Chiral Catalysts Dually Functionalized with Amino Acid and Zn2+ 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 Zn2+ enolates of substrates react with acceptor aldehydes. In this work, Zn2+ complexes of L-prolyl-pendant[15]aneN(5) (ZnL3), L-prolyl-pendant[12]aneN(4) (ZnL4), and L-valyl-pendant[12]aneN(4) (ZnL5) were designed and synthesized for use as chiral catalysts for enantioselective aldol reactions. The complexation constants for L-3 to L-5 with Zn2+ [logK(s)-(ZnL)] were determined to be 14.1 (for ZnL3), 7.6 (for ZnL4), and 9.6 (for ZnL5), indicating that ZnL 3 is more stable than ZnL4 and ZnL5. The deprotonation constants of Zn2+-bound water [pK(a)(ZnL) values] for ZnL3, ZnL4, and ZnL5 were calculated to be 9.2 (for ZnL3), 8.2 (for ZnL4), and 8.6 (for ZnL5), suggesting that the Zn2+ ions in ZnL3 is a less acidic Lewis acid than in ZnL4 and ZnL5. These values also indicated that the amino groups on the side chains weakly coordinate to Zn2+. We carried out aldol reactions between acetone and 2-chlorobenzaldehyde and other aldehydes in the presence of catalytic amounts of the chiral Zn2+ complexes in acetone/H2O at 25 and 37 degrees C. Whereas ZnL3 yielded the aldol product in 43% yield and 1% ee (R), ZnL4 and ZnL5 afforded good chemical yields and high enantio-selectivities of up to 89% ee (R). UV titrations of proline and ZnL4 with acetylacetone (acac) in DMSO/H2O (1:2) indicate that ZnL4 facilitates the formation of the ZnL4 center dot(acac)(-) complex (K-app = 2.1x10(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 Zn2+ ions in ZnL4 and ZnL5 function in a cooperative manner to generate the Zn2+-enolate of acetone, thus permitting efficient enantioselective C-C bond formation with aldehydes.