Total Synthesis of Steroids

Estranes. Investigations into the total synthesis of steroids began in the 1930s shordy after the precise formula for cholesterol was estabUshed. The eadiest studies focused on equilenin (5) because of its relative stereochemical simplicity when compared to other steroid nuclei Initially, equilenin was synthesi2ed in 20 chemical steps with an overall yield of 2.7%. This synthesis helped to confirm the perhydro-l,2-cyclopentenophenanthrene ring system of... 

A more recent ring annulation strategy for the total synthesis of steroids from the Stork group is shown in the following equation (210 — 211 — ... 

A. A. Akhrem and Y. A. Titov, Total Steroid Synthesis, Plenum Press, New York, 1970, for total synthesis of steroids before 1970. 

Recent improvements in the total synthesis of steroids which give as the first tetracyclic products 19-norsteroids bearing a hydroxyl or keto group at C-17 have revived interest in the conversion of androstanes to pregnanes. 

Blickenstaff, R.T. Ghosh, A.C. Wolf, G.C. Total Synthesis of Steroids (Organic Chemistry Vol, 30) p. 187 ff Academic Press, New York, London 1974. 

Soon after returning to the Shionogi Research Laboratories from the University of Basel, he became Section Manager to pursue the total synthesis of steroids. This work led to total or partial synthesis of the racemic form of many steroids and steroidal alkaloids, such as estrone 3-methyl ether, 3a-acetoxy-5/3-pregna-9(ll), 16-dien-20-one, aldosterone, latifoline, and cones-sine (1961-1963). With extensive support and encouragement from the late... 

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. 

J.W. Cornforth, "Total Synthesis of Steroids" in "Progress in Organic Chemistry", Vol. 3, Academic Press, New York, 1955, p. 7. 

Methyl- 1,3-cyclopentanedione is a key intermediate for the total synthesis of steroids.2 A number of methods have been described for its preparation, among them the condensation of succinic acid with propionyl chloride,3 and that of succinic anhydride with 2-buten-2-ol acetate,4 both in the presence of aluminum chloride. It has also been obtained from 3-methylcyclopentane-1,2,4-trione by catalytic hydrogenation5 and Wolff-Kishner reduction 6 The base-promoted cyclization of 4-oxohexanoic acid ethyl ester and diethyl propionylsuccinate with tertiary alkoxides was first reported by Bucourt.7 The present cyclization process provides an experimentally simple route to 2-methyl-1,3-cyclopentanedione. Using the same procedure, 4-oxoheptanoic acid ethyl ester has been cyclized to give 2-ethyl-l,3-cyclopentanedione in 46% yield... 

For leading references, see R T Blickenstaff, A C Ghosh, and G C Wolf, Total Synthesis of Steroids, Academic Press, New York, N Y, 1974... 

Those seeking more depth on the total synthesis of steroids are referred to the very informative book by Blickenstaff et al.60... 

The products of this highly efficient asymmetric synthesis are important intermediates in natural product chemistry, e.g., the total synthesis of steroids and prostaglandins. 

Thus, the enone (67) is the cheapest and most readily available bisanellation reagent, permitting a simple total synthesis of steroids. 

A new synthetic method for steroids has been developed using a butadiene dimer (66) as a building block and the palladium-catalyzed oxidation as the key reaction.3-Acetoxy-l,7-octadiene (66), prepared by the palladium-catalyzed reaction of butadiene with acetic acid, is hydrolyzed and oxidized to l,7-octadien-3-one (67) in high yield. The enone (67) is a very useful reagent for bisanellation because its termiiud double bond can be regarded as a masked ketone which can be readily unmasked by the palladium catalyst to form the l,S-diketone (68) after Michael addition at the enone moiety of (67 Scheme 20). Thus, the enone (67) is the cheapest and most readily available bisanellation reagent, permitting a simple total synthesis of steroids. 

Cydic systems usually adopt distinct preferred conformations, which frequently allow them to pass throu a single reactive conformation in the course of a chemical reaction this may result in the formation of a sin e product. In this contesl, addition of organocuprates to a number of chiral, cydic enone systems frequently occurs vtith high levels of stereoselectivity. Historically, this chemistry has had a major impact on the fidd of total synthesis of steroids and prosta andins [la, k]. In this chapter we would thus like to present an overview of the most general stereochemical trends underlying the addition of organocuprates to chiral cydic enones. 

The English edition of a book dealing with the total synthesis of steroids has been published. A review article has appeared on certain groups of biologically active steroids and raw materials for their production. Several accounts of different aspects of steroid synthesis have also appeared. 

An intramolecular 5n2 displacement at a neopentyl center in (27) gave (28), a precursor for the total synthesis of steroids (equation 11). ... 

Steroid synthesis. In developing a method of cyclization which has been of immeasurable -walue in the total synthesis of steroids, Robinson at first experimented with the condensation of ketones with methyl vinyl ketone itself, but encountered difficulties associated with the tendency of the ketone to polymerize. He then turned to possible prectnsors and met with some success with methyl /3-chloroacetyl ketone, CHsCOCHzCH CI. Still better, however, was the methiodide (2) of the Mannich base (1), l-diethylamino-3-butanone. Treated with a strong base such as sodamide in... 

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