Synthetic Approach to Otamixaban

Significance

Otamixaban is a lead anticoagulant that inhibits factor Xa, a serine protease implicated in thrombin activation. A salient feature of the synthesis of the key β-amino ester G is an asymmetric conjugate addition of the achiral lithium amide A to ester B in the presence of chiral ligand C. The methyl ester analogue of I has been converted into otamixaban: K. R. Guertin et al. Bioorg. Med. Chem. Lett. 2002, 12, 1671-1674. This report by Tomioka and co-workers was evaluated from a different point of view with the emphasis on metal-mediated synthesis in an earlier issue of Synfacts (Synfacts 2006, 942).