Conformational steroids

Just as cyclohexane can be drawn in a chair conformation, the three-dimensional representation for 5a-cholestane is shown by the following conformational formula. Although cyclohexane may undergo a flip in conformation, steroids are rigid structures, because they generally have at least one trans fused ring system and these rings must be diequatorial to each other. 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

Many stereoselective reactions have been most thoroughly studied with steroid examples because the rigidity of the steroid nucleus prevents conformational changes and because enormous experience with analytical procedures has been gathered with this particular class of natural products (J. Fried, 1972). The name steroids (stereos (gr.) = solid, rigid) has indeed been selected very well, if one considers stereochemical problems. We shall now briefly point to some other interesting, more steroid-specific reactions. 

X-Ray Crystallography. Structural data exists on more than one thousand steroids. Comparisons of the conformations obtained by x-ray crystallography have been made to the conformations obtained by other methods (161). Several studies use x-ray crystal stmctures in the study of progestins. 

This explosion in steroid chemistry both stimulated and was aided by the development of conformational analysis (10). Many basic, physical organic chemistry principles were estabUshed as a result of the study of the logically predictable chemistry of the rigid perhydro-l,2-cyclopentenophenanthrene, steroid skeleton. 

The optical rotatory dispersion curves of steroidal ketones permit a distinction to be made between the conformations, and assignment of configuration is possible without resorting to chemical methods (see, e.g. ref. 36) which are often tedious. The axial halo ketone rule and, in the more general form, the octant rule summarize this principle and have revealed examples inconsistent with the theory of invariable axial attack in ketone bromination. 2-Methyl-3-ketones have been subjected to a particularly detailed analysis. There are a considerable number of examples where the products isolated from kinetically controlled brominations have the equatorial orientation. These results have been interpreted in terms of direct equatorial attack rather than initial formation of the axial boat form. 

This chapter will deal exclusively with three-membered rings containing the hetero atoms O, S and N, and fused to the steroid skeleton. Because of the conformational requirements in steroids, not all of the usual methods of synthesis of three-membered rings are applicable to the fused ring system. For the synthesis of steroids to which an aziridine, oxirane or thiirane is attached either in the side chain or at a ring position but not directly fused to the nucleus, the methods discussed in this chapter, as well as others, are applicable. 

Aziridines can best be obtained by ring closure of amine derivatives which contain a tm 5-oriented leaving group at the -position, see (89). The variable conformational and steric influences in the steroid skeleton limit the generality of a particular synthetic method and necessitate a selection of reagents based on the position of fusion of the aziridine ring. 

Ethers have been prepared by the thermal lead tetraaeetate method in 60-71% ° yield. Introduction of an axial 3a-acetoxy function into 5a-H steroids, however, seems to change the conformation of ring A in such a way that the distance of the 2/ -oxygen from the angular methyl group is considerably increased. Consequently the 2/5,19-ether is formed in only 0.7% to 24% yield. " 02... 

In 6j5-hydroxy-19-iodo steroids (Figure 12-2) the orientation of the reacting centers O—CH2—I resembles the arrangement in the transition state of an S 2 displacement reaction and consequently the activation energy for the transition (3) (4) is low. It has been suggested that the conformation... 

With 11/3-hydroxy steroids, 11/3, 19-ether formation competes with hemi-acetal formation.This is a consequence of steric hindrance of the 11/5-oxygen by the C-18 and C-19 iodomethyl groups which reduces the rate of hypoiodite formation [(3) (5)] even though the conformation of the... 

The [4-1-3] cycloaddition has also been realized in acceptors containing a nitrogen atom. While a,/ -unsaturated aldimines, and structurally flexible ketimine such as (87), generally only undergo [3-1-2] cycloadditions (see Scheme 24), the ketimine (112), which is rigidly held in a cisoid conformation, does give exclusively the [4-1-3] adduct azepine (113). On the other hand, the steroidal imine (114) produces a quantitative yield of a 1 1 mixture of the [4-1-3] and [3-1-2] cycloadducts (115) and (116), respectively (Scheme 2.31) [36]. 

As noted previously, triarylethylenes substituted by a basic group, such as clomiphene, exhibit estrogen antagonist activity. Formal cyclization of that molecule to a more steroid-like, rigid conformation enhances potency in this series. 

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. 

Figure 27.11 Steroid conformations. The three six-membered rings have chair conformations but are unable to undergo ring-flips. The A and B rings can be either cis-fused or trans fused.

Problem 27.9 Lithocholic acid is an A-B cis steroid found in human bile. Draw lithocliolic acid showing chair conformations as in Figure 27.11, and tell whether the hydroxyl group at C3 is axial or equatorial. 

Steroid, 1079-1089 adrenocortical, 1083 anabolic. 1083 androgens, 1082 biosynthesis of, 1084-1089 cis A-B ring fusion in, 1081 conformation of, 1081... 

In steroids and other rigid systems, a functional group in one part of the molecule can strongly affect the rate of a reaction taking place at a remote part of the same molecule by altering the conformation of the whole skeleton. 

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. 

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