18-Hydroxydeoxycorticosterone is an adrenal steroid hormone causing salt and water retention and is secreted in greatly increased amounts in response to the pituitary hormone adrenocorticotropic hormone. Its production is abnormally high in some forms of hypertension in man and rat. Direct proof that 18-hydroxydeoxycorticosterone is capable of causing hypertension is present. Daily subcutaneous injections of 200 micrograms, a low physiological dose, significantly increase the blood pressure of unilaterally nephrectomized saline-treated rats after 2 weeks. This strengthens the hypothesis that 18-hydroxydeoxycorticosterone contributes to the etiology of hypertension, possibly by a mechanism involving stressinduced release of adrenocorticotropic hormone.

Hydroxy-11 -deoxycorticosterone (18-OH-DOC) has been prepared in two steps from 18-hydroxyprogesterone in high yield. 18-Hydroxyprogesterone has in turn been prepared in ~20% yield by photolysis of the ethylene ketal of deoxycorticosterone 21-acetate followed by acidic and then basic hydrolysis and column chromatography. The circular dichroic spectra of 18-OH-DOC and related compounds are reported. From the induced circular dichroism of 18-OH-DOC with Pr(dpm)s, it is concluded that 18-OH-DOC has the 20-»-18-cyclohemiketal structure with C-20 having the R configuration.18-Hydroxy-ll-deoxycorticosterone (18-OH-DOC) was first isolated and identified as a naturally occurring steroid from incubated sectioned rat adrenal by Birmingham and Ward in 19611 and by Péron in the same year.2 It was characterized to be in the 20-»-18-cyclohemiketal form. The in vivo secretion of 18-OH-DOC in rats was demonstrated by Cortes et al.3 The endogenous formation of 18-OH-DOC has also been demonstrated in the camel by Race and Wu in 1964,4 and in man by Melby and collaborators,5,6 who isolated and identified 18-OH-DOC from human adrenal vein blood. They obtained levels comparable to those of aldosterone and deoxycorticosterone in normal subjects, and elevated levels in patients suffering from various forms of hypertension, including Cushing's syndrome and essential hypertension.Because of the possibly important role of 18-OH-DOC in the etiology of essential hypertension,7 a careful study of the structure and the biological activities of 18-OH-DOC appears to be necessary. To this end, we embarked on a synthesis of 18-OH-DOC so that a reasonable amount of the steroid may be at hand. When we began our synthetic work, the synthesis of 18-OH-DOC had been described by Pappo in 1959 only in a preliminary communication8 and in U.S. Patents.9 It involves a 15-step synthesis starting from the alkaloid conessine. This ingenious but long synthesis was, however, not practical in our hands. We decided to adopt a simpler synthesis of 18-OH-DOC starting from 18-hydroxyprogesterone according to Scheme II. This route to 18-OH-DOC has been reported by us in preliminary form.10 Recently, several groups have reported on similar preparations with varying degrees of success.11,12 In this paper, we wish to describe in greater detail our synthesis, and some physicochemical studies on 18-OH-DOC and related compounds. Chemical Synthesis. A. 18-Hydroxyprogesterone. As the immediate precursor for the synthesis of 18-OH-DOC, we chose the structurally similar steroid 18-OH-progesterone