Lactones, hydrolysis with lithium iodide

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

The 13,17-seco-acid lactone (258), obtained from a Baeyer-Villiger oxidation of 5a-androstan-17-one has been reduced to yield 13,17-seco-5a-androstan-13a,17-diol, whose diacetate on pyrolysis furnished the endocyclic seco-olefin (259 R = OAc) as the major reaction product. A minor product is the corresponding A12 13-olefin.115 Hydrolysis of the acetate (259 R = OAc) to its alcohol (259 R = OH) and formation of the tosylate and the iodide (259 R = I), followed by reaction with lithium dimethylcuprate, afforded a route to A1314-13,17-seco-5a-D-homoandrostene (259 R = Me). The [17a,17a,17a-[2H3]androstene (259 R = CD3) was prepared by treating the iodide (259 R = I) with lithium perdeuteriodimethyl-cuprate. 

The total synthesis started with a Birch reduction of p-methoxytoluene (382) to obtain the dihydro compound 383, which was treated with p-toluenesulfonic acid to obtain acetal 384. CyclopropanatiOTi with ethyl diazoacetate and transaceta-lization led to compound 385, which reacted to the unsaturated keto ester 386 on treatment with base. In the next step, the keto ester 386 was methylated with methylmagnesium chloride, and it reacted selectively at the 2-positon to yield 387. Lactonization with further methylation with methyl iodide afforded homo-lactone 389, which reacted with lithium salt 390 to alkyne 391 and was reduced with sodium borohydride to diol 392. Partial reductiOTi of the triple bond to the double bond was obtained with sodium in ammonia and further treatment with acid led to hydrolysis of the acetal, which subsequently cychzed to 394 (Scheme 8.1). 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

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