In the fall of 1941, just prior to the entry of the United States into World War II, adrenal cortical hormones were sought as potential therapeutics for the treatment of shock and battle fatigue. This was, in part, due to a bizarre rumor, erroneously circulated by allied intelligence, which suggested that Germany was buying the adrenal glands of cattle from Argentinian slaughterhouses and administering extracts to their Luftwaffe pilots. The prevailing thought at the time was that German scientists had unraveled the secret of the adrenal glands and were providing the Nazis with an adrenal product that enabled pilots to fly at unusually high altitudes without suffering ill effects from lack of oxygen. At the behest of the US government, industrial, university and foundation laboratories were joined in a massive effort to uncover and provide allied forces with this coveted ‘miracle drug’ substance of unknown molecular composition.
By 1941, 26 cortical steroids had been isolated from the adrenal cortex by the independent laboratories of E. C. Kendall, T. Reichstein and Wintersteiner. Only a few milligrams of these compounds can be isolated from a ton of adrenals and, thus, synthesis is required to procure meaningful amounts. During the war, a 30-step partial synthesis of Kendall’s ‘Compound A’ was accomplished by Merck and Co. By 1944, nearly 100 grams of Kendall’s A, 11-dehydrocorticosterone, had been synthesized. The molecule was shown to be devoid of any significant biological activity. However, in the same year, L. H. Sarett (depicted below) of Merck prepared the 17-hydroxylated analog of Kendall’s A by a 39-step synthetic sequence starting from cholic acid (vida infra). Kendall referred to this substance as ‘Compound E,’ but to avoid confusion with ‘vitamin E,’ Kendall agreed to call it ‘cortisone.’ Cortisone failed in the treatment of adrenal insufficiency (Addison’s Disease).
Since the late-1920s, the nobel laureate-to-be, P. S. Hench of the Mayo Foundation, had astutely observed that the condition of women suffering from rheumatoid arthritis improved during pregnancy. He hypothesized that the improvement was due to the release of some hormone. In 1948, acting solely on the basis of this rather vague hypothesis, Hench injected 100 mg of Sarett’s synthetic cortisone into a patient suffering from a serious case of rheumatoid arthritis. The dramatic results are now legendary. In a few days the previously bedridden patient went downtown on a shopping spree and the event was covered extensively by the popular press of the day. Demand for the new wonder drug for the treatment of inflammatory diseases became enormous.
|Lewis Sarett (left) and Max Tishler (right) of Merck|
The second phase of Merck’s manufacturing process transforms the cholate side chain to the requisite dihydroxyactone of cortisone. In the course of phase 2, the C17 side chain is first converted into a diene (5) and then oxidatively cleaved to furnish the pregnane dione 7. Seven subsequent conversions are then required for additional oxidative elaboration of the C17 substituent. And, finally, phase 3, which simply introduces unsaturation into the A-ring, is completed in four steps, marking the completion of Merck’s cortisone manufacturing process.
|Russell E. Marker|
|Carl Djerassi at Syntex in 1951|