1.3- Diaxial interaction, substituted

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

On the other hand, Beckwith rules [22] are useful guidelines for predicting the stereoselectivity in the cyclisation of substituted hexenyl radicals i) 1- or 3-substituted radicals give preferentially cij-disubstituted cyclopentane derivatives and ii) 2- or 4-substituted radicals give mainly rrans-disubstituted derivatives. These rules can be explained in terms of 1,3-diaxial interactions present in a chair-like transition state. Some examples which demonstrate such an effect are [19b] ... 

Also, 2,2,3,6-tetra-Me-5-Cl-l,3-dioxan, due to 1,3-diaxial interactions, prefers the 2,5-twist-boat form (76BSF563) the same conformation was reported for the stereoisomeric 2-Ph-4-(2 -furyl)-5-N02-6-Me-l,3-dioxanes and 2,2,6-tri-Me-4-(2 -furyl)-5-N02-l,3-dioxanes (75MI2), for 2-Alk-2,4,4-tri-Me-l,3-dioxane derivatives (78KGS1172) and for the cis isomers of 2-OR-4-Me-l,3-dioxane (R = Et, nPr, /Pr, nBu, n-CsHn) (81DOK116). The corresponding trans isomers adopt the chair conformation with di-eq substitution. The isomeric 2-OR-4,4-di-Me-l,3-dioxanes also prefer the 1,4-twisted-boat conformer (81DOK116). 

The axial-directing effect of the C-l substituent depends on the total stereochemistry and mode of substitution and falls roughly in the order of polarity of the substituents. The axial-directing effects of the C-l substituent is augmented when acetates at the other ring positions are replaced by benzoates possibly there are attractive syn-diaxial interactions between benzoate groups. 

The ketone enolate A of Figure 13.47 is generated in a Z-selective fashion (as we saw in Figure 13.15). The bulky and branched enolate substituent destabilizes the Zimmerman-Traxler transition state C by way of the discussed 1,3-diaxial interaction, while the transition state structure B is not affected. Hence, the aldol addition of enolate A occurs almost exclusively via transition state B, and the -configured aldol adducts D (Figure 13.47) are formed with a near-perfect simple diastereoselectivity. The acidic workup converts the initially formed trimethysilyloxy-substituted aldol adducts into the hydroxylated aldol adducts. 

Determination of the relative stability of many other substituted cyclohexane stereoisomers can be done in a similar manner. However, examples in which there are complications due to 1,3-diaxial interactions between groups or examples in which the rings are substituted with polar groups, whose dipoles interact, are much more complicated. Recently, computer programs have been developed that enable the most stable conformation of many molecules, cyclic and noncyclic, to be determined. These molecular mechanics calculations can provide the most stable shape of even quite complex molecules. 

We are now in a position to interpret the reactions of steroid amines, particularly with respect to the dominant retention of configuration in substitution and the considerable or exclusive elimination of axial amino groups. Shoppee has pointed out [3] that the ratio, elimination/substitution, for a series of axial amines follows the order expected on the basis of steric hindrance to the formation of the axial alcohol. In simple mono- and bi-cyclic systems, as well as in acycUc amines, the proportion of olefinic products is far lower (often ca. 30% than for many steroids. This agrees with the concept that very high yields of olefins result from steric frustration of cis substitution. A semi-quantitative correlation of olefin yield with the number and nature of the sy -diaxial interactions at the reaction centre is even possible (Table 27). 

The relative stabilities of axial and equatorial substituents are revealed in an interesting set of data for equilibration of the bromo-substituents in 5a,6j5-dibromocholestane 3) and its 3 -substituted derivative (5) [40]. In the dibromide (3) not only do the bromine atoms occupy axial positions and so suffer considerable steric compression, but the structure is further destabilised by the syw-diaxial interaction between the axial bromine at C(6> and the angular methyl group at C(io). A solution of this dibromide exhibits mutarotation and... 

Conformational effects also play an important role in determining IMDA diastereoselectivity. For example, trienes like (49) and (50) with two sp hybridized atoms within the connecting chain cyclize preferentially to ci s-fused rather than the trans-fuscd products that would be expected based tm the presence of the C(8)-methyl substituent (Figure 15). The benzo fusion forces the bridging chain to adopt boat-like conformations in the transition states, and the 1,3-diaxial interactions that the C(8)-methyl ordinarily experiences in the cif-fused, chair-like transition state are thus relieved (refer to Figure 12). The preferential formation of the cif-fused diastereomer may then be the consequence of a favored skew butene rotamer at C(6)—C(7) in (51) compared with a less favorable gauche butene rotamer at this position in the trans-fused transition state. This effect is discussed in more detail in Section 4.4.3.2 concerning relative diastereoselection in the IMDA reactions of substituted decatrienones. 

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