~+---+--1--1-+H- :H-rll'#'_· "'!--'+,:1-.-lf-'-"if<'-+,:1 1.,.'',..·++-+--+-+-I11,-l,_.,t -'-t-;-'+1+1~-t-,-'t-',,t-1\lr-fr---{• --t-Hlt--i-i-,i--i--1--H/--'I--+--+--+--+-..+-...__'-" 1 ~ 1 ' :'t i:. 1 :1: :I i.. !:i • 11 r, 1· . , , : ,'. 1 '. 1! j , 11 1 : . · P ,,· il '!1 I! J '. ! !;l __.• ·· , I. -; i ·r , 'L , i ·' 1 ' 1 ; .. 1 f·. L !' ,\: ;: 1j,i· j; ,;I . '. 11: ; i' f ~11~:r1:i~•triqr+·+!·rl ~· ·+-':ci:!+·+.;+· -+:.+'~"'+! ~:·:4+1:1i+ ~,+-+l'1+,~:;+1~-1-,-~:·~t4· +··~'-H-H~~::~!lf.+-!•~;-_.f-"-Hi!!r·~l+.,,.'1;*,~··+ .;.~~·:- ··~,t--+--t-:-+---t-:t--t--t--t-,-!-t--t-'-1' 1 1 • ! !!:: 1 1:;· . 1:1: 1 • ,',, ' : :: !: ., I .,; p 1'", !i !•! 1, 1 :i: ij; I IP 1! 1! 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I I i I -253- Page 145 - - - i - - - --l - . - l _ _L___ _ _ _ - - l -, - -_J - 900Hz 7SO 600 I I I •~o I 300 37' I 1 0 I ISO 180 ··--- i ----- ---- --1- - •;o..., ,. ., r.:~ 1'!) ·r--'-- - - -L · ·1 t-- - -- 3~0 1jo 0 ~o 1~ ! I 90 0 30 ! ,---'- - - - - - - - + - - -·-·- · ... ··- - - -----+---- - • -- - - - - - - --'i .. I ,-..1----~ ,._w i """ i - ' O~d '7 _, I 2.5 3.0 3. -; ~t::;~n1r - , i'.J! ~ j~ ; •• 0 -254- Page 146 -. 600 ~00H l ' .,o 180 •so 1'0 300 I I 75 i 3 60 2>5 1>0 120 90 6 I f - -- +-.! 0 -----j I i 0 I 30 I i I 0 ! ' ---. - - -- -- l------+--~-----+--I i I t- i I I -, -----+-~ ' ~ i --.---,-+- !l ·---+'- - - - - - 4 · ~ - - + - - · - -··- - ·-· I I I i I • . __ i._--+--· _··-···· -1-·- - - - - - -·- - ·· ·· ' --·- I I I 10 ' :1100 "" I 7 IOOO 100 600 I -255- Page 146 r -----'9 00 11 1 600 4$0 I 375 300 22$ 1$0 I I I 60 I ! 1~0 · -- -~ - 150 --- - -~- J__ j 7>0 3()0 I 1 0 ! 90 !> ---------1---;,___ _ _ -+------~--+-..--...--+--+-,j,.. i----J __ ______.._____.. l I II ';cl ' ' ' r----r-:-:i::10 9 8 7 J•J.1 . ,;,. 'j;-1,.1,1 ' ' - · ,--·_ 6 MOOMETBS ,.,., 6 -256 - ~ o Page 147 ~o ~ OCH 3 10 - ---i -· - - - - - - l . . - - -·· · ~· --- -- -l - - ~ --'-- -- - ·- 7 -· - · · -- · J __ __ IK>OHJ 7!,0 600 4!,0 •1I 0 3 r5 300 2r 1~0 150 120 9() • I I --+- :____ _l___ ;___:_· - -------i . I .• r - - - + - - - 7 - -.- -~ L r .. I ,~ l __ _ ISO I 7, 30 ·•,_j I I ...;----+- - ' I I ' 1---;- , 1 3 ) : v•' ___1_ , _ ___,1___ _ .-1. I I I f ' I i G : :U ! '! -~ 1! ' '' I - l : . 1 i __J t - · - -- l : ! .. 1 i __ _J--+---+--1 , i· I I __ _ ! i , I ' ;l J._ _ ___, _ . I ' • I ~: ; ·- i. ! I ! i _,' I 11 ! - __J __J__L__~l------"'---'---_J L 1)- I ij ;_i ! -1 I - ,o t 5 4 ! · -l : I i n-'--'-'-'-'- , , 1 ,, ~ i1; ' :1 1 11 :; :!.· ,J , -iTitl! : 1-,· - • ,..:~ ,,I' 'l l !I 1 ·-'.i l,' ,I! ' ,, ,, :• II· ·:: -, _ 'Ii I; :: !· -25 7 - PROPOSITIO~S -258- ABSTRACTS PROPOSITION I: The development of a new asymmetric ketone synthesis is suggested and its application to the synthesis of the ci ga rette beetle sex pheremone is proposed. PROPOSITIO\ II: The utilization of cuprate reagents for as ymme tric synthesis is proposed. PROPOSITIOJ'\ III: A modification of current therapeutic methods for the treatment of aphasia is suggested. The limitations and risks are discussed. PROPOSITIO\ IV: Synthesis of chamaecynone by an intramolecular Diels-Alder Reaction is proposed. PROPOSITIO N V: A mechanism for the reaction of cuprates ¼ith propargylic alcohol derivatives is proposed. -259- PROPOSITION I Abstract: The development of a new asymmetric ketone synthesis is suggested and its application to the synthesis of the cigarette beetle sex pheremone is proposed. During the past few years much emphasis has been placed on asymmetric synthesis in organic chemistry. 1 As complexity of synthetic targets increased, the need to control the relative and the absolute configuration of newly introduced asymmetric centers became essential. Two basic strategies have been used to cope with asymmetry. The first was the use of readily available chiral synthons. 2 Several elegant syntheses have recently been reported which take advantage of this approach. 3 - 5 The major drawback is that often, the required chiral precursor was either not available in the correct chirality, or conversion of the available chiral precursor to the desired synthon was very laborious Therefore, much attention has recently been directed toward utilizing available chiral sources as recyclable ligands to induce chirality during bond forming reactions. 1 Among the most successful of these have been asymmetric hydrogenationslc,b and asymmetric alkylations.lc, 7 A new approach to asymmetric alkylations of acids and its application to the determin- -260- Sche me I -~~-~~~~ Sch eme II -..,.~ ~ ~~ ~ ~ ~ ~ -261- ation of the relative and absolute configurations of a new pheremone are the subject of this proposal. During the past three to five years, amazing progress has been made in asymmetric alkylation reactions. By alkylating chiral imines or hydrazones derived from an 7a 7b aldehyde . or a ketone and a chiral amine or hydrazine, enantiomeric excesses 8 in the range of 50-80 % have been mad e routinely accessible. The problem with alkylating ketones, however, is that unless they are symmetrical or methyl ketones, 9 the regiochemistry of alkylation may be uncontrollable; making asymmetric alkylation of unsymmetri- cal ketones difficult. One ~ay of avoiding this would be to alk y late an aldehyde, free the aldehyde, do a Grignard addition and ox idize (Scheme I). Synthetically, this procedure is unattractive due to the many steps (imine formation, alkylation, hydrolysis, grignard and oxidation) required to obtain the desired product. Alternatively, one could start with a chiral acid derivative, alkylate 10 and then, in the case of an amide, add an alkyllithium to directly obtain the desired ketone (Scheme II). To date, only a fe~ chiral acid derivatives have been utilized for asymmetric alkylations. The most successful (for asymmetric induction) of these have been the chiral le 11 oxazolines used by Meyers and coworkers. ' Although enantiomeric excesses of 70-80% were obtained, application -262- of this method suffers from the same disadvantage as does the aldehyde procedure, a long sequence from starting acid to desired ketone. Recently three more studies on asymmetric alkylation of acid derivatives have been 12 described. Newcomb used the dianion 1, but the optical yields \,'ere lo\,' (ca. 10-40% ee). Larcheveque 10 reported 00 CH 3 R~N~Ph I CH~ .) ; oG 2 1 the alk y lation of dianion 2 and then direct conversion to a ketone in 60-80% ee. While this is encouraging the optical yields are not high enough so as to be useful 1n a multistep synthesis or synthesis of pheremones where very high enantiomeric purity is required. The third method, pioneered by Sch5llkopf, 13 gave high asymmetric induction, but was only applicable to amino acid synthesis. Based on recent results of Enders, 14 in which symmetrical hydrazones like 3 could be alkylated in >98% ee (eq 1), the amide 4 is proposed as a possible solution for asymmetric alkylation of acids. Direct conversion of the amides to unsymmetrical ketones should then be possible, -263- R (1) 3 making unsymmetrical, chiral ketones readily available (Scheme I I I). In such an asymmetric reaction, there are two components which control the level of asymmetric induction. The first is the enolate geometry (Sa vs Sb) and the second is the enantioface selectivity in the alkylation step. . . t h e 1 1terature, . lla,lS imines From severa 1 stu d 1es 1n and hydrazones show a very strong preference for the geometry represented by 6a. If one assumes that the 16 tent • Sb eaves h 1·k • • h h e secon d mono-anion_ 1 e an 1m1ne, deprotonation should give 6a. Alkylation of 6a from the top face (a, 'from above the plane of the paper) would lead to 7a whereas attack from the bottom face (b, below the plane of the paper) would lead to diastereomer 7b. 14 Again using Enders 1 examples as a mode1 (see structure 8), 7b should be obtained in very high enantiomeric yields. -264- Scheme III 0 "~9 CH3~~: /H CH_Q N 4 j ~ b b 0 CH30NH+ R 7b -265- 0:-1 - Cr-L - '< 0 /: H _,,~I "l \~ CH I I I / .. - ---: ___ ,,, \ / I 7 ' D ,, ,, RX H '' 8 If th e mono-anion resulting from alkylation of~~ were to be tre a ted with methyl iodide followed by methyllithium 10 one should realize an essentiall y one-pot synthesis of chiral methyl ketone~~ (Scheme IV). Subs ti tut ion of other lithium rea ge nts would provide analogous chiral ketones. In go in g from propionic acid to higher homo- logs, the percent ee should increase since the ratio of 6a to 6b should be improved, while the enantioface selectivity would probably rem ai n unchanged. Several applications for this procedure can be envisioned. One of these is the synthesis of the sex -266- Scheme IV MeI 6a - R 7b 9 MeLi 10 attractant (11), isolated from the female cigarette beetle (lasioderma serricorne F.). 18 OH 11 0 The cigarette beetle causes widespread damage to cured tobacco leaves. Since the use of pesticides is increasing- ly being discouraged, the use of pheremones for pest management is becoming more popular. 19 Because insects are frequently sensitive to changes in the diastereomeric (and enantiomeric) constitution of pheremones, 19a com- -267- mercially produced pheremones must mimic the exact constitution of the naturally produced pheremone to be effective. An approach to the synthesis of the eight possible diastereomeric constituents of 1 is outlined retrosynthetically in Scheme V. Asymmetric alkylation of an amide could give either enantiomer at c 4 simply by Scheme V CH ~H3 CH 3 3 2 5 9 e OH 0 11 CH CH., I + .) 3 CHM OR Br ] + 0cH-CO H 2 + EtLi 12 changing the order of alkylation (ie., introduce CH 3 - or !3 first). Chiral halide 12 could be obtained by an 1 addition of ethyllithium to chiral aldehyde 14 d (available from chiral acid 13 20 ) to give the two diastereomers -268- 15a and!~~ which should be separable by chromatography (Scheme VI). !Z~i~ (the enantiorners As shown in Scheme VII, of !~~l~) should also be readily available from 13. Treatment of the silyl ethers with fluoride 21 would give the corresponding alcohols. Then mesylation and bromide exchange by the method of Servis 24 would give the required bromides. The synthesis of (4~,6~,7R)-!! and (4S,6~,7R)-!! are detailed in Scheme VIII, as representative examples. Alky lation of amide 4 with bromide 18a followed by Scheme VI ~H3 - - OH rY OH ~H3 1) RC1 21 2) LAH 3) Cr0 3 •Py 22 0 rYH OR 13 0 1) EtLi 2) c 5H80, H+ 14 ~H3 ~ C H3 OR OTHP 15a + ~ C H3 OR OTHP 15b -269- Scheme VII 1) PhCH 2Br 23 2) LAH (YOH OH 1) Hz/Pd~ NCH3 22 H 2) Cr0 3 •Py OR 0 = fl 3) RC1 21 0 ~H3 PhCH 20 OR 13 1) EtLi ---~►- 2) C H 0, 5 8 + + H 1 7a 17b frCH3 Br OTHP 18a 18b -270- quenching with methyl iodide should give (4S,6R,7R)-!~· Addition of eth y llithium10 and removal of the THP protecting group would yield (4S,6R,7R)-ll. usin g amide By ~2 and first alkylating with !~a followed by me th y l iodid e, (4R,6R,7R)-19 would be available. Reaction Kith ethyllithium Kould then yield (4 ,6R,7R)-!!· In a similar fashion the other six diastereomers should be available. Each synthesized diastereomer should be enantiomericall y pure at c6 and c7 . If th e third center (C 4 ) were not adequately pure folloKin g the alkylation step, intermediate !~ coul d be purified by conventional chromatograph y 25 s inc e this no~ involves merely a separation of diastereomers. App lication of this method should supply large enou gh quantities of the eight diastereorners for biolo g ical testin g of each pure diastereomer as well as mixtures. The preparation of the pherernone 11 outlined above provides a reasonable beginning project for testing the applicability of the proposed asymmetric alkylation reaction. Applications to asymmetric aldol reactions 26 might also be successful -271- Scheme VIII 18 a (4S,6R, 7R)-19 4 CH.., =.) CH.., ::.:> OH 0 ( 4S , 6 R, 7 R) - 11 CI-l3 CH3Y:'''-!HR CH 3 0 CH -- OH 20 ! 0 (4R,6R,7R)-ll 18a CH CH 2 Lit 3 ~H3 ~H3 -- CH 3 ~ N H R ~ OTHP 0 MeI CH 3 -= OTHP CH 3 NCH R 3 0 (4R,6R, 7R)-19 R=~ OCH3 I 3 -272- References and Notes 1. (a) T. D. Inch, Svnthesis, 466 (1970); (b) D. Valentine, Jr., and J. W. Scott, Science, 184, 943 (1974); (c) D. Valentine, Jr. and J. W. Scott, Synthesis, 320 (1978); (d) J. D. Morrison and H~ S. Mosler, "Asymmetric Organic Reaction," American Chemical Society, Washington, D. C., 1976. 2. D. Seebach and H.-0. Kalino~ski, Nachr. Chem. Tech., 24, 415 (1976). 3. Biotin: 2 7 65 4. H. Ohrui and S. Enato, Tetrahedron Lett., (19 7 5). Prosta g landins: K. G. Paul, F. Johnson, and D. Flavra, J . Arn . Chem . Soc . , 9 8 , 1 2 8 5 (1 9 7 6 ) ; G. Stork and S. Raucher, ibid., 98, 1583 (1976); K. Ogura, ~!. Yamashita, and G. Tsuchihashi, Tetrahedron Lett., 759 5. (1976). Pheremones: K. Mori, Tetrahedron, 30, 4223 (1974); K. Mori, ibid., 31, 3011 (1975); S. Iwaki, S. Maruma, T. Saito, M. Yamada, and K. Kalagiri, J. Arn. Chem. Soc., 96, 7842 (1974). 6. For examples see: 43, 401 (1975); H. B. Kagan, Pure and Appl. Chern., C. Fisher and H. S. Mosher, Tetra- hedron Lett., 2487 (1977); ibid., 2525 (1977). R. Glaser and J. Blumenfeld, -273- 7. (a) D. Enders and H. Eichenauer, Tetrahedron Lett. , 191 (1977); A. I. Meyers, G. S. Poindexter, and Z. Birch, J. Org. Chern., 892 (1978); (b) J. K. Whitesell and M.A. Whitesell, ibid . , 42, 377 (1977); -.,~ A. I. Meyers and D. R. Williams, ibid., 43, 3245 (1978); D. Enders and E. Eichenauer, Angew. Chern. Int. Ed., Engl., 8. ~~' 549 (1976). Enatiorneric excess (ee) is the same as optical purity. 8 8 % ee means that there is 94 % of one enantiorner and 6 % of the other. 9. Irnines and hydrazones of methyl ketones can be selectively rnetallated on the methyl side: H. Eichenauer, E. Friedrich, W. Lutz, and D. Enders, Ange w . Chern . , Int . Ed . , Eng 1 . , ~ Z, 2 06 ( 1 9 7 8 ) ; T. Curigny, M. Larcheveque , and H. Norrnant, Justus Liebigs Ann. Chern., 719 (1975). 10. M. Larcheveque , E. Inatovia, and T. Cuvigny, Tetrahedron Lett . , 3961 (1978). 11. (a) A. I. Meyers, E. S. Snyder, and J. J. H. Ackerman, J. Arn. Chern. Soc., !22, 8186 (1978); (b) A. I. Meyers, G. Knaus, K. Karnata, and M. E. Ford, ibid., ~~' 567 (1976). 12. T. Kaneko, D. L. Turner, M. Newcomb, and D. E. Bergbreiter, Tetrahedron Lett., 103 (1979). 13. U. Schollkopf, H. Heinrich, I. Happe, M. Segal, and -274- U. Reiter, Ange,,·. Chem. Int. Ed., Engl., !~, 117 (1978). 14. D. Enders and H. Eichenauer, Angew. Chem. Int. Ed., Eng 1. , 15. ~ ~, 3 9 7 ( 19 7 9) . H. Albrecht, E. 0. Dilber, H. Eichenauer, and P. Weuster, Tetrahedron Lett., 3691 (1978); M.A. Haabler, D. E. Bergbreiter, and M. Newcomb, J. Arn. Chem. Soc., 100, 8182 16. (1978). Since oxygen is more electronegative than nitrogen (3.07 vs 3.50) 17 one might expect more of the negative char ge to be localized on oxygen. See also D. M. von Schriltz, E. M. Kaiser, and C. R. Hauser, J. 0rg. Chem., 17. ~~. 2610 (196 7 ). F. A. Cotton and G. \\"ilkinson, "Advanced Inorganic Chemistry," John \\"iley and Sons, New York, 1962, p. 92. 18. T. Chuman, M. Kohno, K. Kato, and M. Noguchi, Tetrahedron Lett., 2361 (1979). 19. (a) 0. Chapman, J. Am. Chem. Soc., 100, 4878 (1978); (b) C. A. Henrick, Tetrahedron, 33, 1845 (1977). 20. C. T. Goodhue and J. R. Schaeffer, Biotechnol. Bioeng., !~, 203 (1971). 21. S. Hanessian and P. Lavallee, Can. J. Chem., 53, 2976 (1974). 22. R. Ratcliffe and R. Rodehorst, J. 0rg. Chem., 35, 4000 (1970). 23. Q. Branca and A. Fischli, Helv. Chim. Acta, 60, 925 -275- (1977). 24. R. K. Crossland and K. L. Servis, J. Org. Chern., ~~' 3195 (1970). 25. G. Helrnchen, G. Nill, D. Flackerzi, 1\1. Schule, and ~l. s. K. Youssef, AngeK. Chern. Int. Ed. , Engl., ~~' 62, 63 (1979). 26. D. Enders, Angew. Chern. Int. Ed. , Eng 1. , !Z, 206 (1978). -276- PROPOSITION II Abstract: The utilization of cuprate reagents for asymmetric synthesis is proposed. The 1,4 addition of cuprate reagents has proven extremely • c h em1st. • l use ful t o t h e synt h et1c D . ur1ng t h e 1 ast ten years several attempts have been made to induce asymmetry in the 1,4-addition reaction. 2 - 4 Addition of chiral com2 plexing agents such as ephledrine (1) b and sparteine (2)Zc have met with only marginal success (6-10% ee). Preparation of "chiral-cuprates" such as 3 2a ' f have also not met with much success. The best results to date have been those of Kawana 2e and Meyers 3 who chose to modify the enone partner. Meyer~ oxazolines have routinely afforded 70% ee 5 or better. Unfortunately, the nucleophile must be an organolithium reagent, thus precluding any be present. base sensitive functionality which may Also, since this method relies on initial derivatization of an acid, it is not applicable to substrates like a,8-unsaturated ketones, thereby limiting its generality. While Kawana's method, using a,8- unsaturated esters derived from carbohydrates permits the use of the milder cuprate reagents, it too relies on derivatization of an acid. To overcome these -277- difficulties two new approaches to asymmetric cuprate reactions are proposed. H 1 2 3 The first of th ese methods i s based on a recent report by Corey and Enders. 6 The y found that the cuprate (~) derived from dimethylhydrazone anions Kould under go 1,4addition to o , S-unsaturat e d ketones. If a chiral unit could b e incorporated into the hydr azone, a symme t ric induction should result. The easiest way to incorporate chirality mi ght be by use of the hydrazine 7, whose synthesis is depicted in Scheme I. Treatment of the known N-nitroprolinol 7 (5) with sulfene and displacement - ~ of the mesylate with thioacetic acid anion would give the -278- Scheme I ~ I OH ... ~ I NO NO s SCOCH3 6 LAH ... ~ I SH NH 2 7 thioacetate ~' ~hich would be reduced with lithium aluminum hydride 7 to yield the desired hydrazine z. Hydrazone formation followed by deprotonation and trans8 metallation with CuBr· (CH 3 ) 2s should give a cuprate which would be capable of asymmetric conjugate additions. For example, if acetone were converted to cuprate 8, 7 9 reacted with cyclohexenone and hydrolyzed,' the 1,5- dicarbonyl 9 would be obtained (Scheme II). This approach to asymmetric cuprate reactions suffers from two basic problems. First is the lack of generality of cuprate substrates since only aldehydes and methyl or symmetrical ketones can be used. The product must there- -2 79 - Scheme II 7 1) LDA .. 8a 8b 0 H 9 fore contain a carbon y l which, in some cases, might result in extra steps for it s removal. If an unsymmetrical ketone were used, the regiochemistry of deprotonation, unless controlled, would give rise to more than one product. However, use of a symmetrical ketone would allow the possibility of introducing two asymmetric -280- centers in one C-C bond forming step as illustrated in equation 1. The second problem is that since the direction of equilibrium between 8a and 8b is unknown 0 - 0 (1) * and since the mechanis m of the cuprate 1,4-addition . . st1·11 1n . d out, b l,l0 no pre d.1ct1ons · reaction 1s as to dir e ction or extent of asymme tric induction can easily be made a pr1or1. Similar to this approach and suffering from the same faults, would be utilization of chiral imines rather than hydrazones (Scheme III). 11 Sche me III ... -281- An alternative to the above method wo uld be to use a cuprate derived from !2, the synthesis of whi ch is displayed in Scheme IV. Mesylation of ~ -m ethylpro linol, displacement with thioacetic acid anion and reduction with lithium aluminum hydride would give the thiol !2· Formation of the lithium thiolate and quenching with 12 • d"d • ld t h e copper reagent 11 . cuprous 10 1 e ~ou Id y1e Addition of an organometallic would then afford the mixed hetero cuprate reagent 12. Scheme IV ~ CH 3 OH 1) ... CH 2=SO ~ 2) CH 3Cos 0 3) LAH CH.,.) SH 10 RLi 11 ... 1) BuLi 2) Cul ... -282- Utilization of!! would permit use of cuprates other· than those derived from carbonyl containing reagents thereby increasing the generality of the method. As 2 noted earlier, chiral cuprates similar to 12 (ie. ~ a) were investigated and found to give only low asymmetric y ields. Comparison of 3 and!~, however, reveals that in 12 th e copper is in a more highly ordered, less symme tric environment than 1n 3 (see Figure 1). The chiral environment of 3 is provided entirely by a methyl group which is two atoms removed from the copper center 3 Figure 1 whereas the chiral environment in 11 is provided by a cis-fused (3,3,0)-bicyclooctane. Again, as for systems like 8, the direction and magnitude of asymmetric induction are difficult to predict due to a lack of necessary information about the mechanism of the reaction. -283- Study of the above reactions should prove useful for organic synthesis. If successful, they would allow asymmetr i c synthesis of a wide range of molecules now 1 constructed by cuprate additions. Even if the asymmetric induction were low, the direction and magnitude of asymmetr y • could yield valuable information as to the mechanism of 13 1,4-addition. For example, one proposed mechanism is e transfer follo~ed by transfer of the alkyl group. From thi s mechanism one might expect fairl y low levels of asymmetric induction. Alternativel y , a mechanism involvin g a char ge tran sfe r co mp lex followed by formation • d.1ate h as b een propose d . o f a Cu III 1nterme Since the co ppe r a to m i s effectively chiral, high levels of asymmetric induction might be expected fro m this mechanism. -284- References and Notes 1. For reviews in this area see: Svnthesis, 63 (1972); I~, 1 (1972); 2. J. F. Normant, G. H. Posner, Org. Reactions, G. H. Posner, ibid., 22, 253 (1975). Chiral cuprates: (a) R. B. Banks and H. M. Kalbrosky, J. Am. Chem. Soc., 98, 3734 (1976); (b) J. S. Zweig, J. L. Luche, E. Barreiro, and P. Crabl~, Tetrahedron Lett., 2355 (1975); (c) R. A. Kretchmer, J. Org. Chem., 37, 2744 (1972); (d) Y. Inouve and H. M. \\'alborsky, ibid., 27, 2707 (1962); (e) M. Kawana and S. Emote, Bull. Chem. Soc., Japan, 39, 910 (1966); · (f) B. Gustafsson, Tetrahedron, 34, 3023 (1978); (g) A.-T. Hansson, M. T. Rahman, and C. Ullenius, Acta Chem. Scand., 32, 483 (1978); (h) M. Asami and T. Mukaiyama, Chem. Lett., 569 (1979). 3. Oxazolines: A. I. Meyers, R. K. Smith, and C. E. Whitten , J . 0 r g . Chem . , 4. General examples: Agric. Biol. Chem., ~~ , 2 2 5 0 ( 1 9 7 9) . Y. Nakajima, J. Oda, and Y. Inouye, ~~' 2065 (1975); H. Wynberg and R. Helder, Tetrahedron Lett., 4057 (1975); G. Tsuchihashi, S. Mitamura, S. Inouye, and K. Ogura, ibid., 323 (1973); T. Mukaiyarna, Y. Hirako, and T. Takeda, Chem. Lett., 461 (1978); T. Mukaiyama, -285- T. Takeda, and K. Fujimoto, Bull. Chem .. Soc., Japan, 51, 3368 (1978). 5. "ee" stands for enantiomeric excess. See: J. D. J\lorr i son and H. S. Mosher, "Asymmetric Organic Reactions," American Chemical Society, Washington, D. C., 1976, p. 10. 6. E. J. Corey and D. Enders, Ber.,!!!, 1362 (1978); E. J. Corey and D. Enders, Tetrahedron Lett., 4597 (1978). 7. D. Enders and E. Eichenauer, Angew. Chem. Int. Ed., ~~. En g l., 8. 549 (19 7 6). H. 0. House, C.-Y. Chu, J. M. Wilkins, and M. J. Green, J. Org. Chem., 9. 11. 1460 (1975). E. J. Corey and D. Enders, Tetrahedron Lett., 3 (1976); E. J. 10. ~~. Corey and S. Knapp, ibid., 3667 (1976). H. 0. House, Accts. Chem. Res., 59 (1976). ~' For examples of chiral imines see: A. I. Meyers, G. S. Poindexter and Z. Brich, J. Org. Chem., 43, 892 (1978). 12. G. H. Posner, C. E. Whitten, and J. J. Sterling, J . Am . Chem . Soc . , 13. ~~, 7 7 8 8 (1 9 7 3) . R. A. Smith and D. J. Hannah, Tetrahedron, 35, 1183 (1979). -286- PROPOSITION II I Abstract: A modification of current therapeutic methods for the treatment of aphasia is suggested. The limitations and risks are discussed. "Communicate: 1) share, impart, partake ... to make known: inform a person of ... convey knowledge or information of ... to send information or messages back and forth: speak, gesticulate or write to another to convey information: interchange thoughts .... " 1 For most of us communication is a way of life. We take for granted that everyone can learn to communicate. Ke assume that after a certain age communication will remain with us for life. The entire basis of civilization is founded on communication. Unfortunately, for a large number of the population, communication is extremely difficult. Even being understood may be impossible, yet these same people may be fully cognizant of their surroundings and what is being said to them. Unable to answer a question verbally, some may be able to answer in \\'r i t in g . Un ab 1 e to name a co mm on obj e ct ( e g . a fork) , some can describe its function (used to eat food; used to pick up food, etc.). can be Unable to verbally reply to a question (What is a ball?), they can pick the requested object out of a group of objects. This class of people -287- have on e thin g in common, they all suffer from a language disorder. Language disorders can be subdivided into two broad cate gories, dysarthria and aphasia. Dysarthria is any one of a number of motor disorders which affect speech. It can be further subdivided into subgroups, 2 based on age of onset, etiology (cause), neuroanatomic area of impairment (part of central nervous system, CNS, affected), cranial nerve involvement, speech process involved or disease entit y . All of the dysarthrias aie similar in that the y are motor dysfunctions caused by some form of injury or insult of the motor control processes of the CNS . Quite often they can be treated merely by a repetition t ype of therap y , similar to treatment given to paralysis victims. That is, as the impaired motor sy s tems are called upon to do work, the patient can learn to regain control of the muscles. This may be the result . of new neural connections being made 1n the CNS but no hard evidence of that is available. Aphasia, on the other hand, although also caused by CNS injury is ascribed to injury of higher sections of the brain, the so called speech centers. 3 Whereas dysarthria is characterized by impaired motor function, for example, difficulty in placement or movement of the tongue, weak or nonresponsive jaw muscles, lack of control of the larynx -288- musculature, aphasics may show none of these symptoms. Aphasia, then, is a speech disorder characterized by inability to make a correct response despite the fact that, at least physically, the patient is capable of making the response. Three of classifications of aphasia; the more common broad Broca's aphasia, Wernicke's aphasia and amnesic aphasia; are represented in Table 1 4 to further clarify the problems suffered by aphasics. ' 5 The three examples are, of course, very simplified. Kone of them is usually manifested in a pure form. Also, depending on the severity of the insult to the CNS, aphasics may additionally suffer from dysarthria. Aphasia is believed to be caused by an injury to speech centers, specifically areas in the left hemisphere. For many years scientists have believed that the brain is asymmetric, that the two halves perform different functions. By a series of ingenious techniques designed to feed information selectively to either the left or right hemisphere they have shown that, generally, the left hemisphere controls language and is better at discriminating letters and verbal features whereas the right hemisphere is better for nonsense figures, recognition 5 ' 6 Th 1 f h • • d 1scr1m1nat1on. • • • • o f f aces an d spatial e e t em1sphere, since it is the one which communicates, has also 7 been designated as the dominant hemisphere. That is, -289- Table 1~ Below is an outline of the characteristics of three common forms of aphasia. At the end of each description is an example of how each class might respond to a question. Broca 's aphasic : expressive disorder, poor articulation, tel egrap hic speech mostly of content words, impo verished or i mpaired gra mma r. How was your Easter holiday? ''Uh, uh, uh, Easter ... ho, ho, ho holiday . .. I like ... eat turkey ... many li ghts ... people ... very good. " The speech i s labored and the patient is aware of his own deficit; ma y become depressed about it. Wernicke's aphasia: impaired auditory language compre- hension, fluently articulated but nonsensical speech. How was your Easter holiday? "Oh, yes, we have done it. Could be different but nevertheless done. Go, go, gone. And however succe ssful, it still fails. I wish indeed. Good morning." The patient is often unaware of his own deficit and will deny it vehemently. -290- Amnesic aphasia: Word finding difficulties, spoken and written, relatively intact auditory language comprehension. What is this? (Display a fork.) "It's a, ah, ah ... (eating motions). It's a spoon. No. No. I mean it's a .... You eat with it, a, ah, I can say it." If prompted with a question -- Is it a knife? -- he will say no, but if prompted with a clue -- "Use your knife and ... " -- he can often complete the sentence. a -The above examples are excerpted from ref. 5. in order to express itself the right hemisphere must first communicate with the left which then communicates with the outside world (at least verbally). The evolutionary reason and actual physical causes for such a dominance of one hemisphere over another are currently unknown. Recently, morphological studies have uncovered a physical 8 asymmetry between the two hemispheres. Whether this asymmetry is inherent or develops due to some other factor is unknown. -291- Some of the most exciting results in the area of brain asymmetry come from studies of patients who have undergone 9 a commissurotomy. These are patients who have had the major communication link between the left and right hemispheres (the corpus callosum) surgically severed. These patients are interesting because there is now no communication between the left and right hemispheres. For example, if an object is placed in the patient~ left hand (controlled by right hemisphere) while his eyes are closed and he is asked to name it he cannot because the left hemisphere (the one with speech) does not know what the object is. However, if the subject is then asked to pick that object out of a mixture of objects (still without looking) he can do it. By study of these patients Zaidel discovered that the right hemisphere is indeed . 1s . 1n . an immature . f arm. 5 ' 10 capa bl e o f 1 anguage b ut 1t For some reason, as we develo~ the left hemisphere somehow shuts down development of language in the right side. From an evolutionary standpoint, this is probably quite useful since it prevents duplication of effort. Unfortunately, from the point of view of an aphasic it can be disasterous. The current therapy consists mostly of attempts to retrain the patient, which may or may not be successful. If the left hemisphere inhibition of the right hemisphere could be removed, perhaps the right -292- hemisphere could be trained to communicate. That is the subject of this proposal. Recently several researchers have found that not onl y do neurons release neurotransmitters but they also 11 release macromolecules. Further, they have found that if the source of macromolecules is removed from an . 12 a x on tat h axon d 1es. The de generation then continues down the neural chain. Thi s degeneration has been applied to tracin g neural pathways. Ile One can conceive that the left he misphere relea se s so me form of inhibitor y macro- molecule which keeps the language centers of the right sid e shut down. Alternativel y , the shutdown might be caus e d by release of inhibitory neural transmitters • b ut y r1c • ac1·a) . 13 ( sue h as gamma amino Under normal cir- cum s tances the fact that the right hemisphere lacks speech is unimportant. But, when the left hemisphere suffers injur y to the speech areas then the inability becomes a disability. Even thou gh the left hemisphere speech centers are disabled the right side centers may be unaffected, but they are still unuseable. If the inhibition could be removed perhaps the right side could be taught to speak. 14 At first, this seems like an insurmountable task due to the complexity of the human brain but it may not be as complex as it seems. The first task would be to locate the neuronal network responsible for the inhibition. -293- Second that network would have to be shut down without excessive damage to the surrounding CNS. One promising new method for tracing neuronal paths might be applicable to locating the necessary network. Graybielllb and others 15 have found that injections of radiolabeled amino acids are incorporated into the macromolecules which are transported by neurons. Injection of the active amino acids into the cellular matter of the left speech center or surrounding tissues might allow the mapping of the inhibitory network. In order to shut that network down two methods could be considered . Either a mechanical destruction by cutting or freezing could be used or a drug which inhibits neuronal transmission could be applied topically. Recent findings by Feldberg 16 indicate that the brain (at least for cats) is sensitive to the topical application of drugs. Studies have indicated that if the right hemisphere speech center could be freed from inhibition it would be capable of learning communication skills. 8 , 14 , 17 The limitations and risks of the proposed studies are fairly obvious. The major limitation is suitable cases. The patients would have to be people who had suffered left hemisphere brain damage without corresponding right side damage. Additionally, they would have to be willing to risk more severe damage or possibly death. One -294- interesting possibility which would be more ethical than experimenting on human beings, would be to utilize primates or dolphins. Both of these species have been shown capable of communication. Studies to determine whether their brains are asymmetric in function might prove invaluable to further understanding of the human brain. -295- References and Notes 1. P. B. Gove, Ed. in Chief, "Webster's Thi rd International Dictionary of the English Language," G. & C. Merriam Co., Springfield, Mass., 1967, p. 460. 2. For a general review of dysarthria see: F. L. Darley, A. E. Aronson, and J. R. Brown, "Motor Speech Disorders," W. B. Saunders Co., Philadelphia, Pa., 1975. 3. For a general review of aphasia see: "Adult Aphasia: J. E. Eisenson, Assessment and Treatment," Prentice- Hall, Inc., Englewood Cliffs, N.Y . , 1973. 4. N. Geschwind in Speech, Language and Communication, E. C. Carterette, Ed., "Brain Function," University of California Press, 1966, pp. 1-16. 5. E. Zaidel, Eng. Sci . ,~~' 10 (1978). 6. B. Milner, Br. Med. Bull., 27,272 (1971); K. Langden, S. D. Ellis, and S. D. Iversen, Neuropsycologia, 7. 195 (1976). M. S. Kennedy and D. Shankweiler, J. Acoust. Soc. Am . , ~~' 8. ~~' 579 (1970). J. A. Wada, R. Clarke, and A. Hamm, Arch. Neurol. Chicago,~~' 239 (1975). 9. R. E. Saul and R. W. Sperry, Neurology, (1968); S. P. Springer and J. Eisenson, ~~' 307 -296- Neuropsycologia, 10. ~~' 287 (1977). A. R. Luria and E. G. Simernitskaya, Neuropsycologia, 15, 179 (1977). 11. (a) B. Graf stein, Nature, 172, 177 (1971); (b) A. M. Graybiel, J. Comp. Neural., 175, 37 (1977); ( C) ~~~ T. N. Wiesel, P. H. Hubel, and D. M. K. Lam, Brain Res., 79, 2 7 3 (1974). 12. J. C. Eccles, "The Understanding of the Brain, II McGray-Hill Book Co., New York, N.Y., 1977, pp. 176177. 13. For a review of neurotransmitters see: J. R. Cooper, F. E. Bloom, and R. H. Roth, "The Biochemical Basis of Neuropharmacology," 3rd ed., Oxford University Press, New York, N.Y., 1978. 14. Recent studies by Zaidel with split brain patients reveals that the right hemisphere can understand complex speech . 17a Also, left side lesions in females, whose brains show less differentiation than males, are not as detrimental to speech as are • • 1 ar 1 es1ons • • men, 8 ' l 7b 1n • d 1ca . t.1ng th a t per h aps s1m1 1n the right side takes up some of the language function formerly controlled by the left side. 15. For a recent review see: W. M. Cowan and M. Cuenad, Eds., "The Use of Axonal Transport for Studies of Neuronal Connectivity," Elsevier, Amsterdam, 1975. -297- 16. i'i. Feldberg, Neurosci., 1, 427 (1976). 17. (a) E. Zaidel, Cortex, 12, 179 (1976); BradshaK, A. Gates, and K. Neuropsycologia, 15, 277 C. Nettleton, (1977). (b) J. L. -298- PROPOSITIO~ IV Abstract: Synthesis of charnaecynone by an intrarnolecular Diels-Alder Reaction is proposed. Chamaecynone (!) was originally isolated from Chamaecyparis formosensis Matsum., Cupressaclae. 1 Inve s tigation of the termite-resistant quality of the wood fro m this tree revealed that Chamaecynone was the 2 active agent. To date, two syntheses of this natural termiticide have been published. 3 , 4 The first, 3 based on modifying a -santonin, is inefficient from a standpoint of overall yield and number of steps required. Recently, a s horter route, based on an intermolecular Diels-Alder reaction (Scheme I), was published. 4 The cycloaddition, however, gave a low yield of a mixture of three diastereomers. Since intramolecular versions of the Diels-Alder reaction generally give better isomer ratios and higher yields than do the corresponding intermolecular counterparts, application of an intramolecular Diels-Alder approach to Chamaecynone is proposed. The retrosynthetic approach to! (whose preferred 5 conformation is 1 15 b) is outlined in Scheme II. a Disconnection of bonds a and b reveals that an intramolecular Diels-Alder could be used to control the -299- Scheme I 0 0 + 0 isomer s H 16 % 4 stepsj4 % yield l CH 3 0 1 relative stereochemistry of three of the four required stereocenters (control of the fourth center, c 7 , will be discussed below). ~' dianion ~ Diene 2, could be obtained from diene and olefin~- Since the key step in the proposed synthesis is the intramolecular cycloaddition, further discussion of the stereo- and regiochemical outcome of that reaction is important. During the last ten years, the intramolecular -3 00- H Scheme II I Ill 0 0 l' 1 0 RO RO 3 c::=:::::::::> 4 2 -301- version of the Diels-Alder reaction has played a key part in many syntheses. Some of these applications have recently been reviewed by Oppolzer. 6 The most important aspect of the Diels-Alder is that four new stereocenters can be formed in one step. Due to steric constraints imposed by intramolecularity, the normal endo- and ortho rules 7 for predictin g products do not always appl y . 6a Examination of the six possible transition states for an intra mo lecular Diels-Alder 6 a (Scheme III) reveals that for cis-dien es , the transition state leading to cis-fused rings (B), is favored over that leading to trans fused rin gs (A) even though B requires an exo transition state. Also, annelated (B) rather than bridged (C) adducts are gene rally favored. 6a However, in the case of trans- diene s, either cis-(D) or trans-CE) fused rings may result, while bridged systems are generally not observed, presumably because transition state Fis too strained. Therefore, control of the olefin geometries ( ~ , 2) would give the cis-fused decalin with the correct relative configurations at c5 and c10 , with the configuration at c4 controlled by equilibration. 5 The last remaining consideration is the fate of the stereocenter at c7 . Although no close analogies exist, 9 reports by Wilson 8 and more recently Taber indicate that a stereocenter located on the carbon chain linking -302 - Scheme III cis-diene s trans-dienes D .\ (strained) H B (favored) E H C F (strained) -303- the diene and dienophile can have a profound effect on the confi gurations at the newly formed stereocenters. Thus, 6 8 gave both trans-fused products CZ and 8) but only one cis-fused product (~), while !~g gave only~! and 12 (Scheme IV). Examination of models of 2 reveals that either the boat, or chair transition states should c5 , c7 and c10 as give the correct configurations at shown in Scheme V. Scheme IV OH 6 + OH 9 0 0 0 12 10 9 ~ 1 -304- Scheme V ► ~I RO _-H i OR 13 RO ~ CH_ j CH_j . H-C .) RO 7 CH 3 OR 13 ~ '---- H I The synthesis of the diene component (~, R = C5 H9 0) is outlined in Scheme VI. Treatment of the anion of 3-chloro-1-butyne with diethyl carbonate should give the ester 14. Reaction of~~ with Li(CH 3 ) 2Cu, • 11 an d lAI" • n1tt1g reduction to the alcohol, 10 ox1"d at1on 10 -305- Scheme VI ... O\ Li(CH ) Cu 3 2 CH 0 / - = ~ C l 3 --- 14 0 + H Cl O D II (CH CH 0) P-~HO 3 2 2 O Li j 15 3 (R = reaction of the resulting f-aldehyde with phosphonate 12 15 would yield diene ~' with the desired I,I-dieneolefin predominating. If necessary, the intermediate 1,3-adducts from the phosphonate addition could be isolated and separated before elimination to give stereochemicall y pure 3. Alternatively, 3 (R = CH 3 ) could be prepared by Wittig reaction of 1-chloro-3-butanone with the ylide developed by Martin (Scheme VII). The final steps of the synthesis could be completed -306- Scheme VII 0 ~Cl + 3 Ph P ~ O C H 3 (R = 3 CH..,) ,) as outlined in Scheme \'I I I. Acetylene dianion could be 14 alkylated by chloromethyl phenylsulfone and trimethylsilylchloride to give acetylene 16. Anion formation and then quenching Kith 3 14 would give diene 17. Anion generation a second time and quenching with transl-chloro-2-butene would give the desired diene 2. 14 Removal of the sulfone group by Al(Hg) reduction, 15 Diels-Alder reaction and removal of silicon (nBuLi or F) would give the cis-decalin 18. Removal of the alcohol 5 protecting group, oxidation and epimerization would then afford Chamaecynone (!)This approach to Chamaecynone is attractive because of the stereochemical control made possible by using an intramolecular Diels-Alder reaction. It is also efficient because of the high degree of convergency and the minimum amount of refunctionalization necessary- -307- Scheme VIII 3 Li-==-Li (CH ) 3 3 Si-=~ \ SO Ph 2 16 OR 2 17 1 2 18 -308- References and Notes 1. T. Nozoe, Y. S. Cheng, and T. Toda, Tetrahedron Lett., 36 63 (1966). 2. I. Saeki, ~l. Sumimoto, and T. Kondo, Halzforschung, ~~' 3. 93, (1973). T. Nozoe, T. Asao, M. Ando, and K. Takase, Tetrahedron Lett., 2821 (1967). 4. T. Harayama, H. Cho, and Y. Inubushi, Tetrahedron T. Harayama, H. Cho, and Y. Inubushi, Chem. Pharm. Bull., 26, 1201 (1978). 5. (a) The natural configuration at c4 can be obtained by equilibration of the final product; 3 (b) T. Toda, M. C. Koods, and K. Takahashi, Tetrahedron, 27, 5391 (1971). 6. (a) 1,· . Oppolzer, Ange\\'. Chem. Int. Ed., Engl., 16, 10 (197 7); 7. (b) W. Oppolzer, Synthesis, 793 (1978). J. Sauer, Angew. Chem. Int. Ed., Engl., 5,211 (1966); J. Sauer, ibid., 6, 16 (1967). 8. S. R. Wilson and D. T. Mao, J. Am. Chem. Soc., 100, 6290 (1978); see also: Helv. Chim. Acta, 9. ~~' W. Oppolzer and W. FrBstl, 590 (1975). D. F. Taber and B. P. Gunn, J. Am. Chem. Soc., 101, 3992 (1979). 10. E. J. Corey and J. A. Katzenellenbogen, J. Am. Chem. -309- Soc., 11. ~!, 1851 (1969). R. Ratcliffe and R. Rodehurst, J. Org. Chem., ~~' 4000 (19 7 0). 12. A. F. Kluge, Tetrahedron Lett., 3629 (1978); also: see A. Dehnel, J. P. Finet, and G. Lavielle, Synthesis, 474 (1977). 13. S. F. Martin, P. J. Garrison, Tetrahedron Lett., 3875 (1977). 14. P. J. Kocienski, Tetrahedron Lett., 441 (1979); ~I. Julia and B. Badet, Bull. Soc. Chim. Fr., 525 (1 9 76); 15. P. D. ~!agnus, Tetrahedron, ~~' 2019 (1977). B. ~l. Trost, H. C. Arndt, P. E. Strege, and T. R. Verhoeven, Tetrahedron Lett., 3477 (1976); E. J. Core y and ~I. Chaykovsky, J. Am. Chem. Soc., 87, 1345 (1965); V. Pascali and A. Umani-Ronchi, J. Chem. Soc., Chem. Commun., 351 (1973). -310- PROPOSITIOK V Abstract: A mechanis m for the reaction of cuprates with propargylic alcohol derivatives is proposed. Organocopper and cuprate rea ge nts have received a lot of attention. Due to their ability to form carbon-carbon bond s without disturbin g sen s itive functionalit y , the y h a v e proven extre mel y u s eful. 1 Unfortunately, the availabl e information about the mechanis m of these reactions has not kept pace with the information on synthetic applica. 1-4 t1ons. Th e little th a t is available is often confusing and contradictory . Contributin g to th e confusion is the lack of careful s y ste matic studies utilizing similar rea gent s , solvents and substrates. Also, different t ypes of bond formin g reactions seem to proceed by different mechanism s . For e x am p le, 1,4-conjugate addition seems to occur via an initiall y formed charge transfer complex 5 followed by e transfer and alky l migration. Some 111 authors also impl y that a Cu intermediate may form but 2 no fir m evidence has been found to support such a claim. Couplin g with halides and tosylates, on the other hand, seems to proceed via a simple nucleophilic displacement, 4 but the exact nature of the SN2 process is not clear. Some authors support a direct displacement of the leaving -311- group by the alkyl of the cuprate while others prefer to • • d.iate consi·ct er a SN2 b y copper to give a Cu III interme which under goes reductive elimination. 6 Compounding the confusion is the fact that variations in purification of reagents, differences in cuprate ligand s and counterions, trace impurities, different solvents and inorganic salts can all have profound effects on the course of the . 7 reaction. One of the more interesting reactions noK being utilized in cuprate chemistry is that of allene formation fro m propargylic alcohols and their derivatives as shown in equation 1 (X = leaving group). Several mechanisms (1) can be postulated Khich explain the overall transformation. Pasto, et al., 8 postulated an initial charge transfer complex which then went to products (eq 2) via transfer of an alkyl group in an SN2' type of reaction. analogous study of organoaurates, 9 Based on an Pasto ruled out an intermediate CuIII intermediate (Scheme I) . • 1·1cate d a H01vever, studies by Crabbe. . l0 strong 1 y imp -312- Scheme I Predict R A. I L-Cu- Al I Rl R B. I I L-Cu-R 1 Al Al C. I L-Cu-Al I 1 R Al D. I L-Cu-Al I Al 2 1 L = ligand, Al= allene, R - alkyl Observe -313- . a·1ate. Cu III 1nterme Crabbe found that if the reaction wer e carried out at low temperature and quenched, not onl y were the expected alkylated allenes observed but also reduced allenes were found. By changing the te mperature and reaction time he could obtain varying ratio s of alkylated or reduced allenes, the alk y lated product bein g favored by long er reaction times or higher temperatures. Further, he showed that the proton source for the reduction did not originate from solvent or the cuprate reagent but from the quenching reagent (Scheme II). Crabbe therefore postulated an SN2' reaction to give an initial CuIII allene which could reductively eliminate or be quenched during workup. A glaring inconsistency is readily apparent. Pasta's evidence precludes a CuIII intermediate while Crabbe's evidence requires at least a metalloallene. To further compound the confusion Crabbe, Pasto and others have shown that if the carbon bearing the leaving group is I -314- Scheme II H-==\ OAc H H chiral,B,lO,ll a chiral allene results with the configuration of the major enantiomer best explained by a SN2' reaction that proceeds in an anti manner (eq 3). To LiCu(R)z (3) -315- explain all of the available data an alternative mechanism is proposed which entails an initially formed • 1 - Cu III interme • d.iate ass h own 1n • Sc h eme III . lZ viny This mechanism is consistent with the Pasto findings in that the results of the control experiments Pasto performed are not applicable. The results of Crabbe may be rationalized by supposing that at low temperature the rate of rotation (k ,) and elimination (k 3 ,) for 1 are 2 competitive with the alkylation path (k 1 and k 2 ). That is, this mechanism presumes the rate of alkyl transfer is more sensitive to temperature than is the rate of rotation and elimination,implying that (if this mechanism holds) alkyl transfer might be intermolecular. 13 Other supportive evidence of this mechanism comes from studies of the reaction of cuprates with acetylenes. Several authors have shown that cuprates do indeed add to acetylenes in a cis fashion to give an intermediate vinyl cuprate (2) (eq 4). Also directive effects of acetals have been noted. Studies of the metallation (4) -3 1 6 - /r R R~ + Cu M •· X R - -=- ,_/,,Rz 1 R., .) l R R "- Cu "'III k2 , i 1 .. + M R '-..Cu/'r R I I X i,,'Rz Rl kz k3 + M R3 i I Cu I . . . . . . R3 Rl Rz X k3 •j ~.\ Rl R R . . . . . .R3 . Rz Rl Cu R\ R II X R., ,~' J Rz -317- of heterosubstituted aromatics and vinyl groups have also indicated a strong kinetic and ~-directing effect by 4 heteroatoms~ That would explain the high levels of asymmetric induction possible. Further tests of the proposed mechanism are immediately obvious. If the alkylation step is indeed intermolecular then changes in concentration should have a dramatic effect on the rate of formation of the alkylated allene. Also, the intermediate vinyl anion could be trapped by reaction with carbonyls. Cuprates are known to be very unreactive toward ketones. Thus if the intermediate could be trapped that would be strong evidence against Crabb§'s mechanism and in favor of Scheme III. 15 Another possible test might include low temperature Li, 1 H and 13 c-NJ,JR examination of the allenes. Since both 8 copper and lithium allenes should be readily available, , 16 comparison of the experimental spectra with the authentic samples should be productive. Finally, an examination of a series of 0-alkyl acetylenes (~) in which the relation between the level of asymmetric induction and the electron donating ability of the oxygen would allow a determination of the importance of the leaving group on the course of . 17 t h e reaction. Another interesting aspect of the proposed mechanism is that it could also be used to explain some of the -318- results in the reaction of cuprates with allylic alcohols . d er1vat1ves. . . 18 an d t h eir For example, Claesson recently reported the reaction in equation 5. 18b He postulated that the reaction went via a n-allyl cu 111 (5) 4 species, but the data are also consistent with an addition across the double bond followed by elimination (Scheme IV). To date however, no examples of cuprate addition to non19 conjugated olefins have been observed. An alternative mechanism for propargylic displacements has been proposed. The new mechanism explains the avail- able data and is amenable to experimental tests. -319- Sch eme I\' --~~~~~-- CH~ OH H l 4 rotation/elimination -320- Refer ences and Notes 1. For recent reviews of ~rganocuprates see: Posner, Org. Reactions, 19, 1 (1972); (a) G. H. (b) G. H. Posner, ibid., 22, 253 (1975). 2. i'lechanisrn of 1,4-additions: R. A. Smith and D. J. Hann~h, Tetrahedron, 35, 1183 (19 79). 3. Me cha nism of vin y l halide couplin g : C. V. Maffeo, G. Ma ichese, F. Noso, and L. Ron z ini, J. Chem. Soc., Perkin Tran s . 1, 92 (1979). 4. i'lec hani s m of alk y l halide couplin g : C. R. Johnson and G. A. Dutra, J. Am. Chem. Soc., 95, 7783 (1973). 5. H. 0. Hou s e, Acct. Che m. Re s., 9, 59 (1976). 6. P. Vermeer, J. Meijer, and L. Brandsma, Reel. Trans. Chim. Pays-Bas, 94, 112 (1975); G. H. Posner, J. S. Ting, and C. M. Lentz, Tetrahedron, 32, 2281 (1976). 7. H. 0. House and J. M. Wilkins, J. Org. Chem., 2443 (1978); ~~' H. 0. House and T. V. Lee, ibid., 43, 4369 (1978). 8. D. J. Pasto, S. K. Chou, E. Fritzen, R. H. Schulz, A. Waterhouse, and G. F. Hennion, J. Org. Chem., 43, 1389 (1978). 9. S. Kamiya, T. A. Albright, R. Hoffmann, and J. Kochi, J. Arn. Chem. Soc. , 9 8, 7 2 5 5 (19 7 6) . 10. J.-L. Luche, F. Barreiro, J.-M. Dollat, and P. Crabbe, -321- Tetrahedron Lett., 4615 (1975); J.-Jll. Dollat, J.-L. Luche, and P. Crabbe, J. Chem. Soc., Chem. Commun., 761 (1977). 11. W. H. Pirkle and C. W. Boeder, J. Org. Chem., 43, 2091 (1978); W. H. Pirkle and C. W. Boeder, ibid., 43, 1950 (1978). 12. Note that the intermediate Cu III postulated is different than that used in the control experiments by Pasto. 8 13. . Cu III species, if they exist, have been suggested to be alkylating agents. 2 14. (a) J. J. Eisch and J. H. Merkley, J. Am. Chem. Soc., 101, 1149 (1979); (b) J. J. Eisch, J. H. Merkley, and J. E. Galle, J. Org. Chem., 44, 587 (1979); (c) A. Alexakis, A. Commergon, J. Villifras, and J. F. Normant, Tetrahedron Lett., 2313 (1976). 15. Even if the capture with carbonyls fails, that does not rule out Scheme III since the elimination reaction might be 1 -+ ii. • • ---.... Cu (R) 2 ,R R R2 i X ii -322- 16. R. Bandov, F. Delbecq, and J. Gore, Tetrahedron Lett., 937 (1979). 17. By making the oxygen a better e- donor the levels of asymmetric induction should increase because of the increase in the directing effect on the initial step of the reaction. 18. See: (a) R. J. Anderson, C. A. Henrick, and J. B. Siddall, J. Am. Chem. Soc.,~~' 735 (1970); (b) A. Claesson and L.-I. Olsson, J. Chem. Soc., Chem. Commun., 621 (1979). 19. Addition of Grignard reagents across olefins which have a ~-hydroxyl group has been reported. 13a ' b