12,13-Isotaxanes:  Synthesis of New Potent Analogs and X-ray Crystallographic Confirmation of Structure

Journal of Medicinal Chemistry
1997.0

Abstract

In a previous communication,1 we described a new structural modification of taxanes in which, in effect, the normal 11,12-double bond of taxol2 (1, R ) Ph) has been transposed into the 12,13-position creating enol ester structures as shown for 2. We have named these isomeric taxanes as the 12,13-isotaxanes. We have also described, in a separate communication,3 the synthesis of a series of taxol analogs in which modifications of the C-ring such as a 7R-fluoro,4 a 7β,8β-methano (cyclopropyl),5 or a 6,7-olefin6 were combined with tert-butyloxycarbonyl (BOC)7 or tert-butylurea (TBU)8 variations of the side chain. In vitro assay results indicated enhanced antitumor potency in the 6,7-olefinic analogs when compared to the otherwise identical 7-hydroxyl analogs. In this communication, we outline the preparation of a series of 12,13-isotaxol analogs having the 7β,8β-methano, 6,7-olefin, BOC side chain, and TBU side chain modifications and describe an improved synthesis of these compounds. We give in vivo assay results for these new analogs and report an X-ray crystallographic study showing both the enol ester and cyclopropane structural features. As illustrated by the results described below, the 12,13-isotaxanes are chemically stable under essentially all of the reaction conditions to which they have been exposed and they also retain antitumor potency which in some cases is enhanced over that of the normal 11,12-taxanes.

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