Chiral Aldehydes Research Articles

One-Pot Biosynthesis of 2-Keto-4-hydroxybutyrate from Cheap C1 Compounds Using Rationally Designed Pyruvate Aldolase and Methanol Dehydrogenase.

One-carbon chemicals (C 1s) are potential building blocks as they are cheap, sustainable, and abiotic components. Methanol-derived formaldehyde can be another versatile building block for the production of 2-keto-4-hydroxyacid derivatives that can be used for amino acids, hydroxy carboxylic acids, and chiral aldehydes. To produce 2-keto-4-hydroxybutyrate from C 1s in an environment-friendly way, we characterized an aldolase from Pseudomonas aeruginosa PAO1 (PaADL), which showed much higher catalytic activity in condensing formaldehyde and pyruvate than the reported aldolases. By applying a structure-based rational approach, we found a variant (PaADLV121A/L241A) that exhibited better catalytic activities than the wild-type enzyme. Next, we constructed a one-pot cascade biocatalyst system by combining PaADL and a methanol dehydrogenase (MDH) and, for the first time, effectively produced 2-keto-4-hydroxybutyrate as the main product from pyruvate and methanol via an enzymatic reaction. This simple process applied here will help design a green process for the production of 2-keto-4-hydroxyacid derivatives.

Sterically Hindered and Deconjugative α-Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement-Intermediate.

Compared to γ-addition, the α-addition of α-branched β,γ-unsaturated aldehydes faces larger steric hindrance and disrupts the π-π conjugation, which might be why very few examples are reported. In this article, a highly diastereo- and enantioselective α-regioselective Mannich reaction of isatin-derived ketimines with α-, β- or γ-branched β,γ-unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N'-dioxide/ScIII catalysts. A series of chiral α-quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α-regioselectivity.

Unique phosphine ligand synergy in asymmetric hydroformylation of styrene over the Rh@MOF-5 heterogeneous catalysis system

For the heterogeneous reaction of asymmetric hydroformylation (AHF), a highly decentralized active Rh site played a key role in enhancing the yield of chiral isomeric aldehydes.

Diastereoselective C-alkylation of aldimines, derived from chiral α-carbon heteroatom-substituted aldehydes, with triethylborane. Application to the synthesis of benzylisoquinolines.

The one-pot reaction of a chiral aldehyde, p-methoxyaniline or p-fluoroaniline, and triethylborane produces the corresponding alkylated chiral amine with high yields and diastereoisomeric ratios. Stereocontrol is induced by the presence of a heteroatom in the α-position to the aldehyde. In the case of alkylation of imines derived from chiral aliphatic amines, good yields and moderate to high diastereoselectivity are obtained: yields are significantly better when the preformed imine is used in the reaction with triethyl borane, and diastereoselectivity of the reactions largely depends on the structure of the chiral aliphatic amine. The methodology is successfully applied to the synthesis of romneine, a natural benzylisoquinoline.

Chiral aldehyde catalysis enables direct asymmetric α-substitution reaction of N-unprotected amino acids with halohydrocarbons.

The direct catalytic α-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α-disubstituted non-proteinogenic α-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct α-hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric α-arylation, α-allylation, and α-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing α,α-disubstituted α-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric α-arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

AbstractAsymmetric functionalization of amines and their derivatives is of great significance in synthetic chemistry and is widely used in the preparation of natural products and pharmaceuticals. In recent years, chiral aldehyde catalysis has emerged as a well-established and recognized tool, providing excellent catalytic activation and stereoselective control in asymmetric reactions of N-unprotected amino acid esters and amino acid ester analogues. In this short review, recent advances in enantioselective aldehyde catalysis, including chiral aldehydes as organocatalysts and co-catalysis combined with transition metals, will be summarized. Lastly, continued development of enantioselective aldehyde catalysis is prospected in the future.1 Introduction2 Chiral Aldehyde Catalysis for Tethering Strategy3 Chiral Aldehyde Catalysis for Imine Activation4 Chiral Aldehyde/Transition Metal Cooperative Catalysis5 Conclusion

Palladium‐catalyzed Atroposelective Interannular C−H Arylation of Biaryl Aldehydes with Aryl Iodides Enabled by a Transient Directing Group Strategy

AbstractA concise synthesis of axially chiral biaryl aldehydes through Pd/amino acid‐catalyzed atroposelective interannular C−H arylation of biaryl aldehydes with aryl iodides is developed. This reaction proceeds smoothly involving excellent enantiocontrol and accomplishes with good tolerance of functional groups. Moreover, the readily accessible scale‐up synthesis and further transformation of products has highlighted the potential utility of this asymmetric catalytic protocol.magnified image

Methyl acetoacetate derivatisation for improving liquid chromatography analysis of short chain aldehydes and water sensitive and chiral aldehydes

The importance of aldehydes in a number of industries has been well established, and therefore there is a resulting need to effectively and accurately monitor them. We report the application of a methyl acetoacetate derivatisation reaction to enable the analysis of aldehydes by HPLC-UV. This derivatisation reaction has been compared to alternative derivatisation reactions with nitrophenylhydrazines, resulting preferable since it yielded a more intense signal of the compound of interest and less interfering peaks. The derivatisation reaction was then optimised and applied for the analysis of short chained aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde and isobutyraldehyde, investigating parameters such as sensitivity, linearity, accuracy, and precision. This strategy has been successfully deployed also for determination of formaldehyde in a 25% w/w sodium methoxide solution in methanol at a target level of 200 ppm. Finally, this derivatisation reaction has been adjusted to enable the development of a robust chiral analytical method for a water sensitive aldehyde.

Rhodium-Catalyzed Chemo-, Regio- and Enantioselective Hydroformylation of Cyclopropyl-Functionalized Trisubstituted Alkenes.

The first rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of cyclopropyl-functionalized trisubstituted alkenes affording useful chiral cyclopropyl entities is reported. Compared to generally used diphosphine ligands for asymmetric catalysis, the modified hybrid phosphorus ligand, named (R,S)-DTBM-Yanphos, can convert a series of readily available cyclopropyl-functionalized trisubstituted alkenes into high-value chiral cyclopropyl-functionalized aldehydes with high selectivities (81-98 % ee). Gram-scale reactions (TON up to 1500) and follow-up transformations to the corresponding alcohol, acid, esters and nitrile are also presented. Finally, a possible hydroformylation mechanism involving ring-open-hydroformylation pathways is proposed based on control and deuteroformylation reactions.

Catalytic asymmetric Tsuji-Trost α-benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives.

Catalytic asymmetric Tsuji–Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

Light triggers select isomers to flip

Converting a mixture of mirror-image forms, or stereoisomers, of a molecule into a single isomer is a big deal in making pharmaceuticals, because usually only one isomer is useful as a drug. But current options for this process, called deracemization, are complicated and fiddly. Research by Sanzhong Luo and coworkers at Tsinghua University and the Haihe Laboratory of Sustainable Chemical Transformations has now made it as simple as turning on a light. The group used an iridium compound, an enamine, and violet light to transform a mixture of branched aldehyde isomers into a single one ( Science 2022, DOI: 10.1126/science.abl4922 ). The work combines two well-understood reactions: double-bond photoisomerization and enamine catalysis, which was recognized with the 2021 Nobel Prize in Chemistry . The group’s straightforward approach can be used to deracemize mixtures of many types of chiral aldehydes. The method works by transferring the chirality, or handed-ness, from the

Synthesis of Axially Chiral Aldehydes by N‐Heterocyclic‐Carbene‐Catalyzed Desymmetrization Followed by Kinetic Resolution

AbstractAxially chiral aldehydes have received increasing attention in enantioselective catalysis. However, only very few catalytic methods have been developed to construct structurally diverse axially chiral aldehydes. We herein describe an NHC‐catalyzed atroposelective esterification of biaryl dialdehydes as a general and practical strategy for the construction of axially chiral aldehydes. Mechanistic studies indicate that coupling proceeds through a novel combination of NHC‐catalyzed desymmetrization of the dialdehydes and kinetic resolution. This protocol features excellent enantioselectivity, mild conditions, good functional‐group tolerance, and applicability to late‐stage functionalization and provides a modular platform for the synthesis of axially chiral aldehydes and their derivatives.

Synthesis of Axially Chiral Aldehydes by N-Heterocyclic-Carbene-Catalyzed Desymmetrization Followed by Kinetic Resolution.

Axially chiral aldehydes have received increasing attention in enantioselective catalysis. However, only very few catalytic methods have been developed to construct structurally diverse axially chiral aldehydes. We herein describe an NHC-catalyzed atroposelective esterification of biaryl dialdehydes as a general and practical strategy for the construction of axially chiral aldehydes. Mechanistic studies indicate that coupling proceeds through a novel combination of NHC-catalyzed desymmetrization of the dialdehydes and kinetic resolution. This protocol features excellent enantioselectivity, mild conditions, good functional-group tolerance, and applicability to late-stage functionalization and provides a modular platform for the synthesis of axially chiral aldehydes and their derivatives.

N-Heterocyclic Carbene (NHC)-Catalyzed Desymmetrization of Biaryldialdehydes to Construct Axially Chiral Aldehydes

N-Heterocyclic Carbene (NHC)-Catalyzed Desymmetrization of Biaryldialdehydes to Construct Axially Chiral Aldehydes

Process Development of the Copper(II)-Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co-Substrate.

The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal‐catalyzed dehydration of chiral aldoximes, which are generated from chiral pool‐derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co‐substrate and water acceptor. Dehydration of N‐acyl α‐amino aldoximes such as N‐Boc‐l‐prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N‐acyl α‐amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by‐product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co‐substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N‐Boc‐cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.

Total Synthesis of Dolabriferol C by a Highly Stereoselective One-Pot Coupling of a meso-3,7-Diketone with Two Chiral Aldehydes.

Total synthesis of the noncontiguous polypropionate dolabriferol C was achieved by retro-Claisen fragmentation of its putative contiguous precursor under mild conditions, thus establishing the former as a plausible isolation artifact. The precursor was prepared by a novel one-pot three-component bisaldol coupling of a meso (Z,Z)-bisenolate (generated in situ from a 3,7-diketone) with two enantioenriched aldehydes to set the absolute configuration of seven stereocenters in one step. The first aldol reaction proceeded with enantioselective desymmetrization of the bisenolate to produce an enantiomerically pure enolate-aldolate. Quenching at this stage enabled a streamlined synthesis of dolabriferol. Addition of a racemic aldehyde to the enolate-aldolate resulted in aldol coupling with kinetic resolution of the "matched" aldehyde; overall, a sequential enantiotopic-group-selective (SEGS) bisaldol reaction. Because the desired adduct results from the "mismatched" aldol reaction, use of enantioenriched aldehyde was required.

Total Synthesis of Dolabriferol C by a Highly Stereoselective One‐Pot Coupling of a meso‐3,7‐Diketone with Two Chiral Aldehydes

AbstractTotal synthesis of the noncontiguous polypropionate dolabriferol C was achieved by retro‐Claisen fragmentation of its putative contiguous precursor under mild conditions, thus establishing the former as a plausible isolation artifact. The precursor was prepared by a novel one‐pot three‐component bisaldol coupling of a meso (Z,Z)‐bisenolate (generated in situ from a 3,7‐diketone) with two enantioenriched aldehydes to set the absolute configuration of seven stereocenters in one step. The first aldol reaction proceeded with enantioselective desymmetrization of the bisenolate to produce an enantiomerically pure enolate–aldolate. Quenching at this stage enabled a streamlined synthesis of dolabriferol. Addition of a racemic aldehyde to the enolate–aldolate resulted in aldol coupling with kinetic resolution of the “matched” aldehyde; overall, a sequential enantiotopic‐group‐selective (SEGS) bisaldol reaction. Because the desired adduct results from the “mismatched” aldol reaction, use of enantioenriched aldehyde was required.

Process Development of a Copper(II)-Catalyzed Dehydration of an N-Acyl Prolinal Oxime: Cascade Process and Application at an Elevated Lab Scale

AbstractChiral N-acyl amino nitriles are important structural motifs in several pharmaceuticals such as Vildagliptin or Saxagliptin. Cyanide-free access to such nitriles is provided by a copper-catalyzed dehydration of oximes, which are readily available by condensation of chiral aldehydes resulting from the chiral pool with hydroxylamine. The application in a cascade process without the need for intermediate purification as well as a demonstrated scalability show the robustness of this methodology.

Chemo-Enzymatic Cascade for the Generation of Fragrance Aldehydes

In this study, we present the synthesis of chiral fragrance aldehydes, which was tackled by a combination of chemo-catalysis and a multi-enzymatic in vivo cascade reaction and the development of a highly versatile high-throughput assay for the enzymatic reduction of carboxylic acids. We investigated a biocompatible metal-catalyzed synthesis for the preparation of α or β substituted cinnamic acid derivatives which were fed directly into the biocatalytic system. Subsequently, the target molecules were synthesized by an enzymatic cascade consisting of a carboxylate reduction, followed by the selective C-C double bond reduction catalyzed by appropriate enoate reductases. We investigated a biocompatible oxidative Heck protocol and combined it with cells expressing a carboxylic acid reductase from Neurospora crassa (NcCAR) and an ene reductase from Saccharomyces pastorianus for the production fragrance aldehydes.

Palladium/TY-Phos-Catalyzed Asymmetric Intermolecular α-Arylation of Aldehydes with Aryl Bromides.

Despite much progress has been made in the asymmetric α-arylation reactions of cyclic ketones, lactones and lactams, the enantioselective α-arylation of acyclic carbonyl compounds lagged much behind due to the in situ generated Z/E-enolate intermediates leading to opposite enantiomers. Especially, the asymmetric α-arylation of acyclic aldehydes is a long-standing challenge, because of the highest activity among carbonyl compounds leading to various competitive side reactions. Herein we reported an efficient Pd-catalyzed asymmetric intermolecular α-arylation reaction of α-alkyl-α-aryl disubstituted aldehydes with aryl bromides, which provides a rapid access to chiral aldehydes bearing an α-all-carbon quaternary stereocenter in moderate to good yields with good er in most cases. In addition, a pair of enantiomers could be easily prepared with the use of the same ligand by exchanging the aryl groups of aldehyde and aryl bromide.