Enolate substituents, steric influence

Steric influences of enolate substituents (Ri R2) play a dominent role in kinetic diastereoselection. 

The steric influence of the enolate substituents Ri and Rj plays a dominant role in the alteration of kinetic stereoselectivity, whereas the aldehyde ligand appears to contribute to a minor extent. Good correlation between enolate geometry and aldol stereochemistry is possible when Rj is sterically demanding and Rj.is sterically subordinate (Rj = methyl or n-alkyl). In this case dominant path A stereoselection is observed. When R2 becomes sterically demanding (R2 = t-Bu) path B stereoselection is observed and becomes dominant. 

The E/Z substrate-dependent absolute stereochemistry and the steric influence of tin-substituents on the enantioselectivity observed in these reactions suggest that the mechanism is essentially different from that of sily 1 enol ethers. Although the detailed stereochemical course is not ascertained, it is possible that the protonation may occur via a two chlorine-bridged intermediate involving allyltrimethyltin and LBA. 

For cyclopropanations with ethyl diazoacetate, a rather weak influence of the olefin structure has been noted 59 60, (Table 7). The preference for the sterically less crowded cyclopropane is more marked for 1,2-disubstituted than for 1,1-disubstituted olefins. The influence of steric factors becomes obvious from the fact that the ratio Z-36/E-36, obtained upon cyclopropanation of silyl enol ethers 35, parallels Knorr s 90> empirical substituent parameter A.d of the group R 60). These ZjE ratios, however, do not represent the thermodynamic equilibrium of both diastereomers. 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

Alkylation of enolates, such as 4, produces products that are consistent with the preferred approach of the electrophile from either the least hindered face of an T -cnolate of conformation C or the least hindered face of a Z-enolate of conformation D88. Steric factors influencing approach of the electrophile appear to be similar in both of these models since the steric bulk of the hydridotris(3,5-dimethyl-l-pyrazolyl)borate ligand and the phosphite are both considerable any stereoelectronic and dipolar factors due to interaction of the enolate ligand with the carbon monoxide ligand would likely be similar for both geometries. The is-enolate geometry C appears to benefit from reduced steric interactions between the R substituent and the metal ligands. 

A convenient enantioselective catalytic oxidation of a variety of differently substituted, cyclic (E) and acyclic (Z)-enol phosphates with (salen)manganese(III) complex has been reported. The influence of electronic and steric effects of the enol phosphate substituents on the stereoselectivity of oxidation has been studied.50... 

This copper-catalysed phenylation reaction with triphenylbismuth diacetate is not limited to glycols as it has been extended to the arylation of other hydroxylic substrates such as phenols and enols.27 Variously substituted phenolic substrates have been selectively 0-phenylated under very mild neutral conditions (1 to 24 hours at room temperature in methylene dichloiide). The best yields were obtained with metallic copper used as the catalyst. The electronic nature of the substituents of the phenol did not influence the yields (4-nitro, 97% 3,5-dimethoxy, 90%). Only steric hindrance of the 2- and 6-substituents interfered with the reactivity. Thus only 26% of the 0-phenyl ether was obtained in the phenylation of 2,4-di-rerr-butylphenol, and no phenylation took place in the case of 2,4,6-tri-rer/-... 

The influence of adjacent stereogenic centers on the diastereoselectivity of the cyclization is addressed in entries 4 13. Alkyl or aryl substituents in the homoallylic position lead only to a moderate preference for the 4,6-m-product (Table 14, entries 4 7)9. Surprisingly, the triflu-oromethyl group exerts complete stereocontrol, which is attributed to its steric and additional electronic repulsion of the enolate moiety in the cyclization transition state (for a detailed discussion see the preceding section). The intramolecular reactions of the bissulfone derivatives (Table 14, entries 11 -14)19 feature a contrathermodynamic production of mainly civ-substituted vinylcyclopentanes. Epimerization of the zr-allyl complex is faster than cyclization, so that an equilibrium between the different isomeric zwitterions is established. Due to unfavorable steric interactions with the substituent R, palladium is preferentially located irunx to R in the cyclization transition state favoring the m-product. The use of toluene, tetrahydrofuran, and acetonitrile as solvents results in poorer diastereoselectivities. Some restrictions apply to the kind of nucleophile employed, thus 2-oxo esters may only give the 0-alkylated product (cf. Table 12)2 19-20. 

Michael reactions. The ester group exerts profound influences on the steric course of the reaction. Thus diastereocontrol is possible by changing solvent, enolate counterion, and activating group at the a-carbon of the acceptor. The phenylthio group increases reactivity, but electron-withdrawing substituents at this position tend to erode the diastereoselectivity. Temperature effects are also dramatic. 

In addition to steric interactions, other structural features may influence the stereoselectivity of aldol condensations. One such factor is chelation by a donor substituent. Several )8-alkoxyaldehydes show a preference for syn aldol products on reaction with Z-enolates. A chelated transition state can account for the observed stereochemistry. The chelated aldehyde is most easily approached from the face opposite the methyl and R substituents. 

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form -ketoalcohols, have been promoted by new chiral lanthanide-containing complexes and a chiral Fe(II)-bipyridine complex with 0 outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselec-tivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the a-carbon of the silyl ether, and the aldehyde. The relative steric effects of the Lewis acid and 0 trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with /-unsaturated a-ketoesters has been reported for the first time and studied extensively. ... 

The induced diastereoselectivity in a Paterno-Biichi reaction resulting from a stereogenic center in the alkene part was recently described by Bach and co-workers in the photocycloaddition of chiral silylenol ethers 67 with benzaldehyde 18. The substituents, R, at the stereogenic center were varied in order to evaluate the influence of steric bulk and possible electronic effects. In accord with the 1,3-aUyhc strain model, the facial diastereoselectivity was at a maximum with large (R = t-Bu, SiMejPh) and polar (R = OMe) substituents at the y-position of silyl enol ether (diastereomeric ratio of oxetanes 68 > 95 5). 

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