William R. Bartlett

Nonenzymic, biogenetic-like cyclization of a trienic acetal

Abstract The stereoselective synthesis of the trans,trans trienic acetal 9 is described. Alkylation of the lithio derivative of 2-methyl-1-hexene-5-yne ( 10 ) with ethylene oxide gave the acetylenic alcohol 11 , which on reduction with sodium in liquid ammonia afforded the trans diene 12 . Alkylation of the sodium enolate of acetylacetone with 13 , the mesylate derived from 12 , gave the dione 14 ; chlorination of 14 and deacylation of the resulting chloro dione 15 provided the α-chloro ketone 16 . Conversion of 16 to the trans,trans acetal 9 was accomplished by means of a Cornforth olefin synthesis. Thus, stereoselective attack by the Grignard reagent derived from 1-ethylenedioxy-4-chlorobutane afforded from 16 the chlorohydrin 17 , which on treatment with methanolic base was converted to the trans epoxide 18 . Deoxygenation of 18 to give the trans,trans acetal 9 was accomplished via the intermediacy of the iodohydrin 19 . Cyclization of the acetal 9 with stannic chloride in benzene gave as the sole isolable tricyclic products the 4b-methyldodecahydrophenanthrene mixtures 20 and 21 , with the “natural” trans,anti,trans ring fusion, in yields of 45 and 17.5%, respectively. In contrast, cyclization of 9 with stannic chloride in nitromethane at −25°C gave rise to the rearranged system 37 in 44% yield as the major tricyclic product. The structures of 20 and 21 were determined by degradation of each to the same ketone mixture 24 , conversion of 24 to the hydrocarbons 25a and 25b , and comparison of 25a and 25b with authentic materials prepared from the known ketone 26 . The structures of the rearranged tricyclic system 37 and its degradation products, inferred on spectroscopic grounds, were confirmed by X-ray crystallographic analysis of the p -bromobenzoate 48 derived from 37 .

The biomimetic cyclization of I,3-dimethyl-2-(trans-trans-7,II-dimethyl-3,7,II-dodecatrienyl)-2-cyclohexenol to give the d-homosteroid nucleus (I)

Abstract The cyclization of tetraenols 3 and 4 has been studied. The tetraenols were prepared as follows: alkylation of the lithium salt of 1-benzyloxy-3-butyne with the previously known trans -tosylates 19 and 20 gave the dienynes 21 and 22 . Reduction with sodium in ammonia gave the trans,trans -trienols 25 and 26 , which were used to alkylate, via the tosylates 27 and 28 , the sodio salt of Hagemanns ester 7 . Decarbethoxylation gave the tetraenones 29 and 30 which were converted with methyllithium to 3 and 4 . Treatment of tetraenol 3 with trifluoroacetic acid in pentane at −78°C to −10°C gave tetracyclic diene 5 stereoselectively in 45% yield, along with 5% tricyclic triene 32 and a mixture of esters. The esters were reduced and eliminated, giving a mixture (25% yield based on 3 ) of 66% diene 5 and 34% triene 32 . Tetraenol 3 was cyclized with stannic chloride in nitromethane at 22°C giving a 77% yield of a 4:1 mixture of 5 and 32 . Treatment of tetraenol 4 with anhydrous formic acid followed by cleavage of the formate esters gave tetracyclic alcohol 6 (isolated in 9% yield) and a mixture of tricyclic trienes 36 and alcohols 37 . Cyclization of 4 in trifluoroacetic acid led to larger amounts of tetracyclic diene 40 . The structure and configuration ( anti,trans,anti,trans ) of the cyclization products, 5 and 6 , were established by conversion of 6 into the dl ketone 38 and comparison with authentic d - 38 . Also d - 38 was converted into authentic d - 5 which was compared with the synthetic dl - 5 . The comparison substances were prepared as follows. Testosterone benzoate ( 41 ) was methylated at C-4, and the C-3 carbonyl group was removed by conversion to the acetate 44 , followed by reductive cleavage of the allylic acetate with lithium in ethylamine. Oxidation of the C-17 alcohol gave the ketone 46 , which was converted to the carbinolamine 49 by epoxidation with dimethylsulfonium methylide, followed by conversion to the hydroxyazide and reduction with lithium aluminum hydride. Nitrous acid deamination led to the d -homoketone d - 38 . Treatment of d - 38 with methyllithium followed by dehydration led to a mixture of dienes from which d - 5 was isolated.