Conformation of Steroids

Draw the structures and conformations of steroids and other fused-ring systems. 

Fig. 5.5 Ring conformations of steroids described in text. (From Bernstein 1987, with permission.)...

Duax, W. L., Fronkowiak, M. D., Griffin, J. F. and Rohrer, D. C. (1982a). A comparison between crystallographic data and molecular mechanics calculations on the side chain and backbone conformations of steroids. In Intermolecular dynamics (ed. J. Jortner and B. Pullman), p. 502. D. Reidel, Dordrecht. [160]... 

Seminal papers on the conformation of steroids go back to Sir Derek Barton (1918-1998), and are the basis of our understanding of selective reactions at the steroid skeleton. [44, 45] Barton was also the first to discover specific functionalisations of non-activated carbon atoms in steroids. 

In the absence of other evidence, such as n.m.r. results in the case of (102), considerable care must be exercised in extrapolating the solid-state conformations of steroids to other environments. This is emphasized by the analyses of two crystalline modifications of 2,4-dibromo-oestradiol (107). In the orthorhombic form, the packing of the molecules is characterized by short Br Br intermolecular contacts of 3.63 A and by 0(3)-H 0(17)... 

Above and below are oversimplified concepts. The molecular model reveals that the 0—0 bonds protrude either nearly in the plane of the ring, called equatorial, or more perpendicular to the plane of the ring (above or below), called axial. Here, the ring is represented as planar for greater clarity for a more oorrcict representation see conformation of steroids, Chapt. XIV-2. 

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. 

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... 

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... 

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. 

We saw in Chapter 3 that bisubstrate reactions can conform to a number of different reaction mechanisms. We saw further that the apparent value of a substrate Km (KT) can vary with the degree of saturation of the other substrate of the reaction, in different ways depending on the mechanistic details. Hence the determination of balanced conditions for screening of an enzyme that catalyzes a bisubstrate reaction will require a prior knowledge of reaction mechanism. This places a necessary, but often overlooked, burden on the scientist to determine the reaction mechanism of the enzyme before finalizing assay conditions for HTS purposes. The importance of this mechanistic information cannot be overstated. We have already seen, in the examples of methotrexate inhibition of dihydrofolate, mycophenolic acid inhibiton of IMP dehydrogenase, and epristeride inhibition of steroid 5a-reductase (Chapter 3), how the [5]/A p ratio can influence one s ability to identify uncompetitive inhibitors of bisubstrate reactions. We have also seen that our ability to discover uncompetitive inhibitors of such reactions must be balanced with our ability to discover competitive inhibitors as well. 

Deoxycholic acid (DCA) (17) and apoeholic acid (ACA) (18) are typical examples of the bile acid family of materials, but with the unique property of forming inclusion compounds with a wide variety of guest molecules 92). Partly due to the cis ring junction between rings A and B, and partly due to the conformation of the steroidal side chain these compounds present a convex hydrophobic P-face and a concave hydrophilic a-face, as shown for DCA (19), a classical aid to the formation of inclusion compounds 93). 

Sir Derek H. R. Barton (1918-1998, formerly Distinguished Professor of Chemistry at Texas A M University) and Odd Hassell (1897-1981, formerly Chair of Physical Chemistry of Oslo University) shared the Nobel prize in 1969 for developing and applying the principles of conformation in chemistry. Their work led to fundamental understanding of not only the conformations of cyclohexane rings, but also the structures of steroids (Section 23.4) and other compounds containing cyclohexane rings. 

The addition of organocuprates to chiral decalin enone systems has been explored in the context of steroid synthesis. For the addition of lithium dimethylcuprate to enones 28, 31, and 34, the major diastereomer obtained can easily be predicted by employment of a qualitative conformational analysis (Scheme 6.6) [11-13]. Thus,... 

Reduction of steroid enones like cholestenone 26, with a rigid ring conformation, leads to head-to-head pinacol dimers because of steric hindrance at the alternative dimerization site, and reaction occurs tlnough the a-face of the radical intermediate [101, 102]. The a-face is opposite to the angular methyl substituent... 

The deformed-chair conformation of ring A in a 4,4-dimethyl-3-oxo-5or-steroid has been confirmed by an X-ray study of a 17 -benzoyloxyandrostane derivative. The results agree with those of an earlier study of the 17-iodoacetate, and with the geometry indicated by force-field calculations. Dipole moments calculated by the application of molecular mechanics to 5a-androstane-3,17-dione and its distorted 4,4-dimethyl derivative are larger than those observed the reasons for these deviations are not yet clear. 

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