An asymmetric sp3–sp3 cross-electrophile coupling using ‘ene’-reductases

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

“…Recently, we reported that flavin-dependent "ene"-reductases (EREDs) can catalyze asymmetric cross-electrophile coupling (XEC) between alkyl halides and nitroalkanes. 10 This reaction involved the formation of an alkyl radical reacting with the nitronate to form a nitro radical anion. Enzyme-mediated mesolytic cleavage forms a tertiary radical that could be stereoselectively quenched via hydrogen atom transfer (HAT).…”

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

“…Enzyme-mediated mesolytic cleavage forms a tertiary radical that could be stereoselectively quenched via hydrogen atom transfer (HAT). 10 We envisioned the identification and evolution of an enzyme that could favor oxidation of the nitro radical anion to synthesize tertiary nitroalkanes (Figure 1B). Photoinduced reduction of the alkyl halide 1 gives an alkyl radical 4 that can add to an in situ-generated nitronate 5 to forge a new C-C bond and a nitro radical anion 6, which can be terminated through single-electron oxidation to afford the C-alkylated nitroalkane 3 (Figure 1B).…”

“…A variety of α-benzyl nitroalkanes are well accepted as C-alkylation acceptors with αchloroamide 1a. α-Benzyl nitroalkanes possessing electron-donating or electron-withdrawing substituents at the ortho, meta, and para positions were efficiently converted to the desired enantioenriched β-stereogenic tetrasubstituted nitroamides (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) in yields of 56-98% with high levels of enantioselectivity (>93:7 er, Figure 3). Furthermore, GkOYE-G7 also accommodates the larger α-naphthalenylmethyl substituted nitroalkane, providing the corresponding product 17 (60% yield, 93:7 er,).…”

“…14 We recently demonstrated that CsER can efficiently catalyze the reductive XEC between 1a and α-aryl nitroalkanes 38 to provide β-stereogenic amides 39b-43b as the major products in high yields and enantioselectivities (82-93% yield, up to 99:1 er), only a minimal amount of C-alkylated products 39a-43a were observed (b/a > 27:1, Figure 4). 10 Remarkably, when the engineered GkOYE-G7 was used under identical reaction conditions, the product selectivity is reversed, forming the Calkylated nitroalkanes 39a-43a as the major products (65-92%, up to 99:1 er) and negligible formation of the XEC products 39b-43b (a/b > 25:1, Figure 4). Note that the NADPH turnover system (NADP + /GDH/glucose) is not required for the GkOYE-G7-catalyzed redox-neutral C-alkylation of nitroalkanes (SI page 49-53), nevertheless, it was supplied to enable direct comparison.…”

“…18 Having ruled out ground-state FMNsq, ground-state, or excited-state FMNhq as a reductant, we hypothesized that an enzyme-templated charge-transfer (CT) complex was responsible for reducing α-chloroamide 1a over the thermodynamically favored nitroalkane 2a. 10,11,19 To probe this possibility, when flavin mononucleotide (FMN) in GkOYE-G7 was fully reduced to FMNhq with sodium dithionite, a diagnostic FMNhq spectrum with minimal absorption longer than 460 nm was observed (Figure 6B). Upon the addition of chloroamide 1a, a new broad absorption band (450-470 nm) was observed, suggesting the formation of a CT complex between the FMNhq and 1a (Figure 6B).…”