Enzymatic Desymmetrising Redox Reactions for the Asymmetric Synthesis of Biaryl Atropisomers

Abstract

Atropisomeric biaryls carrying ortho-hydroxymethyl and formyl groups were made enantioselectively by desymmetrisation of dialdehyde or diol substrates. The oxidation of the symmetrical diol substrates was achieved using a variant of galactose oxidase (GOase), and the reduction of the dialdehydes using a panel of ketoreductases. Either M or P enantiomers of the products could be formed, with absolute configurations assigned by time-dependent DFT calculations of circular dichroism spectra. The differing selectivities observed with different biaryl structures offer an insight into the detailed structure of the active site of the GOase enzyme.

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

“…BINOLderived phosphoric acids have been utilized as Brønsted acid catalysts, [2] and atropisomeric quinoline N-oxides such as QUINOX [3] are excellent Lewis base catalysts for various asymmetric transformations including asymmetric allylation of substituted benzaldehydes, [4,5] asymmetric desymmetrizations of meso epoxides, [6] and asymmetric aldol reactions. [12] Thep otential for subtle control of racemization rates in atropisomeric and near-atropisomeric structures allows the efficient use of dynamic kinetic [13] or thermodynamic [14] resolution. [12] Thep otential for subtle control of racemization rates in atropisomeric and near-atropisomeric structures allows the efficient use of dynamic kinetic [13] or thermodynamic [14] resolution.…”

“…[7] Then eed for efficient methods for the enantioselective synthesis of atropisomers [8] has encouraged the development of atropselective transition-metal couplings, [9] kinetic resolution by metal catalysis [10] and organocatalytic methods, [11] and desymmetrization. [12] Thep otential for subtle control of racemization rates in atropisomeric and near-atropisomeric structures allows the efficient use of dynamic kinetic [13] or thermodynamic [14] resolution. Although biocatalytic methods are particularly effective for achieving kinetic resolution and dynamic kinetic resolution, [15] biocatalytic dynamic kinetic resolution (DKR) has never been used to synthesize atropisomers enantioselectively.…”

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

“…The need for efficient methods for the enantioselective synthesis of atropisomers has encouraged the development of atropselective transition‐metal couplings, kinetic resolution by metal catalysis and organocatalytic methods, and desymmetrization . The potential for subtle control of racemization rates in atropisomeric and near‐atropisomeric structures allows the efficient use of dynamic kinetic or thermodynamic resolution.…”

Recent advances and new concepts for the synthesis of axially stereoenriched biaryls

“…In 2014 Turner and Clayden performed enzymatic redox reactions converting prochiral dialdehydes and diols into enantioenriched monoaldehydes (Scheme 9A). 33 The model product, 3-(hydroxymethyl)-2-(naphthalene-1-yl) benzaldehyde, was obtained in good yield and excellent enantiomeric excess either by the monooxidation of a diol with galactose oxidase or by the monoreduction of a dialdehyde with ketoreductase. Intriguingly, the optical purity of the products was further improved via in situ partial kinetic resolution occurring during the second oxidation of the monoaldehyde product.…”