DAPHNIPHYLLUM ALKALOIDS .13. ASYMMETRIC TOTAL SYNTHESIS OF (-)-SECODAPHNIPHYLLINE

(-)-Secodaphniphylline (1) has been prepared by total synthesis. The early stages of the synthesis were an asymmetric version of the previously published synthesis of methyl homosecodaphniphyllate (2). The necessary chirality was secured by an asymmetric Michael addition reaction of the lithium enolate of the C2-symmetric amide 9 to alpha,beta-unsaturated ester 10 to give ester amide 12. The conversion of 12 into (-)-2 was modelled after the previously reported synthesis in the analogous racemic series, although there were quantitative differences in the reaction conditions required for some of the succeeding transformations of the relatively hindered 2,5-dimethylpyrrolidine amides. The (-)-2 produced in this synthesis was of 84% ee, which represents the enantioselectivity of the initial Michael addition. Recrystallization of this material provided (-)-2 of 90% ee. The required 2,8-dioxabicyclo[3.2.1]octanecarboxylic acid chloride 5 was assembled in an eight-step synthesis starting with acid 18. The necessary chirality was acquired by an asymmetric reduction of acetylenic ketone 19 with the LiAlH4-Darvon alcohol complex. Alcohol 20, of 92% ee, was obtained and was isomerized to isomer 21 without loss of enantiomeric purity. Concomitant hydration of the triple bond, hydrolysis of the ketal, and cyclization of the resulting keto triol provided a 5:1 mixture of alcohols 23 and 24. After conversion to a similar mixture of methyl esters 25 and 26, the isomers were separated and the major carboxylic acid 27 was converted into acid chloride 5. Ester (-)-2 and acid chloride 5 were joined by a mixed Claisen condensation and the resulting diastereomeric beta-keto esters demethylated and decarboxylated by treatment with NaCN in hot DMSO to obtain (-)-secodaphniphylline (1). Although the two components in the Claisen reaction were enantiomerically enriched only to a modest extent (90% ee and 92% ee), the product alkaloid was > 99% ee.