Total Synthesis of a Key Intermediate for the Triterpene Shionone Citation Kowalski, Conrad John (1971) Total Synthesis of a Key Intermediate for the Triterpene Shionone. Master's thesis, California Institute of Technology. doi:10.7907/JG81-R503. https://resolver.caltech.edu/CaltechTHESIS:04302010-151038761 Abstract Total synthesis of a key intermediate, in a synthetic scheme aimed at the tetracyclic triterpene Shionone, has been accomplished by two closely related routes. Item Type: Thesis (Master's thesis) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Ireland, Robert E. Thesis Committee: Unknown, Unknown Defense Date: 25 September 1970 Record Number: CaltechTHESIS:04302010-151038761 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:04302010-151038761 DOI: 10.7907/JG81-R503 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 5762 Collection: CaltechTHESIS Deposited By: Tony Diaz Deposited On: 04 Aug 2010 15:52 Last Modified: 24 Jun 2024 19:00 Thesis Files Preview PDF - Final Version See Usage Policy. 1MB Repository Staff Only: item control page

TOTAL SYNTHESIS OF A KEY TTERMEDIATE FOR THE TRITERPENS SHIONONE Thesis by Gonrad John KowalsicL Tn Partial Fulfillment of the Requirements For the Degree of Master of Science California Institute of Technology Pasadena, California 1971 (Submitted September 25, 1970) ACKNOVWLEDGHENTS I wish to thank professor Robert E, Ireland for his guidance and patience, and the National Institutes of Health for financial support, during the period of this research, > aimed et the tetracyclic triterpene Shionone, has been accomplished by two closely related routes. -1s While the synthetic pathways towards the pentacyclic triterpene structure a» of the oleanenes, A-ayrin, and germanicol have been explored with some success (1a,2), few efforts have been directed to- werds the backbone rearranged triterpenes alnusenone Ai, friedelin iii, and shionone jiv (1b,3,h). As yet, no synthesis has been published for any of these molecules, due in part to the great difficulty of introduc- ing the trans angular methyl groups at the C-D ring juncture. Recent iv Gta developments by We. Nagata (5), however, on the trans incorporporation of cyanide at ring junctures, have opened potentiel new pathways to these molecules; an important key intermediate along one of these paths, which contains the elusive trans angular methyl groups, and allows for the synthesis of ii, iii, and iv, is the molecule A-15. The toval NAT fn ow POOBRN synthesis of this intermediate has been the object of this research. The original synthetic plan is outlincd in Chart A. vinen the plan ~2- was proposed, compound Acd had already been made by H. Smith and co- workers (6), using essentially the same annellation procedure. Nagata's hydrocyanation techniques (5) were to generate the trans-fused compound Ac2 (possibly utilizing a protecting group for the alcohol function, to prevent base cleavage), and this was to be reduced to the trans-dimethyl compound Acl2 via the imine ( 7). The only remanining crucial step, acid cyclization, had been worked out by S.C. Welch in our lab (8) on the model compounds v(a)s (o) and (e). In all three cases, treatment with polyphosphoric acid (PPA) at 60° gave the same mixture of trans-anti-trans and cis-anti-trans cyclized material DE in the ratio of 70:30 respec- vivly. The intermediate A-15 thus seemed an attainable goal. H 0 : R Um =3 ; Cis CH, 0 CHO % (2) BRCH3., R'=0H vi (d) R=OH , RI=CH3 In practice, the unsaturated ketone Ane could be obtained in O7% overall yield. Hichael addition to this compound appeared to work well, but subsequent ring closure lowered the two step yield to 5uS3 the reaction conditions have been variously modified, but with no improvment. Sodium borohydride reduction gave a high (80% crystalline) yield of Ab Treatment of ps8 with EtoA1CN in benzene (5b) gave a mixture from which a single cyeno ketone crystallized in 80% yield. while chromatog- raphy of the mother liquors could not be made to efficiently separate the romonining components, a small amount (iS), though not all, of an ~3- CHART A ete . Et,0, THF CH,0 @NMez | a’ tad PAN, Oo CHO 2) re E40 CHO CR, Cl 2 a 6 | n°) 1S aL @ CON, EtyN 0 ad : —————__——3> MeOH, E4,N A, XYLENE CH,0 cH, ae £ 2 9H NaBH, E42 ALCN ———— —__-—--——-$e E4OH or G4, AL, HCR, CH,O THE IN @ -))- CHART A fw ante ce -)H,0, Het HaNNH,-2HCt oe ae | meok ce 2) Me Mg. Et,0 1 a ~5- isomeric cyano ketone was obtained from the mixture. Comparison of the nitrile absorption in the infrared spectra of the two compounds, shows. the minor product to have a much more intense absorption, indicative of a cis ring fusion (9); thus the major isomer eppears to be the desired compound A=9. Further comparisons of the NMR spectra of these compounds, with the closely analogous series of S.C. Welch, vii(a), (b) and (c) (10), leads to assignment of viil as the structure of the minor isomer. mes vii (a) &-H, B-CH (b) B-H, _e-Ci (c) of-H, &-CN Interestingly enough, treatment of A-8 with #b3A1 and HCN in THF (5¢) gave the identical (by NMR) product mixture obtained with Et,ALCH. 9 worked well (91%), but diisobutyl Ketalization of the product A- aererr aluminum hydride (DIBAH) reduction of the nitrile to an imine, with sub- sequent Wwlff-Kishner reduction to a methyl, could not be accomplished in appreciable yield. The DIBAH reduction proceeded with difficulty, resulting in wheat appeared to be a mixture of non~, mono-, and di-reduced material; even when the imine seened maximized in the mixture, the wlff- Kishner reduction resulted in very low return, concentrated in the unre~ duced cyano starting material. Other trans-cyeno ketals have been successfully reduced using similar techniques (7), but none with a sub- stituent eZ to the ring junction bearing the nitrile, nor with a nearby J res ; . -6- hydroxyl. An attempted iittig reaction of $3P=CH, with the cyano ketone AQ also failed, returning pure starting material. | Upon failure of the direct conversion of the nitrile to a methyl, a 9 different approach (Chart B) was tried. Grignard addition of MeMgI to A- (excess did not affect the nitrile), gave the cyano di-ol Bol in good (80% crystalline) yield. Treatment of this di-ol with acid or base gave the imino lactone B52, which could not be hydrolyzed further even with HNOp (11). Jones oxidation of the alcohol function, however, allowed easy acid hydrolysis to the lactone Bee (93%), presumably via assistence of the hydrated ketone. While it was hoped to cyclize this lactone to Bh, using either PPA or P505 in benzene, such attempts always led to decarboxylation. Attempts to reduce the keto lactone with BH3 in THF to obtain the lactol alcohol (hopefully susceptible to Wolff-Kishner reduction) >» gave only the lactone alcohol Bobs which equilibrated with B68 in acid or base. Treatment of these lactone alcohols with hot PPA, gave Be? (153), BB (66%), and Bo (9%), the structures of which were assigned on the basis of IR and NMR spectra (12). Although all these hindered lactones resisted reduction with BH3 in THF and with LiAlH, in refluxing THF/ether, treatment of E58 with diisobutyl aluminum hydride (DIBAH) in benzene gave the di-ol Bel. DIBAH has been used to reduce lactonesto lactols (13), and by using an equivalent amount of DIBAH at 0°, a 1:1 mixture of Bel0 and the lactol Bo was obvained, yolff-Kishner reduction of the lactol gave mostly starting material, but also yielded 20% of an alcohol Bele, containing three angular methyl groups by NMR; Jones oxidation of this alcohol gave ng of a ketone, spectrally consistent with the structure A<15. LV PAAS \) Me Mgt SD 2 >H,0 CH, 0 A-S 7 = 9H Z ty ) TONES COE ere OL 0—— Ce 2) K, H,0 Cw CH,O NA CHO “6 2 PES ma CH,0~ (>), AH , + TOLUENE 0° cho g 10 WOLFF- KISHNER ————— CHO 1! 2 ~J- Although not enough of this material was available for analysis, it was later shown to be spectrally identical and have the same melting point as the product finally characterized as Ar1. The roundaboutness of the lactone route brotght attention back to the problem of directly reducing the nitrile group. Gutlined in Chart G, a reduction scheme was proposed via.a derivative containing no free hydroxyl group. The mixture of olefinic ketones Ge2a was formed by careful Jones ~: oxidation of B-1, followed by dehydration of the tertiary alcohol. Ketalization of this mixture led to a new mixture Gaeb, which proved inert to LiAlH), in refluxing TH. DIBAH in benzene geve much the same results as Anl0; unsatisfactory reduction leading to a mixture which could not effectively undergo wolff-~Kishner reduction. An attempt to hydrolyze the supposed imine to an aldehyde (7), did not give any recognizable aldehyde product. It would appear that the hydroxyl group in A=10 is thus not respon= Sible for the difficulty in converting the nitrile to a methyl group. As angular nitriles bearing 1-3 dlaxial relationships to ketais have been successfully reduced (7), it was thought that perhaps the bulky £-(a-methoxyphenyl )-ethyl side chain might be responsible for the problem. In this respect, it appeared worthwhile to investigate the reduction of 6-6. Addition of EtjAlcN in benzene, or EbjAl and HCN in THF, to the eneone alcohol Sol (14), gave the same (by NMR) product in both cases. A pure cyano ketone erystalized from each of these vroducts ( 50% yield from the first crop), which, except for some very minor impurities, was identical in the NMR with the crude product; no isomeric nitriles could be isolated from the mother liquors by chromatogranohy (very much the ~10+. CHART C re b) pIsOH, oH on Con, A 2) WOLFF- KISHNER THE CN zs 3 H CO Et AICN, GH ~~ pTs0H, Coy oye or EAL HEN, 4 gH, a 4. wou 00>) Aten 2) WOLFF- KISHNER -li- same situation as encountered with small scale hydrocyanation reactions of A-8). Due to the close analogy of the compounds A-8 and C-l, and their very similar reaction patterns on hydrocyanation by both methods, it seems likely that the reaction products Ax? and 0-5 would be sterio- chemically similar; that is, it seems likely that Gn5 would also have a trans ring fusion. Attempts at reducing the cyanide in C-5 after ketalization to 0-6, on patel met with no success, yielding results similar to those obtained with A-10 and C-3. Even a single methyl group, then, o to both the ketal and ring juncture bearing the nitrile, is sufficient to block the reduc- tion sequence. S.C. Welch has since realized this same difficulty in his unsuccessful attempts to convert the nitrile in compound 3x His subse+ quent success with the olefin mixture x however, showed that substituted cyano compounds of this type are susceptible to reduction if no serious 1,3 diascial interactions exsist (15). Oct CH,0 | CHO forte ow The next logical approach at reducing the nitrile of A-9, therefore, one involves the route outlined in Chart D, through the intermediate D-2 which contains no serious 1,3 diaxial interactions with the nitrile. Selective acetylation of the cyano di-ol B-1 proceeded well to give crystalline mono-acetate P-1 in 759 yield. This was dehydrated to the Olefinic isomer mixture D-2 in 91% yield (after chromatography), which POON ~j2Q— CHART OD )O-) ary 2) WOLFF- KISH. CH,0 & 2. TOLUERE CH,O -13- was submitted to the same cyanide reduction procedures which had failed so frequently before. Happily, the di-methyl olefin mixture Dw3 resulted, in 71% yield. The major obstacle to the synthesis of Az15 had been over- come. Jones oxidation of the D=3 olefinic alcohols, yielded the corres- ponding ketones Do in 93%. Cyclization of these with strong acid in refluxing toluene, gave a mixture of two components in the ratio of 82:18 by GLG. A portion of the major component crystallized out to give 52g of a pure white solid; the mother liquors, still containing both cononents could not be separated by chromatography. MR spectrm of the mother licuors reveals a very high field angular methyl signal (J =.33) due to the minor component, indicative of a cis fused B-C ring in which the aromatic ring strongly shields the angular methyl derived from the nitrile (8). On the basis of the model compounds v(a), (b) nd (c) men- tioned earlier, one would also expect the cis closed compond to be the minor isomer. The major isomer, then , should. be the desired end product of this research, the tetracyclic ketone Av15, and indeed it appears to. be so. Spectrally identical with the material obtained via the lactone route (chart B), this compound analyzes correctly for, and is spectrally hn the structure A-715. pone consistent iwi Tyo other routes aimed at the tetracyclic Azl have since reached their ends; the final products obtained by C. Lipinski (16) and J.W.Tilley (17) in this leb, heve proved to be identical with the product from Chart D. Except for the very last cyclization step, all three routes are very different; thus there is no doubt that the Cand D rings are correct. The spectral evidence and evidence from model compounds, coupled with the identical product from Chart B (with somevhat differnt last steps), =~ strongly indicates that the A,B anda G rings are properly connected, The synthesis is done. The total yield of A-15 from A~1 is 3%; the scheme. represents-a PON MAnwws reasonable pathway to an important intermediate for the total synthesis of some polycyclic triterpenes, and better defines some of the important reactions along that route. EXPERT OOTAL RUN UNDER A NITROGEN! ATHOSPHEZE unless otherwise ts) ALL REACTIONS WEA noted. "Dry" ether and THF were distilled from LiAlH and subsequently protected from moisture; dry benzene was distilled from calcium hydride; dry pyridene and CHpCly were distilled from P05. Al] melting points labled "(vac)" were taken in evacuated capil- aries on a Hoover Capillary Melting Point Apparatus; all others were taken on a Kofler Hot Stage. All melting and boiling points are uncor- rected. Nuclear magnetic resonance spectra were run on a Yaricn T-60 Analytical N.M.2. Spectrometer. Infrared spectra were run on a Perkin-Elmer Kodel 2378 Infrared Spectrometer. Analytical G.L.C. work was done on an Féki Model 610 Gas Chromatograph, using $9 SE-30 colums. Microanalyses were performed by Spang Microsnalytical Laboratory, Ann Arbor, Michigan. -16— h=2 : 3-(m-methoxyphenyl)-n-propenol (18) hd . To a rapidly stirred suspension of 52g (1.38 moles) of Lialy, in 640ml of dry ether, a solution of 100g (.56 moles) of m-methoxy cinamic acid in 00m. of dry THF was added over a period of 2 hrs so as to main- tain gentle reflux. The mixture was then stirred at reflux for an addi- tional 2 hrs, cooled in an ice bath, and the excess LiAly destroyed with 95% EtOH. The mixture was poured onto 1500g ice + 100ml conc. HpS0),» extracted with ether (6 x 500ml), and the combined organic phases washed with 5% NaOH soln. (2 x 150m1) and brine (150m1). The organic phases were dried over NajS0), and the solvent removed in vacuo to give 85g (91%) of a yellow oil, 97% pure by GLC. Short path distillation of the oil at 98-1069, O.inm, resulted in 56.8g (61%) of a nearly colorless liquid. Infrared: ap fiin mant 3330 em7!, broad (alcohol) 1601,1580,1490 cm™? (aromatic) 1270em=! = (Ar-OCH3) A-3 : 3-(m-methoxyphenyl)-n-propyl chloride (49} awe ; To a stirred solution of 56.6g (0.342 moles) of the alcohol A-2 in hom of N,N-dimethyl aniline, chilled in an ice bath, 26.5m1 (0.37 moles) of thionyl chloride (freshly distilled) was added dropizise over a period of 20 min.. Stirring was continued first for 30 min. more in the ice bath, then at 100° for 15 min., after woich the mixture was cooled, treated with 200ml of 109 HCl + 100ml of brine. This mixture was excrac~ ted with ether (5 x 150mL), and the combined organic phases wasned with 5% NacH soln. (2 x 100ml), water (2 x 100m1L), dried over MgSO), and stripped of solvent in vacuo to give a quantitative yield of browm Liquid. Short path distillation of the product at 62-87°, -l5m, resulted in 58.6¢ (93%) of a yellow liquid. -17= Infrared; 49 filn 1601,1580,1495 em! (aromatic) mare 1270 (Ar-OCH; ) 6-(m-nethoxyphenyl- )-hex-1-ene-3-ol A-h-: WAAL In a dried apparatus, 6.36g (0.262 moles) of Mg shavings were cov- ered with 15ml dry ether, stirred, and about 6ml of a solution of 13.82 (0.237 moles) of the chloride A-3 in 35ml of dry ether was added. A drop of MeI initiated the reaction, and once reflux had begun 150m of dry ether was added. The remainder of the chloride soln. was added over a period of 15min. so as to maintain reflux, after which reflux and stirring were continued for two hrs. more. To this solution, rapidly stirred and chilled in an ice bath, 17.lml (0.262 moles) of freshly distilled acrolein in 30ml of dry ether, was added over 30 min., after which the temperature was raised to room temperature for 30 min. more. The mixture was then poured onto 500g ice+water, 200ml of satid NH),CL soln. added, and the organic phase separated. The aqueous layer was extracted with ether (14 x 300ml), and the combined orgenic phases washed with water (300m), sabid NaHco 5 (2 x 300m) and brine (300ml). After drying over MgS0),, they were stripped of solvent in vacuo leaving a green liquid; the liquid was distilled from a trace of BaO”, giving 0.92g¢ of forerm, bp 39-l0°, .15mm, and l1.0g¢ (84%) of greenish tinged product, bo 112-115°, .O7mn. 7 Infrared: filn 3360 cm’, broad ( -OH8 ) mens 16u5 ( vinyl ) 1601, 1580,1495 (aromatic) 1260 ( Ar-CHée ) *note: the product must be protected from acid av all tines. -~i16— A-5 : 6-(m-methoxyphenyl )-hex-1-en-3-one MAA To a vigorously stirred solution of hhelig (170 mmoles) of Cr03°2Pyr in 600m of dry CHpCl2 (freshly distilled from P20), 540g (26.2 moles) of the vinyl alcohol A-l was added in SOml dry CHpClj. After stirring for 15 min., the solution was filtered through 250g alumina, and the reaction flask and filter washed with an additional 300ml CHjCl,. The solvent was stripped in vacuo, and the resultant oil pumped under high vacuum for 1 hr., leaving 4.98g (934) of a clear oil (smelling faintly of pyridine). As the eneone tends to polymerize, it was used directly. Infrared: qyfilm 1675 om™! (unsat'd carbonyl) mee 1601,1550,1485 (aromatic) 1260 cw! = (Ar-ORe) - oe ba s€3) ae A-7? ¢ 1-3t-methoxyphenethyl-10B-methyl«A° octal-2,5-dione -.-2..2. (6) twas Freshly prepared crude vinyl ketone A-5 (.98g, 2h.) mmoles) was conbined with 125ml MeOH, 2.86¢ (22.7 mmoles) of 2-methyldihydroresorcinol and 1.iml Bt3N, and stirred at room temperature for 23 hrs.. The reaction mixture wes stripped of solvent in vacuo to give the yellow brown oil o filn 4 - A-6. Infrared nace 1695,1715,1725 em™! (carbonyls). Ring closure was done following the method of H, Smith and co-workes (6). The above trione Ao was combined with SimlL xylene, 3.3g of benzoic acid, and 2,75ml Et3N, and refluxed through a Dean-Stark apparatus. Ten ml of xylene were collected in the side arm, and reflux continued for 2) hrs.. The solution was cooled, combined with 500ml ether, and washed with Sat'd NaHCO3 (5 x 100ml), 2% HCl (3 x 100m1), and brine (2 x 100ml). The solvent was removed in vacuo leaving 6.52¢ of a brownish oil. Fractional distillation of this oil gave one major fraction, bp 175~205° =19— at .Oimm, which contained a small amount of sublimed 2-methyldihydr- resorcinol. The product was washed from the impurity with acetone to give l.11 4) of th -di ~7. give h.iig (542) é ene-dione A-7 Infrared qyfiin 1710, 1665 on™! (sat'd and unsat'd ketone) mens 1601, 1580, 1485 (aromatic) ASB 3 58 ~hydroxy~1-31!-methoxyphenethyl-10f -methyl- A 1¢9) octal-2-one (6) Mone The selective reduction of the ene-diketone was done using the method of H, Smith and co-workers (6). To a rapidly stirred solution of 11.0g (35.2 mmoles) of Bel in 290ml absolute ethanol, chilled betireen 0-5°, a solution of 2.0g (53 mmoles) of NaBH, in 390ml of absolute ethanol was added dropwise over a 20 min. period, so that the internal temperature never rose above 5°. After the addition, stirring was con- tinuedat the low temperature for 10 minutes, then ilml of acetic acid was carefully added, followed by 50m1 of water. Host of the ethenol was then removed in vacuo, 150 ml water added, and the mixture extracted with ether (S x 150 ml). The combined organic phases were washed with 2% NaOH soln. (3 x 150ml), water (2 x 150mL), dried over MgSO), and stripped of solvent in vacuo to give a yellow oil. This oil was crystal- lized from ether/hexane to give 8.7lig (79%) of white crystals in 2 crops. Infrared: np CHCL3 3615 em71, sherp ( -OH ) mex 1665 (unsat'd ketone) A-9 : way a) Hydrocyanation using Eb oALON in benzene (5b). To a stirred solution, ice bath cooled, of 21.9¢ (69.8 mmoles) of As8 in 230ml dry benzene, 1)Oml (210 mmoles) of 1.5! EtoalcN in benzene was added in a slow stream over several minutes. Stirring was then ~20~ continued at room temperature for 2.5hrs., after wiich the mixture was poured into a solution of 100g NaOH in 2000 ml of ice + water with vigorous stirring. The solution was extracted with CHjCl, (4 x 800ml), and the combined organic phases washed with 10% NaOH soln (500m) , water (2 x 500 m1), dried over NagS0), and stripped of solvent in vacuo to give @ quantitative yield of. a heavy gum. The gum was erystalized from ether/ hexene to give 19.04g (80%) of white, crystalline trans-cyano ketone Ar? in two crops (mp 135-121°), Two more recrystallizations raised the melt- ing point to a constant 122-125°, Analysis calc. for Co1Hp7i!05: Cy 73.873 H, 7.973 N, 4.10 found C, 73.963; H, 7.963 H, 4.06 Infrared: apoits 3615, 3480 omm1 ( -OH ) max 2225 ( -CN ) 1720 ( sattd ketone ) NER: DoL S,. 3 1.l2pom (ss) C 10 methyl, 3 3.70ppm (m) C 5 proton, h 3.50ppéh (s) -OCH3 6.7-7.4 ppm (m) aromatic hy NUR of the mother liquars showed two compounds other than A-9 to be wo present, with C 10 methyl signals at § 1.03 and 1.18 ppm. Colum chromatograshy over 1 kz of silica gel, eluted with pure ether, gave almost no seoeration of the three compounds, exceot for several of the very last fractions which contained 947 mg ( 4%) of pure viii (much of Aww this compound wes eluted impure in earlier fractions). The compound formed erystals in EtOH, put turned into a white glass on standing. Analysis calc. for Co,He7N03 C 73.87; HW 7-973 MN U.10 found C 736733 H 7-973; H 4.07 ~24- Infrared: 49 C223 3620, 3500 cm! ( -OH ) max 2250 ( -cy ) 1720 (sat'd ketone) MAR: O13 4.18 ppm (s) 6 10 methyl THS 3.80 ppm (s) -OMe 4.0 ppm (m) CG 5 proton 6.7-7.4 ppm (m) aromatic b) Hydrocyenation using Et3Al and HCN in THF (5c). To 2.0nl (.34 mmoles) of a stirred solution of 0.696M Et3Al in THF, chilled vith an ice bath, 0.16 ml (1.05 mmoles) of a 5.814, soluti on of HCN in dry benzene was added dropwise. To this mixture, 108 mg (0.3) mmoles) of the ene-one 408 was added dropwise in dry THF (3 x iml), and stirring continued for 2 hrs. with ice bath cooling, and for 18 hrs. at room temperature. The mixture was voured into 60 ml of 5% NaOH soln. + 40g ice, extracted with CHC13 (4 x 50mL), and the combined CHC13 extracts washed with water (2 x 50m1) brine (2 x 50m), dried over NaoSO}, and stripped of solvent in vacuo. A quantitative yield of a yellowish oil wos obtained, having an NMR spectrum essentially identical with the crude product spectrum from pert (a) above. Pure A-9 (60mg, 513) crystallized from the oil, but no other products could be isolaved from the mother licuors. A-10 3 ww In a flask were combined 23mg (1.2) mmoles) ofeyano ketone A-9, . “— 1m. of ethylene glycol, 6mg of p-toluene sulfonic acid, and 20 ml ben- zene. The mixture was stirred and refluxed with separation of water Dean-Stark apparatus) for 160 minutes, after waich it was cooled, 25.2.2 ifb 3 > ~22~ washed with sattd Haicd; (3 x 50 ml), water (5 x 50 m1), dried over MgSO), and stripped of solvent in vacuo to give a quantitative yield of white gum. Preparative TLC of the product on a 20 x 4O em silica plate, eluted twice with 60% ether/petroleum ether, gave one major band, rf = .26. This band contained 436 mg (91%) of the ketal A-10 as a glass,.96% pure by GLC. Infrared: ny CHCL3 3620, 3480 cm~1 ( -OH ) max 2230: ( nitrile) 1150, 1100, 1050 (ketal ) WR: CDc1, 97 ppm (s) G10 methyl, 3 3.75 ppm (m) C 5 proton 3.80 ppm (s) -OCH3 h.05 ppm (m) ketal protons 6.7-7.4 ppm (m) aromatic yore’ To a stirred solution of 180 mg (.468 mmoles) of the cyano ketal A-10 in \Onl dry Benzene, 3,46 ml (1.17 mmoles) of the .338 1f diisobuty] elum- inum hydride (DISA) in benzene soln. was added dronwise. Attempts to follow the reaction by GLO and PLO were wholly unsuccessful. After 8 hrs. of stirring, the mixture was poured into 20ml of 5% NaOH soln, wita 1S¢ of ice, separated, end the aqueous phase extracted with ether (4 x 25m1). The combined organic phases were washed with water (3 x 30mL), brine (30m), dried over MgSO), and stripped of solvent in vacuo to give 156 mg (86%) of a yellow oil, hoped to be the imine Avi. Infrared shows considerably weaker nitrile (2230), with a slight new band at 1625 (imine). The crude product from above was combined with 13.5ml of trietylene =~23— glycol, 1.35 ml of 85% hydrazine hydrate, and 338 mg of hydrazine di- hydrochoride, md stirred for 3 hrs. in a 1)0-i5°bath. Pellets of 85% KOH (2.12g) were added portionwise as a stream of No was passed through the vessel, and the bath temperature raised to 175-180°. The temperature was so maintained,as was the No stream, for 4.5 hrs., after which the mixture was cooled, poured into 50ml of water, and extracted with ether (6 x 30 ml). The combined organic phases were washed with water (10 x 20m1) dried over Hgs0),, and stripped of solvent in vacuo to give 110 mg of a yellow oil. Preparetive TLC of the product on a 20 x 20 cm silica gel plate, eluted once with 30% acetone/petroleum ether, gave two major com pon-nts, rf= .21 and .39. The fraction having rf=.21, amounted to 30mg end appeared to be mostly starting material by GLC. The fraction having rf=,.39 emmounted to elmg (145) of an oil, 809 pure by GLC. IDR: cDcl3 95 ppm (s) TS 1.00 ppm (s) 3.80 ppm (s)} -Cle trens enguler met thyls 3.9 ppm (m) ketvel protons It would appear that this was the desired product 4-12 Qs hovever, not AANNA~ enough wes available to characterize, and upon varying the reaction conditions, no better, or even comperable yield could be cbiained to generate more. Bel ; wor fo ea stirred solution of .50g (1.05 maoles) of the cyano ketone A-9 in 30 ml dry benzene + 70 ml dry ether, 50 ml (70 mioles) of 1.4 H 7. Heligt in ether (prepared by the traditional method) was added dropiise Lt with ice bath cooling. The white suspension formed was stirred et R.T. for 1 hr.,poured into 100 g-ice + 150ml sat'd NHLC1l, and extracted with -2h- chloroform (6 x 100ml); the combined orgenic extracts were washed with ywater, brine, dried over lMgS0}|, and stripped of solvent in vacuo to leave a quentitative yield of white solid. This solid was treated once again with MelgI, exactly as before, to give h.75< (95%) of a white solid. Upon recrystalization from ether/acetone, l.02g (80%) of the desired diel B-1 was obtained, mp 170-1739. After two more recrystalizations, constent melting material mp 175-178°was obtained. Analysis calc. for C2zHy,N03: C 73.92: H 8.7h: BH 3.92 found 73.82 8.69 3.81 infrared: + COL, 3610 cl ( -OH ) 2220 ( -c ) 1601, 1550, 1455 (aromatic) HRs os 93 pon s, ~CH3, 3 1.13 ppm s, ~CH3; 3 3.80 ppm s, ~CHe, 3.6 ppm nm, . C 5 proton 366 6.7-7.l ppm on, arom atic ‘ hi Bee? A solution of 375mg of the cyeno diol B-1 in 20m1 EtOH, lL ml cone. fw HCl, snd 2 ml water, was stirred with mild warming (so? ) for five hours. It wes poured into 25ml sat'd NaHCO.,extracted with ether (5 x 30n1), a and the combined extracts washed with water and brine, end dried over lgS0j,. The solvent wes removed in vacuo leaving 335mg (593) of a dirty solid. Uson recrystalizetion from MeOH/ether, 26mg (70%) of fine white erystals were obtained, mo 150-1529, after a second recrysicligzation, the melting point was const.nt at 153-153.5°, Analysis for C22Hzji03: © 73.92: H 8.7h: No 3.92 found: 73.79 8.73 3.51 -25- Infrared: CCL; 3610 crt! ( -oH ) 1675 (imino lactone) WER: ¢ CDcls 97 ppm 8, -CH i 1.37 ppm ss, ~CH3 3.80 ppm s, ~OCH3 3.585 ppm nm, C 5 proton Be3 3 Ww“ ; To a stirred solutionof 195mg (.S2mmoles) of imino lactone B-2, in 2ml acetone, chilled in en ice bath, 1 mi of 8 N Jones reagent was added end stirring continued for 15 win.. Tsoprosanol (3m) was added, then 5Sml water and 5ml conc. HCl. The mixture was stirred for three hours inth mild heating (50°), poured into 20ml water, extracted with CHCL3 (5 x 30mL), md the combined organic extracts washed with brine. After drying over HES} s the solvent was stripped in vacuo to give a ycllow oil, which. crystallized from ether/chloroform to give 1Simg (93%) of the desired lactone B~3. Uoon three recrystalizations from ether, the nelting point became constsnt at 162-16)°, Analysis calc. for Cp,Hog0): C 7he13: H 7.92 Found: 73.91 7.356 Infrared: CHC13 1770 cn7! ( y-lactone) 1715 (ketone) HER: CDCl, 41.22 ppm ss, ce, 3 S nus 1.42 ppm os, He 3 3.00 ppm os, -OHe 3 6.7-7. ppm m, aromatic, 4k ~26- B-5 : few To a stirred solution of 106 mg (.30mmoles) of the y-lactone 5-3 LAAN in 2 ml dry TH, .9 ml (.9 moles) of BH3°THF soln was added at R.T. and stirring continued for 2 hrs.. This mixture was then poured into 20 ml -ice/ 24 NaOH soln, extracted iith CH Cl; (5 x 25m1), and the combined rgenic phases washed wita water and brine. After drying over NgSC),, the . + solvent was stripped in vacuo to give a quantitatine yield of a cloudy -OL1. Upon crystallization from ether/hexcne, 05mg (793) of isomeric ar 5 2 ; lactone Ane? mp06.5~85.5°. One final crystalization raised the melting point to 87-39°, Infrared: HCl 3550 em=1 = (_ -OH ) 1740 (&-lactone ) L651, 1580, 1185 (aromatic) NHR: CDo13 .96 ppm sy lie iS 1.45 ppm sy, -Me 3.33 ppm m, C 5 proton 3.80 ppm s, -Ole B-?, BS, BO: Wwe, Pew HOw To 1.215¢ (3.39 mmoles) of the -lactones B-5 md B~6 and 7 drops Prero = fewer YZ hd - oy £ io] mL of polyphosphoric acid (preheated to 76°) was re or benzene, abous added rapidly, and rapid stirring begun. The temperature was maintained at 78° for 4S min, after which the mixture was poured into 300 g ice + 100 ml water, extracted with ether (6 x 100 m1), md the combined etherial § phases vasned with naHCG 3 soln and brine. ter drying over NESO;, the -27- solvent was removed in vacuo to give 1.093 g (95%) of a white foam. This product was chromatograyhed over 200 g silica gel, eluted with og ether/petroleum ether to give three fractions B-9, B-8, and 3-7 in order On ee ae ae of elution. 105mz (9.1%) of B-9 was obtained reasonably pure from the (nen column. Upon two recrystallizations from EtOH, it gave a constant melting point, 1h2-1h°. Analysis for CooHog0,: calculated C 77.61: H 8.29 203 found 771s 8.38 Infrared: CHC13 1770 em! (S-Lactone) 1599,1575,1470 (cyclized aromatic) NHR: CDC13 1.05 ppm s, -He > 3 . 1.32 ppm s, ~Me, 3 3.75 ppm sy, -OMe 3 4.2 m, CS proton, 1 6.6-7.y i, aromatic 3 760 mg (65.8%) of 8-3 was obtained from the colwm; upon two recrystaliz- : : , . 2 2 o y ations in EtOH, a constent melting point 1:2-1)3° was reached. Anélysis for Co9H2{03: calculeted C 77.61: H 8.29 found 77.58 8.27 Infrared: CHC13 1770 cm71 ( ¥ -lactone) 1605, 1500 ( aromatic) WR: gone! 3 1.06 ppm sy -He 3 aad 1.17 s, -He 3 3.75 s, -OMe 3 4.21 m, CS proton 1 6.6=7 64 m aromatic 3 -26~ 167 ms (14.5%) of Be? was opbained from this column. infrared: CHCL3 1775 cm™! ( ¥ -lactone) 1605,1575,1500 (aromatic) HMR: S35? 1.13 pom s, -He 3 Tis 6 1.17 ppm s, ~M 3.75 ppm os, -OMe 3 h.O ppm m, C 5 proton 1 6.5=7.3 ppm om, aromatic 3 B-10, Bell ;: Mans WW" Jo a stirred solution of 237 mg (.7Ommoles) of the tetracyclic lactone B-8 in 25 ml toluene, chilled in an ice bath, 1.7 ml (.035 mmoles) of u92 EH DIBAY an benzene was added, After 1 hour, the bath was removed and stirring was continued at R.T. for 3 hours; the mixture vas wen poured onto 70m) of 10% HCl + lO g ice, extracted with ether (i x 75 ml), and the combined organic pheses washed with water and brine, dried over Nag 50), and stripped of solvent in vacuo +o give a white foem in quanti- tative yield. Preparative TLC on a silica gel plate gave 3 bends, rf's = oS, sulpeand. 19. The first bend, rf=.54, contained mostly starting lactone. The second bane, rf=.l contained 55mg (23%) of the Lactol B-11. Two re- erystalizations from EtOH/acetone gave write needles, mp 176-177°(vac). Analysis for C29H3303: calculated C 77-16; H G03 found 77.06 8.96 Infrared; CHiC13 3600, 3350 em! = (s ~08 ) 1605, 1575; 1500 (aromatic) Wik: goder3 93 ppm s, ~He 3 tes 1.25 S, ~He 3 3.70 m, C 5 proton 3476 s, -Gle i 6.05 m, hemiacetal 1 6.6=7 6h mM, aromeic The finel band, rf=.19, gave 60mg (25%) od the diol B-10, recrystalized ; . , . . ° from acetone to constent melting point, 185-187" (vac). Analysis for Cooll3503: calculated C 76.70: H 9.36 found 76.58 9.43 Infrared: CHL, 3620, 3400 em! = ( ~0H +) 1605,1575, 1500 (aromatic) NuRs pes 1.00 ppm s, ~le 3.1 THS 1.27 Sy ~He 3.0 3.76 Ss, -OHe 3655- 3.9h m, R-CHp-0 a 4.35- 4.60 m, C5 proton 1.0 6.5 - 7.2 m, aromatic | 3.0 B-12, (A=15) 3 were worn In a flask, 55mg (.l6mmoles) of the tetracylic lectol B-11 was cor- nw bined with 2.7 ml of trietylene glycol,.27 ml of hydrazine hydrate (99%), and 81 mg of hydrazine dihydrochloride, and stirred at 10° (bath temp.) for hours. The mixture ws cooled to 95°, a strean of nitrogen blow through the vessel, .52 g of 859 KOH added portionwise over ten minutes, and the teap. raised to 150°. The nitrogen stream was stopped after one hour, but the 150 temp. was maintained for a total of five hours. The mix- ture was then cooled, dissolved in 50 ml water + 50 ml brine, extracted with ether (5 x 25 mL), end the combined extracts washed with water -30- (5 x 25 ml), brine (2 x 25 ml), dried over NagS0,, end stripped of solvent in vacuo to give a yellow foam. Preparative TLC of the foam, on a 20 x 20 cm silica gel plate, eluted twice with O% ether/ petroleum ether, gave two bends. The major band, rf=.25 contained 39mz (71%) of slightly impure starting lactol B-11. The minor band, rf=.43, contained 11 mg of a compound that appeared to be B-12 (by MPR ip 3) on (by ). Crude iDR: £83 95ppm s, angular methyl 3 . Te 1.23 Ss, 2 angular methyls 6 3.76 S; “=OMe 3 6.5-7 eh m, aromatic . 3 As insufficient material was evailable for an enalysis, the above product was oxidized to the ketone 4-15, to see whether it would remain spectrally MOON consistent with the assigned structure. Thus 9mg of the alcohol B12 was oe combined with .Sml of 8 N Jones rea gent in 31 of acetone with ice cool- ing. After ten min., one ml isopropanol was added, then 10 ml water; the acetone was removed in vacuo, the product extracted with ether (i. x 20mlL), and the extracts washed with water and brine. After drying over Nao SO} the solvent was stripped in vacuo to give 7 mg of a yellowish oil which crystallized on standing. Uoon recrystalization from Ether, the product melted at 149-152° (vac). Infrared: CH13 1700 cxnl (carbonyl ) 1595,1575,1500 (aromatic) MER: CDCL3 .90 pom 5s, 3 TES 4a angular 1.18 Ss methyls 6 1.22 S, 3-76 8, Ole 3 6.5= Teh Ty aromatic 3 -31~ C-1 AMAn To a stirred solution of 702 mg (1.96 mmoles) of the cyano diol R+1 aaa in 10 ml acetone, chilled in m ice bath, 2 ml of 8 W Jones reagent was added dropwise. After stirring for 5 min., 5 mi of isopropanol, followed by 30 ml satid HaHCO3 soln. was added. The mixture was extracted with ether (5 x hOml), and the combined orgeninic phascs washéd with water and brine, dried over MgSO), and stripped of solvent in vacuo to give 672 mg (96%) of a white solid. The product was crystalized tiice from EtOH to give crystals mp12y-126°, Analysis for Co0Ho903N: calculated C 74.33: H 8.22: NN 3.9 found 74426 8.15 3.87 Infrered: CHCL; 3600 em? = ( -0# +) 2230 ( -GN ) 1720 (Ketone) 1601,1550, 1485 (aromatic) NMR: CDC13 1.17 pon s, THS 1.20 i; -C53 . 3.80 S; ~Olie 6.7-76h m, aromatic C-2a : ww To a stirred solution of 52) mg (1.47 moles) of the keto alcohol C-l.in ten ml dry pyridine, chilled in an ice-salt bata at -10°, .52 ml (7.2 mmoles) of thionyl chloride was added dropiise and the stirring con- tinued at the low temperature for one.hour, and then for 15 min. while warming to room temoerature. The mixture was diluted with Ether (250m1), weshed with 10% HCl, sat'D NaHO03, and brine, stripped of solvent in... ‘ vacuo to give Wo mg (98%) of a yellowid: solid. =32- Infrered: CHCl 2220 em7! (nitrile) 1715 (ketone) NER: fol; 1.15 ppm s, angular methyl ad 1.65 ppm s, olefinic methyl 3.80 Ss, Ar-OHe 4.98 j ' olefinic protons (very weal) 5.10 C-2b ;: pow In 25ml of benzene, 397 mg of the olefin mixture C-2a was combined with 4 ml of ethylene glycol and 6 mg p-toluenesulfonic acid, and refluxed with stirring through ea Dean-Stark apparatuus. After 80 min, 20mg more p-TsCH wes added to hurry the reaction, woich anpeared completed by GLC after five hours. The mixture was cooled, diluted with ether (200 mL), washed with sat'd NalicO3, water, and brine, dried over MgSO), and stripped of solvent in vacuo to give (quentitatively) a yellow oil. The oil was eryst2lized from ether/petroleum ether to give li7 ng (93%) of a white solid (95% pure by GLC). Infrared; CHC13 2200 em=! (nitrile) 1150, 1690, 1075, 1060 (ketal) WER: CDCL3 TLS 1.02 ppm s, angular methyl 1.62 S,; Olefinic methyl »80 Ss, ArO-ie hoo m, ketal protons h.99 m, Olefinic protons 5.10 (very weak) Attempted reduction of C-2b nitrile to a methyl group. Tow" w The reaction conditions employed for tne attexpted conversicn of -33- 85 mg of ore were essentially identical to those described for the parallel reduction of A=103 1.2 equivalents of DIBA were emplowyed, and the reduction carried out for 22hours. The Wolff-Kishner reaction was. done in exectly the same way (slight scale difference) to give 59% of a yellow oil. IR showed a great deal of nitrile still remaining, while the NER was that mainly of starting material. Varying conditions did not improve the result, and none of the desired C-3 was ever isolated. wor C-5 ; we a) Hydrocyandtion using EtoALCN in benzene. The ene-one elcohol C- (500 ng, 2.5% mmoles) was treated witn tN Ae 4.7 mi (6.45 mmoles) of 1.37 H Et,ALCN in benzene exactly as described —_ in the procedure used to make cyano ketone A-9. Upon workup, a quentita- “ne tive yield of a white solid was obtained, which gave a first crop of 308 mg of white crystals. A portion of these was purified by sublimation at 130°, .25mm, to give crystels mo 173-17h° (vac). Analysis for C13Hj9i02: Calculated:G 70-56; H 8.65; N 6.33 Found 70.53 8.51 6.27 Infrared: CHCL, 3610, 3:70 em™! = ( -~oH ) 2225 (nitrile) 1715 (ketone) Nis CDC1 1.17 ppm d, J=8cps C-1 methyl ie 1.23 s, C-10 methyl 3.8 ma, C-5 proton 4 The crude product had essentially identcal spectiaas the purified sample; no other conpouncs coulda be isolated from the mother liquors by preparative TLC. -3h- b) Hydrocyenation using Et3Al and HCN in THF. The ene-one alcohol C- (500mg, .55 mmoles) in 15 ml of dry THF, was treated with 19.6 ml (10.3 mmoles) of .525 ML Bt3Al in THF, and 1.33mi (7.73 mmoles) of 5.81 Ji HCN in benzene, exactly as describ:d for the making of Ag (part b). The 560 mg (99%) of crude product obtained, was identical (I2 and Wim) with that obtained in pert a above. C-6 ; In 35 ml of benzene, 511 mg (2.31 mmoles) of the cyano ketone C5 was combined ‘with 2 ml of ethylene glycol and 18 mg p-TsOH, and refluxed through a Dean-Stark apparatus for 1 hr. The reaction was then cooled, diluted with 400ml of ether, washed with sat'd WaHCo, » water, and brine, and stripped of solvent in vacuo to give 2h mg (695) of a white solid, This solid was sublimed at 130°, .O5mm, and recrystallized tiice from EtOH to give pure product, mo 165-166? (vac). Analysis for 045119 3N03 3 calculated C 67.90: H 8.7h: HN 5,23 found 67277 8.68 5.31 Infrared: CHL; 3610, 3460 cm7! ( -OH ) 220 (nitrile) 1105, 1070, 1030 (ketal) MER: CDC13 1.02 ppm s, C-10 methyl THS 1.03 ppn od, J@7eps C-1 cot} ° 3.8 ppm m C-5 proton h.Ocppm om ketal protons + ? rr ws wer Atiennted reduction of the nitrile in ¢-6 : a Jo a stirred solution of 51mg (.192 mmoles) of thebyano ketal C-6, ~35- in Sml of dry benzene, .86 mL (2.3 equivalents) of freshly prepared 0518 Ir DISAH in benzene was added. Stirring was continued at R.T. for 19 hrs, after vhich the mixture was poured into 10% NaH + ice, extracted with CHCl, and washed with water and brine to give 26mg (55%) of a semi- crystalline oil. IR of the oil showed large amounts of nitrile still present 3; other attemts did no betcer, for aoparently she nitrile is not susceptible to mild reductian by DIEAH. fo a stirred solution of 200 mg (.56 mmoles) of the cyano diol B-1 ao in ml of pyridine, .0ml of acetic anhydride was added at R.T. and stirring continued for 22 hours, The solution was diluted with 250.m1 ether + 100 ml ethyl acetate, washéd with water, sattd NaHCO 3 water, and brine, dried over NapSO}, and stripped of solvent in vacuo to give a quantitative return of a sticky solid. The solid was crystallized from ethyl acetate/chloroform to give 167mg (75%) of fine white crystals. Two more recrystealiactions gave pure material, mm 163-165". Analysis for Co),H33NO,: calewlated © 72.15: H 8.33: N .3.51 found 12.22 8.22 3.48 Infrared: CHC13 3600 em™! ( -0H ) 2220 ( -CiH ) 1730 (acetate carbonyl) TBR s CDoI : . d ms > 1.02 ppm s, -He 3 1.12 S3 ~le 3 2,03 28+ Sy acetate 3 3.80. s, Ard-ie 3 501 m, GS hyd. 1 if 6.7-764 my aromatic ~36- D-2 ; MA" To a stirred solution of 167 mg (.l16 mmoles) of the cyano alcohol. Dol in 3.5 ml of dry pyridine, chilled in an ice-salt bath to -10°, .15ml (2.1 mmoles) of thionyl chloride was added slowly;:stirving was continued for 1.25 hrs with the tem. between -10 and 0°, then for .5 hrs as the mixture warmed to R.T. The mixture was diluted woth 100ml ether + 100ml ethyl acetate, washed with water and brine, dried over HagS0) and stripped of solvent in vacuo to give 157 mg (99%) of an oil. Preparative TLC of the product on a 20 x 20 cm silica gel plate, eluted once with 50% ether/ petroleum etier, gave one major band, rP=.34, containing 1lSme (91%) of a semicrystaline white gun. A portion of this gum was crystallized fron Manse . : . Ago EvOH, resulting in crystals mp 89-108. a énalysis for Co},H34N03: calculated C 75.56: H 6.19: H. 3.67 found 75.64 8.21 3.66 Infrered: CHCL3 2220 em™! (nitrile) 1730 (acetate carbon: 1) 1650 olefin NARs eee .95 ppm s, C 10 methy oa . 1.08 Sy nL 1.62 s, C 2 methyl 2.04 Sy acetate 5.0 m, CG 5 proton D-3 : fo a stirred solution of 57 mg(.15 mmoles) of the cyano acetate Olefin mixture D-2 in 2.3 ml dry benzene, .79%1L (2575 miles) of .73 MH PA DIBAH in benzene was added at R.T., and stirring continued for 3.5 hrs. After this time, the reaction mixture vas poured into 2%ml 7.5SNeOH, ex- ~37- eracted with ether (4 x 20 m1), and the combined organic phases washed with water, bring, dried over Na5S0}, and stripped of solvent to give white foam quantitavely. IR of the product shoved no nitrile (2220), but a broadened band in the region of 1620 (imine). -The crude product from cbove wes mixed with 2.3 ml of triethylene glycol, 25m hydrazine hydrate (99%), and 75mg of hydrazine dihydrochloride, and stirred for four hours in a 1)0° oil bath, ‘The temperature was then cooled below 1009, and 85% KOH (.u8g) added porticnwise as a steam of nitrogen was passed over the mixture. The temo. was then raised to 150° for five hours, while the No stream continued, after which the mixture was cooled, dissolved in 25ml water, and extracted with ether (k x 25 ml). The combined extracts were washed with water (6S X 20ml), brine, dried aver YagS04, and stripped of solvent in vacuo to give hi3ng (88%) of an cil. Preparative TLC of the oil on:a 10 x 20 cm silica gel plate, eluted once with 353 ether/ petroleum ether, gave one major band, rf=.20. this bend contained 3lme (69%) of a white crystalline solid. The product was re- erystallized twice from ether/hexene to give the olefin mixture D-3, mp 98-105°. Analysis for CpoH3002: calculated GC 60.44: H 9.82 found 80.23 9.82 Infrered: CHC1, 3610 comm! (alcohol) 1601, 1580, 1485 (arometic) Akt DCLA NER oe 2 -90 ppm 8; We 1.62 Ss, angular methyls 1.63 ‘s, olefinic methy 3.72 m, CG 5 hydrogen 3.80 Sy ArO-He ~33~ D-l : prrrnan To a stirred solution of 269 mg of the alcchol po3 in 30m1 of acetone, chilled in an ice bath, 2.5 ml of SN Jones reagent was added dropwise. Stirring at the low temperature was continued for 10 minutes, then-.10 ml of isopropenol was added, followed by 100 m of water; most of the acetone was removed in vecuo, the mixture extracted with ether (l, x 60 m1), and the combined etherial extracts washed with water and brine, dried over NagS0),5 and stripped of solvent in vacuo to give’ yellow oil quantitavely. A portion (254mg) of this oil was chromatographed on a 20 x 20 om plate, + + eluved once with 305 Ether/petroleun ether. The only significant bend, y rf=.0, contained 237mg (935) of a semi-crystalline oil; some of this was cryst zed from ether to give a solid isomer mixture D-l, mo 60-93", SOPRA Analysis for Co2H3005: calculated C 80.94: H 9426 found 81.02 9,35 Infrared: CHC13 1700 em™! (ketone) 1601, 1580, Ly85 (aromatic) WR: CDCl, .98 ppn ss, ra 7 3 : . TS 2 angular methyls (major isomer) 1.10 S, 1.65 s, olefinic methyl 50,504 m, olefinic protons (very faint) 6.7-7-k m, aromatic A-15 3 VN Jn 13 ml toluene, 100 mg (.305 mmoles) of the keto olefin mixture D-h was combined with J0G mg of p-TSOH and refluxed through a Dean-Stark ww apparatus (10 ml of toluene were distilled into the sideari); afver one a hour, another 100 mg p-TsOH wes added, and reflux with stirring continued ~39- for 2.25 hours longer, after which the mixture was diluted with 10 i ether, washed with 2.5% NaOH, water,and brine, and dried over Na2S0j,. The solvent was removed in vacuo to give a quantitative yield of brow O11, two peaks on the GLG. The components conid not be soparated by chromatogrephic means, but the major isomer partially crystallized out in ether to give 52 ng (52%) of a white solid. Unoon three recrystalliza- wv tions from ether, very pure A-15 was obtained, mp 150-152° (vac). Analysis for CmH3,02 : calculated C 80.94: H 9.26 found &0.89 9.34 Infrared: CHCL3 1700 en“! — (ketone) mes 1605, 1575, 1500 (aromatic) 1385 (methy1s ) WAR: CDC1 3 .90 ppm ss, 3 THS 1.18 s anguler methyls . 3 6 1.22 By 3.76 Ss, 3 Ar-0-CH3 6.5-7eh Ty 3 aronatic Nia of the motner liquors showed , that in addition to more A-15, there peo was perhaps 35% of an isomer present having a very nigh field resonance at =,33. 1. 26 3e he Se 7. &. 10. 11. Le. 136 =) Cnn 2 REFEREICE: a) D.A. Evans, Ph.D, Thesis, California Institute of Technology, 1967, pp 6-17. b) ibid, entire work. S. Baldiin, Ph.D. Tnesis, California Institute of Technology, 1969. R.E. Ireland, D.A. Evans, D. Glover,;,G. Rubotton, He Young, J. Org. Chen., ple 3717 (1969). Res. Ireland, D.A. Evans, P. loliger, J. Bordner, R.H. Stanford, Jr., R.E. Dickerson, J. Org. Chen., 34 , 3729 (1959). rg a) il, Nagata and M, Yoshioka, "Procedings of International Symposium in Hormone Steroids," Milan, Italy, 1956. b) W. Nagata and M. Yoshioka, Tetrahedron Letters, 1913 (1965). ¢) W, Negata, H. Yoshioka, S. Hirai, Tetrahedron Letters, No. 11, 461 (1962). G.H. Douglis, J.H.H. Graves, D Hartley, G.A. Hughes, B.J. MeLoughlin, J. Siddall, H, Smith, J. Chem. Soc., 5072 (1963). We Nagata, Tetrahedron, 13, 2817 (1961). we S. Welch, research notebook # 2363, pp 35, 2, and 50. We Nagata, M. Yoshioka, M, Narisada, H. Watanabe, Tetrahedron Letters, 3133 (1961) S. Welch, research netebook # 2371, p 12. . Wielend, et al, Ber., 95, 275 (1963). betes 22 D.J. Goldsmith and F. Phillips, J. Am. Chea. soc., $1, 5862 , (~~ (1969). J.5. baren, J. Org. Chem., 30 , 3564 (1955), Dolfini, research notebook II, p60. S. Welch, research notbock # 2591, CG. Lipinsici, research notebook # J.W.Tilley, research notebook # 2615, p 50, -i- 18. D. Glover, research notebook, July 28, 1966. 19. R.Robinson and E. Schlittler, J. Chem. Soc., 1258 (1935).