Steroids Woodward

In connection with the alkylation of o -unsaturatcd keto-steroids, Woodward, Barton, and coworkers [132] devised a... 

In the following decades, chemists tried to utilize more and more the knowledge on reactions which had already been gained. A number of landmark syntheses represent the change to modern chemistry, such as the synthesis of the estrogenic steroid equilenin (W. Bachmann, 1939), of pyridoxine (K. Folkers, 1939), and of quinine (R.B. Woodward, W. von E. Doering, 1944) [23]. 

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

One of the first major pharmaceutical biotransformations was the development of the synthesis of hydrocortisone in the late 1940s by whole-cell hydroxylation (Figure 2.2). Up until then a 40-step synthetic route developed by the Noble Prize winning chemist R.B.Woodward was the only source of this important drug substance and intermediate. Nowadays, a biocatalyst exists for the selective hydroxylation of every position on the steroid nucleus. ... 

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. 

On the other hand, in the synthesis of cholesterol (30) by Woodward and CO workers [10] the less stable fran -configuration between rings C and D is attained through a homosteroid (29). i.e. a steroid analogue in which the C/D indane system is substituted by a decalin in which the rran -configuration is the thermodynamically favoured (Scheme 8.7). The conversion of the six-membered ring into one of five members is carried out at a later stage, under conditions that do not affect the preformed tran -junction. 

Structural analysis from electronic spectra yields little information because of their relative simplicity. In the 1940s, however, before the advent of more powerful identification techniques, UV/VIS visible spectroscopy was used for structural identification. The study of a great number of spectra of various molecules has revealed correlations between structures and the positions of absorption maxima. The most widely known empirical rules, due to Woodward, Fieser and Scott, involve unsaturated carbonyls, dienes and steroids. Using incremental tables based on various factors and structural features, it is possible to predict the position of the n —> n absorption bands in these conjugated systems (Table 11.3). Agreement between the calculated values and the experimentally determined position of absorption bands is usually good, as can been seen by the following four examples ... 

Chemistry of the glycoside linkage. Exceptionally fast and efficient formation of glycosides by remote activation, Carbohydr. Res. 80 07 (1980). (e) K. Wiesner, T. Y. R. Tsai, and H. Jiu, On cardioactive steroids. XVI. Stereoselective P-glycosylation of digitoxose the synthesis of digitoxin, Helv. Chim. Acta 60 300 (1985). (f) R. B. Woodward (and 48 collaborators), Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am Chem. Soc. 103 3215 (1981). (g) P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermecin disaccharide, benzyl ot-L-oleandrosyl-ot-L-4-acetOxyoleandroside, J. Org. Chem. 43 3489 (1983). 

The desired diol can be isolated after hydrolysis. Woodward noted, that his modification of the Prevost reaction offers the opposite facial selectivity as compared to oxidations with 0s04 in the hydroxylation of synthetic steroid intermediates. Here, the steric approach factors first direct the stereochemistry of the iodination, which is followed by hydroxylation from the opposite face, whereas 0s04 leads to the isomeric cw-diol by direct attack from the most accessible face. 

In 1941 and 1942, the young Robert Burns Woodward undertook a careful numerical analysis of published spectral data for various steroidal ketones containing double bonds. These ketones characteristically absorbed ultraviolet light strongly around 230-250 nm. From this data, Woodward drew up general rules that related these absorption maxima to the arrangement of the double bonds and the... 

Since silver salts are expensive, other cheaper reagents have been sought which can bring about the same type of conversion, and the iodine- tassium iodate- tassium acetate combination has been found to provide a useful alternative. Thallium(I) acetate may be used in place of silver acetate in the Woodward procedure, and syn hydroxylation of steroidal alkenes with dialliumflll) acetate in acetic acid has been performed. ... 

Woodward s synthesis of steroids, described in Scheme 3.1, illustrates the value of a carefully thought out general plan for a synthesis. This synthesis targeted the preparation of the tetracyclic keto aldehyde 1, which can be used as an advanced intermediate to be converted into a set of natural steroids that includes progesterone 2, deoxycorticosterone 3, androsterone 4, testosterone 5, cholesterol 6, and cortisone 7 via well-known routes. The synthetic plan for 1 required solving the following key tasks ... 

Draw a stepwise mechanism for the foiiowing Robinson annulation. This reaction was a key step in a synthesis of the steroid cortisone by R. B. Woodward and co-workers at Harvard University in 1951. 

Sometimes people do engage in intense competition. Some like it, and some believe that advances in science are not unrelated to competition. Others disagree. It may play a role. There have been famous competitions, between Woodward and Robinson, for instance, in the steroid synthesis, or in the determination of the structure of strychnine. Some people love the type of competition common in sport Who will make cholesterol first At one time, everybody was fascinated by who would be the first to achieve a four-minute mile, and I must admit that I remember that it was Bannister. Today, many people run the mile in considerably less than four minutes. Is it important who did it first It s not but it is striking. 

Progesterone, a female sex hormone, has been prepared by total synthesis and by modifications of other steroids. Using established methodologies, such as Diels-Alder cycloadditions, Michael additions, Robinson annulations, aldol reactions, and ring contraction reactions, propose a total synthesis of progesterone. Discuss the merits of your approach in comparison with the total synthesis reported by Woodward, R. B., Sondheimer, R, Taub, D., Heusler, K., McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223. 

Woodward, R. B., Brutcher, F. V., Jr. Cis hydroxylation of a synthetic steroid intermediate with iodine, silver acetate, and wet acetic acid. J. 

Another reaction for which I rilon B is a particularly satisfactory catalyst is cyanoethylation. In the steroid total synthesis by the Woodward group, Triton B-catalyzed cyanoethylation initiated construction of ring A. 

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