Enolic Ortho Esters. IV. Synthesis of the 8-α and 8-β Epimers of a 6-Oxa Steroidal Enolic Ortho Ester

Abstract

Reaction of resorcinol (9) with methyl 1β-hydroxy-7aβ-methyl-5-oxo-2,3,3 a α,4,5,6,7,7a- octahydro-1H-indene-4α-carboxylate (10a) or with the corresponding 1,5-dioxo ester (15) in methanesulfonic acid gave ( ±)-3,17 β-dihydroxy-6-oxaestra-l,3,5(10),8(9)-tetraen-7-one (11a) (98%), or (c)-3-hydroxy-6-oxaestra-1,3,5(10),8(9)-tetraene-7,17-dione (14) (91%), respectively. 3-O-Methylation of the phenolic keto lactone (14) followed by reaction with ethylene glycol gave (±)-17,17-ethylenedioxy-3-methoxy-6-oxaestra-1,3,5(10),8(9)- tetrae n-7-one (16). Reduction of this with lithium/ammonia afforded 77% of (±) 17,17-ethylenedioxy-3-methoxy-6-oxa-8 α-estra-1,3,5(10)-trien-7-one (71, which upon base-catalysed epimerization yielded 84% of the 8 β-epimer (19). Reaction of the 8 α-H lactone (17) or its 8 β- epimer (19) with ethylene oxide in the presence of boron trifluoride etherate yielded the corresponding phenolic ortho esters (±)-7,7:17,17-bis( ethylenedioxy )-3-methoxy-6-oxa-8 α-estra-1,3,S(10)- triene (23), and its 8 β- epimer (25), in 36 and 42% yields, respectively. Birch reduction of (23) and (25) afforded the corresponding enolic ortho ester ( ±)-7,7:17,17-bis( ethylenedioxy )-3-methoxy-6-oxa-8 α-estra-2,5(10)- diene (26), and its 8 β-epimer (6), in 82 and 64% yields, respectively. Some related chemistry is described.

The enolic ortho esters (26) and (6) were relatively inert to attack by methylmagne sium iodide under normal conditions.