Total Synthesis of Clavepictines A and B. Diastereoselective Cyclization of δ-Aminoallenes

Abstract

The stereocontrolled total synthesis of (−)-clavepictine A (1A) and (+)-clavepictine B (1B) has been accomplished in an enantioselective fashion, which has unequivocally established the absolute configuration of 1A and 1B. The pivotal step in the synthesis is diastereoselective silver(I)-promoted cyclization of δ-amino allenes. Another key method includes cross-coupling of enol triflates of N-acyl lactams, which allows stereocontrolled functionalization of otherwise unreactive lactams under mild conditions. The utility of Beak's α-lithiation-substitution chemistry of N-BOC piperidines involving a functionalized aldehyde as the electrophile is demonstrated in the preparation of highly substituted nitrogen heterocycles. These new synthetic strategies should be of general synthetic utility in the stereoselective syntheses of quinolizidines, indolizidines, and related aza-heterocylces. Also included is the unique conformational preference of the highly substituted cis-quinolizidine core of clavepictines; the (superfluous) m-(trifluoromethyl)benzoate substituent has a surprisingly significant influence on the relative energies of the two possible chair−chair conformations.