The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1-5 mol %) is reported. Based on principles gained from the study of (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. Computational studies of the above reaction using HF/6-31G* level of theory suggested that this design would be highly effective. The catalyst was subsequently synthesized and studied in organocatalytic Mannich-type reactions between unmodified aldehydes and N-PMP-protected alpha-imino esters. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6 to 98:2, >97 to >99% ee).

Chiral 1,2-amino alcohols and 1,2-diols are common structural motifs found in a vast array of natural and biologically active molecules. 1 Recently, significant efforts have been applied toward the development of direct catalytic asymmetric approaches to the construction of these units based on the addition of unmodified R-hydroxyketones to imines or aldehydes in Mannich-type and aldol reactions, respectively. 2,3 Although the elegant studies of Shibasaki and Trost have provided routes to both syn-and anti-1,2-amino alcohols and diols using metal-based catalysis, 2 highly enantioselective organocatalytic approaches have been limited to syn-1,2-amino alcohols and anti-1,2-diols. 3 Here we describe simple and efficient routes to highly enantiomerically enriched anti-1,2-amino alcohols and syn-1,2-diols through direct asymmetric Mannich, Mannich-type, and aldol reactions catalyzed by primary aminecontaining amino acids.To generate anti-1,2-amino alcohols and syn-1,2-diols, we sought to design novel catalysts. In the reactions of R-hydroxyketones with (S)-proline, products form via a reaction involving an (E)-enamine A for both Mannich-type and aldol reactions 3 (Scheme 1). With pyrrolidine-derived catalysts or secondary amines, (E)-enamine intermediates predominate because of steric interactions in (Z)-enamine B. The stereochemistry of the product can be explained by transition state C or D because the si face of the (E)-enamine reacts (Scheme 1a). To selectively form anti-Mannich products in reactions involving alkylaldehydes and alkanone-derived nucleophiles, we previously designed catalysts (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid ((R)--proline), respectively. 4,5 With the latter catalyst, reactions proceed through transition state E, and the reaction face of the (E)-enamine is reversed from that of the (S)-proline-catalyzed reaction (Scheme 1b). These catalysts were, however, less than optimal for reactions of R-hydroxyketones. 6 For reactions of R-hydroxyketones, we reasoned that the use of a (Z)-enamine in the C-C bond-forming transition state should generate anti-Mannich and syn-aldol products. In our early studies of aldol reactions involving unmodified hydroxyacetone mediated by antibody catalysis, we noted preferential reaction of a (Z)-enamine of hydroxyacetone formed with the primary amine of the lysine side chain, the key catalytic residue of the aldolase, rather than reaction through an (E)-enamine as we had observed with cyclic ketones. 7 We reasoned that, with primary amines, (Z)-enamines of R-hydroxyketones F should predominate over (E)-enamines G. 8 When (Z)-enamine F reacts in the C-C bond-forming transition state (H or I), anti-Mannich or syn-aldol products should form predominately (Scheme 1c). Studies of direct asymmetric aldol and Mannich-type reactions catalyzed by primary amine-containing amino acids have been reported. 9 However, within these studies, reactions of R-hydroxyketones were either not tested or, when tested, enantioselectivities of the ...

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.

We report the development of direct catalytic, enantioselective, anti-selective Mannich-type reactions between unmodified ketones and alpha-imino esters under mild conditions. The reactions were performed using 5-10 mol % of (R)-3-pyrrolidinecarboxylic or (R)-beta-proline as catalyst in an environmentally benign solvent, 2-PrOH, at room temperature. The anti-Mannich products were obtained in good yields with high diastereo- and enantioselectivities (up to anti/syn >99:1, 99% ee). While (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid is an excellent catalyst for the anti-Mannich-type reactions of aldehydes, it did not efficiently catalyze the corresponding Mannich-type reactions of ketones; (R)-3-pyrrolidinecarboxylic acid did efficiently catalyze the Mannich-type reactions of ketones. (S)-Proline or (S)-2-pyrrolidinecarboxylic acid has been reported to catalyze the Mannich-type reactions of ketones to afford the syn-products. Thus, the position of the carboxylic acid group on the pyrrolidine ring directs the stereoselection of the catalyzed reaction, providing either syn- or anti-Mannich products.

Enantiomerically enriched b-amino carbonyl compounds bearing an a-alkylidene group can be prepared by azaMorita-Baylis-Hillman (aza-MBH) reactions and are versatile chiral building blocks for pharmaceutical candidates and other important compounds. [1,2] Consequently, the development of efficient methods for enantioselective aza-MBH reactions is of interest.[1] For example, quinidine derivatives, [1a-c] 1,1'-bi-2-naphthol (binol) derivatives containing a pyridyl group, [1d,e] phosphinyl derivatives, [1f-i] and thiourea derivatives [1j] have been used as catalysts for enantioselective aza-MBH reactions. These methods are, however, typically limited to the reactions of cyclic enones (such as 2-cyclopenten-1-one) or of b-unsubstituted acyclic enones and related esters (such as methyl vinyl ketone and methyl acrylate). There have been no reports of highly enantioselective aza-MBH reactions of b-substituted a,b-unsaturated acyclic carbonyl compounds.[3] It has been demonstrated that aza-MBH and MBH reactions of b-substituted acyclic enones are more problematic than those of b-unsubstituted enones. [3, 4] This may be related to a relatively slow Michael addition of a nucleophilic reagent (or Lewis base) to bsubstituted enones because of steric interaction between the nucleophilic reagent and the b substituent on the enones.[4] To overcome this difficulty, we propose an alternative route to access aza-MBH-type products with b-substituted a,b-unsaturated carbonyl moieties: Mannich-type reaction of in situ generated enamines of b-substituted a,b-unsaturated carbonyl compounds followed by isomerization of the double bond (Scheme 1). Here we report the catalytic enantioselective formation of aza-MBH-type products from b-substituted a,b-unsaturated aldehydes and a-imino esters protected with a p-methoxyphenyl (PMP) group through a Mannich-type reaction/isomerization sequence.We used (S)-proline to demonstrate the Mannich/isomerization sequence as it is a good asymmetric catalyst for Mannich-type reactions of alkyl aldehydes.[5] We reasoned that isomerization of the double bond of the Mannich products should occur spontaneously, because epimerization at the a-position of the aldehyde group of Mannich products generated from alkyl aldehydes is facile.[5] In the case of Mannich products generated from b-substituted a,b-unsaturated aldehydes, the acidity of the proton at the a-position of the aldehyde group of the product is increased by the presence of a neighboring alkene; this increased acidity should favor the isomerization of the double bond. Table 1 shows the results of the (S)-proline-catalyzed reaction Scheme 1. a) An aza-MBH reaction route. b) Formation of aza-MBHtype products through Mannich-type reaction/isomerization.

Mannich reactions between aldehydes and N-p-methoxyphenyl-protected alpha-imino ethyl glyoxylate have been performed using (S)-pipecolic acid as catalyst. The reactions give both syn- and anti-products (dr=1.4-2:1) with high enantioselectivities (>98% ee). In contrast, (S)-proline-catalyzed reactions give mainly syn-products with high enantioselectivities. Computational studies reveal that the energetic preference between the transition structures involving the s-cis-enamine and the s-trans-enamine is smaller for the pipecolic acid as compared to proline, yielding the (2S,3R)-anti and the (2S,3S)-syn Mannich product in nearly equal amounts.

Enantioselective syntheses O 0031Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid. -A new asymmetric, organocatalytic and anti-selective Mannich reaction is based on utilization of a rationally designed amino acid (DAA). -(MITSUMORI, S.; ZHANG, H.; CHEONG, P. H.-Y.; HOUK, K. N.; TANAKA, F.; BARBAS*, C. F. I.;

Enantiomerically enriched b-amino carbonyl compounds bearing an a-alkylidene group can be prepared by azaMorita-Baylis-Hillman (aza-MBH) reactions and are versatile chiral building blocks for pharmaceutical candidates and other important compounds. [1,2] Consequently, the development of efficient methods for enantioselective aza-MBH reactions is of interest.[1] For example, quinidine derivatives, [1a-c] 1,1'-bi-2-naphthol (binol) derivatives containing a pyridyl group, [1d,e] phosphinyl derivatives, [1f-i] and thiourea derivatives [1j] have been used as catalysts for enantioselective aza-MBH reactions. These methods are, however, typically limited to the reactions of cyclic enones (such as 2-cyclopenten-1-one) or of b-unsubstituted acyclic enones and related esters (such as methyl vinyl ketone and methyl acrylate). There have been no reports of highly enantioselective aza-MBH reactions of b-substituted a,b-unsaturated acyclic carbonyl compounds.[3] It has been demonstrated that aza-MBH and MBH reactions of b-substituted acyclic enones are more problematic than those of b-unsubstituted enones. [3, 4] This may be related to a relatively slow Michael addition of a nucleophilic reagent (or Lewis base) to bsubstituted enones because of steric interaction between the nucleophilic reagent and the b substituent on the enones.[4] To overcome this difficulty, we propose an alternative route to access aza-MBH-type products with b-substituted a,b-unsaturated carbonyl moieties: Mannich-type reaction of in situ generated enamines of b-substituted a,b-unsaturated carbonyl compounds followed by isomerization of the double bond (Scheme 1). Here we report the catalytic enantioselective formation of aza-MBH-type products from b-substituted a,b-unsaturated aldehydes and a-imino esters protected with a p-methoxyphenyl (PMP) group through a Mannich-type reaction/isomerization sequence.We used (S)-proline to demonstrate the Mannich/isomerization sequence as it is a good asymmetric catalyst for Mannich-type reactions of alkyl aldehydes.[5] We reasoned that isomerization of the double bond of the Mannich products should occur spontaneously, because epimerization at the a-position of the aldehyde group of Mannich products generated from alkyl aldehydes is facile.[5] In the case of Mannich products generated from b-substituted a,b-unsaturated aldehydes, the acidity of the proton at the a-position of the aldehyde group of the product is increased by the presence of a neighboring alkene; this increased acidity should favor the isomerization of the double bond. Table 1 shows the results of the (S)-proline-catalyzed reaction Scheme 1. a) An aza-MBH reaction route. b) Formation of aza-MBHtype products through Mannich-type reaction/isomerization.