Stereoselective amino acid synthesis by photobiocatalytic oxidative coupling.

Photobiocatalysis-where light is used to expand the reactivity of an enzyme-has recently emerged as a powerful strategy to develop chemistries that are new to nature. These systems have shown potential in asymmetric radical reactions that have long eluded small-molecule catalysts1. So far, unnatural photobiocatalytic reactions are limited to overall reductive and redox-neutral processes2-9. Here we report photobiocatalytic asymmetric sp3-sp3 oxidative cross-coupling between organoboron reagents and amino acids. This reaction requires the cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts and an oxidizing agent. We repurpose a family of pyridoxal-5'-phosphate-dependent enzymes, threonine aldolases10-12, for the α-C-H functionalization of glycine and α-branched amino acid substrates by a radical mechanism, giving rise to a range of α-tri- and tetrasubstituted non-canonical amino acids 13-15 possessing up to two contiguous stereocentres. Directed evolution of pyridoxal radical enzymes allowed primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, to be coupled in an enantio- and diastereocontrolled fashion. Cooperative photoredox-pyridoxal biocatalysis provides a platform for sp3-sp3 oxidative coupling16, permitting the stereoselective, intermolecular free-radical transformations that are unknown to chemistry or biology.

Biomimetic Total Synthesis of Bimagnolignan: A Natural Anti-Breast Cancer Agent.

A short scalable biomimetic route to bioactive natural product bimagnolignan (1) was accomplished. Compound 1 was successfully prepared through a three-step metal-free synthesis from honokiol (2). Alternatively, 1 was also synthesized by biomimetic transformations that mimic tyrosinase in four steps. The key reactions feature a regioselective acetylation, a highly efficient C(sp2)-H oxidation, a cascade aerobic oxidative cyclization/coupling, and a Cu-catalyzed direct oxidative coupling. In addition, cell-based assays validate that 1 is a promising natural lead for HER2-positive breast cancer treatment.

Recent advances in oxidative phenol coupling for the total synthesis of natural products.

Covering: 2008 to 2023This review will describe oxidative phenol coupling as applied in the total synthesis of natural products. This review covers catalytic and electrochemical methods with a brief comparison to stoichiometric and enzymatic systems assessing their practicality, atom economy, and other measures. Natural products forged by C-C and C-O oxidative phenol couplings as well as from alkenyl phenol couplings will be addressed. Additionally, exploration into catalytic oxidative coupling of phenols and other related species (carbazoles, indoles, aryl ethers, etc.) will be surveyed. Future directions of this particular area of research will also be assessed.

Regioselective Synthesis of Directly Connected BODIPY Dimers through Oxidative Coupling of α-Amino-Substituted BODIPYs.

A family of directly ß,ß-linked BODIPY dimers with amino groups at α-positions were regioselectively prepared by the oxidative coupling reaction of α-amino-substituted BODIPYs. The structure of one representative dimer was elucidated by X-ray diffraction analysis, showing its twisted orientation of two BODIPY units with a dihedral angle of 49°. Comparing with the corresponding monomers, these dimers showed red-shifted absorptions and emissions along with efficient intersystem crossing, giving ΦΔ of 43% for dimer 4b in toluene, indicating potential use as heavy-atom-free photosensitizers.

Roles of Natural Phenolic Compounds in Polycyclic Aromatic Hydrocarbons Abiotic Attenuation at Soil-Air Interfaces through Oxidative Coupling Reactions.

Little information is available on the roles of natural phenolic compounds in polycyclic aromatic hydrocarbons (PAHs) attenuation at dry soil-air interfaces. The purpose of this study was to determine the roles of model phenolic constituents of soil organic matter (SOM) on the abiotic attenuation of PAHs. The phenolic compounds can significantly change the attenuation rates of PAHs, among which hydroquinone was the most effective in promoting anthracene and benzo[a]anthracene attenuation. Product identification and sequential extraction experiments revealed hydroquinone enhanced the formation of oxidative coupling products and promoted the incorporation of PAHs into humic analogues, thereby reducing potential risks to humans and ecosystems. Electron paramagnetic resonance spectroscopy analyses showed both PAHs and phenolic compounds could donate electrons to Lewis acid sites of soil minerals, resulting in the generation of persistent free radicals (PFRs). PFRs could promote the generation of ·OH to enhance PAH oxidation and could cross-couple with PAHs, resulting in high-molecular-weight oxidative coupling products. This study revealed for the first time the reaction mechanism between PAHs and phenolic components of SOM under relatively dry conditions and provided new insights into promoting PAHs detoxification in soils but also a potential strategy to increase the organic carbon sequestration.

Photocatalytic Oxidative Coupling of Methane to Ethane Using Water and Oxygen on Ag3PO4-ZnO.

Photocatalytic oxidative coupling is an effective way of converting CH4 to high-value-added multi-carbon chemicals under mild conditions, where the breaking of the C-H bond is the main rate-limiting step. In this paper, the Ag3PO4-ZnO heterostructure photocatalyst was synthesized for photocatalytic oxidative coupling of methane (OCM) to C2H6. In addition, an excellent C2H6 yield (16.62 mmol g-1 h-1) and a remarkable apparent quantum yield (15.8% at 350 nm) at 49:1 CH4/Air and 20% RH are obtained, which is more than three times that of the state-of-the-art photocatalytic systems. Ag3PO4 improves the adsorption and dissociation ability of O2 and H2O, benefiting the formation of surface hydroxyl species. As a result, the C-H bond activation energy of CH4 on ZnO was obviously reduced. Meanwhile, the improved separation of photogenerated carriers on the Ag3PO4-ZnO heterostructure also accelerates the OCM process. Moreover, Ag nanoparticles (NPs) derived from Ag3PO4 reduction by photoelectrons promote the coupling of *CH3, which can inhibit the overoxidation of CH4 and increase C2H6 selectivity. This research provides a guide for the design of catalyst and reaction systems in the photocatalytic OCM process.

Site-Selective C-H Amination of Phenol-Containing Biomolecules.

A C-N bond-forming cross-dehydrogenative coupling of a collection of Tyr-containing peptides and estrogens with heteroarenes is described. This oxidative coupling is distinguished by its scalability, operational simplicity, and air tolerance and enables the appendance of phenothiazines and phenoxazines in phenol-like compounds. When incorporated into a Tb(III) metallopeptide, the Tyr-phenothiazine moiety acts as a sensitizer for the Tb(III) ion, providing a new tool for the design of luminescent probes.

Generation and structure elucidation of a red colorant formed by oxidative coupling of chlorogenic acid and tryptophan.

In view of the poor acceptance of synthetic food colorants by consumers, there is intense interest in novel natural compounds, preferably from plant-derived sources. We oxidized chlorogenic acid using NaIO4 and reacted the resultant quinone with tryptophan (Trp) to obtain a red-colored product. The colorant was precipitated, freeze-dried, purified by size exclusion chromatography, and subsequently characterized using UHPLC-MS, high-resolution mass spectrometry, and NMR spectroscopy. Additional mass spectrometric studies were performed on the reaction product generated with Trp educts labeled with 15N and 13C. The data obtained from these studies allowed the identification of a complex compound consisting of two Trp and one caffeic acid moieties, and the proposition of a tentative pathway of its formation. Thus, the present investigation expands our knowledge about the formation of red colorants based on the reaction of plant phenols and amino acids.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, Vellosimine, (+)-Normacusine†B, and (-)-Alstomutinine†C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (-)-alstomutinine C.

Molecular identification of a laccase that catalyzes the oxidative coupling of a hydroxycinnamic acid amide for hordatine biosynthesis in barley.

Plants produce dimerized phenolic compounds as secondary metabolites. Hordatine A (HA), a dehydrodimer of p-coumaroylagmatine (pCA), is an antifungal compound accumulated at high levels in young barley (Hordeum vulgare) seedlings. The enzyme responsible for the oxidative dimerization of pCA, which is the final step of the hordatine biosynthetic pathway, has not been identified. In this study, we first verified the presence of this enzyme activity in the crude extract of barley seedlings. Because the enzyme activity was not dependent on H2 O2 , the responsible enzyme was not peroxidase, which was previously implicated in HA biosynthesis. The analysis of the dissection lines of wheat (Triticum aestivum) carrying aberrant barley 2H chromosomes detected HA in the wheat lines carrying the distal part of the 2H short arm. This chromosomal region contains two laccase genes (HvLAC1 and HvLAC2) that are highly expressed at the seedling stage and may encode enzymes that oxidize pCA during the formation of HA. Changes in the HvLAC transcript levels coincided with the changes in the HA biosynthesis-related enzyme activities in the crude extract and the HA content in barley seedlings. Moreover, HvLAC genes were heterologously expressed in Nicotiana benthamiana leaves and in bamboo (Phyllostachys nigra) suspension cells and HA biosynthetic activities were detected in the crude extract of transformed N. benthamiana leaves and bamboo suspension cells. The HA formed by the enzymatic reaction had the same stereo-configuration as the naturally occurring HA. These results demonstrate that HvLAC enzymes mediate the oxidative coupling of pCA during HA biosynthesis.

Insertion of Chemical Handles into the Backbone of DNA during Solid-Phase Synthesis by Oxidative Coupling of Amines to Phosphites.

Conjugation of molecules or proteins to oligonucleotides can improve their functional and therapeutic capacity. However, such modifications are often limited to the 5' and 3' end of oligonucleotides. Herein, we report the development of an inexpensive and simple method that allows for the insertion of chemical handles into the backbone of oligonucleotides. This method is compatible with standardized automated solid-phase oligonucleotide synthesis, and relies on formation of phosphoramidates. A unique phosphoramidite is incorporated into a growing oligonucleotide, and oxidized to the desired phosphoramidate using iodine and an amine of choice. Azides, alkynes, amines, and alkanes have been linked to oligonucleotides via internally positioned phosphoramidates with oxidative coupling yields above 80 %. We show the design of phosphoramidates from secondary amines that specifically hydrolyze to the phosphate only at decreased pH. Finally, we show the synthesis of an antibody-DNA conjugate, where the oligonucleotide can be selectively released in a pH 5.5 buffer.

Modification of Cysteine-Substituted Antibodies Using Enzymatic Oxidative Coupling Reactions.

Cysteines are routinely used as site-specific handles to synthesize antibody-drug conjugates for targeted immunotherapy applications. Michael additions between thiols and maleimides are some of the most common methods for modifying cysteines, but these functional groups can be difficult to prepare on scale, and the resulting linkages have been shown to be reversible under some physiological conditions. Here, we show that the enzyme tyrosinase, which oxidizes conveniently accessed phenols to afford reactive ortho-quinone intermediates, can be used to attach phenolic cargo to cysteines engineered on antibody surfaces. The resulting linkages between the thiols and ortho-quinones are shown to be more resistant than maleimides to reversion under physiological conditions. Using this approach, we construct antibody conjugates bearing cytotoxic payloads, which exhibit targeted cell killing, and further demonstrate this method for the attachment of a variety of cargo to antibodies, including fluorophores and oligonucleotides.

Guanidinium Hypoiodite-Catalyzed Intramolecular Oxidative Coupling Reaction of Oxindoles with ß-Dicarbonyls.

Spiro[indoline-3,4'-piperidine] is a fundamental motif present in various biologically active compounds. Here, we report an intramolecular oxidative coupling reaction of oxindoles with ß-dicarbonyls in the presence of a guanidinium hypoiodite catalyst, providing spiro-coupling products in moderate to excellent yields. Furthermore, a chiral hypoiodite catalyst derived from the chiral guanidinium organocatalyst is effective for the challenging asymmetric carbon-carbon bond-forming reaction, affording optically active spiro[indoline-3,4'-piperidines].

Efficient Aerobic Oxidative Coupling of Methyl Heteroarenes with Indoles.

Direct oxidative coupling of inert C(sp3 )-H bond has been a great challenge. Herein, an environmentally friendly aerobic oxidative coupling of α-methyl substituted N-heteroarenes with indoles is reported. A variety of diheteroaryl ketones were prepared in good yields (up to 72 %). This protocol features simple operation and broad substrates scope (26 examples). Significantly, a plausible mechanism about catalytic cycle was proposed, and two key intermediates were confirmed by high resolution mass spectrometry.

Oxidative coupling of dibenzyl disulfide with amines catalyzed by quinoline-bromine complex: access to thioamides.

The reaction of dibenzyl disulfide with various bromine complexes as oxidants and DMSO as solvent can produce thioamides in high yield at 110 °C. Tertiary amines like pyridine and quinoline, which were utilized in this catalyst, are known to generate bromine-addition complexes. The approach is metal- and additive-free, making it a simple and cost-effective way to make a variety of thioamides under favorable circumstances.

Biomimetic Enzymatic Oxidative Coupling of Barley Phenolamides: Hydroxycinnamoylagmatines.

Oxidative coupling of hydroxycinnamoylagmatines in barley (Hordeum vulgare) and related Hordeum species is part of the plant defense mechanism. Three linkage types have been reported for hydroxycinnamoylagmatine dimers, but knowledge on oxidative coupling reactions underlying their formation is limited. In this study, the monomers coumaroylagmatine, feruloylagmatine, and sinapoylagmatine were each incubated with horseradish peroxidase. Their coupling reactivity was in line with the order of peak potentials measured: sinapoylagmatine (245 mV) > feruloylagmatine (341 mV) > coumaroylagmatine (506 mV). Structure elucidation of fourteen in vitro coupling products by NMR and MS revealed that the three main linkage types were identical to those naturally present in Hordeum species, namely, 4-O-7'/3-8', 2-7'/8-8', and 8-8'/9-N-7'. Furthermore, we identified two linkage types that were not previously reported for hydroxycinnamoylagmatine dimers, namely, 8-8' and 4-O-8'. We conclude that oxidative coupling by horseradish peroxidase can be used for biomimetic formation of natural antifungal hydroxycinnamoylagmatine dimers from barley.

Sulfur-DMSO promoted oxidative coupling of active methylhetarenes with amines: access to amides.

The elemental sulfur-DMSO couple was found to efficiently promote the oxidative coupling of active methylhetarenes with amines to yield amides under simple heating conditions. When 2-methylquinoline was used as the methylhetarene component, the formation of the expected 2-quinolinecarboxamides from anilines could be efficiently catalyzed by iron, nickel and cobalt salts. The method displayed good functional group tolerance and was applicable to aromatic, heteroaromatic and aliphatic amines. Other substrates such as phenylacetic acid, dibenzyl disulfide, and benzylamine could act as competent partners in place of methylhetarenes.

Oxygen mediated oxidative couplings of flavones in alkaline water.

Catalyzed oxidative C-C bond coupling reactions play an important role in the chemical synthesis of complex natural products of medicinal importance. However, the poor functional group tolerance renders them unfit for the synthesis of naturally occurring polyphenolic flavones. We find that molecular oxygen in alkaline water acts as a hydrogen atom acceptor and oxidant in catalyst-free (without added catalyst) oxidative coupling of luteolin and other flavones. By this facile method, we achieve the synthesis of a small collection of flavone dimers and trimers including naturally occurring dicranolomin, philonotisflavone, dehydrohegoflavone, distichumtriluteolin, and cyclodistichumtriluteolin. Mechanistic studies using both experimental and computational chemistry uncover the underlying reasons for optimal pH, oxygen availability, and counter-cations that define the success of the reaction. We expect our reaction opens up a green and sustainable way to synthesize flavonoid dimers and oligomers using the readily available monomeric flavonoids isolated from biomass and exploiting their use for health care products and treatment of diseases.

Copper/Nitroxyl-Catalyzed Synthesis of Pyrroles by Oxidative Coupling of Diols and Primary Amines at Room Temperature.

The Cu/ABNO-catalyzed aerobic oxidative coupling of diols and primary amines to access N-substituted pyrroles is highlighted (ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl). The reaction proceeds at room temperature with an O2 balloon as the oxidant using commercially available materials as the substrates and catalysts. The catalyst system is characterized by a broad range of substrates and a good tolerance to sensitive functional groups. The gram-scale experiment proves this system's practicability.

Visible-light-promoted iron-catalyzed C-H functionalization of 1,4-naphthoquinones via oxidative coupling with sulfoximines.

A catalytic oxidative addition of sulfoximines to naphthoquinones via C-H functionalization has been achieved using an iron catalytic system, which exhibits good reactivity and high regioselectivity in the presence of visible light. This is the first report offering an efficient protocol for obtaining (naphtho)quinone-sulfoximine hybrid analogs in moderate to good yields with wide scope for both the substrates. This protocol has also been applied on natural products for their modification, including vitamin K3, Juglone and some other modified natural scaffolds as well.