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

✍ Scribed by Songnian Lin; Xudong Geng; Chuanxing Qu; Robert Tynebor; David J. Gallagher; Elizabeth Pollina; Jessica Rutter; Iwao Ojima

• Book ID: 102660344
• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 569 KB
• Volume: 12
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/(sici)1520-636x(2000)12:5/6<431::aid-chir24>3.0.co;2-m

✦ Synopsis

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.