SYNTHESIS OF 2-OXACORTEXONE AND ITS EFFECT ON CA2+ UPTAKE IN BOVINE SPERMATOZOA

Low temperature base catalyzed autoxidation (BCA) of the A-ring of 21- acetoxypregn-5-ene-3,20-dione 20-ethylene ketal (7) resulted in the sa ponification of the ester with the concomitant formation of 2,21-dihyd roxypregna-1,4-diene-3,20-dione 20-ethylene ketal (8). Continued BCA a t ambient temperature, converts the latter to 1,21-dihydroxy-2-oxaprog esterone 20-ethylene ketal (9), which is reduced by NaBH4 to the 2-oxa steroid, 21-hydroxy-2-oxaprogesterone 20-ethylene ketal (10), Treatmen t of enol 8, lactol 9, and lactone 10 with aqueous acid generates the corresponding deprotected analogs 2,21-dihydroxypregna-1,4-diene-3,20- dione (enol 11), 1,21-dihydroxy-2-oxaprogesterone (lactol 12), and 2-o xacortexone (2-oxadesoxycorticosterone, 21-hydroxy-2-oxaprogesterone, lactone 13). In bovine spermatozoa, neither 2-oxasteroid ketal 10 nor its deprotected analog 13 stimulated Ca2+ uptake. In high concentratio n (0.5 mM), the inhibition of Ca2+ uptake is only 37% for 13, as compa red to 83% found with the parent steroid, cortexone (desoxycorticoster one, 21-hydroxyprogesterone. 5). The difference in molecular structure between 13 and 5 indicates the importance of the oxygen atom in ring A in achieving the protective effect of the steroid. Ketalization of t he C-20 carbonyl is not important for protection. Thus it seems that b y replacing C-2 by an oxygen atom we can reduce the biological damage caused by relatively high concentrations of steroid treatment, These r esults are highly significant when treatment of patients with high dos es of steroids is considered.