Photochemical Rearrangement of a 6–Azasteroid Oxaziridine to a Novel 17β–Carbomethoxy–A–homo–B–seco–6–aza–3, 5–androstanedione

Stephen Frye^*

Department of Medicinal Chemistry, Glaxo Inc. Research Institute, Five Moore Drive, Research Triangle Park, North Carolina.

Received June 23, 2009
Accepted August 31, 2009

^* Current contact information:
UNC Eshelman School of Pharmacy,
Division of Medicinal Chemistry and the Center for Integrative Chemical Biology and Drug Discovery,
120 Mason Farm Road,
Campus Box 7363,
University of North Carolina,
Chapel Hill, NC 27599–7363;
e–mail: svfrye@email.unc.edu;
phone: 919 843 5486.

Abstract

4– and 6–azasteroids have been shown to be potent inhibitors of human 5α,–reductase and certain azasteroids have shown significant clinical benefit in the treatment of androgen–related disorders. In an effort to expand the diversity of steroidal heterocycles synthetically accessible for structure–activity relationship exploration, a novel reaction sequence was applied to the preparation of the 6–aza–steroid framework. To this end, photolysis of the oxaziridine derived from 17β–carbomethoxy–3β–triisopropylsilyloxy–6–azaandrost–5–ene (1) yielded a novel 7, 5–steroidal ring system that was evaluated for inhibition of human type 1 and 2 5α–reductase.

Key words: Azasteroids, 5α–reductase, steroidal heterocycles, photochemistry, synthesis, oxaziridine.

Resumen

Los 4– y 6–azaesteroides mostraron ser potentes inhibidores de la 5α,–reductasa humana, y otros azaesteroides fueron eficientes en el tratamiento clínico de desórdenes relacionados a los andrógenos. En un esfuerzo para ampliar la diversidad de heterociclos esteroidales que se obtengan sintéticamente, con el fin de explorar sus relaciones de estructura–actividad, se empleó una novedosa secuencia de reacciones para la preparación de 6–azaesteroides. De esta forma, la fotólisis de la oxaziridina derivada del 17β–carbometoxi–3β–triiso–propilsililoxi–6–azaandrost–5–eno (1) proporcionó un nuevo sistema esteroidal de anillos fusionados de 5 y 7 miembros, el cual se evaluó en la inhibición de la 5α–reductasa humana de tipos 1 y 2.

Palabras clave: Azaesteroides; 5α–reductasa; heterociclos esteroidales; fotoquímica,; síntesis; oxaziridina.

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Acknowledgments

This paper is dedicated to the memory of Professor Ernest Eliel – a gentleman and scholar who gave so much to chemistry and the world.

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