Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Syntheses of Indolizidine Alkaloids (−)-205A, (−)-207A, and (−)-235B

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Abstract
Concise asymmetric syntheses of indolizidine alkaloids (−)-205A, (−)-207A, and (−)-235B were accomplished with a high degree of stereocontrol in eleven steps. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 5, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of (+)-trans-2-(α-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 6. Oxidative cleavage of 6 and subsequent reduction provided alcohol 7 in 81% yield. Removal of the chiral auxilliary and TIPS group (NaOMe; 10% HCl), N-acylation with BnOCOCCl, and treatment with NCS/Ph3P gave chloride 10. Methylation at C-3, copper-mediated conjugate addition of 4-(benzyloxy)butylmagnesium bromide, and vinyl triflate formation provided 13 in a stereoselective fashion. Catalytic reduction of the vinyl triflate moiety, simultaneous cleavage of the benzyl ether and Cbz groups, and cyclization to give amino alcohol 14 was effected via a one-pot reaction. Oxidation of 14 with the Dess−Martin reagent gave a 97% yield of amino aldehyde 4. Synthesis of each of the three title alkaloids was accomplished in one step from 4. The Seyferth−Gilbert reaction provided a 41% yield of (−)-205A. The appropriate Wittig olefination of 4 gave indolizidines (−)-207A and (−)-235B in 70% and 86% yield, respectively.