Synthesis and antileukemic activity of 5-substituted 2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine diesters

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Abstract
Treatment of N-acylproline derivatives, 2, with acetic anhydride-dimethyl acetylenedicarboxylate (DMAD) gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (5). The reaction proceeds via a 1,3-dipolar addition of DMAD with the mesoionic oxazalone intermediate 3, generated in situ, with concomitant elimination of CO2. Reduction of 5 gave the diols 6 which on subsequent acylation gave 1. The bis(N-methylcarbamate) 1d and the diacetate li show a modest level of in vivo antileukemic activity in the mouse L1210 assay. A majority of the diesters, 1, showed significant antileukemic activity in the in vivo P-388 assay. The bis(carbamate) 1d afforded cures at dose levels as low as 12.5 mg/kg; 1q showed potent activity at doses as low as 0.78 mg/kg. Several other compounds showed potent activity against P-388 ober a greater than 4-fold dose range with no acute toxicity. Half-lives for several diacetate derivatives of 1 were determined for aqueous Me2SO [dimethylsufoxide] solutions. The preparation of 7 and 8 shows that 1 may react by O-alkyl ester cleavage.