Acyloin Condensation Research Articles

Recent advances in enzymatic carbon-carbon bond formation.

Enzymatic carbon-carbon (C-C) bond formation reactions have become an effective and invaluable tool for designing new biological and medicinal molecules, often with asymmetric features. This review provides a systematic overview of key C-C bond formation reactions and enzymes, with the focus of reaction mechanisms and recent advances. These reactions include the aldol reaction, Henry reaction, Knoevenagel condensation, Michael addition, Friedel-Crafts alkylation and acylation, Mannich reaction, Morita-Baylis-Hillman (MBH) reaction, Diels-Alder reaction, acyloin condensations via Thiamine Diphosphate (ThDP)-dependent enzymes, oxidative and reductive C-C bond formation, C-C bond formation through C1 resource utilization, radical enzymes for C-C bond formation, and other C-C bond formation reactions.

Identification of 2-Hydroxyacyl-CoA Synthases with High Acyloin Condensation Activity for Orthogonal One-Carbon Bioconversion

Identification of 2-Hydroxyacyl-CoA Synthases with High Acyloin Condensation Activity for Orthogonal One-Carbon Bioconversion

Mechanistic details of the actinobacterial lyase-catalyzed degradation reaction of 2-hydroxyisobutyryl-CoA

Actinobacterial 2-hydroxyacyl-CoA lyase reversibly catalyzes the thiamine diphosphate-dependent cleavage of 2-hydroxyisobutyryl-CoA to formyl-CoA and acetone. This enzyme has great potential for use in synthetic one-carbon assimilation pathways for sustainable production of chemicals, but lacks details of substrate binding and reaction mechanism for biochemical reengineering. We determined crystal structures of the tetrameric enzyme in the closed conformation with bound substrate, covalent postcleavage intermediate, and products, shedding light on active site architecture and substrate interactions. Together with molecular dynamics simulations of the covalent precleavage complex, the complete catalytic cycle is structurally portrayed, revealing a proton transfer from the substrate acyl Cβ hydroxyl to residue E493 that returns it subsequently to the postcleavage Cα-carbanion intermediate. Kinetic parameters obtained for mutants E493A, E493Q, and E493K confirm the catalytic role of E493 in the WT enzyme. However, the 10- and 50-fold reduction in lyase activity in the E493A and E493Q mutants, respectively, compared with WT suggests that water molecules may contribute to proton transfer. The putative catalytic glutamate is located on a short α-helix close to the active site. This structural feature appears to be conserved in related lyases, such as human 2-hydroxyacyl-CoA lyase 2. Interestingly, a unique feature of the actinobacterial 2-hydroxyacyl-CoA lyase is a large C-terminal lid domain that, together with active site residues L127 and I492, restricts substrate size to ≤C5 2-hydroxyacyl residues. These details about the catalytic mechanism and determinants of substrate specificity pave the ground for designing tailored catalysts for acyloin condensations for one-carbon and short-chain substrates in biotechnological applications.

Total synthesis of tanshinone IIA

A novel synthetic route toward tanshinone IIA has been developed. Key steps involve a base mediated furan ring formation, and an acyloin condensation reaction to construct the ortho-quinone ring.

Conservation of the Biocatalytic Activity of Whole Yeast Cells by Supported Sol – Gel Entrapment for Efficient Acyloin Condensation

In this study, an efficient and generally applicable 2nd generation sol – gel entrapment method was developed for immobilization of yeastcells. Cells of Lodderomyces elongisporus, Candida norvegica, Debaryomyces fabryi, Pichia carsonii strains in admixture with hollow silica microspheres support were immobilized in sol – gel matrix obtained from polycondensation of tetraethoxysilane. As biocatalysts in theselective acyloin condensation of benzaldehyde catalyzed by pyruvate decarboxylase of the yeast, the novel immobilized whole-cell preparations were compared to other states of the cells such as freshly harvested wet cell paste, lyophilized cells and sol – gel entrapped preparations without hollow silica microspheres support. Reusability and storability studies designated this novel 2nd generation sol – gel method as a promising alternative for solid formulation of whole-cells bypassing expensive and difficult downstream steps while providing easy-to-handle and stable biocatalysts with long-term preservation of the biocatalytic activity.

How to Turn Yeast Cells into a Sustainable and Switchable Biocatalyst? On-Demand Catalysis of Ketone Bioreduction or Acyloin Condensation

In this study, yeast strains were screened and immobilized in a form preserving the multifaceted biocatalytic activity. Immobilization of the silica-supported whole cells of various yeasts, such as...

2-Hydroxyacyl-CoA lyase catalyzes acyloin condensation for one-carbon bioconversion.

Despite the potential of biotechnological processes for one-carbon (C1) bioconversion, efficient biocatalysts required for their implementation are yet to be developed. To address intrinsic limitations of native C1 biocatalysts, here we report that 2-hydroxyacyl CoA lyase (HACL), an enzyme involved in mammalian α-oxidation, catalyzes the ligation of carbonyl-containing molecules of different chain lengths with formyl-coenzyme A (CoA) to produce C1-elongated 2-hydroxyacyl-CoAs. We discovered and characterized a prokaryotic variant of HACL and identified critical residues for this newfound activity, including those supporting the hypothesized thiamine pyrophosphate-dependent acyloin condensation mechanism. The use of formyl-CoA as a C1 donor provides kinetic advantages and enables C1 bioconversion to multi-carbon products, demonstrated here by engineering an Escherichia coli whole-cell biotransformation system for the synthesis of glycolate and 2-hydroxyisobutyrate from formaldehyde and formaldehyde plus acetone, respectively. Our work establishes a new approach for C1 bioconversion and the potential for HACL-based pathways to support synthetic methylotrophy.

Biotransformation using halotolerant yeast in seawater: a sustainable strategy to produce R-(−)-phenylacetylcarbinol

Acyloin condensation between benzaldehyde and decarboxylated pyruvate results in the production of R-(-)-phenylacetylcarbinol, a chiral precursor of the drug ephedrine. Huge research efforts have been made to improve the conditions of this reaction and to avoid the generation of by-products. Recently, we reported the advantages of using whole cells of the yeast Debaryomyces etchellsii as biocatalysts for this purpose. In this work, a new strategy, which fulfills green chemistry principles, is proposed and is based on using seawater as a gentle solvent. We demonstrate that, under these conditions, several improvements can be made compared to employing freshwater: (1) the conversion of the starting material in (R)-PAC is higher and with a minimum production of by-products; (2) it is possible to increase at least twofold the benzaldehyde load in the reaction medium; (3) cells can maintain their activity after several recycling rounds, which makes (R)-PAC production an easy and economical process.

Asymmetric Total Syntheses of Kopsia Indole Alkaloids.

The asymmetric total syntheses of a group of structurally complex Kopsia alkaloids, (-)-kopsine, (-)-isokopsine, (+)-methyl chanofruticosinate, (-)-fruticosine, and (-)-kopsanone, has been achieved. The key strategies for the construction of the molecular complexity in the targets included an asymmetric Tsuji-Trost rearrangement to set the first quaternary carbon center at C20, an intramolecular cyclopropanation by diazo decomposition to install the second and third quaternary carbon centers at C2 and C7, respectively, and a SmI2 -promoted acyloin condensation to assemble the isokopsine core. A radical decarboxylation of an isokopsine-type intermediate results in a thermodynamic partial rearrangement to give N-decarbomethoxyisokopsine and N-decarbomethoxykopsine, two key intermediates for the syntheses of Kopsia alkaloids with different subtype core structures.

Asymmetric Total Syntheses of Kopsia Indole Alkaloids

AbstractThe asymmetric total syntheses of a group of structurally complex Kopsia alkaloids, (−)‐kopsine, (−)‐isokopsine, (+)‐methyl chanofruticosinate, (−)‐fruticosine, and (−)‐kopsanone, has been achieved. The key strategies for the construction of the molecular complexity in the targets included an asymmetric Tsuji–Trost rearrangement to set the first quaternary carbon center at C20, an intramolecular cyclopropanation by diazo decomposition to install the second and third quaternary carbon centers at C2 and C7, respectively, and a SmI2‐promoted acyloin condensation to assemble the isokopsine core. A radical decarboxylation of an isokopsine‐type intermediate results in a thermodynamic partial rearrangement to give N‐decarbomethoxyisokopsine and N‐decarbomethoxykopsine, two key intermediates for the syntheses of Kopsia alkaloids with different subtype core structures.

Advances in chemoselective intermolecular cross-benzoin-type condensation reactions.

The intermolecular cross-benzoin and acyloin condensation reactions are powerful approaches to α-hydroxy carbonyls in a single step. However, their potentiality suffers from the occurrence of side reactions including self-condensation and the formation of the undesired cross-acyloin. The broad range of azolium salt precatalysts available confers high tunability to NHC mediated benzoin condensation, assuring a good level of selectivity to the direct coupling between two non-equivalent aldehydes. Many efforts have also been devoted to the design of strategies that expand the range of suitable reaction partners beyond the traditional aldehydes and to the discovery of novel umpolung catalytic systems. The synthesis of both racemic and enantiomerically enriched acyloins is reviewed.

A ThDP-dependent enzymatic carboligation reaction involved in Neocarazostatin A tricyclic carbazole formation.

Although the biosynthetic pathway of Neocarazostatin A (1) has been identified, the detailed enzymatic reactions underlying the assembly of the carbazole ring still remain largely unknown. We demonstrate here that NzsH, a putative thiamine diphosphate dependent enzyme, can catalyze an acyloin coupling reaction between indole-3-pyruvate and pyruvate to generate a β-ketoacid intermediate. Our findings thus shed light on further characterization of the unusual biosynthetic pathway of the bacterial tricyclic carbazole alkaloids.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Highly Chemoselective Intermolecular Crossed Acyloin Condensation of Aromatic Aldehydes with Trifluoroacetaldehyde Ethyl Hemiacetal.

A highly chemoselective intermolecular crossed acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal has been developed under mild reaction conditions using N-heterocyclic carbene as a catalyst. A wide range of aromatic aldehydes bearing electron-withdrawing and -donating substituents underwent a smooth transformation to their corresponding trifluoromethyl containing acyloin derivatives in moderate to good yields.

N-heterocyclic carbene catalyzed highly chemoselective intermolecular crossed acyloin condensation of aromatic aldehydes with trifluoroacetaldehyde ethyl hemiacetal.

A highly chemoselective intermolecular crossed acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal has been developed under mild reaction conditions using N-heterocyclic carbene as a catalyst. A wide range of aromatic aldehydes bearing electron-withdrawing and -donating substituents underwent a smooth transformation to their corresponding trifluoromethyl containing acyloin derivatives in moderate to good yields.

Potential of some yeast strains in the stereoselective synthesis of (R)-(−)-phenylacetylcarbinol and (S)-(+)-phenylacetylcarbinol and their reduced 1,2-dialcohol derivatives

Whole cells of different yeast species have been widely used for a number of asymmetric transformations. In the present study, the screening of several yeast strains revealed the utility of Debaryomyces etchellsii in acyloin condensation for (R)-(-)-phenylacetylcarbinol production. Some conditions for the efficient biotransformation of benzaldehyde and minimization in the production of by-products were explored: pH of the reaction medium, use of additives (ethanol or acetonitrile), temperature, time, and substrate concentration and dosing. The optimal conditions found allowed the transformation of up to 10g/L of the starting material in reactions carried out at high scale. Furthermore, the yeast Kluyveromyces marxianus was seen to be a convenient biocatalyst to carry out the kinetic resolution by the bioreduction of racemic (+/-)-phenylacetylcarbinol, resulting in (S)-(+)-phenylacetylcarbinol with excellent stereoselectivity. Finally, the ketone reduction of both isolated stereoisomers (R and S) by D. etchellsii allowed the obtainment of two of the four diastereoisomers of 1-phenyl-1,2-propanediol. All these compounds are key precursors for the production of interesting pharmaceutical and chemical products.

The cross-selective titanium(iii)-catalysed acyloin reaction

A titanium(III)-catalysed intermolecular reductive coupling of ketones or imines with nitriles is described, which gives direct access to α-hydroxylated and α-aminated ketones. This coupling reaction is cross-selective and a catalytic version of the classical acyloin condensation. A reaction mechanism that is supported by first DFT calculations is discussed.

Large-ring lactones from plant oils

Large-ring lactones and lactams were prepared utilising the full fatty acid chain of common plant oils as a source of the macrocycle. Ring closure via acyloin condensation does not require large volumes of solvents for dilution. Nonadecalactone (NDL) and tricosalactone (TCL) can be converted to novel polyesters by ring opening.

Recent Developments in Enzymatic Asymmetric CC Bond Formation

AbstractSome of the recent developments in enzymatic asymmetric CC bond formation are described in this review. The close relationship of biocatalysis and biosynthesis is highlighted with a special emphasis on diversity and biogenesis. One focus of this review is the creation of tetrasubstituted carbon stereocenters. Members of the supposedly well‐known aldolase and hydroxynitrile lyase enzyme families possess the ability to catalyze the formation of tertiary alcohols. In the case of aldolases, this can occur through intramolecular cyclization or intermolecular asymmetric CC bond formation. Thiamine diphosphate‐dependent YerE has been identified as a potent catalyst for the acyloin condensation with ketones as acceptor substrates. C1 transformations such as methylation or carboxylation are catalyzed in an asymmetric manner by enzymes from different classes, for example S‐adenosylmethionine‐dependent (radical) enzymes or NADPH‐dependent oxidoreductases. Insights from biosynthetic and mechanistic studies of enzymatic reactions proceeding via radical intermediates give valuable hints towards possible applications in biocatalysis. Still, the oxygen sensitivity of many of these biocatalysts poses a considerable challenge for practical applications.

Protecting Group-Free Total Synthesis of (−)-Lannotinidine B

The first total synthesis of (-)-lannotinidine B, a unique tetracyclic constitutent of Lycopodium annotinum, has been accomplished in 10 steps with 23% overall yield. The completed short and efficient synthesis is characterized with three highly chemo- and/or stereoselective reductive-amination steps to furnish the desired trans-fused 6/6 bicycle and the aza seven-membered ring system, and a direct intramolecular acyloin condensation to deliver the cyclopentanone moiety, as well as successful application of a protecting group-free strategy and an optimal redox order.

NHC-catalysed, chemoselective crossed-acyloin reactions

It has been shown for the first time that relatively electron deficient triazolium pre-catalysts promote (at low loadings in the presence of base) highly chemoselective crossed acyloin condensation reactions between aldehydes and α-ketoesters to afford densely functionalized products incorporating a quaternary stereocentre of considerable synthetic potential. Hydroacylation pathways which have hitherto been dominant in these reactions can be completely avoided. The scope of the process is extraordinarily broad with respect to both coupling partners, and a preliminary study has established the principle that a high degree of stereochemical control over the reaction can also be exercised via the use of a chiral NHC precursor. It has also been shown for the first time that coupling of benzyl α-ketoesters with aldehydes followed by acylation and simple hydrogenolysis furnishes a product formally derived from the chemoselective 1 : 1 coupling of two different aliphatic aldehydes in high yield with absolute control over which coupling partner behaves as the acyl-anion equivalent.