Quaternary Charge-Transfer Complex Enables Photoenzymatic Intermolecular Hydroalkylation of Olefins

Abstract

Intermolecular C−C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent 'ene'-reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, αchloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.

Ground-State Electron Transfer as an Initiation Mechanism for Asymmetric Hydroalkylations in Radical Biocatalysis

“…Overall, our study showcases how non-natural reactivities of native EREDs can be exploited, which also can be further enhanced by protein engineering, if needed, to expand the biocatalyst toolbox and address the long-standing selectivity challenge in radical chemistry. We foresee EREDs and other flavin-dependent enzymes can be further leveraged to generate new synthetically applicable reactivities; this is particularly true as other fields, such as photocatalysis, [20][21][22][35][36][37] are increasingly merging with biocatalysis. 38,39…”

“…In the absence of such a mechanism, we would expect to form the hydrodehalogenated product primarily. 21 We tested a panel of wild-type EREDs on the intermolecular hydroalkylation of αbromo acetophenone 11a with α-methyl styrene 12a to provide γ-stereogenic ketone 13a (Supplementary Table 11). Several EREDs afforded the coupled product, demonstrating the feasibility of our hypothesis.…”

“…19 Interestingly, this mechanism can accommodate modestly endergonic electron transfers, making it ideal for α-bromoesters and ketones while also avoiding the need for more complicated photoinduced electron transfer mechanisms that are required for less oxidizing substrates. [20][21][22] Inspired by the simplicity of this initiation mechanism, we questioned whether it could be used for the asymmetric hydroalkylation of olefins, a challenging transformation to render asymmetric using small molecule catalysts. 6,7 As a model, we targeted the cyclization of α-bromoketones 1 to afford βstereogenic cyclopentanone 2 (Fig.…”

Recent trends in biocatalysis

“…Based on similar principles, photocatalytic dehalogenations generated radicals suitable for cyclisation and intermolecular hydroalkylation reactions in the active sites of double bond reductases (''ene reductases'') as protein scaffolds, [496][497][498][499] where a flavin mononucleotide acts as photoredox catalyst for electron and hydrogen transfer reactions. One example is the construction of b-chiral lactams, a motif found, for example, in the antiepileptic drug brivaracetam.…”

“…Interestingly, this radical addition to a double bond is also possible in an intermolecular manner: in this case, a quaternary charge transfer complex suitable for excitation is formed between the protein, FMN hydroquinone, α-chloroamide, and the alkene substrate ( Scheme 16D ). 497 Due to its modularity regarding the choice of different substrates, this hydroalkylation approach is a valuable tool for asymmetric C–C bond formation and creates a stereocentre in the γ-position of the amide function. In addition to α-halogenated ester or amide substrates, the photocatalytic approach was recently also expanded to N -alkyl-iodides, which yield unstabilised radical intermediates after the initial dehalogenation ( Scheme 16E ).…”