Synthesis of Chiral Sulfoxides by A Cyclic Oxidation-Reduction Multi-Enzymatic Cascade Biocatalysis.

Optically pure sulfoxides are valuable organosulfur compounds extensively employed in medicinal and organic synthesis. In this study, we present a biocatalytic oxidation-reduction cascade system designed for the preparation of enantiopure sulfoxides. The system involves the cooperation of a low-enantioselective chimeric oxidase SMO (styrene monooxygenase) with a high-enantioselective reductase MsrA (methionine sulfoxide reductase A), facilitating "non-selective oxidation and selective reduction" cycles for prochiral sulfide oxidation. The regeneration of requisite cofactors for MsrA and SMO was achieved via a cascade catalysis process involving three auxiliary enzymes, sustained by cost-effective D-glucose. Under the optimal reaction conditions, a series of heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were synthesized through this "one-pot, one step" cascade reaction. The obtained compounds exhibited high yields of >90 % and demonstrated enantiomeric excess (ee) values exceeding 90 %. This study represents an unconventional and efficient biocatalytic way in utilizing the low-enantioselective oxidase for the synthesis of enantiopure sulfoxides.

Photomediated One-Pot Three-Component Approach Enables the Formal Direct N-Acylation/Sulfonylation and α-C-H Functionalization of 1,2,3,4-Tetrahydroisoquinoline.

N-Acyl/sulfonyl-α-functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs) are significant structural motifs in organic synthesis and drug discovery. However, the one-pot approach enabling direct difunctionalization of THIQs remains challenging. Herein we report a photomediated one-pot three-component strategy to access N-acyl/sulfonyl-α-functionalized THIQs. This method features the use of oxygen (from air) as the green oxidant, high atom and step economy, and decent structural diversity. The synthetic applicability of the method was further demonstrated via the facile construction of valuable bioactive molecules. Mechanistic studies indicated that oxidation with singlet oxygen and the acceptor-less dehydrogenation were involved in the photoredox process.

Iodomethane in C1 chemistry: application in palladium-catalyzed [2 + 2 + 1] annulation.

An efficient palladium-catalyzed [2 + 2 + 1] annulation of 3-iodochromones, bridged olefins, and iodomethane is described, affording a range of chromone-containing polycyclic compounds. Additionally, the corresponding deuterated products were smoothly obtained with iodomethane-d3 instead of iodomethane. Moreover, the synthetic utility of this method is further substantiated by gram scale preparation and application to late-stage modification of estrone.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF3 C+ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF3 C+ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF3 C+ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD3 -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Asymmetric Bio-epoxidation of Unactivated Alkenes.

Optically active epoxides play important roles in pharmaceutical, agricultural and fine chemical syntheses. There are many chiral medications with pharmacodynamic activity in nature that can be synthesized by chiral epoxides. In recent years, researchers have developed a variety of biocatalysts for the asymmetric epoxidation of alkenes, which use oxygen or hydrogen peroxide as eco-friendly and low-cost oxidants, to provide better chemo-, regio- and stereoselectivity under moderate reaction conditions. In this paper, the advances, opportunities and challenges of the asymmetric epoxidation of unactive alkenes by biocatalyst are reviewed.

Cooperative Tertiary Amine/Palladium-Catalyzed Sequential [4 + 3] Cyclization/[1,3]-Rearrangement for Stereoselective Synthesis of Spiro [Methylenecyclopentane-1,3'-oxindolines].

A cooperative tertiary amine/palladium-catalyzed sequential reaction process, proceeding via a [4 + 3] cyclization of isatin-derived Morita-Baylis-Hillman Expansion (MBH) carbonates and tert-butyl 2-(hydroxymethyl)allyl carbonates followed by a [1,3]-rearrangement, has been found and developed. A range of structurally diverse spiro[methylene cyclopentane-1,3'-oxindolines] bearing two adjacent ß,γ-acyl quaternary carbon stereocenters, which are difficult to obtain by conventional strategies, were obtained in good yields. Further synthetic utility of this protocol is highlighted by its excellent regio- and stereocontrol as well as the large-scale synthesis and diverse functional transformations of the synthetic compounds. Moreover, the control experiments probably established the plausible mechanism for this sequential [4 + 3] cyclization/[1,3]-rearrangement process.

Electrochemically Enabled Intramolecular Amino- and Oxysulfonylation of Alkenes with Sodium Sulfinates to Access Sulfonylated Saturated Heterocycles.

A practical and efficient electrochemical intramolecular amino- or oxysulfonylation of internal alkenes equipped with pendant nitrogen or oxygen-centered nucleophiles with sodium sulfinate was developed. Under undivided electrolytic cell conditions, a variety of sulfonylated N-heterocycles and O-heterocycles, such as tetrahydrofurans, tetrahydropyrans, oxepanes, tetrahydropyrroles, piperidines, δ-valerolactones, etc., were efficiently prepared from easily accessible unsaturated alcohols, carboxylic acids, and N-tosyl amines without the need for additional metal or exogenous oxidant. The robust electrochemical transformation features excellent redox economy, high diastereoselectivity, and broad substrate specificity, which provide a general and practical access to sulfone-containing heterocycles and would facilitate the related synthetic and biological studies based on this electrosynthesis.

Kinetic resolution of sulfoxides with high enantioselectivity using a new homologue of methionine sulfoxide reductase B.

Optically pure sulfoxides are noteworthy compounds that find wide applications in various industrial fields. Here, we report a methionine sulfoxide reductase B (MsrB) homologue that exhibits high enantioselectivity and broad substrate scope for the kinetic resolution of racemic (rac) sulfoxides. This MsrB homologue, named liMsrB, was identified from Limnohabitans sp. 103DPR2 and showed good activity together with enantioselectivity towards a series of aromatic, heteroaromatic, alkyl and thioalkyl sulfoxides. Chiral sulfoxides in the S configuration were prepared in approximately 50% yield and 92-99% enantiomeric excess through kinetic resolution at an initial substrate concentration of up to 90 mM (11.2 g L-1). This study presents an efficient route for the enzymatic preparation of (S)-sulfoxides through kinetic resolution.

Enantiocomplementary synthesis of ß-adrenergic blocker precursors via biocatalytic nitration of phenyl glycidyl ethers.

Enantiopure ß-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of ß-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral ß-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee). In addition, we also demonstrated that the bio-nitration method was able to tolerate the substrate at a high concentration of 1000 mM (150 g/L). Furthermore, representative synthesis of two optically active enantiomers of the ß-adrenergic blocker metoprolol was successfully achieved by utilizing the corresponding chiral ß-nitroalcohols as precursors.

Synthesis of Enantioenriched Sulfoxides by an Oxidation-Reduction Enzymatic Cascade.

Chiral sulfoxides are versatile synthons and have gained a particular interest in asymmetric synthesis of active pharmaceutical and agrochemical ingredients. Herein, a linear oxidation-reduction bienzymatic cascade to synthesize chiral sulfoxides is reported. The extraordinarily stable and active vanadium-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) was used to oxidize sulfides into racemic sulfoxides, which were then converted to chiral sulfoxides by highly enantioselective methionine sulfoxide reductase A (MsrA) and B (MsrB) by kinetic resolution, respectively. The combinatorial cascade gave a broad range of structurally diverse sulfoxides with excellent optical purity (>99 %  ee) with complementary chirality. The enzymatic cascade requires no NAD(P)H recycling, representing a facile method for chiral sulfoxide synthesis. Particularly, the envisioned enzymatic cascade not only allows CiVCPO to gain relevance in chiral sulfoxide synthesis, but also provides a powerful approach for (S)-sulfoxide synthesis; the latter case is significantly unexplored for heme-dependent peroxidases and peroxygenases.

Copper-Catalyzed [5 + 1] Cyclization of o-Pyrrolo Anilines and Heterocyclic N-Tosylhydrazones for Access to Spiro-dihydropyrrolo[1,2-a]quinoxaline Derivatives.

An inexpensive copper-catalyzed sequential reaction process, proceeding via a nucleophilic attack of amine to Cu-carbene generated in situ from heterocyclic N-tosylhydrazone precursors followed by a 1,2-H shift/oxidative cyclization cascade of N-ylides, has been described, smoothly generating the corresponding structurally various spiro-dihydropyrrolo[1,2-a]quinoxaline derivatives. Furthermore, the significance of this protocol can be also highlighted by its diverse conversions of the synthetic compounds to the potentially bioactive molecules such as the 2-substituted pyrrolo[1,2-a]quinoxalins.

Enzymatic approaches to site-selective oxidation of quinoline and derivatives.

Enzyme-mediated oxidation has been a green and efficient strategy for preparation of derivative chemicals from quinoline and its structural analogues. Herein, we report the progress made to date in enzymatic methods to oxidation of the pyridine moieties of quinoline and its structural analogues 1,2,3,4-tetrahydroquinoline, isoquinoline and 1,2,3,4-tetrahydroisoquinoline, including whole cell- and isolated enzyme-based transformations. In addition, methods to tune the site selectivity of the course of enzymatic transformation are also addressed, in particular the protein engineering approaches.

Combined photoredox/engineered P450 enzymatic direct dioxygen-functionalization of arylalkanes to chiral acyloins.

To date, the examples of difunctionalization of alkanes to directly incorporate two functional groups are very limited. In this study, we combined photoorgano redox catalysis and P450 biocatalysts to obtain dioxygen-functionalization of α/ß-C-H bonds of arylalkanes in a straightforward manner. The synthesis of enantiomerically chiral acyloins through a one-pot two-step photoredox/P450-catalyzed cascade reaction is described. Two P450 mutants with stereocomplementary bio-oxidation were obtained using mutagenesis technology and were able to asymmetrically hydroxylate ketones to acyloins with excellent ee values, which were further proved to be efficient on a wide range of substrates. Moreover, a photoredox synthesis of ketones in situ was developed by the direct carbonylation of aromatic methyl C-H bonds and subsequently combined with the aerobic P450-biocatalytic enantioselective hydroxylation of intermediate ketones, thus providing a green and sustainable approach towards optically pure acyloins.

Management and prevention of brachial plexus injury caused by surgical suture of neck dissection induced chylous fistula.

BACKGROUND: The complication of brachial plexus injury (BPI) after surgical suture of chylous fistula caused by neck dissection is extremely rare. For the first time, we investigated the treatment and prevention strategy of BPI caused by surgical suture of neck dissection induced chylous fistula. METHODS: Forty-two patients undergoing surgical suture of neck dissection induced chylous fistula were identified between January 2015 to March 2022 at a single tertiary academic center. All patients were divided into two groups, medial anterior scalene muscle (MASM) group (24 patients) and lateral anterior scalene muscle (LASM) group (18 patients), according to the location of fistula regarding scalene muscle described in the surgical records. The incidence of BPI between the two groups after surgical suture was summarized and compared. RESULTS: There was significant difference in the incidence of different degrees of BPI between the two groups. In the MASM group, the incidence of BPI was 0 % (0/24), while in the LASM group, 6 cases suffered different degrees of BPI immediately after operation and the incidence of BPI was 33.3 % (6/18) (p < 0.05). The neurological function of all BPI cases recovered within 1-3 months after the suture was removed in time. CONCLUSION: The incidence of BPI in patients of LASM group was significantly higher than that of MASM group. When suturing this kind of fistula, the depth of the needle should be properly controlled to avoid BPI. In case of BPI, the suture should be removed as soon as possible to promote the recovery of neurological function.

Multienzyme Redox System with Cofactor Regeneration for Cyclic Deracemization of Sulfoxides.

Optically pure sulfoxides are noteworthy compounds applied in a wide range of industrial fields; however, the biocatalytic deracemization of racemic sulfoxides is challenging. Herein, a high-enantioselective methionine sulfoxide reductase A (MsrA) was combined with a low-enantioselective styrene monooxygenase (SMO) for the cyclic deracemization of sulfoxides. Enantiopure sulfoxides were obtained in >90 % yield and with >90 % enantiomeric excess (ee) through dynamic "selective reduction and non-selective oxidation" cycles. The cofactors of MsrA and SMO were subsequently regenerated by the cascade catalysis of three auxiliary enzymes through the consumption of low-cost D-glucose. Moreover, this "one-pot, one-step" cyclic deracemization strategy exhibited a wide substrate scope toward various aromatic, heteroaromatic, alkyl and thio-alkyl sulfoxides. This system proposed an efficient strategy for the green synthesis of chiral sulfoxide.

Identification and Structure Analysis of an Unusual Halohydrin Dehalogenase for Highly Chemo-, Regio- and Enantioselective Bio-Nitration of Epoxides.

We report the discovery of an unusual halohydrin dehalogenase, HHDHamb, that can work under relatively low acidic conditions and extremely low temperatures for the bio-nitration of epoxides using nitrite as a nitrating agent. The bio-nitration strategy exhibits high chemo-, regio-, and enantioselectivity, catalyzing the kinetic resolution of various epoxides to enantiopure ß-nitroalcohols with nitro-bearing stereocenters in up to 41 % isolated yield and >99 % enantiomeric excess (ee). Additionally, the bio-nitration method displays a high reaction efficiency and can be performed on a gram scale. We also solved the crystal structure of HHDHamb to understand the possible structural determinants of chemoselectivity control in the bio-nitration reaction.

Biocatalytic Thionation of Epoxides for Enantioselective Synthesis of Thiiranes.

Expanding the enzymatic toolbox for the green synthesis of valuable molecules is still of high interest in synthetic chemistry and the pharmaceutical industry. Chiral thiiranes are valuable sulfur-containing heterocyclic compounds, but relevant methods for their enantioselective synthesis are limited. Herein, we report a biocatalytic thionation strategy for the enantioselective synthesis of thiiranes, which was developed based on the halohydrin dehalogenase (HHDH)-catalyzed enantioselective ring-opening reaction of epoxides with thiocyanate and a subsequent nonenzymatic rearrangement process. A novel HHDH was identified and engineered for enantioselective biocatalytic thionation of various aryl- and alkyl-substituted epoxides on a preparative scale, affording the corresponding thiiranes in up to 43 % isolated yield and 98 % ee. Large-scale synthesis and useful transformations of chiral thiiranes were also performed to demonstrate the utility and scalability of the biocatalytic thionation strategy.

Palladium-catalyzed asymmetric allylic alkylation of 3-aminooxindoles to access chiral homoallylic aminooxindoles.

An organometal catalytic conversion of 3-aminooxindoles for the diastereo- and enantioselective synthesis of homoallylic aminooxindoles has been described. The asymmetric allylic alkylation of 3-aminooxindoles with allyl carboxylates proceeded smoothly to afford a series of chiral 3-allyl-3-aminooxindoles. This work offers an alternative route to build these scaffolds. The application of this protocol is also highlighted by a significant conversion of products to the potential applicable spiro[indoline-3,2'-pyrrolidin]-2-one derivatives.

Characterization of a Self-Sufficient Cytochrome P450 Monooxygenase from Deinococcus apachensis for Enantioselective Benzylic Hydroxylation.

A self-sufficient cytochrome P450 monooxygenase from Deinococcus apachensis (P450DA) was identified and successfully overexpressed in Escherichia coli BL21(DE3). P450DA would be a member of the CYP102D subfamily and assigned as CYP102D2 according to the phylogenetic tree and sequence alignment. Purification and characterization of the recombinant P450DA indicated both NADH and NADPH could be used by P450DA as a reducing cofactor. The recombinant E. coli (P450DA) strain was functionally active, showing excellent enantioselectivity for benzylic hydroxylation of methyl 2-phenylacetate. Further substrate scope studies revealed that P450DA is able to catalyze benzylic hydroxylation of a variety of compounds, affording the corresponding chiral benzylic alcohols in 86-99 % ee and 130-1020 total turnover numbers.

Synthesis of chromone-containing polycyclic compounds via palladium-catalyzed [2 + 2 + 1] annulation.

A palladium-catalyzed [2 + 2 + 1] domino annulation of 3-iodochromones, α-bromo carbonyl compounds, and tetracyclododecene (TCD) is described. This approach provides a facile, efficient and atom-economical route to a variety of chromone-containing polycyclic compounds bearing fused/bridged-ring systems in good yields (up to 81%) with excellent diastereoselectivities (99 : 1 dr in all cases).