Generation of axial and metal-centered chirality for chiral analysis based on 2-hydroxyphenyl carbonyl compounds

Abstract

Optically active (chiral) compounds are of great biological importance. Accordingly, significant efforts have been devoted to developing methods of synthesizing chiral compounds with high optical purity and chiral analysis, such as the determination of identity, concentration, and the relative ratio of chiral compounds, is indispensable in contemporary synthetic, medicinal, and biological chemistry. Thus it has been a great challenge to develop the efficient and readily available chiral catalysts and sensors. Easily tunable and rigid structure, multiple functional groups that allow them to bind to reactive metal centers, and minimal structural requirements for signal amplification are necessary to be efficient and readily available chiral ligands and sensors. Fortunately, we found that 2,2’-dihydroxyphenyl carbonyl structures such as 2,2'-dihydroxybenzophenone and 2,2'-dihydroxybenzil satisfy these requirements. These compounds can be synthesized from the commercially available starting materials in one step and their derivatives contain rigid structure and multiple functional groups. Herein, we introduce 2,2'-dihydroxyphenyl carbonyl structures as the privileged scaffold for chiral sensing, asymmetric coordination chemistry and chiral-at-metal complexes.

Chapter 1. 2,2’-Dihydroxyphenyl Carbonyl: Its Unprecedented Reactivity and Synthetic Applications The 2-hydroxyphenyl carbonyl compounds are the most versatile because they constitute a major class of naturally occurring biologically active compounds and ligands for transition-metal catalysis. They have a hydrogen bond between carbonyl group and ortho-hydroxy group. Such hydrogen bond facilitates the imine formation by stabilizing transition state. The enhanced reaction rate of imine formation enables synthesis of various imine products which can be converted to versatile compounds. Although the studies about this enhanced reactivity have already been reported, there was no study about imine formation of 2,2'-dihydroxyphenyl carbonyl compounds such as 2,2'-dihydroxybenzophenone (DHBP). Because 2,2'-dyhydrxoyphenyl carbonyl compounds have a large potential for the privileged scaffold for the ligand design and chiral sensor, we herein report kinetics and DFT calculations to explain its unprecedented reactivity and show synthetic applications.

Chapter 2. 2,2'-Dihydroxybenzil: A Stereodynamic Probe for Primary Amines and Amino Alcohols The induced circular dichroism (ICD) analysis has been used for fast, convenient, sensitive, and accurate determination of configuration and enantiomeric excess (ee) of chiral analytes such as amines, alcohols, carboxylic acids, and others. However, the most reported stereodynamic probes are not readily available due to their lengthy synthetic procedures or difficult to understand the origin of stereoselectivity. Hence, developing simple stereodynamic probe is highly desirable and we became interested in the rational design of a small organic compound with minimal structural requirements for signal amplification of chiral analytes. Herein we report a remarkably simple 1,1'-binaphthalene-like axial compound, 2,2'-dihydroxybenzil, that combines with 2 equiv of monodentate primary amines or amino alcohols to form a diimine, of which axial chirality is controlled by steric strain or hydrogen bond with moderate (1.4:1) to good (> 50:1) stereoselectivity. The observed circular dichroism (CD) spectra have been closely simulated by TD-DFT computations and can be used for determining the absolute chirality and enantiomeric excess of primary amines and amino alcohols.

Chapter 3. Controlling Helical Chirality of Metal Complexes and Its Applications Ever since the 1911 discovery of metal-centered chirality by Alfred Werner, chiral octahedral metal complexes have received increasing attention in catalysis, material science, and pharmaceutics. Unlike well-established asymmetric control of carbon-centered chirality, controlling metal-centered chirality has proved to be challenging because stereogenic metal centers often tend to racemize or epimerize due to the reversible metal？ligand bonds or the structural isomerism of coordination complexes. Given that the asymmetric coordination chemistry is still under development. In light of these challenges, we became interested in controlling chirality of metal complexes and its applications. At first, we report stereoselective cis-trans isomerism and generation of metal-centered helical chirality of an unprecedented $Co^{III}-N_2O_2$ complex by chirality transfer from chiral vicinal diamines to stereodynamic metal complexes. The induced metal-centered helical chirality can be exploited for chirality amplification and asymmetric coordination chemistry. Next, we describe the selective control of metal-centered chirality in an octahedral geometry to prepare negatively charged $Al^{III}$ complexes, which can be used as versatile ^{1}H NMR chiral solvating agents for chiral molecules such as amines, carboxylic acid and alcohol. As a chiral solvating agent, $Al^{III}$ complexes display an unprecedentedly broad substrate scope, good solvent compatibility, and operational simplicity. This simple protocol will find wide application in the analysis of the chirality of chiral compounds.