The structure and function of oestrogens. IV. Synthesis of 17α-ethynyloestradiol specifically polydeuterated in ring C

Abstract

Epoxidation of 17,17-ethylenedioxy-3-methoxyoestra-1,3,5(10),9(11)-tetraene( 5) by a two-phase procedure gave the labile 9α,11α-epoxide (11), treatment of which with lithium perchlorate in benzene gave 17,17-ethylenedioxy-3-methoxy-97#946;-oestra-1,3,5(10)-trien-11-one (7). Deuteration of this by prolonged treatment with the monosodium salt of (O,O'-²H₂)hydroquinone in dry (O-²H)methanol gave mainly the 98,12,12-trideutero ketone (24) (92% ²H₃). Reduction of this with lithium aluminium deuteride to a mixture of the 11-epimeric alcohols (27a) followed by dehydration gave 17,17-ethylenedioxy- 3-methoxy(l1,12,12-²H₃)oestra-1,3,5(10),9(11)-tetraene (26) which upon reduction with lithium/ammonia gave 17,17-ethylenedioxy-3-methoxy(11ζ,12,12-²H₃)oestra-1,3,5(10)-triene (25). Hydrolysis and demethylation of (25) followed by treatment with potassium acetylide in liquid ammonia yielded 3,17-dihydroxy-19-nor-17a-(11ζ, 12, 12-²H₃)pregna-1 ,3,5(10)-trien-20-yne (29) (²H₄, 9.2; ²H₃, 84.1; ²H₃, 3.1; ²H₁, 2.2; ²H₀, 1.3%). Reduction of the trideutero 9(11)-ene (26) with hexadeuterodiborane followed by treatment with alkaline hydrogen peroxide afforded 17,17-ethylenedioxy-3-methoxy(9α,11β,12,12-²H₄)oestra- 1,3,5(10)-trien-11α-ol (30a). Reduction of the corresponding tosylate (30b) with lithium aluminium deuteride, then hydrolysis, demethylation and ethynylation gave 3,17-dihydroxy-19-nor-17α- (9,l 1,11,12,12-²H₅)pregna-1,3,5(10)-trien-20-yne (35) (²H₅, 84.5; ²H₄, 8.5; ²H₃, 4.4; ²H₂, 0.9; ²H₁, 0.8; ²H₀, 0.9%).