STERIC EFFECTS ON THE REGIOSELECTIVITY OF AN AZIDE-ALKYNE DIPOLAR CYCLOADDITION REACTION - THE SYNTHESIS OF HUMAN-LEUKOCYTE ELASTASE INHIBITORS

The cycloaddition reaction of N-(azidomethyl)benzisothiazolone 4 with various electron-deficient acetylenes gave a novel series of 1,2,3-triazoles 5-15 that were prepared for testing as inhibitors of human leukocyte elastase (HLE). Steric effects controlled the reaction regioselectivity, since as the acetylene substituent size increased from hydrogen to phenyl, tert-butyl, and trimethylsilyl, the regioisomer ratios reversed. An electronic effect of silicon appears to be responsible for the formation of only one isomer with the trimethylsilyl acetylenecarboxylate and ethynyl sulfone. For example, the 5-(phenylsulfonyl)triazole 13b was the only regioisomer detected in the reaction of phenyl 2-(trimethylsilyl)ethynyl sulfone with the azide 4. The strongly electron-withdrawing sulfone exerted no control over the regioselectivity of the cycloaddition reaction in comparison to the dominating effect of the trimethylsilyl group. High pressure and water as solvent were separately shown to accelerate the rate of product formation. The structures were unambiguously assigned on the basis of an X-ray crystal structure determination and NOE difference experiments. The derivative 12a, WIN 68123, is a potent HLE inhibitor with an apparent binding constant (K-i*) of 0.38 nM.