A novel solid-phase synthesis of carboxypyrrolinones

A solid-phase organic synthesis method has been developed for the preparati on of 3-carboxypyrrolinones 9. Treatment of polymer-bound malonic acid with amino alcohols afforded the malonamide resin products 6. Benzyl and alkyl amino alcohols were prepared in solution via a two-step procedure without p urification and were coupled to the resin directly using a resin capture st rategy. Polymer loadings and product conversions were determined by direct cleavage of resin-bound materials and analysis by H-1 NMR spectroscopy with an internal standard. Treatment of the polymer-bound malonamides with TFA released the malonamic acids, 10, which underwent further reaction to affor d the trifluoroacetate derivatives 11. Secondary amides underwent an additi onal cyclization to afford oxazoles 12. The malonamide resins 6,can be oxid ized to the corresponding ketones 7 by treatment with CrO2(O-t-Bu)(2), whic h can in turn be cyclized in the presence of LDA or LHMDS to afford the car boxypyrrolinones 8. TFA treatment releases the free carboxypyrrolinones, 9, in 43-80% overall yield.