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-10, and C-14 positions was synthesized through the coupling of racemic cis-beta-lactams with properly protected/modified baccatin and 14-OH-baccatin. A high level of kinetic resolution was observed for all cases examined. The observed highly efficient enantiomer differentiation is ascribed to the markedly different chiral environment between the (+)- and (-)-beta-lactams in their 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-carbonate 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 (+)-beta-lactam, which leads to the observed excellent selectivity.
Lin
S
S
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York, USA.
Geng
X
X
Qu
C
C
Tynebor
R
R
Gallagher
D J
DJ
Pollina
E
E
Rutter
J
J
Ojima
I
I
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry*; D045744:Cell Line, Tumor; D002621:Chemistry / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry*; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry*
D000470:Alkaloids; D043823:Taxoids; D047090:beta-Lactams; C073950:baccatin III