Synthesis of 7beta-sulfur analogues of paclitaxel utilizing a novel epimerization of the 7alpha-thiol group.
Paclitaxel analogues with a sulfur group at the 7beta position were required for SAR studies. Attempts to generate these compounds by displacing a 7alpha leaving group with sulfur nucleophiles were unsuccessful. Instead, these compounds were successfully prepared from a 7beta-thiol intermediate that was obtained by a base-catalyzed epimerization of the 7alpha-thiol derivative. The epimerization presumably proceeds through a thioaldehyde intermediate and exhibits the opposite stereochemical preference of its oxygen counterpart.
Mastalerz
H
H
Bristol Myers-Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. harold.mastalerz@bms.com
Zhang
G
G
Kadow
J
J
Fairchild
C
C
Long
B
B
Vyas
D M
DM
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D013438:Sulfhydryl Compounds; D017239:Paclitaxel