Taxol chemistry. 7-O-triflates as precursors to olefins and cyclopropanes

Taxol, a molecule for all seasons

“…Attachment of the taxol side chain and deprotection gave the C-18 analogs 16 (X = Me, N 3 , OAc or CN), all of which were less cytotoxic than taxol, with the methyl derivative being the most active (Scheme 3). 37 Taxol can be selectively deacetylated at C-10 to give 10-deacetyltaxol by treatment with hydrazine 38 or with sodium bicarbonate and hydrogen peroxide. 39 Deoxygenation of the 10-hydroxy group was originally achieved using Barton's xanthate chemistry, 40 but a simpler method was developed by treating taxol with samarium diiodide.…”

“…45,46 Although the 7-hydroxy group may not be necessary for taxol's activity, modifications at C-7 have yielded analogs with improved properties, and the thiomethyl derivative 21 has been selected by Bristol-Myers Squibb for development as a 'secondgeneration' taxol analog: it is currently in clinical trials, with preliminary reports that it is performing well. 47 Dehydration at C-7 can be accomplished by treatment of the 7-triflate derivative with a non-nucleophilic base such as DBU to give 6,7-dehydrotaxol (22), 38,48 which was slightly less cytotoxic than taxol to CA46 cells. 48 Osmylation of 22 gave the 6a,7a-diol 24.…”

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

“…As before, the 2‘-hydroxyl group was protected with a troc group, and this protected compound ( 4 ) was subjected to reaction with methyl-DAST . This reaction produced 7α-fluoro ( 5 , 8%), 7β,8β-methano ( 6 , cyclopropyl, 54%), and 6,7-olefin ( 7 , 17%) analogs; the ratio of 1:7:2 is significantly different from the ratios of approximately 9:4:1 (fluoro:cyclopropyl:olefin) observed previously . Removal of the the 2‘-troc protecting groups from 5 − 7 gave new 12,13-isotaxol analogs 8 − 10 , respectively.…”

“…Our first preparation of C-ring-modified 12,13-isotaxanes (see Scheme ) began with compound 3 , whose synthesis was reported previously . As before, the 2‘-hydroxyl group was protected with a troc group, and this protected compound ( 4 ) was subjected to reaction with methyl-DAST . This reaction produced 7α-fluoro ( 5 , 8%), 7β,8β-methano ( 6 , cyclopropyl, 54%), and 6,7-olefin ( 7 , 17%) analogs; the ratio of 1:7:2 is significantly different from the ratios of approximately 9:4:1 (fluoro:cyclopropyl:olefin) observed previously .…”

“…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-olefin 6 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.…”