Synthesis of highly potent second-generation taxoids through effective kinetic resolution coupling of racemic beta-lactams with baccatins

A series of highly potent second-generation taxoids bearing a 2-methylprop- 1-enyl or a 2-methylpropyl group at C-3' with modifications at the C-2, C-1 0, and C-14 positions was synthesized through the coupling of racemic cis-p -lactams with properly protected/modified baccatin and 14-OH-baccatin. A hi gh level of kinetic resolution was observed for all cases examined. The obs erved highly efficient enantiomer differentiation is ascribed to the marked ly different chiral environment between the (+)- and (-)-beta-lactams in th eir approach to the chiral framework of the enantiopure lithium alkoxide of a baccatin in the ring-opening coupling process. It was also observed that substantially higher selectivity was achieved when 14-OH-baccatin-1,14-car bonate was used. Analysis of the transition state models revealed that the repulsive interactions between the 3-TIPS group of a (-)-beta-lactam with 1 ,14-carbonate, group of the baccatin substantially increases the asymmetric bias in the kinetic resolution process, favoring the reaction of a (+)-bet a-lactam, which leads to the observed excellent selectivity. (C) 2000 Wiley -Liss, Inc.