A facile access to natural and unnatural dialkylsubstituted maleic anhydrides

A facile new route to the potential building blocks 2-bromomethyl-3-alkylmaleic anhydrides 15a/b for the synthesis of natural and unnatural dialkylsubstituted maleic anhydrides has been demonstrated, starting from dimethyl citraconate (9) via NBS-bromination, S(N)2' Grignard coupling reactions, hydrolysis, molecular bromine addition and dehydrative ring closure peactions pathway with 49-51% overall yield in 5-steps. Chemoselective allylic substitution of bromoatom in 15a/b with Grignard reagents has been described, to obtain the 6 X metrically dialkylsubstituted-maleic anhydrides 25a/b in 55% yield The naturally occcurring unsymmetrical maleic anhydride 16 and symmetrically dialkylsubstituted maleic anhydrides 25a/b in 55% yield. the naturally occurring 2-carboxymethyl-3-hexylmaeic anhydride (1) has been synthesized from 16 via esterification, ozonolysis and an oxidation route. The synthesis of two naturally occurring 2-(beta-carboxyethyl)-3-alkylmaleic anhydrides 2,a/b. have been com leted via a chemoselective coupling reaction foil I owed by acid induced hydrolysis. In our hands the S(N)2 or S(N)2' coupling of Grignard reagent with 21. to obtain 1 and Reformatsky reaction with 15a/b to obtain 2c/d met with failure. (C) 2003 Elsevier Science Ltd. All rights reserved.