The Synthesis of 1beta-Hydroxytestosterone, a Testosterone Metabolite of Xenobiotic Human Cytochrome P450 Enzymes from a Borylation of Androsta-1,4-diene-3,17-dione

Xenobiotic cytochrome P450 enzymes have been shown to hydroxylate testosterone at various positions in the steroid backbone including 1beta-hydroxytestosterone. Despite the potential application to study the biochemistry of these enzymes, 1beta-hydroxytestosterone is not commercially available. A synthesis of 1beta-hydroxytestosterone from commercially available androsta-1,4-diene-3,17-dione was developed. The key step to functionalize C1 was a borylation reaction catalyzed by an in situ generated copper carbene complex. To test the versatility of the borylation reaction, androsta-2,4-dien-1-one was also used as the substrate, which underwent conjugate addition at C3. The synthetic strategy reported will be used to access other biologically relevant C1-hydroxylated steroids to explore the biochemistry of drug metabolizing P450 enzymes.