Development of new amide oxidation methodology and its application to enantioselective total synthesis of the Securinega alkaloids: Approaches to (+)-8,9-dihydronorsecurinine and (-)-norsecurinine

A convenient non-electrochemical amide oxidation method has been developed. The process involves cuprous ion promoted decomposition of o-diazobenzamides 55 to give N-acyliminium intermediate 60 via a 1,5-H-atom abstraction, followed by metal catalyzed oxidation of the resulting {dollar}alpha{dollar}-amidyl radical. The transformation produces {dollar}alpha{dollar}-methoxybenzamides 66 in good yields and is especially efficient for symmetrical cyclic and acyclic amide systems. This oxidation method was applied toward the total synthesis of the alkaloid ({dollar}-{dollar})-anisomycin. The oxidation exhibited good regioselectivities, represented by the methylene/methyne H-atom abstraction ratio, with unsymmetrical C-2-substituted piperidine and pyrrolidine systems. In general, it appears that the larger the C-2 substituent, the greater the methylene/methyne H-atom abstraction ratio. A mechanistic rationale for this regioselectivity is suggested based on amide rotamer populations.; Enantioselective total synthesis of the tetracyclic Securinega alkaloids (+)-8,9-dihydronorsecurinine (283) and a synthetic approach towards ({dollar}-{dollar})-norsecurinine (149) were accomplished using this amide oxidation methodology as a key step. This complex natural product was synthesized starting from readily available enantiomerically pure trans-4-hydroxy-L-proline (213), which was converted to bicyclic intermediates 226/235 via SmI{dollar}sb2{dollar}-mediated coupling reactions. The o-aminobenzamides 242/251 generated from sulfonamides 231/250 underwent amide oxidation to afford key {dollar}alpha{dollar}-methoxybenzamides 243/252. It was possible to transform these compounds to tricyclic A/B/C-ring intermediates 249/260, respectively. Unfortunately, the intended Kharasch cyclization methodology failed in annulation of the D-ring of these alkaloids. Thus, intramolecular Wittig reaction methodology was adopted to construct the D-rings. High pressure procedures were developed to convert hydroxyketone 263 to (+)-8,9-dihydronorsecurine (283) using the Bestmann reagent (282). A number of methods have been investigated to make the tricyclic key enone 286 for completion of ({dollar}-{dollar})-norsecurinine (149).