[Diastereospecific synthesis of antifungal threo-BAY 19139]

BAY 19139, 1-(4-chlorophenoxy)-1-(1-imidazolyl)-3,3-dimethyl-2-butanol is a new imidazolyl derivative of antifungal agent. Its threo-isomer(Ia) shows marked antifungal activity, and the antiprotozoal activity is higher than the well-known metronidazole or clotrimazole, but the activity of the erythro-isomer is weak. This paper reports the sequential reactions of chloro or bromo-oxirane with p-chlorophenolate, and then with sodium imidazolate in two stereocontrolled steps to the threo-BAY 19139 (Ia). Halo-oxirane is accomplished by the stereochemistry of ring closure of alpha, alpha-dihalopinacolone. The molecular structure of Ia was confirmed unambiguously by X-ray crystal analysis. Furthermore, the nucleophilic substitution of chloro-oxirane was investigated. We found that under the solid-liquid PTC condition at room temperature, the reaction time was shortened and a higher yield was obtained.