Stereoselectivity Steric effects

The more stable the LUMO, the stronger is the interaction with the HOMO of the approaching nucleophile. The observed (Cram s rule) stereoselectivity is then a combination of stereoelectronic effects ftiat establish a preference for a perpendicular substituent and a steric effect that establishes a preference for the nucleophile to approach from the direction occupied by the smallest substituent. 

Extensive studies (/ /) of such SE- reactions of allylsilanes have demonstrated a high degree of anti stereoselectivity with the majority of electrophiles, except in cases where steric effects play a dominant role. 

The Z-selectivity seems to be associated primarily with reduced basicity of the amide anion. It is postulated that the shift to Z-stereoselectivity is the result of a looser TS, in which the steric effects of the chair TS are reduced. 

The introduction of an alkyl substituent at the a-carbon in the enolate enhances stereoselectivity somewhat. This is attributed to a steric effect in the enolate minimize steric interaction with the solvated oxygen, the alkyl group is d t °... 

Thus we see that steric effects, chelation, and the polar effects of a- and (3-substituents can influence the facial selectivity in aldol additions to aldehydes. These relationships provide a starting point for prediction and analysis of stereoselectivity... 

The stereoselectivity of the Wittig reaction is believed to be the result of steric effects that develop as the ylide and carbonyl compound approach one another. The three phenyl substituents on phosphorus impose large steric demands that govern the formation of the diastereomeric adducts.240 Reactions of unstabilized phosphoranes are believed to proceed through an early TS, and steric factors usually make these reactions selective for the d.v-alkcnc.241 Ultimately, however, the precise stereoselectivity is dependent on a number of variables, including reactant structure, the base used for ylide formation, the presence of other ions, solvent, and temperature.242... 

There can be significant differences in the rates of elimination of the stereoiso-meric (3-hydroxysilanes. Van Vranken and co-workers took advantage of such a situation to achieve a highly stereoselective synthesis of a styryl terpene. (The lithiated reactant is prepared by reductive lithiation see p. 625). The syn adduct decomposes rapidly at -78° C but because of steric effects, the anti isomer remains unreacted. Acidification then promotes anti elimination to the desired /i-isomer.275... 

Substituted indenes provide other examples of substituent directive effects. Over Pd-alumina, the indenols 6a-c show both cis stereoselectivity and a syn directive effect. The directive effect is reinforced by steric effects as the alkyl group becomes larger.7... 

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... 

Similarly, the 2,8,10-triene 3a gives a mixture of four isomers, but introduction of a TMS group as in 3b gives a single stereoisomer in 89% yield. The reason for the improved stereoselectivity is that the steric effect introduced by the TMS substituent favors a single conformer. 

Ketenes are especially reactive in [2 + 2] cycloadditions and an important reason is that they offer a low degree of steric interaction in the TS. Another reason is the electrophilic character of the ketene LUMO. As discussed in Section 10.4 of Part A, there is a large net charge transfer from the alkene to the ketene, with bond formation at the ketene sp carbon mnning ahead of that at the sp2 carbon. The stereoselectivity of ketene cycloadditions is the result of steric effects in the TS. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis, which is the stereochemistry usually observed in these reactions. 

Similarly to peroxycarboxylic acids, DMDO is subject to cis or syn stereoselectivity by hydroxy and other hydrogen-bonding functional groups.93 However a study of several substituted cyclohexenes in CH3CN —H20 suggested a dominance by steric effects. In particular, the hydroxy groups in cyclohex-2-enol and... 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

The use of ethanol as an achiral auxiliary gave the adduct 53 with 55% ee, while neopentyl alcohol and methanol gave 96 and 87% ee, respectively. These results suggested that the achiral alcohol might exert a steric effect on the stereoselectivity. However, the increase in enantioselectivity from 55% to about 96% when 2,2,2-trifluoroethanol (TFE) was used instead of ethanol indicates a possible significant inductive effect also. Good enantioselectivities were also obtained with carboxylic acids and phenols. 

The solvent has no influence on the stereoselectivity of bromine addition to alkenes (Rolston and Yates, 1969b), but it could have some effect on the regioselectivity, since this latter depends not only on polar but also on steric effects. Obviously, it modified the chemoselectivity. For example, in acetic acid Rolston and Yates find that 2-butenes give 98% dibromides and 2% solvent-incorporated products whereas, in methanol with 0.2 m NaBr, dibromide is only about 40% and methoxybromide 60%. There are no extensive data, however, on the solvent effects on the regio- and chemoselectivity which would allow reliable predictions. 

Although alkylidenecarbenes (R)2C=C and carbenoids 22-24 have an ip-hybridized carbene center similar to that of vinylidenecarbenes, the reactivity will be subject to the steric influence of substituents R3 and R4 because its location is closer to the carbene center than vinylidenecarbenes (Scheme 11). The steric effect was exerted in the reactions of 2-methylpropenylidene 22 generated from 2-methyl-1-chloropropene and butyllithium (BuLi) (Scheme ll).22 23 The results are summarized in Table 5. A more detailed discussion on the stereoselectivity of this reaction will be revisited in Section HI. A. 

An interesting stereochemical profile of this cyclization is that in the five-membered product structures, substituents PhS and OH groups are placed cis to each other, whereas in six-membered products the placement is trans (Table 6, entry 7). The cis selectivity in the five-membered ring systems is not affected by a and fi-substituents of the alkoxides (entries 2, 3 and 4), indicating that the steric effect is not the dominant factor. Instead, interaction between the oxido and carbene center composes a five- (or seven-) membered transition state 28, which allows the carbene to abstract the nearest quasi axial hydrogen as a hydride to produce a carbonyl intermediate 29, leading to the cyclization products 27 and 30 (Scheme 13, Eq. 1). Similarly, the stereoselective stepwise cyclization of cis- and rra s-2-(3,3-dithiopropyl)cyclohexanol to 2-phenylthio-... 

In the design of chiral sulfides for sulfur ylide-mediated asymmetric epoxidation of aldehydes, two factors are important. First, a single sulfur ylide should be produced. Otherwise, the diastereomeric sulfur ylides may react with aldehydes in different ways and thus cause a drop in stereoselectivity. This may be achieved by choosing a rigid cyclic structure to make one of the lone pairs more accessible than the other. Second, the structure should be amenable to structural modification in order to study the electronic and steric effects of the sulfur on the enantioselectivity of the epoxidation reaction. 

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... 

Additions to cyclopentenones.5 Conjugate addition of cuprates to 4-substi-tuted cyclopentenones can show moderate to high trarw-diastereoselection, which can be attributed to a steric effect. Surprisingly, addition of lithium dimethylcuprate to (R)-5-methoxy-2-cyclopentenone also shows high frans-diastereoselectivity (equation I). The stereoselectivity is decreased somewhat by addition of ClSi(CH3)3. 

A direct comparison of the stereochemical efficiency of the fragmentation reaction versus the tandem reaction (Scheme 53) was studied by Porter et al. as a function of the steric effect based on the Taft parameters for different substituents [146]. In general, the tandem reactions perform better and provide higher levels of ee s than the fragmentation reactions. This effect could be due to the tinbromide by-product catalyzing a non-stereoselective process as has been uncovered by the same authors (vide supra) and by Sibi and Ji in their diastereoselective studies [147]. 

In summary, a number of effective chiral reducing agents have been developed based on the modification of LAH. Excellent results have been obtained with aryl alkyl ketones and a,p-acetylenic ketones. However, dialkyl ketones are reduced in much lower enantiomeric excess. This clearly indicates that steric effects alone do not control stereoselectivity in these reductions. Systematic studies have been carried out with the objective of designing improved reagents. A better understanding of the mechanisms and knowledge of the active species is required in order to provide more accurate models of the transition states of the key reduction steps. 

Although relatively weak, it is this last interaction that is essential for determining chiral discrimination. The superior chiral recognition achieved when ref has an aromatic side chain (Table 10) suggests that 7r-cation interactions play an important role in the stereoselectivity. Evidence for such a rr-cation interaction is observed in the CID spectra of the dimeric [A Me° ref-H]and [A -Me -ref-H] diaster-eomers, in which one ligand is an aromatic amino acid, and is supported by ab initio calculations. When an L-aromatic amino acid, such as L-phenylalanine, is used as ref, these interactions are disrupted by the side group on the a-asymmetric carbon of the L-analyte, whereas the side-chain group in the D-analyte has little steric effect on... 

The steric effects may be more pronounced in heterogeneous catalysts than in homogeneous reactions in solution. The rigid, solid surface restricts the approach of the reactants to the active centers and interaction between the reactants. The steric requirements are quite stringent when a two-point adsorption is necessary and when, in consequence, the internal motion of the adsorbed molecules is limited. In this way, the stereoselectivity of some heterogeneous catalytic reactions, for example, the hydrogenation of alkenes on metals (5) or the dehydration of alcohols on alumina and thoria (9), have been explained. 

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