Steroid Conformation Analysis

The conformation of the 1 P side chain of progesterone has been the subject of extensive analyses. For steroids having the D-ring and side chain of progesterone 

In the crystal of one of the 16)8-raethyl substituted compounds, 3)8-acetoxy-16)8-methyl-5-pregnen-20-one [8], there are two molecules in the crystallographic asymmetric unit. The observed values of 0 are -110° and -47°. The co-crystallization of the two conformers is further evidence of their similar energy and suggests that the conformational distribution in the crystal mirrors that in the solution from which the crystals were grown. Another example of this phenomenon is provided in crystals of 18-deoxyaldosterone [9]. Here the formation of an oxygen bridge between C(ll) 

Energy minimization programs are routinely used to calculate molecular energy as a function of conformation. Unfortunately, it is difficult for the average user to esti- 

It is noteworthy in this example that, as better ab-initio calculations are used on larger molecular fragments, the predicted conformation of isolated molecules ap- 

---

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. 

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. 

In this molecule only the bond between the steroid skeleton and the aziridine moiety can rotate freely. A molecular mechanics conformational analysis resulted in two low energy conformations (Fig. 9.4, see p. 264), both of which had almost identical potential energy, as calculated in the Tripos force field [10]. 

Hadler 26) employed conformational analysis to explain the difference in the proportion of cholestane to coprostane derivatives resulting from the reduction of A and d steroids. He suggested that the hydrogenation process involved the formation of a quasi-ring structure between the unsaturated carbon atoms and two hydrogens originally dissolved in the metal, a mechanism which is similar to one proposed by Beeck (27) and by Jenkins and Rideal 28). He assumed, in effect, that the saturated struc-... 

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,... 

Functionalization of the methyl groups in the photolysis of the nitrites of 6-hydroxy-4,4-dimethyl steroids is used as a probe for conformational analysis. It is confirmed that in the 4,4-dimethyl-19-nor-series ring A has the normal chair... 

European Company to produce insulin and important suppliers of oestrone,274 Lederle,275 and Roussel Uclaf and Schering AG in Europe.276 Another development arising from this early research on steroids was Barton s pioneering studies in conformational analysis. The reminiscences include those by Fried on the discovery of the fluorosteroids at the Squibb Institute for Medical Research in New Jersey,277 and of studies of the biochemistry of steroid hormones linked to genetics and the history of cancer.278 Clearly, the problems of unravelling the complex mechanisms of steroid action have aroused considerable interest.279... 

It was a desire to explain the reactions of steroids that led Sir Derek Barton (1918-98) to drseover, in the 1940s and 1950s, the principles of conformational analysis described in this chapter. It was forthis work that he shared the Nobel prize in 1969. We will come back to steroids in more detail in Chapter 51. 

Conformational analysis has been employed [46] with moderate success to explain the stereochemistry of the catalytic hydrogenation of steroidal olefins. In the hydrogenation of an unsaturated A/B trans steroid the steroid molecule will generally be adsorbed on the catalyst by its less hindered a-face, leading to cis addition of hydrogen from the a-direction. This pattern is followed for example by and A -olefins,... 

In order to appreciate the relationship between conformational features and reaction mechanisms it is necessary to understand the general principles of conformational analysis of cyclic structures. The reader is referred to other works for a detailed treatment of this subject [13], but some of the main features relevant to steroids are summarised here. 

A conformational analysis of various substituted A-homo-steroids is reported. The preferred conformation of the amide group in some acetamido-substituted steroids is of the type (5), with anti-periplanar orientation of C—H and N—H bonds the eclipsing of the C—H and C=0 bonds is similar to that accepted for acetates of secondary alcohols. 

Barton, Derek H. R. (1918-1998). An English organic chemist who won the Nobel Prize for chemistry in 1969 with Hassel. The field of conformational analysis in organic chemistry was initiated through his research in the terpene and steroid fields. He did extensive research in the area of carbanion autoxidations. He was instrumental in research concerning the relationship of molecular rotation to structure in complex organic molecules. His education took place in London, France, and Ireland. 

Steroid Properties and Reactions (Chapter 1).— The application of modem computing techniques to valence-force calculations marks a new phase in the conformational analysis of steroids. This approach brings within reach the accurate specification of preferred conformations, and the evaluation of conformational energies and conformational transmission effects and thus promises to complement the chemical and physical techniques used hitherto. The introduction of lanthanide shift reagents in n.m.r. spectroscopy promises to be particularly valuable in the analysis of steroids since it overcomes to a large extent a major limitation, namely the near-equivalence of many protons attached to the steroid nucleus. Further useful advances in applying solvent shifts... 

In addition to the competition to exploit the medical markets so long sought for, other technical factors contributed to the research buildup through the 1950,s. The now readily available steroid substances were ideal models to study stereochemistry, reaction mechanisms and rates, conformational analysis, and the application of new instruments to structure characterization. All of these studies, although not necessarily aimed... 

Crystallographic data on over 1000 steroids or steroid related compounds provide information concerning preferred conformation, relative stabilities, and substituent influence on the interactive potential of steroid hormones. Conformational analysis of these data and comparison with ab-initio and empirical energy calculations indicate that the conformations observed in the solid state are at or near global minimum energy conformations and provide a useful basis for empirical models of structure-function relationships. 

Carbonyl derivatives of steroidal systems presented a number of intriguing puzzles in the early days of conformational analysis. These have now been fairly well tracked down and sorted out, and the results are understood (for a review of the literature up to about 1965, see Eliel et al., 1965, pp. 113, 170). 

Barton, D. H. R., Morrison, G. A. (1961). Conformational analysis of steroids and related natural products, Fortschr. Chem. Organ. Naturst., 19 165. 

---