Structure, Stereochemistry, and Conformational Analysis

Quantitative valence force-field calculations, using the full scope of modem digital computers, seem likely to have a profound effect upon our understanding of molecular structures and conformations in the foreseeable future. Results rivalling in accuracy those obtained by spectroscopic and diffraction techniques are already being obtained, and accurate prediction of thermodynamic properties is becoming possible. 

This approach has resolved uncertainties concerning the side-chain conformations of the epimeric 5a-pregnane-3j ,20-diols. The method involves minimizing, by variation of atomic co-ordinates, the total strain energy E obtained from the expression  

Such calculations correctly reproduced the geometry of androsterone and various simpler compounds. The results for 5a-pregnane-3/5,20)S-diol (1) indicate essentially a single rotamer (G) about the C(i 7)-C(2o bond, as previously concluded from n.m.r. data. The 20a-isomer (2) exists as a conformational equilibrium (ca. 3 1) of the two fully-staggered forms (E) and (F), and not in the 

Side-chain conformations recently inferred from n.m.r. data for the 5a,17a-pregnan-20-ols (3) must now be regarded with suspicion. The fully-staggered conformation (A) proposed for the 20j9-isomer seems unlikely to be challenged, but the suggested twisted conformation (B) of the 20a-ol may have to give way to 

The supposition of a large barrier to rotation about the C(i7)-C(20) bond, in pregnanes with C-20 tetrahedrally substituted, is said to be supported by the isolation of two distinct rotamers of the compound (5), when the 20-acetal 

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This chapter is divided into two paits. The first, and major, portion is devoted to caibohydrate structure. You will see how the principles of stereochemistry and conformational analysis combine to aid our understanding of this complex subject. The remainder of the chapter describes chemical reactions of caibohydrates. Most of these reactions aie simply extensions of what you have aheady leained concerning alcohols, aldehydes, ketones, and acetals. 

HASSEL, ODD (1897-1981), A Norwegian chemist who won the Nobel pnze for chemistry in I969 with Derek Barton for their contributions to the development of the concept of conformation and its application in chemistry. A great deal of his work was concerned with Using X-ray and electron differentiation methods ol cry stal and molecular structures. He also researched stereochemistry and conformational analysis. His education and leadline career were in his homeland. 

The partially hydrogenated ring of dihydtocorannulene constitutes a 1,3-cyclo-hexadiene ring, a system that has been well-studied with respect to its geometry and the conformational preferences of substituents. However, the curvature of the corannulene surface introduces an additional stereochemical factor that makes the conformational analysis especially interesting. 1,3-Cyclohexadiene (23) and 9,10-dihydrophenanthrene (24) serve as models they are structurally similar systems, and their stereochemistry and conformational preferences are well documented in the literature. In both cases, the reduced ring adopts a nonplanar, semi-chair conformation of symmetry. 

The relative stereostructure of 9-acetyl-7-hydroxy-l,2-dimethyl-7-meth-oxycarbonyl-4-phenyl-6-oxo-l, 4,7,8-tetrahydro-6/7-pyrido[l, 2-u]pyri-midine-3-carboxylate 122 was justified by an X-ray diffraction analysis (97JOC3109). The stereochemistry and solid state structure of racemic trans-6,9-//-l, 6-dimethyl-9 z-ethoxy-9-hydroxy-4-oxo-l,6,7,8,9,9 z-hexahydro-4//-pyrido[l,2- z]pyrimidine-3-carboxylate (123), adopting a cw-fused conformation, were determined by X-ray investigations (97H(45)2175). 

Elucidation of the stereostructure - configuration and conformation - is the next step in structural analysis. Three main parameters are used to elucidate the stereochemistry. Scalar coupling constants (mainly vicinal couplings) provide informa-hon about dihedral bond angles within a structure. Another way to obtain this information is the use of cross-correlated relaxation (CCR), but this is rarely used for drug or drug-like molecules. 

In the 1,2,3-trioxolane series the special interest in structural data arises from questions connected with the mechanism and stereochemistry of the ozonolysis reaction (cf. Section 4.33.3.1.1). Compounds of this type, owing to their extreme instability, are difficult to investigate by conventional experimental methods, and theoretical approaches utilizing conformational analysis are of particular importance. 

There exist two simple rationales to explain the observed direction of the dia-stereoselective bond activation in 7/Fe+, i.e., more pronounced loss of H2 from 7a/Fe+ in comparison to 7b/Fe+. At first, one can safely assume that the reaction proceeds via insertion of the docked Fe+ in a terminal C-H bond to form a six-membered ring. Depending on the relative stereochemistry at C(3) and C(4), the eliminations of H2 and HD, respectively, therefore involve quasi-axial or quasi-equatorial orientations of the methyl substituents in the intermediates eq- and ax-lOa of course, similar considerations apply to the associated transition structures (TSs). By analogy to conventional arguments of conformational analysis, an equatorial position of the methyl group is assumed to be preferred, thereby accounting for the experimentally observed H2/HD ratios. Thus, for the stereoisomer shown in Scheme 8, both the KIE and the equatorial position of the methyl substituent favor loss of H2, whereas the SE favors loss of HD from 7b/Fe+. However, for the latter this path is impeded by the operation of a kinetic isotope effect that slows down activation of a C-D bond. Secondly, one arrives at... 

Elucidation of the carbon framework of natural products often yields substantial information about the three-dimensional structure at the same time, but if there are remaining questions on the stereochemistry of chiral centers or other factors affecting the three-dimensional structure, these can usually be resolved from NOESY svectra and/or an analysis of coupling constants. We will return to the taxol example later in Section 2.2 when describing conformational analysis. 

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