Synthesis of 12,13-didehydroprostaglandin J2 methyl ester

Abstract

A new class of prostanoid has been synthesized. The carboxylic acid ester (3) is an analogue of prostaglandin J, and contains an allene moiety at C,*. The novel compound (3) is available from 7-chloronorbornadiene (5) in a route which has t w o key steps. The first is the reaction of ( 5) with an alkynyl Grignard reagent to give the dienyne (7). The second is the regioseloctive epoxidation of the dienyne ( 7 ) , rearrangement of the epoxide (8) to give the aldehyde (9), followed by an oxa-Cope rearrangement; the derived enol (10) was hydrolysed to give the useful prostaglandin synthon ( 14) directly.In view of the current interest in prostaglandin J, (PGJ,) (1) and related compounds [e.g. (2)] ' as anti-neoplastic agents against a variety of tumour types, we wish to report a short flexible route to the allene (3) (Scheme).

Synthesis and use of 7-substituted norbornadienes for the preparation of prostaglandins and prostanoids

“…C,,H,,S, requires M, 210.3651). (13).-Dimethyl2-0~0heptylphosphonate (1.35 g, 6.127 mmol) in dimethoxyethane (DME) (16.5 ml) was added to a suspension of sodium hydride (0.25 g, 10.42 mmol) (previously freed from an oil dispersion by washing with light petroleum) in DME (66 ml). The mixture was stirred for 1 h at room temperature to form a thick white precipitate which was cooled to 0 "C. 7-Formylbicyclo[2.2.1]hepta-2,s-diene (13) (0.69 g, 5.75 mmol) prepared by the method of Stapersma and Klumpp l4 was extremely sensitive to air and was dissolved without rigorous purificiation in ether (10 ml) and added to the above Wittig reagent dropwise.…”

“…R = n-hexyl (57) R = Ph sescme 9.Attempts to provide 13,14-didehydroprostaglandin 5, were unsuccessful owing to a shift of the hydrogen at C-12 to give 12,13-didehydroprostaglandin J2 13. …”