Stereoselectivity torsional effects

Houk and co-workers examined the role of torsional effects in the stereoselectivity of enolate alkylation in five-membered rings, and their interpretation can explain the preference for C(5) alkylation syn to the 2-methyl group in trans-2,3-dimethylcyclopentanone.59... 

Torsional effects are important in cyclic systems. A PM3 study of the high stereoselectivity of compounds 4a-d found torsional effects to be the major difference between the diastereomeric TSs.81 The computed TSs for 4a are shown in Figure 12.10. The structures all show similar stereoselectivity, regardless of the presence and nature of a 3-substituent. 

In an investigation of the stereoselectivity of nucleophilic addition to larger ring systems, ethyl-, vinyl-, and ethynyl-lithium and -Grignard reagents have been added to 2-(3 -phenylpropyl)cycloheptanone (69). In all cases, the predominant product is the cw-alcohol, and calculations have been used to identify the steric and torsional effects in the transition state that favour this stereochemistry. 

Stereoselectivity in the epoxidation of monocyclic or fused cyclohexene derivatives in a halfchair conformation is governed by steric repulsions torsional effects are mostly negligible. One exception is the epoxidation of sterpurene (1), which forms a single epoxide 2 structural assignment of this epoxide was not attempted171. 

Felkin identified torsional effects in cyclohexanone reductions that accounted for the observed stereoselectivity. Minimization of these torsional effects, in the absence of steric hindrance, led to the predominance of axial attack (equation 2).- Recently, a computational approach has provided quantitative support for this model.- The eclipsing interactions between the incoming nucleophile and the bonds a to... 

Rondan, N. G., Paddon-Row, M. N., CarameUa, R, Houk, K. A. (1981). Nonplanar Alkenes and Carbonyls A Molecular Distortion which Parallels Addition Steroselectivity. J. Am. Chem. Soc., 103,2436. Ess, D. H. Houk, K. N. (2007). Distortion/Interaction Energy Control of 1,3-Dipolar Cycloaddition Reactivity. J. Am Chem. Soc., 129, 10646-10647. Lopez, S. A., Houk, K. N. (2013). Alkene Distortion Energies and Torsional Effects Control Reactivities, and Stereoselectivities of Azide Cycloadditions to Norbomene and Substituted Norbomenes. J. Org. Chem., 78(5), 1778-1783. Hong, X., Liang, Y, Griffith, A. K., et al. (2013). Distortion-Accelerated Cycloadditions and Strain-Release-Promoted Cycloreversions in the Organocatalytic Carbonyl-Olefin Metathesis. Chem. Sci., 5(2), 471-475. 

Scheme 4. Torsional effects of the glycosyl donor on stereoselectivity.

An alternative interpretation is that the carbonyl group rr-antibonding orbital, which acts as the LUMO in the reaction, has a greater density on the axial face.118 At the present time the importance of such orbital effects is not entirely clear. Most of the stereoselectivities that have been reported can be reconciled with torsional and steric effects being dominant.119... 

The interpretation of the basis for this stereoselectivity can be made in terms of the steric, torsional, and stereoelectronic effects discussed in connection with reduction by hydrides. It has been found that crown ethers enhance stereoselectivity in the reaction of both Grignard reagents and alkyllithium compounds.119 This effect was attributed to decreased electrophilicity of the metal cations in the presence of the crown ether. The attenuated reactivity leads to greater selectivity. 

There is one report that showed how torsional, involving allylic CH bonds and steric effects but not orbital distortions, provide an explanation for the stereoselectivity of pyrrolidinone enolate alkylations. A prediction was... 

The orbital tilting argument implies that the size of the dienophile should have no influence on the diastereoselectivity, hence variations in stereoselectivity with different dienophiles could not be explained. More recently an explanation based on torsional and steric effects has been advanced that permits predictions of stereoselectivities for as yet unstudied cases. A computational model has also been developed to provide semiquantitative predictions of stereoisomer ratios in reactions of substituted species118. 

Recent studies have suggested that coordination with a lithium cation may be responsible for the stereochemical outcome in Meyers-type enolate alkylations . In fact, the hypothesis that the diastereofacial selectivity observed in these reactions might result from specific interactions with a solvated lithium cation was already proposed in 1990 . Nevertheless, the potential influence exerted by solvation and lithium cation coordination was not supported by a series of experimental results reported by Romo and Meyers , who stated that it would appear that neither the aggregation state of the enolate nor the coordination sphere about lithium plays a major role in the observed selectivity. This contention is further supported by recent theoretical studies of Ando , who carried out a detailed analysis of the potential influence of solvated lithium cation on the stereoselective alkylation of enolates of y-butyrolactones. The results showed conclusively that complexation with lithium cation had a negligible effect on the relative stability of the transition states leading to exo and endo addition. The stereochemical outcome in the alkylation of y -butyrolactones is determined by the different torsional strain in the endo and exo TSs. 

This relatively straightforward combination of torsional and steric effects as the source of stereoselectivity becomes more complicated when polar substituents are introduced into the picture. Polar effects are discussed in Topic 2.4. 

It is also important to note that several factors influence both the stereoselectivity of hydrogen exchange and enolate formation in base-promoted reactions. Houk, Ando and co-workers found that differing conju-gative stabilization by CH p-orbital overlap does not directly influence stereoselectivity.205 Steric effects only dominate is exceptionally crowded transition structures, but torsional strain involving vicinal bonds contributes significantly to the stereoselectivity of all cases studied. 

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