First synthesis of a C-18 steroid with a 1,5-estradien-3-one system

ORGN 190

Christine Cadot,, Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, (CHUQ-Pavillon CHUL) and University Laval, 2705 Boulevard Laurier, Québec, QC G1V4G2, Canada, Donald Poirier,, Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, (CHUQ-CRCHUL) and Université Laval, Québec, Canada, CHUL Research Center, 2705 Laurier Boulevard, Québec, QC G1V4G2, Canada, and Anie Philip,, Division of Plastic Surgery, Department of Surgery, and Department of Obstetrics and Gynecology, McGill University, Montreal General Hospital, 1650 Cedar Ave, Room C9-177, Montreal, QC H3G1A4, Canada.
Mechanisms involved in the maintenance of pregnancy and the initiation of labour in human are poorly defined. In this context, Anie Philip's group has isolated in pregnant women a novel steroid hormone named ED. They have proposed an unusual 1,5-estradien-3-one structure for this new steroid on the basis of UV spectrum, MS analysis and an aromatization test. However, ED is scarcely available from urine, placenta and blood of pregnant women. For this reason we have considered synthesizing ED in order to confirm its structure. Although a 1,5-dien-3-one system has been already described with a C-19 steroid (no possible aromatization), the synthesis of the C-18 analog is a major challenge because this system is very sensitive to aromatization. We now describe the successful construction of this unstable system, starting from nor testosterone and based on a protection of the 5-6 double bond before introduction of the second 1-2 double bond.