Catalytic promiscuity enabled by photoredox catalysis in nicotinamide-dependent oxidoreductases

Abstract

Strategies that provide enzymes with the ability to catalyse non-natural reactions are of considerable synthetic value. Photoredox catalysis has proved adept at expanding the synthetic repertoire of existing catalytic platforms, yet, in the realm of biocatalysis it has primarily been used for cofactor regeneration. Here we show that photoredox catalysts can be used to enable new catalytic function in nicotinamide-dependent enzymes. Under visible-light irradiation, xanthene-based photocatalysts enable a double-bond reductase to catalyse an enantioselective deacetoxylation. Mechanistic experiments support the intermediacy of an α-acyl radical, formed after the elimination of acetate. Isotopic labelling experiments support nicotinamide as the source of the hydrogen atom. Preliminary calculations and mechanistic experiments suggest that binding to the protein attenuates the reduction potential of the starting material, an important feature for localizing radical formation to the enzyme active site. The generality of this approach is highlighted with the radical dehalogenation of α-bromoamides catalysed by ketoreductases with Eosin Y as a photocatalyst.

Broadening the Scope of Biocatalysis in Sustainable Organic Synthesis

“…Predictably, research has focused on the historically readily available hydrolases, such as the catalysis of the Morita–Baylis–Hillman reaction (which does not occur in nature) by esterases and lipases, and lipase‐catalyzed aldol reactions . However, the enzyme range is expanding to include enzymes such as NAD(P)‐dependent oxidoreductases, decarboxylases, and many others . Interestingly, a single enzyme, MhyADH, derived from a cyclohexanol‐degrading bacterium, catalyzed both the Michael addition of water to α,β‐unsaturated carbonyl compounds and the enantioselective oxidation of the resulting alcohol (Scheme )…”

Biocatalysis Fueled by Light: On the Versatile Combination of Photocatalysis and Enzymes

“…Extension of the enzymatic reaction scope to unnatural reactivities represents a striking concept for overcoming the current boundaries of biocatalytic reactions. Hyster and co‐workers recently presented an innovative strategy for accessing unprecedented reactivities at the interface of photocatalysis and protein science . Irradiation of a genetically engineered.…”

“…In a follow‐up study, this concept was extended to enantioselective deacetoxylations of α‐acetoxyketones 121 by the use of the nicotinamide‐dependent ER from Nicotiana tabacum ( Nt ER) and Rose Bengal ( 16 a ) as photosensitizer (Scheme ). The proposed mechanism involved initiation by photoexcited 16 a , oxidizing NA(D)PH ( 13 ) to form RB .− radical anion and NA(D)PH .+ .…”

“…Extension of the enzymatic reaction scope to unnatural reactivities represents as triking concept for overcoming the current boundaries of biocatalytic reactions.H yster and co-workers recently presented an innovative strategy for accessing unprecedented reactivities at the interface of photocatalysis and protein science. [21,102] Irradiation of ag enetically engineered. Irradiation of LKADHw ith blue light enabled the mesolytic cleavage of the halide moiety in compounds 117,f orming the prochiral radicals 118.S ubsequentH AT then gave the chiral lactone products 119 (Scheme 27 A).…”

“…In af ollow-up study, [102] this concept was extended to enantioselective deacetoxylations of a-acetoxyketones 121 by the use of the nicotinamide-dependentE Rf rom Nicotiana tabacum (NtER) and Rose Bengal (16 a)a sp hotosensitizer (Scheme 28). The proposed mechanism involved initiation by photoexcited 16 a,o xidizingN A(D)PH (13)t of orm RBC À radical anion and NA(D)PHC + .At yrosine residue in NtER was thought to be responsible for substrate binding and might attenuate the redox potentialo ft he substrate in order to enable SET from RBC À to the substrate 121.T his adjustment is crucial, because RBC À was unable to reduce 121 in solution withoute nzyme.…”