Studies toward the synthesis of 3,6-bis-(5-chloro-2-piperidyl)-2, 5-piperazinedione

• Main Author: Moreland, Margaret.
• Format: Others
• Language: en
• Published: McGill University 1979
• Subjects: Chemotherapy.; Cancer > Chemotherapy.
• Online Access: http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=68506

The naturally occurring compound 3,6-bis-(5-chloro-2-piperidyl)-2,5-piperazinedione (1) is a promising new antitumor drug. The mechanisms of action of antitumor alkylating agents, particularly the nitrogen mustards and sesquiterpene lactones, suggest possible modes of antitumor activity of compound 1. A possible synthetic scheme for compound 1 is developed by consideration of methods of synthesis of piperidines, (alpha)-substituted-(alpha),(beta)-unsaturated esters, and (beta)-amino alcohols. === A synthesis of (alpha)-chloro-(alpha),(beta)-unsaturated esters from carbonyl compounds and t-butyl (alpha)-chloro-(alpha)-trimethylsilyl acetate is developed. Oxyamination of the terminal double bond of t-butyl 2-chloro-2,6-heptadienoate occurs by epoxidation and reaction with an amine or azide ion and by osmium tetroxide catalyzed reaction with Chloramine-T. The piperidine ring is formed by an internal Michael raction of t-butyl 2-chloro-6-t-butyldimethylsilyloxy-7-tosylamino-2-heptenoate. The amino acid (1-tosyl-5-hydroxy-2-piperidyl) glycine is synthesized and found to be unstable to acidic esterification conditions. === Strategies for overcoming the problems encountered in the synthesis are discussed.