Photoenzymatic Asymmetric Hydroamination for Chiral Alkyl Amine Synthesis

Abstract

Chiral alkyl amines are common structural motifs in pharmaceuticals, natural products, synthetic intermediates, and bioactive molecules. An attractive method to prepare these molecules is the asymmetric radical hydroamination; however, this approach has not been explored with dialkyl amine-derived nitrogen-centered radicals since designing a catalytic system to generate the aminium radical cation, to suppress deleterious side reactions such as α-deprotonation and H atom abstraction, and to facilitate enantioselective hydrogen atom transfer is a formidable task. Herein, we describe the application of photoenzymatic catalysis to generate and harness the aminium radical cation for asymmetric intermolecular hydroamination. In this reaction, the flavin-dependent ene-reductase photocatalytically generates the aminium radical cation from the corresponding hydroxylamine and catalyzes the asymmetric intermolecular hydroamination to furnish the enantioenriched tertiary amine, whereby enantioinduction occurs through enzyme-mediated hydrogen atom transfer. This work highlights the use of photoenzymatic catalysis to generate and control highly reactive radical intermediates for asymmetric synthesis, addressing a long-standing challenge in chemical synthesis.

Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation

“…Over the past several years, using visible light to unveil novel enzymatic activities, photobiocatalysis has emerged as an appealing strategy for discovering synthetically useful radical reactions, − including those that are not known in either organic chemistry or enzymology. − By leveraging the intimate substrate–protein interactions within the enzyme’s active site, photobiocatalysis illuminates a new avenue to exert stereocontrol over free radical-mediated transformations, a challenging task eluding small-molecule catalysts. − By capitalizing on the excited-state cofactor redox properties of NAD(P)H- ,,− and flavin-dependent − ,− enzymes, including ketoreductases (KREDs), ,,, ene reductases (EREDs) ,,,− imine reductases (IREDs), and fatty acid photodecarboxylases (FAPs), a range of photoenzymatic radical transformations not encountered in the biological world were developed. Recently, by exploiting the synergy between well-established photoredox catalysts and biocatalysts, cooperative photobiocatalysis has allowed the repurposing of a wider range of enzymes, ,,− …”

Asymmetric photoenzymatic incorporation of fluorinated motifs into olefins

“…The surge of interest in photoenzymes has unlocked pathways for extending enzymatic catalysis into uncharted terrain ( 25 – 32 ). Key among these are transformations involving flavin mononucleotide (FMN)–dependent reductases, which have demonstrated potential in modulating the enantioselectivity of prochiral carbon-centered radicals through enantioselective hydrogen atom transfer (HAT) ( 25 – 28 , 33 – 40 ). These enzyme-facilitated reactions typically use photoinduced electron transfer to elevate the substrate to a high-energy and unstable state, followed by the departure of a leaving group (LG), and culminating in radical formation and capture.…”