Asymmetric Aldol Reactions between Acetone and Benzaldehydes Catalyzed by Chiral Zn2+ Complexes of Aminoacyl 1,4,7,10‐Tetraazacyclododecane: Fine‐Tuning of the Amino‐Acid Side Chains and a Revised Reaction Mechanism

We previously reported that chiral Zn²⁺ complexes that were designed to mimic the actions of class‐I and class‐II aldolases catalyzed the enantioselective aldol reactions of acetone and its analogues thereof with benzaldehyde derivatives. Herein, we report the synthesis of new chiral Zn²⁺ complexes that contain Zn²⁺? tetraazacyclododecane (Zn²⁺? 12]aneN₄) moieties and amino acids that contain aliphatic, aromatic, anionic, cationic, and dipeptide side chains. The chemical and optical yields of the aldol reaction were improved (up to 96 % ee) by using ZnL complexes of L ‐decanylglycyl‐pendant 12]aneN₄ (L ‐ZnL⁷), L ‐naphthylalanyl‐pendant 12]aneN₄ (L ‐ZnL¹⁰), L ‐biphenylalanyl‐pendant 12]aneN₄ (L ‐ZnL¹¹), and L ‐phenylethylglycyl‐pendant 12]aneN₄ ligands (L ‐ZnL¹²). UV/Vis and circular dichroism (CD) titrations of acetylacetone (acac) with ZnL complexes confirmed that a ZnL? (acac)^? complex was exclusively formed and not the enaminone of ZnL and acac, as we had previously proposed. Moreover, the results of stopped‐flow experiments indicated that the complexation of (acac)^? with ZnL was complete within milliseconds, whereas the formation of an enaminone required several hours. X‐ray crystal‐structure analysis of L ‐ZnL¹⁰ and the ZnL complex of L ‐diphenylalanyl‐pendant 12]aneN₄ (L ‐ZnL¹³) shows that the NH₂ groups of the amino‐acid side chains of these ligands are coordinated to the Zn²⁺ center as the fourth coordination site, in addition to three nitrogen atoms of the 12]aneN₄ rings. The reaction mechanism of these aldol reactions is discussed and some corrections are made to our previous mechanistic hypothesis.