Cortisone total synthesis

A third variation of this strategy has been appHed to an enantioselective total synthesis of cortisone. From an appropriately functionalized, scalemic hydrindan that possessed an 11-oxo-group and a masked corticoid side-chain, (+)-cortisol was produced in an 11-step total synthesis (213). 

In Sarett s total synthesis of cortisone, mild acid conditions were developed for the hydration of an ethoxyacetylenic carbinol to the ester without complete dehydration of the tertiary hydroxyl group. An acid-sensitive ketal group in another part of the molecule was also maintained. 

Corticoid side chain.5 The final step in a recent total synthesis of cortisone (2) employed a novel double hydroxylation of an enol silyl ether (1) for construction of the side chain. Thus treatment of 1 with 3 equiv. of the peracid and KHC03 in CH2C12 at 0° results in hydroxylation at both Cl7 and C,. 

The first synthesis of cortisone (8), for instance,was a partial synthesis from desoxycholic acid (9), performed in 1948 by a group of chemists at Merck and Co under the leadership of Kendall [19], three years before Woodward [20] and Robinson [21], independently, accomplished the first total synthesis of steroids. 

The total synthesis of cortisone has been achieved from an intermediate prepared by Woodward and co-workers in 1951 by the following route ... 

An anecdote illustrates Tishler s drive. The total synthesis of cortisone, as devised by Lewis Sarrett, comprised approximately 30 steps and required weeks of intense and painstaking effort. Max was in charge of the first commercial production of cortisone in the pilot plant. One of the final steps is the isomerisation of a double bond into conjugation with the 3-ketone function with the formation of a 2,4-dinitrophenylhydrazone, causing the development of a brilliant, scarlet color. Tishler was inspecting the first production run. To his horror, he spotted a bright-red liquid leaking near the vessel. "I hope that s blood ", he exclaimed. Actually, Max was very concerned for individuals, beneath a rather formidable exterior. 

One step in the Sarett total synthesis of cortisone involved addition of ethoxy-vinylmagnesium bromide to the reactive carbonyl group of the diketone (6) to produce... 

Woodward, R.B., Sondheimer, F. and Taub, D. (1951) The total synthesis of cortisone. Journal of the American Chemical Society, 73, 4057. 

It is striking that Diels and Alder finally received the Nobel Prize in chemistry in 1950, more than two decades after their initial publication. The science of total synthesis of natural products was slow to advance and was hindered by World War II. These factors perhaps explain the delay in fuUy appreciating the impact of the Diels-Alder reaction. The modem era of total organic synthesis is generally considered to have started during the 1940s. In 1952, Robert Bums ( R. B. ) Woodward (1917-79) at Harvard would employ the Diels-Alder reaction to brilliant effect en route to total syntheses of the steroids cortisone and cholesterol. 

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. 

During the past eighteen months there appeared in the scientific literature the fruit of a seldom equaled concentrated attack on a chemical problem— the development of feasible syntheses of cortisone from readily available starting materials. Both aspects of the problem— partial as well as total synthesis—have been solved in the academic sense, and the... 

Meyer (1949) has oxidized gamabufotalin to the etio acid (II), which upon dehydration to III followed by hydrogenation produced methyl 3 8,lla-diacetoxy etianate. Katz (1948) had obtained this acid earlier from sarmentogenin and had oxidized it, after saponification, to methyl 3,11-diketo etianate (IV). The further transformations of this acid, which represents also one of the links in the formal total synthesis of cortisone, are considered in Section IX.2. 

In their total synthesis of 6-methyl-5-androstene-3,l 1,17-trione 3-ethylene acetal, which is a building block for 6a-methylprednisolone, Daniewski and co-workers used a modified Wichterle reaction to install the A-ring of the natural product/ A racemic mixture of 56 was used in a reductive alkylation with Wichterle s reagent to afford the product 57 as a mixture that could be separated by chromatography. Upon treatment of each diastereomer of 57 with formic acid and perchloric acid to induce cyclization, it was observed that both diastereomers resulted in the same enantiopure product 58. This preferred conformation of the steroidal skeleton was confirmed by comparison to an authentic sample of the product that can be obtained directly from natural cortisone. 

An additional advantage of the use of cis-decalones is that axial attack on the more readily accessible "convex of-side of the folded molecule of cis-decalone leads exclusively to products with the natural /3-configuration of the methyl group at Ciq. Consequently, intermediates with a cis- B/C linkage have been used in the total synthesis of cortisone (Scheme 62) and of other nonaromatic steroids (Schemes 75, 77), in spite of the necessity for subsequent inversion at C3, which is effected only with great difficulty in many cases. 

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