Biocatalytic Enantioselective β‐Hydroxylation of Unactivated C−H Bonds in Aliphatic Carboxylic Acids

Abstract

Catalytic selective hydroxylation of unactivated aliphatic (sp 3 ) CÀ H bonds without a directing group represents a formidable task for synthetic chemists. Through directed evolution of P450 BSβ hydroxylase, we realize oxyfunctionalization of unactivated CÀ H bonds in a broad spectrum of aliphatic carboxylic acids with varied chain lengths, functional groups and (hetero-)aromatic moieties in a highly chemo-, regio-and enantioselective fashion (> 30 examples, Cβ/ Cα > 20 : 1, > 99 % ee). The X-ray structure of the evolved variant, P450 BSβ -L78I/Q85H/G290I, in complex with palmitic acid well rationalizes the experimentally observed regio-and enantioselectivity, and also reveals a reduced catalytic pocket volume that accounts for the increased reactivity with smaller substrates. This work showcases the potential of employing a biocatalyst to enable a chemical transformation that is particularly challenging by chemical methods.

Hydrogen‐Bonded Organic Frameworks: Structural Design and Emerging Applications

“…Furthermore, Qu and coworkers reported a twophoton catalysis with HOFs binding of tetrakis carboxyphenyl porphyrin groups. [44] Singlet oxygen was generated from HOFs under 1040 nm light irradiation, which could be used for the oxygenation of β-amyloid. In vivo experiment proved that the self-assembly and aggregation of β-amyloid were efficiently reduced.…”

“…The results showed promising applications of HOF materials during NSC transplantation for neurogenesis and cognitive impairment improvement. Furthermore, Qu and coworkers reported a two‐photon catalysis with HOFs binding of tetrakis carboxyphenyl porphyrin groups [44] . Singlet oxygen was generated from HOFs under 1040 nm light irradiation, which could be used for the oxygenation of β‐amyloid.…”

Hot off the Press

“…Directed evolution of a P450 hydroxylase has produced a biocatalyst that can perform β-hydroxylation of unactivated C–H bonds of aliphatic carboxylic acids (Scheme 1). 29 X-Ray crystallography of the evolved variant shows a catalytic pocket with reduced volume that accounts for the observed regio- and enantioselectivity. Preparative scale synthesis of stilbenoids via regioselective hydroxylation by recently discovered P450 monooxygenases from the white-rot fungus Polyporus arcularius has been investigated.…”

Manganese-Catalyzed Regioselective C–H Lactonization and Hydroxylation of Fatty Acids with H2O2

“…In this contribution, we present a novel manganese complex of the bis-amino-bis-pyridine family, capable of catalyzing direct oxidation of fatty acids into the corresponding γ- or δ-lactones with H 2 O 2 with high and tunable regioselectivity. For C7+ acids, the selectivity can be diverted toward synthetically challenging (ω-1)-hydroxylation.…”

“…33 In this contribution, we present a novel manganese complex of the bis-amino-bispyridine family, capable of catalyzing direct oxidation of fatty acids into the corresponding γor δ-lactones with H 2 O 2 with high and tunable regioselectivity. For C7+ acids, the selectivity can be diverted toward synthetically challenging 34 (ω-1)hydroxylation. The novel manganese(II) complex (S,S)-7 was synthesized from the corresponding substituted bis-amino-bis-pyridine ligand and Mn(OTf) 2 (Figure 1; see the Supporting Information (SI) for details).…”