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So S.M.,Diaminopharm Inc. | Kim H.,KAIST | Mui L.,University of Toronto | Chin J.,University of Toronto
European Journal of Organic Chemistry

Biomimetic studies of pyridoxal and pyridoxamine models are of both fundamental and practical interest. This review examines (i) deracemization of α-amino acids with a chiral pyridoxal model, (ii) sensing of chirality of small molecules including α-, β-, and γ-amino acids, peptides, amino alcohols and diamines with an achiral pyridoxal model and (iii) stereospecific synthesis of chiral diamines with a chiral pyridoxamine model. A binol-based aldehyde is useful as a chiral pyridoxal model to deracemize a variety of α-amino acids to make D-amino acids. 2,2′- Dihydroxybenzophenone is useful as an achiral pyridoxal model for sensing the chirality of the above-mentioned small molecules in a unified way. Bis(2-hydroxyphenyl)-ethylenediamine (hpen) is useful as a chiral pyridoxamine model for making chiral diamines. Weak forces (H-bonding, steric and electronic effects) involved in transamination reactions with pyridoxamine for the synthesis of amino acids are compared with those for the diaza-Cope rearrangement reaction with hpen for the synthesis of chiral diamines. Both experimental and computational methods are used to analyze the biomimetic systems. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

So S.M.,Diaminopharm Inc. | Mui L.,University of Toronto | Kim H.,Korea Advanced Institute of Science and Technology | Chin J.,University of Toronto
Accounts of Chemical Research

Chiral diamines are important building blocks for constructing stereoselective catalysts, including transition metal based catalysts and organocatalysts that facilitate oxidation, reduction, hydrolysis, and C-C bond forming reactions. These molecules are also critical components in the synthesis of drugs, including antiviral agents such as Tamiflu and Relenza and anticancer agents such as oxaliplatin and nutlin-3. The diaza-Cope rearrangement reaction provides one of the most versatile methods for rapidly generating a wide variety of chiral diamines stereospecifically and under mild conditions. Weak forces such as hydrogen bonding, electronic, steric, oxyanionic, and conjugation effects can drive this equilibrium process to completion.In this Account, we examine the effect of these individual weak forces on the value of the equilibrium constant for the diaza-Cope rearrangement reaction using both computational and experimental methods. The availability of a wide variety of aldehydes and diamines allows for the facile synthesis of the diimines needed to study the weak forces. Furthermore, because the reaction generally takes place cleanly at ambient temperature, we can easily measure equilibrium constants for rearrangement of the diimines. We use the Hammett equation to further examine the electronic and oxyanionic effects. In addition, computations and experiments provide us with new insights into the origin and extent of stereospecificity for this rearrangement reaction.The diaza-Cope rearrangement, with its unusual interplay between weak forces and the equilibrium constant of the reaction, provides a rare opportunity to study the effects of the fundamental weak forces on a chemical reaction. Among these many weak forces that affect the diaza-Cope rearrangement, the anion effect is the strongest (10.9 kcal/mol) followed by the resonance-assisted hydrogen-bond effect (7.1 kcal/mol), the steric effect (5.7 kcal/mol), the conjugation effect (5.5 kcal/mol), and the electronic effect (3.2 kcal/mol). Based on both computation and experimental data, the effects of these weak forces are additive. Understanding the interplay of the weak forces in the [3,3]-sigmatropic reaction is interesting in its own right and also provides valuable insights for the synthesis of chiral diamine based drugs and catalysts in excellent yield and enantiopurity. © 2012 American Chemical Society. Source

Lee A.,Korea Advanced Institute of Science and Technology | So S.M.,Diaminopharm Inc. | Lough A.J.,University of Toronto | Kim H.,Korea Advanced Institute of Science and Technology | And 2 more authors.
Asian Journal of Organic Chemistry

"Mother diamine" (MD) or 1,2-bis(2-hydroxy-phenyl)ethylenediamine can be rapidly transformed to a wide variety of chiral ligands including vicinal diamines and analogs of binol (MDdiol), binap (MDdiphos), and monophos (MDphos). The reactivity and stereoselectivity of the MDphos ligands in Rh-catalyzed hydrogenation are highly sensitive to the N,N'-dialkyl substituents. © 2014 Wiley-VCH Verlag GmbH & Co. Source

Chin J.,University of Toronto | Chin J.,Diaminopharm Inc. | Kwon S.H.,University of Toronto | Kwon S.H.,Seoul National University | And 4 more authors.
European Journal of Organic Chemistry

γ,δ-Diamino acid structural motifs are commonly found in bioactive molecules.We report a one-pot reaction for the synthesis of γ,δ-diimino esters with two adjacent chiral centers in enantiomerically pure form through diaza-Cope rearrangement reaction of diimines formed from (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (hpen) and alde-hydes. DFT computation provides interesting insights into the stereospecific rearrangement reaction. The crystal structure of a product diimine formed from the reaction of (R,R)-hpen and 2,6-dichlorobenzaldehyde shows that the reaction gives the product diimine in S,S configuration. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Chin J.,University of Toronto | Chin J.,Diaminopharm Inc. | Kwon S.H.,University of Toronto | Kwon S.H.,Seoul National University | And 5 more authors.
Organic and Biomolecular Chemistry

Reaction between 1,2-bis(2-hydroxyphenyl)-ethylenediamine (hpen) and methyl pyruvate gives the diaza-Cope rearrangement product with good yield and excellent stereospecificity. The product containing two chiral quaternary carbon centers is characterized by high performance liquid chromatography and X-ray crystallography. DFT computation provides insight into why the diaza-Cope rearrangement takes place readily with methyl pyruvate but not with other ketones like acetone and substituted acetophenones. © 2013 The Royal Society of Chemistry. Source

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