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

1997; American Chemical Society; Volume: 62; Issue: 23 Linguagem: Inglês

10.1021/jo971448u

1520-6904

Daniel L. Comins, Donald H. LaMunyon, Xinghai Chen,

Asymmetric Synthesis and Catalysis

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-(alpha-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/Ph(3)P 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.