Chiral Brønsted Acid Catalyzed Enantioselective Mannich-Type Reaction

Abstract

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.

Stereoselective synthesis and characterization of new enantiomerically pure phosphoric acids

“…When N-2-hydroxyphenyl imines are used in the Mannich reaction, generally the proposed transition state involves the presence of two hydrogen bondings or tight ion pairs, on a case-by-case basis 11 ; however, recent density functional theory calculations seem to suggest that in the case of binaphthol-derived phosphoric acids the reaction proceeds through a nine-membered zwitterionic cyclic transition state with a double coordination between the phosphoric acid and the imine. 22 On the basis of the experimental results obtained with our catalytic systems, a possible reactants assembly for the nucleophilic attack to imine 15 of benzaldehyde promoted by catalyst 12 is shown in Figure 4. Key features of the proposed complexation mode are the coordination of the Bronsted acidic site to the nitrogen of the aldimine and the binding of the phenolic proton of the imine to the Lewis basic site of the chiral phosphoric acid.…”

The Brønsted Acid Catalyzed, Enantioselective Vinylogous Mannich Reaction

“…In the aqueous reaction medium, the lifetime of TBS-3 a should, however, be very short, if it exists at all. [21] Crystal structure of an imine-bound phosphoric acid: To shed some light on the way the chiral Brønsted acid binds to the imine and possibly on the origin of asymmetric induction, we attempted a cocrystallization of phosphoric acid 3 d and benzaldimine 1 a. Single crystals suitable for X-ray diffraction analysis were eventually obtained by slow evaporation of a solution of both components in CHCl 3 .…”

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

“…and the Mannich reaction reported by Yamanaka et al. we considered the inclusion of 5 may generate a constrained hydrogen‐bonded and activated complex similar to 11 ; we were drawn to the use of 5 to generate 11 due to similarities in the chiral non‐racemic rigid environment proposed by Yamanaka (using a N ‐(2‐hydroxyphenyl)imine starting material) 10. Screening chiral non‐racemic BINOL and VANOL phosphoric acids, as well as a H‐QUIN‐BAM triflate salt11 we were disappointed no reactions were observed.…”