Aldol reaction, self stereoselectivity

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

Scheme 7.19 Stereoselective diarylprolinols catalysed self-aldol and cross-aldol reactions of acetaldehyde.

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

The aldol reaction was first reported in 1838 when Kane described the self-condensation of acetone," and this was later termed an aldol reaction by Wurtz. Since this time, there have been numerous practical advances that have led to adoption of the aldol reaction as one of the most important carbon-carbon, bond-forming reactions. In particular, Dubois and Dubois and Heathcock et al., demonstrated that enolate geometry can influence the diastereochemical outcome of these reactions, and in the late 1970s, Heath-cock et al. also reported that a chiral center on the ketone can control the absolute stereoselectivity of these reactions. This later finding was further developed and... 

The attractiveness of this enzyme resides in its potential to catalyze self-aldol, cross-aldol, and cascade aldol reactions (for a review, see Ref. 87). DERA generally presents a stereoselectivity toward the aldehyde acceptor and catalyzes often the conversion of only one enantiomer. However, it often requires the presence of phosphorylated aldehyde acceptors. The most recent efforts were thus focused on directed evolution of the enzyme in view to improve the scope toward unphosphorylated substrates. DeSantis et al., in particular, performed some saturation site-directed mutagenesis in view to improve the reactivity for the unnatural D-glyceraldehyde substrate 37 for the synthesis of 2-deoxy-D-ribose 38. They reached a 2.5-fold improvement in DERA activity toward the unphosphorylated aldehyde with the mutant S238D (Scheme 28.18). 

The reaction of silyl enol ethers and acetals to form aldol products has been accomplished by the use of trimethylsilyl trifluoromethanesulphonate as catalyst [equation (47)]. No polycondensation, self-condensation, or enone products were observed. When chiral centres were formed, there was a high stereoselectivity for the erythro-adducXs, irrespective of the geometry of the silyl enol ether,... 

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