An Oxidative Mannich Cyclization Methodology for the Stereocontrolled Synthesis of Highly Functionalized Piperidines

Studies focusing on the development and application of a new oxidative methodology for promoting Mannich cyclizations have been conducted. The general features of these processes were explored with selected alpha-silylamino and alpha-silylamido allyl- and vinylsilanes. Representative conditions for affecting conversion of the alpha-silylamine and -amide functionalities into intermediate N-alkyl and N-acyliminium cations involve either 9,10-dicyanoanthracene SET-sensitized photooxidation or ceric ammonium or tetra-n-butylammonium nitrate oxidations. The applicability of these procedures for promoting Mannich cyclizations was first demonstrated by the preparation of methylidenepiperidines and -hydroazepines. Further studies have led to observations which show that Mannich cyclizations of stereochemically labeled alpha-silylamino vinylsilanes proceed to furnish tetrahydropyridines. Also, unlike their amine analogues, alpha-silylamido (E)-vinylsilanes undergo cyclization to produce tetrahydropyridines with retention of absolute and relative stereochemistry. The differences are due to the fact that N-acyliminium cations serve as intermediates in reactions of the alpha-silylamide systems. Moreover, the oxidation procedure is ideally suited for intermediate N-acyliminium cation generation in stereocontrolled reactions of alpha-silylamido allylsilanes. Finally, the preparative utility of the new cyclization method, when used in conjunction with an alpha-amino acid based strategy for substrate generation, was demonstrated by applications in concise routes for the synthesis of the aza-sugars, (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin.