Unusual Enzymatic C-C Bond Formation and Cleavage Reactions during Natural Product Biosynthesis.

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.

Palladium(II) and Platinum(II) Complexes Bearing ONS-Type Pincer Ligands: Synthesis, Characterization and Catalytic Investigations.

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.

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation.

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.

Lignin-Based Catalysts for C-C Bond-Forming Reactions.

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.

Highly Z-Selective Horner-Wadsworth-Emmons Olefination Using Modified Still-Gennari-Type Reagents.

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.

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions.

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.

Current state of and need for enzyme engineering of 2-deoxy-D-ribose 5-phosphate aldolases and its impact.

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.

Substrate specificity of 2-deoxy-D-ribose 5-phosphate aldolase (DERA) assessed by different protein engineering and machine learning methods.

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.

Assessing the Thiamine Diphosphate Dependent Pyruvate Dehydrogenase E1 Subunit for Carboligation Reactions with Aliphatic Ketoacids.

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.

Extension of the 5-alkynyluridine side chain via C-C-bond formation in modified organometallic nucleosides using the Nicholas reaction.

Dicobalt hexacarbonyl nucleoside complexes of propargyl ether or esters of 5-substituted uridines react with diverse C-nucleophiles. Synthetic outcomes confirmed that the Nicholas reaction can be carried out in a nucleoside presence, leading to a divergent synthesis of novel metallo-nucleosides enriched with alkene, arene, arylketo, and heterocyclic functions, in the deoxy and ribo series.

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water.

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.

Lewis Acid Catalyzed Transfer Hydromethallylation for the Construction of Quaternary Carbon Centers.

The design and gram-scale synthesis of a cyclohexa-1,4-diene-based surrogate of isobutene gas is reported. Using the highly electron-deficient Lewis acid B(C6 F5 )3 , application of this surrogate in the hydromethallylation of electron-rich styrene derivatives provided sterically congested quaternary carbon centers. The reaction proceeds by C(sp3 )-C(sp3 ) bond formation at a tertiary carbenium ion that is generated by alkene protonation. The possibility of two concurrent mechanisms is proposed on the basis of mechanistic experiments using a deuterated surrogate.

Regioselective Pd-catalyzed direct C1- and C2-arylations of lilolidine for the access to 5,6-dihydropyrrolo[3,2,1-ij]quinoline derivatives.

The Pd-catalyzed C-H bond functionalization of lilolidine was investigated. The use of a palladium-diphosphine catalyst associated to acetate bases in DMA was found to promote the regioselective arylation at α-position of the nitrogen atom of lilolidine with a wide variety of aryl bromides. From these α-arylated lilolidines, a second arylation at the ß-position gives the access to α,ß-diarylated lilolidines containing two different aryl groups. The one pot access to α,ß-diarylated lilolidines with two identical aryl groups is also possible by using a larger amount of aryl bromide. The synthesis of 5,6-dihydrodibenzo[a,c]pyrido[3,2,1-jk]carbazoles from lilolidine via three successive direct arylations is also described. Therefore, this methodology provides a straightforward access to several lilolidine derivatives from commercially available compounds via one, two or three C-H bond functionalization steps allowing to tune their biological properties.

Indium-mediated C-allylation of melibiose.

The indium-mediated allylation reaction has been applied to melibiose, a disaccharidic substrate. This elongation methodology allows for a short, efficient and diastereoselective approach towards complex glycosylated carbohydrate structures. The stereochemical outcome of the key intermediates, allylated disaccharides, has been determined by X-ray analysis. Ozonolysis of the introduced double bond yielded the unprotected elongated disaccharides in the equilibrium of the pyranoid as well as furanoid isomers in both anomeric forms, respectively. Per-O-acetylation has been performed to facilitate separation of the isomeric mixture for structural identification. The main product revealed to adopt a ß-pyranoid form of the elongated unit at the reducing end of the disaccharide.

Cobalt-catalyzed directed C-H alkenylation of pivalophenone N-H imine with alkenyl phosphates.

A cobalt-N-heterocyclic carbene (NHC) catalyst efficiently promotes an ortho C-H alkenylation reaction of pivalophenone N-H imine with an alkenyl phosphate. The reaction tolerates various substituted pivalophenone N-H imines as well as cyclic and acyclic alkenyl phosphates.

Intermolecular Formation of Two C-C Bonds across Olefins Enabled by Boron-Based Relay Strategies.

Smooth handoff in the relay: Vinyl boronates enable the direct addition of nucleophilic and electrophilic or nucleophilic and radical-generating carbon reagents across the double bond with retention of the valuable boronate group. The key to the success of this difficult twofold C-C bond-formation strategy is the initial relay of the nucleophilic addition to boron and the rearrangement of a 1,2-metalate rearrangement, shuttling it to the carbon atom.

Keratin Protein-Catalyzed Nitroaldol (Henry) Reaction and Comparison with Other Biopolymers.

Here we describe a preliminary investigation on the ability of natural keratin to catalyze the nitroaldol (Henry) reaction between aldehydes and nitroalkanes. Both aromatic and heteroaromatic aldehydes bearing strong or moderate electron-withdrawing groups were converted into the corresponding ß-nitroalcohol products in both DMSO and in water in the presence of tetrabutylammonium bromide (TBAB) as a phase transfer catalyst. Negligible background reactions (i.e., negative control experiment in the absence of keratin protein) were observed in these solvent systems. Aromatic aldehydes bearing electron-donating groups and aliphatic aldehydes showed poor or no conversion, respectively. In general, the reactions in water/TBAB required twice the amount of time than in DMSO to achieve similar conversions. Moreover, comparison of the kinetics of the keratin-mediated nitroaldol (Henry) reaction with other biopolymers revealed slower rates for the former and the possibility of fine-tuning the kinetics by appropriate selection of the biopolymer and solvent.

Palladium/Copper-Cocatalyzed Oxidative Amidobrominations of Alkenes.

In the presence of LiBr, a palladium/copper combination catalyzes dehydrogenative amidobrominations of acrylates with NH-sulfoximines, leading to N-vinylated products by dual NH/CH coupling, followed by oxidative enamide bromination. Mechanistically, the domino process is proposed to involve palladium(II) species as key intermediates. First synthetic applications of the products have been demonstrated.

Recent Advances in the C-H-Functionalization of the Distal Positions in Pyridines and Quinolines.

This review summarizes recent developments in the C-H-functionalization of the distal positions of pyridines, quinolines and related azaheterocycles. While the functionalization of the C2 position has been known for a long time and is facilitated by the proximity to N1, regioselective reactions in the distal positions are more difficult to achieve and have only emerged in the last decade. Recent advances in the transition metal-catalyzed distal C-H-functionalization of these synthetically-important azaheterocycles are discussed in detail, with the focus on the scope, site-selectivity and mechanistic aspects of the reactions.

Pd-mediated rapid cross-couplings using [(11) C]methyl iodide: groundbreaking labeling methods in (11) C radiochemistry.

Prof. Bengt Långström is a pioneer in the field of chemistry-driven positron emission tomography (PET) imaging. He has developed a variety of excellent radiolabeling methodologies using the methods of organic chemistry, with the aim of widening the potential of PET in the study of life. Among his groundbreaking achievements in (11) C radiochemistry, there is the discovery of the Pd-mediated rapid cross-coupling reaction using [(11) C]methyl iodide. It was first reported by his Uppsala group in 1994-1995 and was further investigated by his and other groups with a view of enhancing its generality and practicability. This reaction is currently considered one of the basic methods for (11) C-labeling of low-weight organic compounds. This paper presents a short summary of the background and the development of Pd-mediated rapid cross-couplings of [(11) C]methyl iodide, with a focus not only on organostannanes, but also on organoboranes, organozincs, and terminal acetylene compounds. All these reactions have proven to be dependable (11) C-labeling methodologies that use chemically reliable carbon-carbon bond formation reactions.