Polycyclic Compounds Steroids

The first five volumes in this series each feature a separate chapter that hears the title Steroids. The steady diminution of research on this structural class is illustrated hy the regularly decreasing extent of those chapters. By the time Volume 6 appeared, the discussion of steroid-hased drugs takes up hut a section in the chapter on Carhocyclic Compounds. The relatively small amount of research devoted to this area is reflected in the present volume as well. The compounds that follow are organized by structural class as they each display quite different biological activities from one another. 

---

Polycyclic compounds are common in nature, and many valuable substances have fused-ring structures. For example, steroids, such as the male hormone testosterone, have 3 six-membered rings and 1 five-membered ring fused together. Although steroids look complicated compared with cyclohexane or decalin, the same principles that apply to the conformational analysis of simple cyclohexane lings apply equally well (and often better) to steroids. 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

Somewhat unusual examples, which illustrate the usefulness of cycloadditions in the synthesis of polycyclic compounds, are the controlled synthesis of an unsymmetrically substituted aromatic compound (131 from very simple commercially available compounds (Scheme 6.9), and the one-step thermal cyclisation of compound J6 to the aromatic steroid 14 (Scheme 6.10). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

Methyl-l,3-cyclohexanedione has been used as starting material for the syntheses of several polycyclic compounds for projected syntheses of steroids and terpenoids.11-13 It has also been used to prepare l -diketo-Sa-methyl-l a-octahydro-naphthalene.3 4- 16... 

The Robinson Annulation is a useful reaction for the formation of six-membered rings in polycyclic compounds, such as steroids. It combines two reactions the Michael Addition and the Aldol Condensation... 

Analytical Properties p-Cyclodextrin AC (cycloheptamylose-AC) reverse phase separation of steroids and polycyclic compounds Reference 13-28... 

Model compounds, containing rings C and D, or A, C, and D of lysergic acid, were compared with polycyclic compounds of the steroid series, whose absolute configuration, with respect to the spatial arrangement corresponding to C-5 of lysergic acid, was known. 

Steroid-type molecules, e.g., 48, were generated from (l-alkynyl)carbene complex 11 by [4+2] cycloaddition of a TBSO butadiene to the C2-C3 triple bond of lk and subsequent two-alkyne annulation to the M = C bond (Scheme 17).75 Other polycyclic compounds have been obtained similarly by insertion of several alkyne units tethered by a carbon chain.76,77 It should be noted that an annulation of an aromatic ring instead of a 1,4-cycIohexa-diene is achieved if the diene component contains a potential leaving group, as shown in Schemes 16 and 17. 

The acyl radical cyclizations have been cleverly applied to the synthesis of complex natural and unnatural products (Eq. (13.4)). In one example, tandem radical cyclization of 14 provides access to the steroidal skeleton. The reaction proceeds through a 6-endo-trig cyclization to form the A/B ring and a macrocycliza-tion/transannulation to establish the C/D ring [12]. More recently, a cascade cyclization initiated by an acyl radical has allowed for the establishment of fourteen chiral centers in a single step [13]. Once again the formation of the polycyclic compound 17 involves sequential 6-endo-trig reactions. 

The hydroxylation of steroids at various positions by a range of fungi together with some representatives of other polycyclic compounds is discussed in Chapter 6, Section 6.11.2, and probably involves the cytochrome P-450 system (Breskvar and Hudnik-Plevnik, 1977). 

The method of identifying particular carbon atoms in these polycyclic compounds is by a systematic numbering sequence. Individual rings are also denoted alphabetically. The conventions for steroids and hopanoids are shown in Fig. 2.20a. Numbering for higher plant triterpenoids follows a similar sequence to that of hopanoids, with C-22 being incorporated in the six-membered E ring, and C-29 and C-30... 

Figure 16.5-74. Involvement of enzymatic Baeyer-Villiger processes in the degradation of non-steroidal polycyclic compounds.

The direct bromination of -alkoxylactones at the p position initially generates the a. -unsaturated lactones (eq 14) however, the required radical abstraction is not so facile and further bronii-nation of the Q , -unsaturated lactone proceeds competitively to afford the mono- and dibrominated products. NBS is also used for the oxidative aromatization of polycyclic compounds, including steroids and anthraquinone precursors (eq 15). ... 

All unsaturated steroids, as well as many other unsaturated polycyclic compounds, display a series of colors if treated with cold mineral acids (Fieser and Fieser, 1949, p. 100). The lipid droplets in thecal and lutein cells of the ovary were found to color if treated with sulfuric acid (Dempsey and Bassett, 1943 McKay and Robinson, 1947). Dempsey and Wislocki (1944) observed a positive reaction also in the syncytium of the placenta. Chester Jones and Deane (1949) obtained positive reactions with a number of steroid hormones that had been dissolved in oil, suspended in gelatin, and spread on slides. 

A more refined test is the Schultz (1924) method for cholesterol, which involves the application of a mixture of concentrated sulfuric acid and glacial acetic acid to sections which have been oxidized with ferric ammonium sulfate (iron alum). A blue-green color results. The iron alum apparently oxidizes 3-hydroxy steroids and their esters to 7-oxy steroids, which give the Lifschlltz color reaction on the application of the acids. (Fieser and Fieser, 1949, p. 234). This test is considered to be more specific for a limited group of steroids than is the sulfuric acid method cited above, which reveals a large number of unsaturated polycyclic compounds. Recently, however, Kent (1952) has reported that a positive reaction also occurs with carotene. 

The position of longest wavelength absorption (Xmax) depends in a predictable way on the substitution pattern of these simple molecules. A set of empirical correlations was collated by Robert Bums Woodward (1917-1979) and was known initially as Woodward s rules and now sometimes as Woodward s first rules. These rules were extended by Louis Fieser (1899-1977) and Mary Fieser (1909-1997) to include cyclic dienes in the polycyclic compounds called steroids. Table 12.2 summarizes Woodward s and the Fiesers mles. Woodward s very different second set of rules will appear in Chapter 20. 

---