Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent “Ene”-Reductases

Abstract

𝛼-tertiary amines are a common motif in pharmaceutically important molecules but are challenging to prepare using asymmetric catalysis. Here, we demonstrate engineered flavin-dependent 'ene'-reductases (EREDs) can catalyze radical additions into oximes to prepare this motif. Two different EREDs were evolved into competent catalysts for this transformation with high levels of stereoselectivity. Mechanistic studies indicate that the oxime contributes to the enzyme templated CTcomplex formed between the substrate and cofactor. These products can be further derivatized to prepare a variety of motifs, highlighting the versatility of ERED photoenzymatic catalysis for organic synthesis.

Photobiocatalysis for Abiological Transformations

“…They later extended the strategy of photoexcitation to flavoenzymes and discovered photoexcitation of an alkene-tethered α-chloroamide-flavin EDA complex in ene-reductases (EREDs) permitted an asymmetric reductive cyclization for the production of five- to eight-membered lactams with a β- or γ-stereocenter (Figure B) . Very recently, they expanded the scope of the reductive cyclization to chiral tertiary amine synthesis by altering the radical acceptor from a tethered CC double bond to an oxime . They further used an intramolecular aromatic ring to trap the photogenerated α-amido carbon radicals when developing a stereoselective redox neutral cyclization to create chiral oxindoles (Figure C) .…”

Trendbericht Biochemie 2022: Enzyme in neuem Licht

“…Beispielsweise sind α-tertiäre Amine durch stereoselektive radikalische Addition an Oxime und anschließende chemische Reduktion der gebildeten Hydroxylamine zugänglich (Abbildung c). 6) In vielen Fällen optimierten gezielte Mutationen im aktiven Zentrum die Effizienz und Selektivität der photoenzymatischen Katalyse. Daher arbeiten immer mehr Forschungsgruppen an der gerichteten Evolution von Photoenzymen.…”

A Photoenzyme for Challenging Lactam Radical Cyclizations

“…While the hallmark of this reactivity is high enantioselectivity, we recognized that preferential formation of the lactam product would be synthetically valuable. [21][22][23][24][25][26][27][28] We attribute the high level of product selectivity to the enzyme selectively binding the cis-amide isomer, preorganizing the substrate for cyclization. 21 We found that a small collection of ERED homologues can facilitate different amide radical cyclization.…”