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Conversion of quinoline C-H bonds to C-C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, the direct alkylation and alkenylation at C3-H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3-H alkylation and alkenylation reactions, exhibiting exceptional regio- and stereoselectivity, all achieved under redox-neutral and transition-metal-free conditions. The method involves a three-step, one-pot or two-pot sequence, including 1,4-dearomative addition, functionalization at C3-, elimination or transalkylation to produce 3-alkylated /alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, or simple alkyl derivatives.

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The distinct roles of different chemical species are essential for the discovery of novel chemical transformations in organic synthesis. Here, we have designed a potential strategy for the synthesis of triarylmethanes (TRAMs) using the dual C(aryl)-alkylation process. This protocol was influenced by 1,1,1,3,3,3-hexafluoro isopropanol (HFIP) as a pivotal reagent and proceeds through the selective para C-H functionalization method. The described approach has been proven to be highly efficient in terms of substrate scope with excellent functional group tolerance and gram scale synthesis of the desired product with 90% yield. The recyclability and reusability of HFIP has enhanced the feasibility of this protocol towards the sustainable synthesis of TRAMs.

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This work describes the synthesis of eight new Pd(II) and Pt(II) complexes with the general formula [M(TSC)Cl], where TSC represents the 4N-monosubstituted thiosemicarbazone derived from 2-acetylpyridine N-oxide with the substituents CH3 (H4MLO), C2H5 (H4ELO), phenyl (H4PLO) and (CH3)2 (H4DMLO). These complexes have been characterized by elemental analysis, molar conductivity, IR spectroscopy, 1H, 13C, 195Pt and ESI-MS. The complexes exhibit a square planar geometry around the metallic center coordinated by a thiosemicarbazone molecule acting as a donor ONS-type pincer ligand and by a chloride, as confirmed by the molecular structures of the complexes, [Pd(4ELO)Cl] (3) and [Pd(4PLO)Cl] (5), determined by single-crystal X-ray diffraction. The 195Pt NMR spectra of the complexes of formulae [Pt(4PLO)Cl] (6) and [Pt(4DMLO)Cl] (8) in DMSO show a single signal at -2420.4 ppm, confirming the absence of solvolysis products. Complexes 3 and 5 have been tested as catalysts in the Suzuki-Miyaura cross-coupling reactions of aryl bromides with phenylboronic acid, with yields of between 50 and 90.

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The radical hydroarylation of alkenes is an efficient strategy for accessing linear alkylarenes with high regioselectivity. Herein, we report the electroreductive hydroarylation of electron-deficient alkenes and styrene derivatives using (hetero)aryl halides under mild reaction conditions. Notably, the present hydroarylation proceeded with high efficiency under transition-metal-catalyst-free conditions. The key to success is the use of 1,3-dicyanobenzene as a redox mediator and visible-light irradiation, which effectively suppresses the formation of simple reduction, i.e., hydrodehalogenation, products to afford the desired products in good to high yields. Mechanistic investigations proposed that a reductive radical-polar crossover pathway is likely to be involved in this transformation.

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Electrocatalytic oxidation of alcohols using heterogeneous catalysts is a promising aqueous, energy-efficient and environmentally friendly approach, especially for coupling different alcohols to prolong the carbon chain via co-oxidation. Precisely regulating critical steps to tailor electrode materials and electrolyte composition is key to selectively coupling alcohols for targeted synthesis. However, selectively coupling different alcohols remains challenging due to the lack of effective catalyst and electrolyte design promoting specific pathways. Herein, we demonstrate a paired electrolysis strategy for combining anodic oxidative coupling of ethanol (EtOH) and benzyl alcohol (PhCH2OH) to synthesize cinnamaldehyde (CAL) and cathodic ammonia production. The strategies involve: (i) utilizing the salt-out effect to balance selective oxidation and coupling rates; (ii) developing platinum-loaded nickel hydroxide electrocatalysts to accelerate intermediate coupling kinetics; (iii) introducing thermodynamically favorable nitrate reduction at the cathode to improve coupling selectivity by avoiding hydrogenation of products while generating valuable ammonia instead of hydrogen. We achieved 85% coupling selectivity and 278 µmol/h NH3 productive rate at 100 mA/cm2 with a low energy input (∼1.63 V). The membrane-free, low energy, scalable approach with a wide substrate scope highlights promising applications of this methodology. This work advances heterogeneous electrocatalytic synthesis through rational design principles that integrate anodic oxidative coupling with cathodic nitrate reduction reactions, having synergistic effects on efficiency and selectivity.

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Natural products from plants and microorganisms provide a valuable reservoir of pharmaceutical compounds. C-C bond formation and cleavage are crucial events during natural product biosynthesis, playing pivotal roles in generating diverse and intricate chemical structures that are essential for biological functions. This review summarizes our recent findings regarding biosynthetic enzymes that catalyze unconventional C-C bond formation and cleavage reactions during natural product biosynthesis.

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Bacterial cytochrome P450 enzymes catalyze various and often intriguing tailoring reactions during the biosynthesis of natural products. In contrast to the majority of membrane-bound P450 enzymes from eukaryotes, bacterial P450 enzymes are soluble proteins and therefore represent excellent candidates for in vitro biochemical investigations. In particular, cyclodipeptide synthase-associated cytochrome P450 enzymes have recently gained attention due to the broad spectrum of reactions they catalyze, i.e. hydroxylation, aromatization, intramolecular C-C bond formation, dimerization, and nucleobase addition. The latter reaction has been described during the biosynthesis of guanitrypmycins, guatrypmethines and guatyromycines in various Streptomyces strains, where the nucleobases guanine and hypoxanthine are coupled to cyclodipeptides via C-C, C-N, and C-O bonds. In this chapter, we provide an overview of cytochrome P450 enzymes involved in the C-C coupling of cyclodipeptides with nucleobases and describe the protocols used for the successful characterization of these enzymes in our laboratory. The procedure includes cloning of the respective genes into expression vectors and subsequent overproduction of the corresponding proteins in E. coli as well as heterologous expression in Streptomyces. We describe the purification and in vitro biochemical characterization of the enzymes and protocols to isolate the produced compounds for structure elucidation.

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Catalytic oxidations of tricyclic endo-norbornene-fused tetrahydrofuran with bimetallic nanoclusters Cu/Au-PVP and H2O2 or t-BuOOH as an oxidant provided C-H bond oxidation adjacent to the ether function and 4-oxa-tricyclo[5.2.1.0]-8,9-exo-epoxydecane (4), however, oxidation with Pd/Au-PVP took place at the C=C function giving epoxide 4 and oxidative three-bond forming dimeric product, dodecahydro-1,4:6,9-dimethanodibenzofurano[2,3-b:7,8-b']bisoxolane (5). Formation of the latter suggests the involvement of a reactive Pd-C intermediate. Similarly, oxidative C-C bond forming reactions were found in cycloaddition reactions of N2-Boc-1,2,3,4-tetrahydro-γ-carbolines and 2,3-dihydroxybenzoic acid with 2 - 5 mol% Cu/Au-PVP and H2O2 at 25 °C, providing two-bond-forming [4+2] cycloadducts. Under similar reaction conditions, Pd/Au-PVP did not produce the cycloadduct, indicating a need of complexation between Cu with the carboxylic acid group of 2,3-dihydroxybenzoic acid and allylic amine function of γ-carbolines in the cyclization reaction. The reported intermolecular coupling reactions using Pd/Au-PVP or Cu/Au-PVP nanocluster catalysts under oxidative conditions at 25 °C are unprecedented.

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A one-pot chemoenzymatic approach was developed by combining Palladium-catalysis with selective cytochrome P450 enzyme oxyfunctionalization. Various iodophenyl alkanoic acids could be coupled with alkylphenyl boronic acids to generate a series of alkyl substituted biarylalkanoic acids in overall high yield. The identity of the products could be confirmed by various analytical and chromatographic techniques. Addition of an engineered cytochrome P450 heme domain mutant with peroxygenase activity upon completion of the chemical reaction resulted in the selective oxyfunctionalization of those compounds, primarily at the benzylic position. Moreover, in order to increase the biocatalytic product conversion, a reversible substrate engineering approach was developed. This involves the coupling of a bulky amino acid such as L- phenylalanine or tryptophan, to the carboxylic acid moiety. The approach resulted in a 14 to 49% overall biocatalytic product conversion increase associated with a change in regioselectivity of hydroxylation towards less favored positions.

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Carbon-carbon (C-C) bond formation is the key reaction in organic synthesis to construct the carbon framework of organic molecules. The continuous shift of science and technology toward eco-friendly and sustainable resources and processes has stimulated the development of catalytic processes for C-C bond formation based on the use of renewable resources. In this context, and among other biopolymer-based materials, lignin has attracted scientific attention in the field of catalysis during the last decade, either through its acid form or as a support for metal ions and metal nanoparticles that drive the catalytic activity. Its heterogeneous nature, as well as its facile preparation and low cost, provide competitive advantages over other homogeneous catalysts. In this review, we have summarized a variety of C-C formation reactions, such as condensations, Michael additions of indoles, and Pd-mediated cross-coupling reactions that were successfully carried out in the presence of lignin-based catalysts. These examples also involve the successful recovery and reuse of the catalyst after the reaction.

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Semiconductor quantum dots (QDs) offer many advantages as photocatalysts for synthetic photoredox catalysis, but no reports have explored the use of QDs with nickel catalysts for C-C bond formation. We show here that 5.7 nm CdS QDs are robust photocatalysts for photoredox-promoted cross-electrophile coupling (40 000 TON). These conditions can be utilized on small scale (96-well plate) or adapted to flow. NMR studies show that triethanolamine (TEOA) capped QDs are the active catalyst and that TEOA can displace native phosphonate and carboxylate ligands, demonstrating the importance of QD surface chemistry.

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In this report, new, easily accessible reagents for highly Z-selective HWE reactions are presented. Alkyl di-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetates, structurally similar to Still-Gennari type reagents, were tested in HWE reactions with a series of various aldehydes. Very good Z-selectivity (up to a 98:2 Z:E ratio) was achieved in most cases along with high yields. Application of the new reagents may be a valuable, practical alternative to the well-established Still-Gennari or Ando Z-selective carbonyl group olefination protocols.

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An efficient method for the C-C bond formation via water soluble Na2PdCl4/sSPhos mediated Suzuki-Miyaura cross-coupling reaction of DNA-conjugated aryl iodide with (het)aryl boronic acids has been developed. This reaction proceeds at 37°C in water and acetonitrile (4:1) system. We also demonstrated that numerous aromatic and heteroaromatic boronic acids of different electronic natures, and harboring various functional groups, were highly compatible providing the desired coupling products in good to excellent yields. This DNA-compatible Suzuki-Miyaura cross-coupling reaction has strong potential to construct DNA-Encoded Libraries (DELs) in the context of drug discovery.

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Iron- and cobalt-catalyzed Sonogashira coupling reactions are becoming central areas of research in organic synthesis. Owing to their significant importance in the formation of carbon-carbon bonds, numerous green and nanoparticle protocols have emerged during the past decades. The non-toxic and inexpensive nature of catalysts gained much attention in recent times. In this context, their catalytic nature and activity in Sonogashira coupling reactions were well explored and compared. Most importantly, one of the highlights of this review is the emphasis given to green strategies. This is the first review on iron- and cobalt-catalyzed Sonogashira coupling reactions which comprehends literature up to 2020.

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Deoxyribose-5-phosphate aldolases (DERAs, EC 4.1.2.4) are acetaldehyde-dependent, Class I aldolases catalyzing in nature a reversible aldol reaction between an acetaldehyde donor (C2 compound) and glyceraldehyde-3-phosphate acceptor (C3 compound, C3P) to generate deoxyribose-5-phosphate (C5 compound, DR5P). DERA enzymes have been found to accept also other types of aldehydes as their donor, and in particular as acceptor molecules. Consequently, DERA enzymes can be applied in C-C bond formation reactions to produce novel compounds, thus offering a versatile biocatalytic alternative for synthesis. DERA enzymes, found in all kingdoms of life, share a common TIM barrel fold despite the low overall sequence identity. The catalytic mechanism is well-studied and involves formation of a covalent enzyme-substrate intermediate. A number of protein engineering studies to optimize substrate specificity, enzyme efficiency, and stability of DERA aldolases have been published. These have employed various engineering strategies including structure-based design, directed evolution, and recently also machine learning-guided protein engineering. For application purposes, enzyme immobilization and usage of whole cell catalysis are preferred methods as they improve the overall performance of the biocatalytic processes, including often also the stability of the enzyme. Besides single-step enzymatic reactions, DERA aldolases have also been applied in multi-enzyme cascade reactions both in vitro and in vivo. The DERA-based applications range from synthesis of commodity chemicals and flavours to more complicated and high-value pharmaceutical compounds. KEY POINTS: • DERA aldolases are versatile biocatalysts able to make new C-C bonds. • Synthetic utility of DERAs has been improved by protein engineering approaches. • Computational methods are expected to speed up the future DERA engineering efforts.

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The creation of C-C bonds is an effective strategy for constructing complex compounds from simple synthetic blocks. Although many methods have been developed for C-C bond construction, the stereoselective creation of new C-C bonds remains a challenge. The selectivities (enantioselectivity, regioselectivity, and chemoselectivity) of biocatalysts are higher than those of chemical catalysts, therefore biocatalysts are excellent candidates for use in stereoselective C-C bond formation. Here, we summarize progress made in the past 10 years in stereoselective C-C bond formation enabled by two classic types of enzyme, aldolases and hydroxynitrile lyases. The information in this review will enable the development of new routes to the stereoselective construction of C-C bonds.

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The synthetic properties of the Thiamine diphosphate (ThDP)-dependent pyruvate dehydrogenase E1 subunit from Escherichia coli (EcPDH E1) was assessed for carboligation reactions with aliphatic ketoacids. Due to its role in metabolism, EcPDH E1 was previously characterised with respect to its biochemical properties, but it was never applied for synthetic purposes. Here, we show that EcPDH E1 is a promising biocatalyst for the production of chiral α-hydroxyketones. WT EcPDH E1 shows a 180-250-fold higher catalytic efficiency towards 2-oxobutyrate or pyruvate, respectively, in comparison to engineered transketolase variants from Geobacillus stearothermophilus (TKGST). Its broad active site cleft allows for the efficient conversion of both (R)- and (S)-configured α-hydroxyaldehydes, next to linear and branched aliphatic aldehydes as acceptor substrates under kinetically controlled conditions. The alternate, thermodynamically controlled self-reaction of aliphatic aldehydes was shown to be limited to low levels of conversion, which we propose to be due to their large hydration constants. Additionally, the thermodynamically controlled approach was demonstrated to suffer from a loss of stereoselectivity, which makes it unfeasible for aliphatic substrates.

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In this work, deoxyribose-5-phosphate aldolase (Ec DERA, EC 4.1.2.4) from Escherichia coli was chosen as the protein engineering target for improving the substrate preference towards smaller, non-phosphorylated aldehyde donor substrates, in particular towards acetaldehyde. The initial broad set of mutations was directed to 24 amino acid positions in the active site or in the close vicinity, based on the 3D complex structure of the E. coli DERA wild-type aldolase. The specific activity of the DERA variants containing one to three amino acid mutations was characterised using three different substrates. A novel machine learning (ML) model utilising Gaussian processes and feature learning was applied for the 3rd mutagenesis round to predict new beneficial mutant combinations. This led to the most clear-cut (two- to threefold) improvement in acetaldehyde (C2) addition capability with the concomitant abolishment of the activity towards the natural donor molecule glyceraldehyde-3-phosphate (C3P) as well as the non-phosphorylated equivalent (C3). The Ec DERA variants were also tested on aldol reaction utilising formaldehyde (C1) as the donor. Ec DERA wild-type was shown to be able to carry out this reaction, and furthermore, some of the improved variants on acetaldehyde addition reaction turned out to have also improved activity on formaldehyde. KEY POINTS: • DERA aldolases are promiscuous enzymes. • Synthetic utility of DERA aldolase was improved by protein engineering approaches. • Machine learning methods aid the protein engineering of DERA.

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The indium-mediated allylation followed by ozonolysis has been applied for the elongation of different disaccharides such as cellobiose, lactose and maltose. This reaction sequence and per-O-acetylation produced the expected mixture of α/ß-pyranoid as well as α/ß-furanoid isomers. The main product in all cases adopted the ß-pyranose form and could be isolated and fully characterized with the help of NMR-spin simulations. Thorough investigation of the side products throughout optimization of the conditions for the ozonolysis resulted in the discovery of a novel 12 membered bridged disaccharide.

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A new, mild and efficient protocol for the synthesis of trifluoromethyl(indolyl)phenylmethanols by the reaction of indoles with a variety of aromatic fluoromethyl ketones in the presence of K2CO3 (15 mol %) and n-Bu4PBr (15 mol %) in water. The desired products were obtained in good to excellent yields without requiring a column chromatographic purification. The reusability of the catalytic system and large-scale synthesis of indolyl(phenyl)methanols, which would further transform into biological active indole-derived compounds, are further advantages of this protocol.