Hybrid Chemo-, Bio-, and Electrocatalysis for Atom-Efficient Deuteration of Cofactors in Heavy Water

Abstract

Deuterium-labeled nicotinamide cofactors such as [4- 2 H]-NADH can be used as mechanistic probes in biological redox processes and offer a route to the synthesis of selectively [ 2 H] labeled chemicals via biocatalytic reductive deuteration. Atom-efficient routes to the formation and recycling of [4- 2 H]-NADH are therefore highly desirable but require careful design in order to alleviate the requirement for [ 2 H]-labeled reducing agents. In this work, we explore a suite of electrode or hydrogen gas driven catalyst systems for the generation of [4- 2 H]-NADH and consider their use for driving reductive deuteration reactions. Catalysts are evaluated for their chemoselectivity, stereoselectivity, and isotopic selectivity, and it is shown that inclusion of an electronically coupled NAD + -reducing enzyme delivers considerable advantages over purely metal based systems, yielding exclusively [4 S - 2 H]-NADH. We further demonstrate the applicability of these types of [4 S - 2 H]-NADH recycling systems for driving reductive deuteration reactions, regardless of the facioselectivity of the coupled enzyme.

Role of geochemical protoenzymes (geozymes) in primordial metabolism: specific abiotic hydride transfer by metals to the biological redox cofactor NAD+

“…There were two reasonable options: either protons from H 2 O and metal electrons (formed to surface‐bound hydrides) or surface‐bound hydrides from H 2 gas. Previous work on reducing NAD + and 2 H sources [ 59 , 60 ] provided us with mechanistic details and reference 1 H‐NMR spectra for NAD 2 H species, the presence of which can be monitored via the duplet of duplet at 2.7 p.p.m. (position 4 as shown in Fig.…”

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives

“…Accordingly, much attention has been paid to exploit various methods for the incorporation of a deuterium atom into the stereogenic center of chiral pharmaceutical molecules or their key building blocks. [15][16][17][18][19][20][21] Catalytic asymmetric synthesis, as one of the most straightforward approaches towards this goal, mainly focuses on asymmetric reduction and asymmetric deuteration of prochiral compounds [22][23][24][25][26][27][28][29][30] (Scheme 1a). In contrast, catalytic asymmetric 1,3-dipolar cycloaddition reactions, [31][32][33][34][35] occupying an important position in the eld of organic synthesis and medicinal chemistry, have never been documented to install a deuterium-containing stereogenic center in heterocyclic adducts presumably due to the difficulty and unavailability of generating the corresponding deuteriumcontaining starting materials or key intermediates.…”

Bioinspired Metalation of the Metal‐Organic Framework MIL‐125‐NH2 for Photocatalytic NADH Regeneration and Gas‐Liquid‐Solid Three‐Phase Enzymatic CO2 Reduction

“…[7][8][9] Such process usually requires the stoichiometric consumption of NADH for sustained CO 2 reduction, which necessitates the regeneration of NADH. [10][11][12] Over the years, various methods have been developed to regenerate NADH, including enzymatic, chemical, electrochemical and photocatalytic routes. [13][14][15][16] Among them, light-driven NADH regeneration, featuring green, economic and sustainable nature, has aroused great attention recently.…”

“…Among various redox enzymes in biocatalysis, formate dehydrogenase (FDH) converts CO 2 to formic acid by activating thermodynamically unfavorable CO 2 reduction process through the stabilization of intermediates via proton‐coupled electron‐transfer reactions [7‐9] . Such process usually requires the stoichiometric consumption of NADH for sustained CO 2 reduction, which necessitates the regeneration of NADH [10‐12] . Over the years, various methods have been developed to regenerate NADH, including enzymatic, chemical, electrochemical and photocatalytic routes [13‐16] .…”