Severe 1,3-diaxial

It is possible to change the stereochemical result of the alkylation by replacing the 3-ketal protecting group with a A -enol ether. This structural change eliminates a severe 1,3-diaxial interaction to a-face methylation and results in the formation of the 5a-methyl steroid (15) in about 35% yield, ... 

The stereoselectivity of these reactions has been interpreted in terms of chair-like six-membered ring transition states in which the substituents a to tin adopt an axial position, possibly because of steric and anomeric effects. The cc-substituted (Z)-isomers are less reactive because the axial preference of the a-substituent would lead to severe 1,3-diaxial interactions17. 

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

Other examples of the formation of six-membered rings by means of an intramolecular alkylation of an ester enolate are given in Table 7. Entry 6, i.e., stereoselective transformation of the epoxy ester into the cyclohexane derivative, should be discussed briefly as a representative for the other cases. The probable reason for the unexpectedly high selectivity i.e., the nonappearance of the diastereomer 8, can be demonstrated by the two transition-state-like conformations 9 and 10. 9 displays a very severe 1,3-diaxial interaction in comparison to 10, thus, formation of the diastereomer 7 from conformation 10 is highly favored113. 

The stereoselectivity of the second and key Michael-type conjugate addition reaction can be rationalized as follows. The conformation of 63 will be restricted to 63-A due to A(l 3) strain between the N-methoxycarbonyl and w-propyl groups in 63-B. Attack of the vinyl anion from the stereoelectronically favored a-axial direction provides the adduct 64 exclusively. It is noteworthy that the stereochemical course of the above reaction is controlled by the stereoelectronic effect in spite of severe 1,3-diaxial steric repulsion between the axial ethyl group at the 5-position and the incoming vinyl anion. This remarkable stereoselectivity can be also explained by Cieplak s hypothesis[31]. On the preferred conformation 63-A, the developing a of the transition state is stabilized by the antiperiplanar donor Gc-h at the C-4 position. 

The large energy difference between conformations is due to the severe 1,3 diaxial interaction between the two methyl groups. 

Beckett and coworkers have also discovered that protonation reduced the population of the conformer with C5-axial methyl to less than 50 % of the total [5-7]. Only the conformers 5a and 5b (5a 5b = 43 57) were detected in the case of the N-ethyl salt 5. The increased interaction of the C5-axial-methyl group with the axial hydrogen atom on the nitrogen as against the electron pair orbital in 4a is considered as the primary cause for the observed shift in the conformer distribution. The conformers 5c and 5d are destabilized due to severe 1,3-diaxial interactions as shown. The conformer 5d is destabilized by A(1,2) strain as well. 

K+ as discussed above. A 2p-methyl group occupies the axial position in which it is free from interaction with the ion pair, i.e., devoid of A(1,2) interaction but in severe 1,3-diaxial interaction with the nearby angular methyl group. 

On the other hand, homoallylic alcohols containing a (Z)-vinylic silane moiety transfer the allylic group to afford ( )-l-aryl-2-alkenylsilanes (Scheme 5,18). The -selectivity would originate from the absence of severe 1,3-diaxial repulsion between the Si group and the R group in the transition state toward ( )-crotylsilane. 

In a slow but clean reaction, the seven-membered ring 142 was formed exclusively. No six-membered ring products (attack at C2) could be detected and this is very probably due to severe 1,3-diaxial O-S-interactions in both transition states (see and ) leading to a cyclohexane. 

The H s and CH3 of the sp3 hybridized C have severe 1,3-diaxial interactions with the two other axial H s. 

Finally, we compare both chair drawings and determine which one has fewer or less severe 1,3-diaxial interactions. In the first drawing, both substituents occupy axial positiorrs, but in the second drawing, both substituents occupy equatorial positions. As such, the latter is more stable, since it lacks 1,3-diaxial interactions. 

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