Steroids Sarett

In order to illustrate what "the maximum correlation" and "the simplest possible solution" mean, we can compare the formation of ring A of the steroidal skeletons, in the synthesis of cortisone (8) by Sarett et al, accomplished in 1952 [28], with the synthesis of conessine (141 by Stork and his co-workers, accomplished ten years later, in 1962 [29] (Scheme 1.3). 

CrOs-pyridine complex The oxidation of alcohols to aldehydes and ketones with CrOs in the presence of pyridine solvent is known as the Sarett oxidation. Sarett used the CrOs-pyridine complex in the synthesis of steroids. Although primary alcohols give poor yield, benzylic, allylic and secondary alcohols give good yields with Sarett reagent. 

This method of dehydration has become widely used by steroid chemists and proved of service in Sarett s synthesis of cortisone." Thus dehydration of the 20-cyanohydrin (4) was accomplished with POCI3 in pyridine at room temperature, and saponification gave (5) in very high yield. 

Aldol cyclization of keto aldehyde intermediates has been used in several steroid syntheses, as pan of a strategy for conversion of a six-membered o-ring into a five-membered ring. An example is seen in equation (105), a step in the Sarett steroid synthesis. A similar transformation has been utilized by Johnson and coworkers in a steroid synthesis. 

B.i. Chromium Trioxide—Pyridine. In 1948, Sisler and co-workers isolated and characterized a stable complex from the reaction of chromium trioxide and pyridine. Sisler did not use this reagent for the oxidation of organic molecules but Sarett and co-workers recognized its utility in the synthesis of steroids. In this connection, alcohol 24 was oxidized to 26 in 89% yield. The reagent, which probably has the trigonal bipyramidal structure shown in 25, proved useful for the general oxidation of primary and secondary alcohols, even in the presence of double bonds and thioethers,. The oxidation usually requires pyridine as a solvent and... 

In 1948, Edward C. Kendall, who clarified steroid structures during the 1930s (see chapter 4), and Philip S. Hench (1896-1965), at the Mayo Clinic, demonstrated that the steroid hormone cortisone relieves symptoms of rheumatoid arthritis. Kendall, Hench, and Tadeus Reichstein would share the 1950 Nobel Prize in physiology or medicine. Although Lewis Sarett (1917-99) at Merck had accomplished a total synthesis of cortisone in 1944 (Woodward published a more elegant one in 1951), cortisone and its close derivatives would have remained extremely expensive were it not for the efforts of Percy L. Julian (1899-1975). As soon as he learned of the Mayo Clinic discovery, Julian developed a rapid, inexpensive synthesis of Reichstein s Substance S, also isolated ftom the adrenal cortex. This steroid is easily converted to dihydrocortisone and Julian s pathway remains today the major commercial route to this over-the-counter topical remedy for sunburn, mosquito bites, and other uncomfortable skin irritations. 

Slightly more than one year after the completion of the two formal total syntheses of cortisone by Robinson and Woodward there appeared a report by Sarett et al. (1952), describing a total synthesds of cortisone in the truest sense of the word. In contrast to the preceding two formal syntheses which utilized the relay method by synthesizing a certain steroid which had already been converted previously to cortisone, Sarett s synthesis meets the most rigorous criterion by leading directly to d -cortisone, thus excluding the use of a known (and hence optically active) steroid as an intermediate. 

Arth GE, Fried J, Johnston DBR, Hoff DR, Sarett LH, Silber RH, Stoerk HC, Winter CA. 16-Methylated steroids, n. 16a-methyl analogs of cortisone, a new group of anti-inflammatory steroids. 9a-halo derivatives. J. Am. Chem. Soc. 1958 80 3161-3163. 

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