A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric anti‐Selective Mannich Reactions and syn‐Selective Cross‐Aldol Reactions

Abstract

A direct asymmetric Mannich reaction using a novel axially chiral amino sulfonamide (S)-3 that is highly anti- and enantioselective has been developed. For instance, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and alpha-imino esters proceeded smoothly to give anti Mannich products with a significantly higher anti/syn ratio and enantioselectivity than previously possible. By utilizing N-Boc-protected aromatic imines instead of alpha-imino esters, the synthetically useful Boc protecting group and various aromatic or heteroaromatic substituents were installed into the anti Mannich products and consequently the substrate scope of the anti-selective Mannich reaction and the synthetic utility of the anti Mannich products have been expanded. The axially chiral amino sulfonamide (S)-3 has also been successfully applied to asymmetric direct cross-aldol reaction between two different aldehydes. The catalyst (S)-3 has the advantage of giving mainly syn products, whereas proline shows the opposite anti selectivity.

Development of Highly Selective Organic Reactions Catalyzed by Designed Amine Organocatalysts

“…We then examined the cross-aldol reaction between hexanal and 4-nitrobenzaldehyde using the binaphthylbased amino acid (S)-13 as catalyst. 30 The reaction proceeded to give the anti-aldol adduct as a major diastereomer with excellent enantioselectivity (Scheme 16), and the transition state seemed to involve the s-trans-enamine intermediate which is similar to that of the proline-catalyzed reaction ( Figure 13). Interestingly, however, a substantial amount of the syn-aldol adduct was also obtained, suggesting the existence of s-cis-enamine intermediate, in which a steric repulsion between the enamine and the carboxylic acid group is much smaller than that of proline.…”

“…30,31 Since it would be difficult for the s-trans-enamine, which is generated from a donor aldehyde and (S)-16, to react with an acceptor aldehyde that is activated by the distal acidic proton of the triflamide of (S)-16, the cross-aldol reaction catalyzed by (S)-16 would be expected to proceed through the s-cis-enamine, thus giving the desired unusual syn-product as shown in Scheme 17.…”

“…The axiallychiral amino sulfonamide (S)-16 was also successfully applied to the direct asymmetric Mannich reaction of aldehydes with ¡-imino esters. 30,33,34 This catalyst (S)-16 has the advantage of giving mainly anti-products, while proline shows the opposite syn-selectivity. 35 In the case of primary-alkyl aldehydes, 1 mol % of (S)-16 was sufficient to produce the corresponding ¢-amino aldehydes in high yields (>92%) with virtually complete enantioselectivities (99% ee) and excellent antiselectivities (>11/1) (Scheme 19).…”

“…Unfortunately, however, the reaction between the N-PMP-protected aromatic imine and 3-methylbutanal did not proceed under the optimal conditions for the reaction of N-PMP-protected ¡-imino esters, probably due to the low reactivity of the aromatic imine (Scheme 23). 30 We then decided to explore the anti-selective Mannich reaction using more reactive N-Boc-protected aromatic imines, 30,39 which have been successfully utilized by the groups of List 40 and Córdova 41 in the syn-selective Mannich reaction catalyzed by proline.…”

A Convenient Method for Preparation of α-Imino Carboxylic Acid Derivatives and Application to the Asymmetric Synthesis of Unnatural α-Amino Acid Derivative

“…12,13) Enabling easy access to diverse α-amino acids only by changing nucleophiles employed, Mannich-type reaction of α-imino ester has been widely utilized for the asymmetric synthesis. [14][15][16][17][18][19][20] Generally, condensation of glyoxalates and primary amines affords α-imino esters as the requisite substrate for Mannich-type reaction (Chart 1a); however, the glyoxalates are unstable, and suffer easy hydrolysis or polymerization at room temperature. Additionally, high susceptibility of the resulting α-imino ester to silica gel has forced us to directly use the imino esters for the Mannich reaction without purification, thereby leading to difficulty in maintaining the reaction outcome.…”