Stereochemistry conformationally mobile

Reactions of propynyl alcohols and their derivatives with metal hydrides, such as lithium aluminum hydride, constitute an important regio- and stereoselective approach to chiral allenes of high enantiomeric purity63-69. Formally, a hydride is introduced by net 1,3-substitution, however, when leaving groups such as amines, sulfonates and tetrahydropyranyloxy are involved, it has been established that the reaction proceeds by successive trans-1,2-addition and preferred anti-1,2-elimination reactions. The conformational mobility of the intermediate results in both syn- and ami- 1,2-elimination, which leads to competition between overall syn- and anti-1,3-substitution and hence lower optical yields and/or a reversal of the stereochemistry. 

The 3-benzyl-6-phenyl-l,4-diazepine-2,5-diones 21 and 22 exhibited complex NMR spectra indicative of limited conformational mobility in which the ring geometry is dictated by the two air-amide elements, which define individual planes <2003MI187>. Based on an analysis of the nuclear Overhauser effect (NOE) between protons on the ring, the preferred boat conformation in solution projects the 3-benzyl moiety pseudoequatorially with the 6-phenyl substituent disposed axially or equatorially, dependent upon the relative stereochemistry. This conformation is also observed in the solid state for the air-substituted isomer 21 in which the phenyl group is axial. In contrast, the bis-phenyl derivative 23 is conformationally mobile based on the H NMR spectmm where resonances were not resolved. 

Much of the chemistry of reserpine and its congeners becomes clear and compelling if the conformational mobility of the CDE rings of its 3-epialloyohimbane nucleus is remembered (134). It was the gradual realization of this property and how to take advantage of it that led to the very elegant experiments which established the complete relative stereochemistry of the reserpine molecule (135, 136). Not unexpectedly, it is found that reserpine under normal conditions prefers the cis-trans-cis CDE conformation (137, 138), but this does not prevent it from assuming the trans-trans-cis shape to make possible the formation of reserpic acid lactone (125) and the quaternary salt III (136). 

Stereochemistry for the cis-fused series in this system is readily specified by exo and endo. While there are two, relatively conformationally mobile rings present, this sytem is especially well behaved in terms of shift additivity. No significant quantity of data was found for trans-fused bicyclo[3.3.0]octanes. 

The stereochemistry of enolisation has been mostly examined in cyclic systems where the relative positions of the enolisable hydrogen atoms are fixed. Over the last decade, these studies have benefited from important improvements in the experimental methods, namely mass spectrometry and nmr spectroscopy. Of great interest is the comparison of the relative mobilities of diastereoisomeric axial and equatorial protons from ketones in the cyclohexane series. Indeed, since axial a(C—H) bonds of rigid cyclohexanones are closer than equatorial a(C—H) bonds to the desirable conformation in which the breaking C—H bond is perpendicular to the direction of the C=0 bond, it can be expected that the axial a(C—H) bond-breaking is easier than that of the equatorial one. 

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