Enolates reaction transition states

However, this is not so easy without the tertiary structure of the enzyme. The possible clues are the homology search with functionally resembling enzymes and computer simulation of the tert-structure of the enzyme. The characteristic features of AMDase are (i) the reaction proceeds via an enolate-type transition state, (ii) the cysteine residue plays an essential role and (iii) the reaction involves an inversion of configuration on the a-carbon of the carboxyl group. 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

Gennari, C., Hewkin, C. T., Molinari, F., Bemardi, A., Comotti, A., Goodman, J. M., Paterson, I. The rational design of highly stereoselective boron enolates using transition-state computer modeling a novel, asymmetric anti aldol reaction for ketones. J. Org. Chem. 1992, 57, 5173-5177. 

The stereochemical outcome of the reaction can be explained by comparison of the relevant transition states of the rearrangement (Scheme 5.2.47). If secondary propargylic alcohols are used, the rearrangement preferentially proceeds via transition state A, where the substituent is oriented in an equatorial position, in comparison to B with in an axial position (Scheme 5.2.47). As expected, the selectivity increases as the size of R increases, because of stronger sterical interactions of the axial R and the chelated enolate in transition state B. 

Scheme 4.65 Masamune s aldol reaction mediated by the Cj-symmetric borolane as a chiral controller in enolates 283. Transition state model for the propionate and acetate aldol additions 286 and 287, respectively.

Distinct from the classical aminocatalysis, Tsogoeva and co-workers documented the first example of enol activation in the typical Mannich-type reaction catalyzed by primary amine-thiourea 63 (Scheme 5.48) [76], The isotope experiments exclude the involvement of a covalent enamine/iminium intermediate and theoretical calculation proves an enol type transition state in this reaction. 

In 1981, Wynberg and Hiemstra already identified the unmodified cinchona alkaloids as chiral bifunctional catalysts for enantioselective conjugate additions to cycloalkenones [3]. They proposed that the OH group of cinchonine would act as a hydrogen bond donor site and stabilize the enolate-Uke transition state of the conjugate addition reaction (Scheme 6.1). 

Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

There has been little study of the stereoselectivity of the reaction under acidic conditions. In the absence of a coordinating Lewis acid, there is no preference for a cyclic transition state. When regioisomeric enols are possible, acid-catalyzed reactions tend to proceed through the more substituted of the enols. This reflects the predominance of this enol. (See Section 7.2.)... 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

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