SYNTHESIS OF A NOVEL PYRROLO[2,3-D]PYRIMIDINE ALKALOID, RIGIDIN

An efficient nine-step synthesis of the brain phosphodiesterase inhibitor, rigidin, has been accomplished in 26% overall yield starting from 6-chlorouracil and ethyl (2,4-dimethoxybenzyl)glycinate. A key feature of the synthetic route reveals a new method for the annulation of pyrrole rings onto pyrimidine rings starting from 6-chlorouracils and N-benzylglycine sodium salts. Thus, initial condensation adducts 7a,b were converted into 5-acetoxypyrroles 8a,b upon warming in acetic anhydride. The readily derived 5-(trifluoromethanesulfonyl)oxy materials 8c,f undergo palladium-catalyzed cross couplings with aryltin reagent 9 and afford C-5 aryl compounds 10a,b. Acylation at the C-6 position in 10a,b was best effected using a mixed anhydride reagent derived from acid 11 and TFAA. The optimal route to ridigin (1d) involved a one-pot deprotection procedure of intermediate lb using excess TMSI followed by heating in water.