The enantioselective Mannich-type reaction of an enolate or an enolate anion equivalent with aldimines constitutes a useful method for the preparation of chiral b-amino carbonyl compounds, which are the precursors of biologically important compounds such as b-lactams and b-amino acids. The development of chiral catalysts for the asymmetric Mannichtype reaction has attracted the attention of synthetic organic chemists.[1] Although stoichiometric amounts of chiral acid were employed initially, [2] a number of enantioselective catalysts such as chiral Lewis acid catalysts [3] and chiral base catalysts [4] have been developed lately. In addition to metal-based chiral catalysts, [5] the use of small organic molecules as catalysts to promote asymmetric reactions has emerged as a new frontier in reaction methodology.[6] Accordingly, l-proline derivatives [7] and peptide derivatives [8] have been developed as catalysts for the Mannich-type reactions. We previously reported that Mannich-type reactions [9] and the aza-Diels-Alder reaction [10] proceed smoothly in the presence of a catalytic amount of a strong Brønsted acid. We thus postulated that the use of a chiral Brønsted acid, in which the proton is surrounded by bulky substituents, may lead to effective asymmetric induction. We report herein an enantioselective Mannich-type reaction of silyl enolates with aldimines catalyzed by a chiral metal-free Brønsted acid. [11,12] First, treatment of aldimine 1 a (Scheme 1, R 1 = Ph) and ketene silyl acetal 2 (3.0 equiv) with 0.3 equivalents of the chiral phosphate 4 a [13,14,15] (which is readily prepared from (R)-BINOL; Scheme 2) in toluene at À78 8C led to a smooth Mannich-type reaction to give 3 a (R 1 = Ph). However, no enantioselectivity was observed (Table 1, entry 1), as deterScheme 1. Mannich-type reaction of aldimines 1 and ketene silyl acetals 2 to form b-aminoesters 3.

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Hydrogen bond catalysis and Brønsted acid catalysis are rapidly growing areas in organocatalysis. A number of chiral acid catalysts has been developed recently. Recent progress in the chiral Brønsted acid catalysis has been reviewed with a focus being placed on thiourea, TADDOL, and phosphoric acids.

Mannich-type reaction of ketene silyl acetals with aldimines proceeded catalytically by means of a phosphoric acid diester, derived from (R)-BINOL, as a chiral Brønsted acid to afford beta-amino esters with good diastereoselectivity in favor of the syn isomer and high enantioselectivity (up to 96% ee). The highest enantioselectivity was achieved by the phosphoric acid diester bearing 4-nitrophenyl groups on the 3,3'-positions of BINOL. The N-2-hydroxyphenyl group of aldimine was found to be essential for the present Mannich-type reaction. In combination with these experimental investigations, two possible monocoordination and dicoordination pathways were explored using density functional theory calculations (BHandHLYP/6-31G*). The present reaction proceeds via a dicoordination pathway through the zwitterionic and nine-membered cyclic transition state (TS) consisting of the aldimine and the phosphoric acid. The re-facial selectivity was also well-rationalized theoretically. The nine-membered cyclic structure and aromatic stacking interaction between the 4-nitrophenyl group and N-aryl group would fix the geometry of aldimine on the transition state, and the si-facial attacking TS is less favored by the steric hindrance of the 3,3'-aryl substituents.

[reaction: see text] A cyclic phosphoric acid derivative, derived from (R)-BINOL, was used as a chiral Brønsted acid (10 mol %) in hydrophosphonylation of aldimines with diisopropyl phosphite at room temperature. Alpha-amino phosphonates were obtained with good to high enantioselectivities.

Inverse electron-demand aza Diels-Alder reaction of aldimine with enol ethers proceeded under the influence of a phosphoric acid diester, derived from (R)-BINOL, to give tetrahydroquinoline derivatives with excellent enantioselectivity.

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