Synthesis and Application of Novel Glyoxylate-derived Chloroformates

Abstract

A convenient process for the synthesis of glyoxylate-derived chloroformates has been developed. The approach involves the reaction of glyoxylate esters with triphosgene and pyridine in various solvent systems. These novel glyoxylate-derived chloroformates are multifunctional, possessing a chloroformate, ester, and haloalkyl moiety. Further elaboration via a thiocarbonate route afforded highly functionalized carboxylic acid-derived alkoxycarbonyl-chlorocarbonyloxy-methyl esters. Application of a benzyl glyoxylate-derived chloroformate to halofenozide was also accomplished, affording halofenozide-N-carbonyloxy-chloro/iodoacetic acid benzyl ester derivatives, which were further derivatized to carboxylic acid-derived (halofenozide-N-carbonyloxy)-benzyloxycarbonyl-methyl esters. The trifunctional nature of the glyoxylate moiety was demonstrated through conversion of the benzyloxycarbonyl moiety of a carboxylic acid-derived (halofenozide-N-carbonyloxy)-benzyloxycarbonyl-methyl ester to its respective diethyl-amide.

glyoxylate esters - chloroformates - alkyl halide - carboxylic acids - aldehydes

References

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One could imagine the attack of the free carboxylate at the Z¹/Z² ester or the carbamate moiety therefore forming a mixed anhydride, which would rapidly degrade to the aldehyde, CO₂, and the parent biologically active molecule (in our case, halofenozide 17). Also, a simple hydrogen bonding effect from the free carboxylic acid to the ester or carbamate moiety under aqueous conditions could afford activation of the system and subsequent degradation.