Prolines anti-aldol formation

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

S)-Proline-catalyzed aldol reactions involving 2-butanone afforded the products of C-C bond formation at the methyl group, the less substituted a-position of the ketone as the major regioisomers (Fig. 2.1) [6, 9]. The regioselectivity of the aldol reaction of 2-butanone was reversed using a proline amide derivative as the catalyst, as shown in Scheme 2.2 [13]. The (S)-proline-catalyzed aldol reactions of cyclohexanone and of cyclopentanone afforded both anti- and syn-products (anti syn 2 1) with moderate enantioselectivities (63-89% ee) [6]. The selectivity... 

This proline-catalysed aldol proceeds via initial formation of an enamine with the donor component. This enamine then reacts with the re-face of the acceptor through a closed-transition state, as depicted in Figure 7.4, to give the anti-product as the major diastereomer. The proline also activates the acceptor by hydrogen bonding within this ensemble and thus plays a bifunctional role in the reaction. The resulting iminium ion is then hydrolysed to close the catalytic cycle. 

Lewis acid for this last Mukaiyama-aldol reaction afforded the diastereomeric mannose derivative with similarresults. Thehomo-aldolreaction depicted in Schetne4.13 showed a positive non-linear effect [83], which was attributed to the formation of the inactive imidazolidinone derivative of both enantiomers of proline with anti-21 (R=Bn) in the different reaction rates, resulting in a kinetic resolution of proline by the final product. The cross-aldol reaction between a-silyloxyacetaldehydes of type 30 with propanal has been used in the synthesis of one key fragment for the preparation of (H-)-spongistatin 1 [84]. 

The direct proline-catalysed aldoi in the presence of water has been screened with water-compatible Lewis acid cocatalysts. Chlorides of zinc s group proved best, and the optimized formation of anti-products in >99% ee was obtained with L-proline/ZnCl2 in 4 1 DMSO/water. Adding cobalt(II) chloride as a co-catalyst to L-proline-promoted direct aldols substantially improves selectivity, giving yield/de/ee up to 93/96/99%. Cobalt(II) is proposed to preorganize two proUnes. (g)... 

Di[3,5-(trifluoromethyl)phenyl]prolinol has been used to effect enantioselective formation of y-oxo- -hydroxy-a-substituted aldehydes with anti selectivity.Homoboro-proline bifunctional catalysts have been fine-tuned for asymmetric aldol reactions in DMF by adjusting the Lewis acidity of boron through in situ esterification with mildly sigma-electron-withdrawing diols. NMR study of the more stable five-ring boronate esters has shed light on their mode of action (17) was particularly effective. 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

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