Chiral Catalysts Dually Functionalized with Amino Acid and Zn 2+ Complex Components for Enantioselective Direct Aldol Reactions Inspired by Natural Aldolases: Design, Synthesis, Complexation Properties, Catalytic Activities, and Mechanistic Study

Aldolases are enzymes that catalyze stereospecific aldol reactions in a reversible manner. Naturally occurring aldolases include class I aldolases, which catalyze aldol reactions via enamine intermediates, and class II aldolases, in which Zn 2+ enolates of substrates react with acceptor aldehydes. In this work, Zn 2+ complexes of L ‐prolyl‐pendant[15]aneN 5 (ZnL 3 ), L ‐prolyl‐pendant[12]aneN 4 (ZnL 4 ), and L ‐valyl‐pendant[12]aneN 4 (ZnL 5 ) were designed and synthesized for use as chiral catalysts for enantioselective aldol reactions. The complexation constants for L 3 to L 5 with Zn 2+ [log K s (ZnL)] were determined to be 14.1 (for ZnL 3 ), 7.6 (for ZnL 4 ), and 9.6 (for ZnL 5 ), indicating that ZnL 3 is more stable than ZnL 4 and ZnL 5 . The deprotonation constants of Zn 2+ ‐bound water [p K a (ZnL) values] for ZnL 3 , ZnL 4 , and ZnL 5 were calculated to be 9.2 (for ZnL 3 ), 8.2 (for ZnL 4 ), and 8.6 (for ZnL 5 ), suggesting that the Zn 2+ ions in ZnL 3 is a less acidic Lewis acid than in ZnL 4 and ZnL 5 . These values also indicated that the amino groups on the side chains weakly coordinate to Zn 2+ . We carried out aldol reactions between acetone and 2‐chlorobenzaldehyde and other aldehydes in the presence of catalytic amounts of the chiral Zn 2+ complexes in acetone/H 2 O at 25 and 37 °C. Whereas ZnL 3 yielded the aldol product in 43 % yield and 1 %  ee  ( R ), ZnL 4 and ZnL 5 afforded good chemical yields and high enantioselectivities of up to 89 %  ee  ( R ). UV titrations of proline and ZnL 4 with acetylacetone (acac) in DMSO/H 2 O (1:2) indicate that ZnL 4 facilitates the formation of the ZnL 4 ⋅ (acac) − complex ( K app =2.1×10 2   M −1 ), whereas L ‐proline forms a Schiff base with acac with a very small equilibrium constant. These results suggest that the amino acid components and the Zn 2+ ions in ZnL 4 and ZnL 5 function in a cooperative manner to generate the Zn 2+ ‐enolate of acetone, thus permitting efficient enantioselective CC bond formation with aldehydes.