Synthesis and evaluation of antileukemic activity of 5-thienyl- or 5-(2-furyl)-2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine bis(alkylcarbamates) and derivatives

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Abstract
Treatment of N-(2-furoyl)proline (1a) or N-thenoylprolines (1b, 1c) and N-(2-thenoyl)thiazolidine-4-carboxylic acid (1d) with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (2a, 2b, 2c) and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole (2d). Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c, and 3d. These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride. The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy (8b, 8c) and 1-oxo (9b, 9c) analogues. The action of hydrochloric acid on 1-acetoxy derivatives (7b, 7c) gave 3H-pyrrolizines (10b, 10c). Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates). The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.