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

Abstract

We previously reported that chiral Zn(2+) 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 Zn(2+) complexes that contain Zn(2+)-tetraazacyclododecane (Zn(2+)-[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-ZnL(7)), L-naphthylalanyl-pendant [12]aneN4 (L-ZnL(10)), L-biphenylalanyl-pendant [12]aneN4 (L-ZnL(11)), and L-phenylethylglycyl-pendant [12]aneN4 ligands (L-ZnL(12)). 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-ZnL(10) and the ZnL complex of L-diphenylalanyl-pendant [12]aneN4 (L-ZnL(13)) shows that the NH2 groups of the amino-acid side chains of these ligands are coordinated to the Zn(2+) 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.

Design and Synthesis of Chiral Zn2+ Complexes Mimicking Natural Aldolases for Catalytic C–C Bond Forming Reactions in Aqueous Solution

“…It is very likely that this Zn 2+ -bound NO 3 anion is replaced by H 2 O in aqueous solution, based on our previous findings [23,24]. The Zn 2+ center in 50 ( l -ZnL 18 ) was also coordinated by the nitrogen atom of diphenylalanyl moiety and by one water molecule [35]. …”

“…Zn 2+ complexes were formed in situ ;cIsolated yield;dCatalytic Turnover Number (=yield/equivalents of catalyst);eDetermined by HPLC analysis using a chiral column (reference [35]).…”

Automated Reaction Path Search for Asymmetric Catalytic Reaction: Elucidation of Mechanism and Efficient Analysis by Machine Learning

“…163-164 (2017) ©2018 Society of Computer Chemistry, Japan Scheme 1. Asymmetric aldol reaction catalyzed by the chiral Zn (II) complex[4].…”