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-tri azoles 5-15 that were prepared for testing as inhibitors of human leuk ocyte elastase (HLE). Steric effects controlled the reaction regiosele ctivity, since as the acetylene substituent size increased from hydrog en to phenyl, tert-butyl, and trimethylsilyl, the regioisomer ratios r eversed. An electronic effect of silicon appears to be responsible for the formation of only one isomer with the trimethylsilyl acetylenecar boxylate and ethynyl sulfone. For example, the 5-(phenylsulfonyl)triaz ole 13b was the only regioisomer detected in the reaction of phenyl 2- (trimethylsilyl)ethynyl sulfone with the azide 4. The strongly electro n-withdrawing sulfone exerted no control over the regioselectivity of the cycloaddition reaction in comparison to the dominating effect of t he trimethylsilyl group. High pressure and water as solvent were separ ately shown to accelerate the rate of product formation. The structure s were unambiguously assigned on the basis of an X-ray crystal structu re determination and NOE difference experiments. The derivative 12a, W IN 68123, is a potent HLE inhibitor with an apparent binding constant (K-i) of 0.38 nM.