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.