Synthesis of Highly Potent Second-Generation Taxoids Through Effective Kinetic Resolution Coupling of Racemic -Lactams with Baccatins SONGNIAN LIN, XUDONG GENG, CHUANXING QU, ROBERT TYNEBOR, DAVID J. GALLAGHER, ELIZABETH POLLINA, JESSICA RUTTER, AND IWAO OJIMA* Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York ABSTRACT A series of highly potent second-generation taxoids bearing a 2-meth- ylprop-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--lactams with prop- erly protected/modified baccatin and 14-OH-baccatin. A high level of kinetic resolution was observed for all cases examined. The observed highly efficient enantiomer differ- entiation is ascribed to the markedly different chiral environment between the (+)- and (-)--lactams in their approach to the chiral framework of the enantiopure lithium al- koxide 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 (-)--lactam with 1,14-carbonate group of the baccatin substantially increases the asymmetric bias in the kinetic resolution process, favoring the reaction of a (+)--lactam, which leads to the observed excellent selectivity. Chirality 12:431–441, 2000. © 2000 Wiley-Liss, Inc. KEY WORDS: kinetic resolution; baccatin; second-generation taxoids; paclitaxel; doce- taxel; diastereoselective; asymmetric synthesis Taxol (paclitaxel) 1 and its semisynthetic analog, Taxo- te `re (docetaxel), 2 are currently considered two of the most exciting drugs in cancer chemotherapy. 3–12 Both pa- clitaxel and docetaxel exhibit significant antitumor activity against various cancers through their unique antimitotic mechanism of action. 13,14 Paclitaxel was approved by the FDA for treatment of advanced ovarian cancer in Decem- ber, 1992, and for the treatment of breast cancer in April, 1994. It is also currently undergoing clinical trials for other cancers. Docetaxel was approved by the FDA for the treat- ment of breast cancer in May, 1996, and is currently un- dergoing Phase II and III clinical trials for various cancers worldwide. However, despite their potent antitumor activ- ity, these drugs often result in a number of undesirable side effects 15 and are subject to multidrug resistance (MDR). 16 Thus, it is essential to develop new anticancer agents possessing fewer side effects, improved pharmaco- logical properties, and activity against cancers not effec- tively treated by existing anticancer drugs. In the course of our structure–activity relationship study of taxoids, 11,12 we developed a series of highly potent sec- ond-generation taxoids (Fig. 1). 17–21 Most of these taxoids exhibited one order of magnitude higher potency than that of paclitaxel against drug-sensitive cancer cell lines, and some of these taxoids showed 2–3 orders of magnitude higher potency than that of paclitaxel against the drug- resistant cell lines, which makes them highly promising clinical candidates for cancer chemotherapy (Table 1). In fact, one of these second-generation taxoids, IDN5109 (1b) (Fig. 2), is entering human clinical trials. These second-generation taxoids were originally synthe- sized in excellent yields from properly modified baccatins and enantiopure -lactams using the coupling protocol de- veloped in these laboratories. 9,11,12,22 The enantiopure (3R,4S)--lactams were prepared through asymmetric eno- late-imine cyclocondensation using a relatively expensive chiral TIPSO-acetate. 22 During the course of our explora- tion of the -Lactam Synthon Method, we found that the kinetic resolution coupling of racemic cis-1-t-Boc-4-CF3-- This article is dedicated to Professor Ryori Noyori for his outstanding contributions to synthetic organic chemistry, especially catalytic asymmet- ric synthesis, and his leadership in the advancement of chemical science. Contract grant sponsor: National Institutes of Health; Contract grant num- ber: GM417980; Contract grant sponsor: National Science Foundation; Contract grant number: CHE 9413510; Contract grant sponsor: Indena, SpA. *Correspondence to: Iwao Ojima, Department of Chemistry, State Univer- sity of New York at Stony Brook, Stony Brook, NY 11794-3400. E-mail: iojima@notes.cc.sunysb.edu. Received for publication 7 December 1999; Accepted 17 January 2000 CHIRALITY 12:431–441 (2000) © 2000 Wiley-Liss, Inc.