Braca

Nature Communications, Published online: 14 December 2023; doi:10.1038/s41467-023-44097-y

Selective defluorinative functionalization is a synthetic route to pharmaceutically important fluorine-containing compounds but activation of inert C–F bonds remains challenging. Here the authors report activation of di-or trifluoromethylated arenes for radical C–N coupling with carbazoles and aromatic amines using photoexcited copper catalysis.

Intermolecular functionalization of tertiary C–H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, the state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp3-carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C–H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme’s remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst’s compatibility with diverse functional groups and tertiary C–H bonds. Mechanistic studies, incorporating both experimental and computational data, elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity.

The carbene transfer reaction was realized in the biosynthetic pathway. Using L-limonene as the precursor, L-carveol was biotransformed by P411-PFA to generate unnatural terpenoid derivatives with trifluoromethyl group.

Abstract

Protein engineering of cytochrome P450s has enabled these biocatalysts to promote a variety of abiotic reactions beyond nature‘s repertoire. Integrating such non-natural transformations with microbial biosynthetic pathways could allow sustainable enzymatic production of modified natural product derivatives. In particular, trifluoromethylation is a highly desirable modification in pharmaceutical research due to the positive effects of the trifluoromethyl group on drug potency, bioavailability, and metabolic stability. This study demonstrates the biosynthesis of non-natural trifluoromethyl-substituted cyclopropane derivatives of natural monoterpene scaffolds using an engineered cytochrome P450 variant, P411-PFA. P411-PFA successfully catalyzed the transfer of a trifluoromethyl carbene from 2-diazo-1,1,1-trifluoroethane to the terminal alkenes of several monoterpenes, including L-carveol, carvone, perilla alcohol, and perillartine, to generate the corresponding trifluoromethylated cyclopropane products. Furthermore, integration of this abiotic cyclopropanation reaction with a reconstructed metabolic pathway for L-carveol production in Escherichia coli enabled one-step biosynthesis of a trifluoromethylated L-carveol derivative from limonene precursor. Overall, amalgamating synthetic enzymatic chemistry with established metabolic pathways represents a promising approach to sustainably produce bioactive natural product analogs.

Reported here is a radical-based three-component defluorinative alkylboration of alkenes with trifluoromethyls and bis(pinacolato)diboron via dual photoredox/copper catalysis. This protocol offers efficient access to synthetically valuable γ-gem-difluoroalkyl boronates with high efficiency and reversed regioselectivity.

Abstract

A regioselectivity reversed three-component defluorinative alkylboration of alkenes with trifluoromethyls and bis(pinacolato)diboron via dual photoredox/copper catalysis is reported. The mild conditions are compatible with a wide array of nonactivated trifluoromethyl aromatics bearing electron-donating or electron-neutral substituents, trifluoroacetamides, and various nonactivated terminal and internal alkenes, enabling straightforward access to synthetically valuable γ-gem-difluoroalkyl boronates with high efficiency. Furthermore, this protocol is applicable to alkene-tethered trifluoromethyl aromatics to furnish gem-difluoromethylene-containing cyclic compounds. Synthetic applications and preliminary mechanistic studies are also presented.

Nature Catalysis, Published online: 06 December 2023; doi:10.1038/s41929-023-01068-2

Chiral lactams are important pharmacophores and strategies for their synthesis through direct C–H functionalization are highly sought after. Now, intramolecular C–H amidation of dioxazolones via biocatalytic nitrene transfer enables the synthesis of enantioenriched lactams with various ring sizes.

Nature Chemistry, Published online: 06 December 2023; doi:10.1038/s41557-023-01385-w

Methods for transition-metal-catalysed enantioselective C(sp3)–S bond construction are underdeveloped. Now, by taking advantage of the biomimetic radical homolytic substitution manifold, the copper-catalysed enantioconvergent C(sp3)–S cross-coupling of racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles has been realized. This reaction provides access to an array of α-chiral alkyl organosulfur compounds.

We report a vitamin B₁₂-photocatalyzed strategy for the cyclopropanation of electron-deficient alkenes using dichloromethane (CH₂Cl₂) as the methylene source. The reaction has excellent functional group tolerance, is highly chemoselective, and the scope can be extended to other 1,1-dichloroalkanes for the preparation of D₂-cyclopropyl and methyl-substituted cyclopropyl adducts, all of which are important isosteres in medical chemistry.

Abstract

The cyclopropyl group is of great importance in medicinal chemistry, as it can be leveraged to influence a range of pharmaceutical properties in drug molecules. This report describes a Vitamin B₁₂-photocatalyzed approach for the cyclopropanation of electron-deficient alkenes using dichloromethane (CH₂Cl₂) as the methylene source. The reaction proceeds in good to excellent yields under mild conditions, has excellent functional group compatibility, and is highly chemoselective. The scope could also be extended to the preparation of D₂-cyclopropyl and methyl-substituted cyclopropyl adducts starting from CD₂Cl₂ and 1,1-dichloroethane, respectively.

Science, Volume 382, Issue 6674, Page 1056-1065, December 2023.

A mild electrocatalytic system is reported for the reductive alkylation of primary, secondary, or tertiary alkyl chlorides with conjugated alkenes.

Abstract

Reactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt-catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes. Co-catalyzed activation of alkyl chlorides is performed under electroreductive conditions, and the resulting reactions constitute formal alkyl-alkyl bond formation. In addition to developing an operationally simple methodology, detailed mechanistic studies provide insights into the elementary steps of a proposed catalytic cycle. In particular, we propose a switch in the mechanism of C−Cl bond activation from nucleophilic substitution to halogen atom abstraction, which is critical for efficiently generating alkyl radicals. These mechanistic insights were leveraged in designing ligands that enable couplings of primary, secondary, and tertiary alkyl chlorides.

The development of new methods for enantioselective reactions that generate stereogenic centres within molecules is a cornerstone of organic synthesis. In this minireview we highlight the recent advances in enantioselective main group catalysis of the p-block elements including boron, phosphorus, bismuth and aluminium.

Abstract

The development of new methods for enantioselective reactions that generate stereogenic centres within molecules are a cornerstone of organic synthesis. Typically, metal catalysts bearing chiral ligands as well as chiral organocatalysts have been employed for the enantioselective synthesis of organic compounds. In this review, we highlight the recent advances in main group catalysis for enantioselective reactions using the p-block elements (boron, aluminium, phosphorus, bismuth) as a complementary and sustainable approach to generate chiral molecules. Several of these catalysts benefit in terms of high abundance, low toxicity, high selectivity, and excellent reactivity. This minireview summarises the utilisation of chiral p-block element catalysts for asymmetric reactions to generate value-added compounds.

Metallaphotoredox cross-coupling is a well-established strategy for generating clinically privileged aliphatic scaffolds via open-shell reactivity. The introduction of new C(sp3)-coupling partners within this paradigm can provide entry to novel, medicinally-relevant chemical space. Alkenes are abundant, bench-stable and undergo facile C(sp3)-radical reactivity via metal-hydride hydrogen atom transfer (MHAT), yet metallaphotoredox methodologies invoking this strategy remain underdeveloped. Importantly, the merger of MHAT activation with metallaphotoredox catalysis could enable cross-coupling of olefins with feedstock radical partners only activated via photocatalysis, such as alcohols. Herein, we report the first C(sp3)–C(sp3) coupling of MHAT-activated alkenes with alcohols (i.e. deoxygenative hy-droalkylation) via triple co-catalysis. Through synergistic Ir photocatalysis, Mn MHAT and Ni radical sorting pathways, this branch-selective protocol pairs diverse olefins with methanol or primary alcohols, displays remarkable functional group tolerance, and enables the rapid construction of complex aliphatic frameworks.

We report a vitamin B₁₂-photocatalyzed strategy for the cyclopropanation of electron-deficient alkenes using dichloromethane (CH₂Cl₂) as the methylene source. The reaction has excellent functional group tolerance, is highly chemoselective, and the scope can be extended to other 1,1-dichloroalkanes for the preparation of D₂-cyclopropyl and methyl-substituted cyclopropyl adducts, all of which are important isosteres in medical chemistry.

Abstract

The cyclopropyl group is of great importance in medicinal chemistry, as it can be leveraged to influence a range of pharmaceutical properties in drug molecules. This report describes a Vitamin B₁₂-photocatalyzed approach for the cyclopropanation of electron-deficient alkenes using dichloromethane (CH₂Cl₂) as the methylene source. The reaction proceeds in good to excellent yields under mild conditions, has excellent functional group compatibility, and is highly chemoselective. The scope could also be extended to the preparation of D₂-cyclopropyl and methyl-substituted cyclopropyl adducts starting from CD₂Cl₂ and 1,1-dichloroethane, respectively.

A directed evolution strategy called corner engineering was developed to tailor enzyme resistance towards deep eutectic solvents (DESs) and high temperatures.

Abstract

Deep eutectic solvents (DESs), heralded for their synthesis simplicity, economic viability, and reduced volatility and flammability, have found increasing application in biocatalysis. However, challenges persist due to a frequent diminution in enzyme activity and stability. Herein, we developed a general protein engineering strategy, termed corner engineering, to acquire DES-resistant and thermostable enzymes via precise tailoring of the transition region in enzyme structure. Employing Bacillus subtilis lipase A (BSLA) as a model, we delineated the engineering process, yielding five multi-DESs resistant variants with highly improved thermostability, such as K88E/N89 K exhibited up to a 10.0-fold catalytic efficiency (k _cat/K _M) increase in 30 % (v/v) choline chloride (ChCl): acetamide and 4.1-fold in 95 % (v/v) ChCl: ethylene glycol accompanying 6.7-fold thermal resistance improvement than wild type at ≈50 °C. The generality of the optimized approach was validated by two extra industrial enzymes, endo-β-1,4-glucanase PvCel5A (used for biofuel production) and esterase Bs2Est (used for plastics degradation). The molecular investigations revealed that increased water molecules at substrate binding cleft and finetuned helix formation at the corner region are two dominant determinants governing elevated resistance and thermostability. This study, coupling corner engineering with obtained molecular insights, illuminates enzyme-DES interaction patterns and fosters the rational design of more DES-resistant and thermostable enzymes in biocatalysis and biotransformation.

Engineered enzymes provide a green chemistry solution for synthesis of complex molecules.

Single component flavin-dependent halogenases (FDHs) possesses both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C-H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1’-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.