Taxol cyclopropanation

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Another Japanese group developed the Taxol synthesis shown in Scheme 13.47. The eight-membered B ring was closed early in the synthesis using a Lewis acid-induced Mukaiyama reaction (step B-l). Note that a trimethylsilyl dienol ether served as the nucleophile. The C-19 methyl group is introduced via a cyclopropanation in step C-5, followed by a reduction in step D-l. 

Based on the experimental results of azetidine, thia- and cyclopropane analogs of D-ring in paclitaxel, as well as a computational prediction of a taxol minireceptor model, some taxoids devoid of the D-oxetane ring, including D-seco analogs, were proposed to bind to tubulin in similar free energies to that of paclitaxel, which... 

Chen, S.-H. Huang, S. Wei, J. Farina, V. Serendipitous synthesis of a cyclopropane-containing taxol analog via anchimeric participation of an unexpected angular methyl group. J. Org. Chem., 1993, 58 4520-4521. 

The bioactivity of derivatives 4.1.3.10 and 4.1.3.11, as well as the dehydro compound 4.1.3.7 were reported by Chen and his colleagues 148) the latter compound was also reported by Johnson and his colleagues (59). The dehydrotaxol 4.1.3.7 and the fiuorotaxol 4.1.3.11 were both more active than taxol in a tubulin-assembly assay, but the cyclopropane derivative 4.1.3.10 was less active. None of the three compounds was quite as cytotoxic to HCT 116 cells as taxol, although the differences were not great. 

Johnson RA, Nidy EG, Dobrowolski PJ, Gebhard I, Qualls SJ, Wicnienski NA, Kelly RC (1994) Taxol Chemistry. 7-O-Triflates as Precursors to Olefins and Cyclopropanes. Tetrahedron Lett 35 7893... 

Chen S-H, Huang S, Wei J, Farina V (1993) Serendipitous Synthesis of a Cyclopropane-Containing Taxol Analog via Anchimeric Participation of an Unactivated Angular Methyl Group. J Org Chem 58 4520... 

An attempt to convert the C-7 hydroxy group of 7-epi-taxol to a fluoride failed. Instead, a high yield of a cyclopropanated product with A-ring contraction was obtained (eq 20). A cyclopropane... 

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