Regio-, Enantio-, and Diastereo-selective Aldol Reactions

Regio-, Enantio-, and Diastereo-selective Aldol Reactions 

Other reviews deal with aldol additions of group 1 and 2 enolates,103 direct catalytic asymmetric aldol reactions catalysed by chiral metal complexes,104 the exploitation of multi-point recognition in catalytic asymmetric aldols,105 and recent progress in asymmetric organocatalysis of aldol, Mannich, Michael, and other reactions.106 

Hartree-Fock and density functional theory (DFT) calculations have been used to probe the enantioselectivity of the direct aldol reaction of acetone and 2,2-dimethyl-propanal, catalysed by (S)-proline, in DMSO solution.107 

Carefully matched acid and base catalysis has been used to select the pyrrolidine-p-nitrophenol combination as an efficient organocatalyst for direct aldol reactions.108 

Direct intermolecular aldol reactions, catalysed by proline, between tetrahydro-4H-thiopyranone (25) and racemic aldehydes exhibit enantiotopic group selectivity and dynamic kinetic resolution, with ee% of 98% in some cases.109 

Formyl hydrogen bonds, in which die C—H bond of a formyl group acts as an acceptor (typically to oxygen), have recently been identified in Lewis acid-catalysed reactions of aldehydes.523 An X-ray crystal structure of such a complex has been reported.5213 This type of hydrogen bond is now suggested as a likely organizing stereochemical element in a variety of enantioselective aldol, allylation, and Diels-Alder reactions catalysed by Lewis acids reported in the literature.520 Further examples of such reactions are also discussed.53 

Asymmetric aldol additions of geometrically defined trichlorosilyl enolates of ketones to aliphatic and aromatic aldehydes have been carried out uncatalysed, and with a chiral phosphoramide as Lewis base promoter.54 Significant differences in rates and diastereoselectivities are interpreted in terms of the changeover from a boat-like transition state, with pentacoordinate siliconate, to a chair-like transition state with hexacoordination. 

5-Asymmetric induction is reported in the addition of enolates of methyl ketones to aldehydes.55 Double stereo-differentiation—in which simultaneous 1,3-control can be obtained hi the aldehyde moiety—is shown to be achievable with proper selection of the aldol type. 

7r-Stacking interactions in the transition state are one factor suggested for the highly diastereoselective synthesis of syn- and a 7 -aldols from the reaction of an arylsulfonamidoindanyl titanium enolate with bidentate aldehydes.56 

A straightforward method for aldolizing unsymmetrical ketones on the more hindered side involves the use of catalytic titanium(lV) chloride in toluene at room temperature. For examples using acyclic and cyclic ketones, and linear, branched, and aromatic aldehydes, the regioselectivity varied from 7 1 to 99 1, while the symanti ratios were moderate to good, and yields were in the range 62-91%. In contrast to other methods, base is not required, and the ketone can be used as is (i.e. the silyl enol ether is not required). 

Silyl enol ether (38), derived from D-glucose, undergoes a useful one-carbon extension by way of an asymmetric aldol reaction the conditions of the indium(ni) catalysis in water are very convenient. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and 

The lithium enolate of di-i-butyl malonate undergoes a stereoselective aldol reaction with Qf-alkoxyaldehydes to give anft-l,2-diol derivatives in the case of the highly hindered 2-trityloxypropanal, the stereochemistry is reversed. 

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The Exterior Frontier Orbital Extension (EFOE) model has been applied to predict r-facial selectivity in nucleophilic additions to imines and iminium ions of the cyclohexanone, tropinone, and adamantan-2-one systems." A review of the EFOE model," and other references to its use, are described later under Regio-, Enantio-, and Diastereo-selective Aldol Reactions. 

A catalytic enantioselective vinylogous Reformatsky-aldol reaction exploits iridium catalysis, gives excellent regio-, diastereo-, and enantio-selectivities, and can be carried out with approximately equal facility from the alcohol or aldehyde oxidation level. 

The first asymmetric direct aldol of 1,2-diketones and ketones, to give 2-hydroxy-1,4-diketones, has been reported.100 L-Proline derivatives give high regio-, diastereo-, and enantio-selectivity in the reaction of l-arylpropane-l,2-diones with simple ketones. 

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