Enantiopure N-Acyldihydropyridones as Synthetic Intermediates:  Asymmetric Synthesis of (−)-Septicine and (−)-Tylophorine

• Published in: Journal of organic chemistry Vol. 62; no. 21; pp. 7435 - 7438
• Main Authors: Comins, Daniel L, Chen, Xinghai, Morgan, Lawrence A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17-10-1997
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo9711495

A concise asymmetric synthesis of (−)-septicine (1) and (−)-tylophorine (2) was accomplished with a high degree of stereocontrol in eight and nine steps, respectively. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 3, 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 7. Oxidative cleavage of 7 and subsequent reduction provided alcohol 6 in 81% yield. Conversion of 6 to the chloride followed by treatment with sodium methoxide gave indolizidinone 9 in high yield. Bromination and conjugate reduction of 9 with L-Selectride, and trapping the intermediate enolate with N-(5-chloro-2-pyridyl)triflimide, provided bromovinyl triflate 11. Palladium-catalyzed cross-coupling of excess (3,4-dimethoxyphenyl)zinc bromide and 11 gave (−)-septicine (1). On the basis of this synthesis, (−)-1 was assigned the R configuration. Reaction of 1 with vanadium(V) trifluoride oxide in TFA/CH2Cl2 effected oxidative coupling to give a 68% yield of (−)-tylophorine (2).