SYNTHESIS OF AND CHEMICAL-MODEL REACTION STUDIES WITH 3-DEOXYANDROGENS - EVIDENCE SUPPORTING A 2,3-ENOLIZATION HYPOTHESIS IN HUMAN PLACENTAL AROMATASE CATALYSIS

A number of hitherto undescribed Delta(2)- and Delta(3)-3-deoxy-5 alph a-androgen derivatives (17 beta, 19-diols 12 and 13, 19-hydroxy-17-ket ones 16 and 17, 19-oxo-17-ketones 18 and 19) were synthesized in good yield. The lithium-ammonia reduction of -(tetrahydropyran-2-yloxy)andr ost-4-ene-3,17-dione 7 followed by Shapiro reaction allowed easy const ruction of both Delta(2)- and Delta(3)-3-deoxy-5 alpha-steroid systems . An improved synthesis of the known Delta(4)-3-deoxyandrogen derivati ves (28, 30, 31) was accomplished in high yield. Masking of the 19-hyd roxy group was necessary in order to generate the Delta(4)- 3-deoxyand rogen system in good yield, in contrast to the account of an earlier s ynthesis of compounds 28 and 30 by Numazawa. Chemical model reactions of the third oxidative process in aromatase action were carried out wi th Delta(2)-, Delta(3)-, Delta(4)- and Delta(2,4)-3-deoxy-19-oxo-17-ke to steroids (18, 19, 31 and 5, respectively). The findings illustrate the need for both Delta(2)- and Delta(4)-unsaturation in order to gene rate Delta(1(10))-unsaturation under the model reaction conditions. Th is study supports our 2,3-enolization hypothesis in the proposed catal ytic mechanism for human placental aromatase. The importance of the st ereoelectronic nature of substrate 1 beta-H in the enzyme-catalysed th ird oxidative process is discussed.