Radical Termination via β-Scission Enables Photoenzymatic Allylic Alkylation Using “Ene”-Reductases

Abstract

Allylations are practical transformations that forge C–C bonds while introducing an alkene for further chemical manipulations. Here, we report a photoenzymatic allylation of α-chloroamides with allyl silanes using flavin-dependent “ene”-reductases (EREDs). An engineered ERED can catalyze annulative allylic alkylation to prepare 5, 6, and 7-membered lactams with high levels of enantioselectivity. Ultrafast transient absorption spectroscopy indicates that radical termination occurs via β-scission of the silyl group to afford a silyl radical, a distinct mechanism by comparison to traditional radical allylations involving allyl silanes. Moreover, this represents an alternative strategy for radical termination using EREDs. This mechanism was applied to intermolecular couplings involving allyl sulfones and silyl enol ethers. Overall, this method highlights the opportunity for EREDs to catalyze radical termination strategies beyond hydrogen atom transfer.

Photobiocatalytic Strategies for Organic Synthesis

“…The β-scission strategy was also extended to other cleavable groups, such as sulfones and silyl enol ethers (Figure 27B). 97 Cross-electrophile couplings are difficult to achieve using traditional metal catalysis due to the metal's inability to distinguish between coupling partners. 98 They are also difficult to render asymmetric.…”

“…Intermolecular couplings were also afforded to form amides with terminal alkenes. The β-scission strategy was also extended to other cleavable groups, such as sulfones and silyl enol ethers (Figure B) …”

Photoenzymatic Enantioselective Synthesis of Oxygen‐Containing Benzo‐Fused Heterocycles

“…Versatile benzo‐fused products with multifarious functional groups and different ring sizes are successfully obtained in high yields and great enantioselectivities by variant GluER‐W100H (Figure 1d). Different from other reported photoenzymatic intramolecular hydroalkylation reaction of alkenes towards monocyclic rings, [23a–e] this work demonstrates a rare platform for the enantioselective synthesis of a series of rigid bicyclic compounds through hydroalkylation reaction.…”

Non‐native Intramolecular Radical Cyclization Catalyzed by a B12‐Dependent Enzyme**

“…Mono-substituted olefin product 15 b was obtained from allyl sulfone 15 a. [37] Alkyl bromide 16 a also reacted with CarH* to give pyrrolidine 16 b, albeit in relatively low yield, even with prolonged time. [38] These examples show that CarH* can not only accommodate different radical acceptors for diverse annulation reactions but also manage redox-neutral and net reductive transformations under generalized conditions.…”