Critical profiles of chiral diether-mediated asymmetric conjugate aminolithiation of enoate with lithium amide as a key to the total synthesis of (-)-kopsinine

Chiral diether-mediated asymmetric aminolithiation of indolylpropenoate with lithium amide in toluene at -78 degrees C for 15 min gave, after aqueous ammonium chloride quench, the corresponding conjugate addition product with 97% ee in 89% yield. If hydrogen chloride in methanol was selected as a quencher, however, aminolithiation at -78 degrees C for 3 h gave the corresponding adduct with 97% ee in 54% yield, along with recovery of the starting enoate in 39% yield. Based on this finding of an incomplete and slow reaction at -78 degrees C, the aminolithiation conditions were optimized to be at -60 degrees C for 15 h and subsequent enolate trap with alkyl halide upon an addition of DMPU afforded the desired aminoalkylation product with 98% ee in 89% yield. Further approach toward total synthesis of (-)-kopsinine was carried out by examining asymmetric aminolithiation with N-hydroxyethylamine equivalent, one-pot piperidine formation, and Claisen condensation. (C) 2013 Elsevier Ltd. All rights reserved.