Chiral Β-hydroxy Research Articles

L-Cysteine-Catalysed Hydration of Activated Alkynes.

Hydration reactions consist of the introduction of a molecule of water into a chemical compound and are particularly useful to transform alkynes into carbonyls, which are strategic intermediates in the synthesis of a plethora of compounds. Herein we demonstrate that L-cysteine can catalyse the hydration of activated alkynes in a very effective and fully regioselective manner to access important building blocks in synthetic chemistry such as β-ketosulfones, amides and esters, in aqueous media. The mild reaction conditions facilitated the integration with enzyme catalysis to access chiral β-hydroxy sulfones from the corresponding alkynes in a one-pot cascade process in good yields and excellent enantiomeric ratios. These findings pave the way towards establishing a general method for metal-free, cost-effective, and more sustainable alkyne hydration processes.

Chromium Catalyzed Asymmetric Reformatsky Reaction.

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral β-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, we achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism. Preliminary mechanistic insights, supported by DFT calculations, identify the nucleophilic aldehyde addition as the key stereo-determining step. This approach not only overcomes the limitations of existing Reformatsky reactions but also provides a versatile strategy for accessing complex chiral molecules.

Biocatalytic Enantioselective Synthesis of Chiral β-Hydroxy Nitriles Using Cyanohydrins as Cyano Sources

Biocatalytic Enantioselective Synthesis of Chiral β-Hydroxy Nitriles Using Cyanohydrins as Cyano Sources

A catalytic enantioselective stereodivergent aldol reaction.

The aldol reaction is among the most powerful and strategically important carbon-carbon bond-forming transformations in organic chemistry. The importance of the aldol reaction in constructing chiral building blocks for complex small-molecule synthesis has spurred continuous efforts toward the development of direct catalytic variants. The realization of a general catalytic aldol reaction with control over both the relative and absolute configurations of the newly formed stereogenic centers has been a longstanding goal in the field. Here, we report a decarboxylative aldol reaction that provides access to all four possible stereoisomers of the aldol product in one step from identical reactants. The mild reaction can be carried out on a large scale in an open flask, and generates CO2 as the only by-product. The method tolerates a broad substrate scope and generates chiral β-hydroxy thioester products with substantial downstream utility.

New Catalysts Derived from Natural Products as Highly Stereoselective Chiral Inductors for Diethylzinc Addition to Aromatic Aldehydes

Asymmetric addition of organozinc compounds to carbonyl groups is one of the most useful methods for the synthesis of alcohols with high enantioselectivity. There is a wide range of chiral catalysts, although their synthesis requires more than one step and not often readily available starting materials. In this work, chiral β-hydroxy oxazolines derived from (+)-camphor and (−)-fenchone were easily synthesized through a one-step method, with good yields. Both ligands were evaluated as catalysts for the stereoselective addition of diethylzinc to aromatic aldehydes. All ligands showed good catalytic activity, leading both to the preparation of the R enantiomer of chiral secondary alcohols. As ligand 2 provided slightly better enantioselectivities, it was used as chiral inductor for the addition of diethylzinc for a larger number of aldehydes, resulting in good to excellent yields (88-98%) and enantiomeric excess up to 96%.

From optically pure pyridinium salts to some new dihydro-2H-oxazolo[3,2-a]pyridines

Treatment of 2,4,6-triphenylpiridinium salts, bearing a chiral β-hydroxy alkyl N-substituent with diluted aqueous sodium hydroxide afforded four new dihydrooxazolo[3,2a]pyridines,as an almost equimolar mixture of diastereomers. However, a highly selective ring closure reaction was observed for the pyridium salt derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol.

Enantioselective synthesis of chiral β-hydroxy sulfonesviamanganese catalyzed asymmetric hydrogenation

The first example of manganese catalyzed asymmetric hydrogenation of β-keto sulfones for the construction of chiral β-hydroxy sulfones with up to 97% yield and 97% ee.

Highly Enantioselective Hydroxylation of 3-Arylpropanenitriles to Access Chiral β-Hydroxy Nitriles by Engineering of P450pyr Monooxygenase

Highly Enantioselective Hydroxylation of 3-Arylpropanenitriles to Access Chiral β-Hydroxy Nitriles by Engineering of P450pyr Monooxygenase

Efficient synthesis of an apremilast precursor and chiral β-hydroxy sulfones via ketoreductase-catalyzed asymmetric reduction.

Ketoreductase (KRED)-catalyzed asymmetric reduction of prochiral ketones is an attractive method to synthesize chiral alcohols. Herein, two KREDs LfSDR1-V186A/E141I and CgKR1-F92I with complementary stereopreference were identified towards reduction of apremilast prochiral ketone intermediate 1a. LfSDR1-V186A/E141I exhibited >99% conversion and 99.2% ee yielding an apremilast chiral alcohol intermediate ((R)-2a) at 50 g L-1 substrate loading. Furthermore, we investigated the substrate scope of β-keto sulfones by using LfSDR1-V186A/E141I and CgKR1-F92I to produce both enantiomers of the corresponding β-hydroxy sulfones, with good-to-excellent conversion (up to >99%) and enantioselectivity (up to 99.9% ee) being obtained in most cases. Finally, the gram-scale synthesis of (R)-2a was performed by employing the crude enzyme of LfSDR1-V186A/E141I and BsGDH to afford the desired enantiomer with >99% conversion, 85.9% isolated yield and 99.2% ee. This study presents a biocatalytic strategy to synthesize chiral β-hydroxy sulfones.

Diastereoselective Reduction of Selected α-substituted β-keto Esters and the Assignment of the Relative Configuration by 1H-NMR Spectroscopy

Background:: Chiral β-hydroxy esters and α-substituted β-hydroxy esters represent versatile building blocks for pheromones, β-lactam antibiotics and 1,2- or 1,3-aminoalcohols. Objective:: Synthesis of versatile α-substituted β-keto esters and their diastereoselective reduction to the corresponding syn- or anti-α-substituted β-hydroxy esters. Assignment of the relative configuration by NMR-spectroscopy after a Curtius rearrangement of α-substituted β-keto esters to 4-substituted 5-methyloxazolidin-2-ones. Methods: Diastereoselective reduction was achieved by using different Lewis acids (zinc, titanium and cerium) in combination with complex borohydrides as reducing agents. Assignment of the relative configuration was verified by 1H-NMR spectroscopy after Curtius-rearrangement of α-substituted β-hydroxy esters to 4-substituted 5-methyloxazolidin-2-ones. Results:: For the syn-selective reduction, titanium tetrachloride (TiCl4) in combination with a pyridine-borane complex (py BH3) led to diastereoselectivities up to 99% dr. High anti-selective reduction was achieved by using cerium trichloride (CeCl3) and steric hindered reducing agents such as lithium triethylborohydride (LiEt3BH). After Curtius-rearrangement of each α-substituted β-hydroxy ester to the corresponding 4-substituted 5-methyloxazolidin-2-one, the relative configuration was confirmed by 1H NMR-spectroscopy. Conclusion:: We have expanded the procedure of Lewis acid-mediated diastereoselective reduction to bulky α-substituents such as the isopropyl group and the electron withdrawing phenyl ring.

Asymmetric Palladium-Catalyzed Oxycarbonylation of Terminal Alkenes: Efficient Access to β-Hydroxy Alkylcarboxylic Acids.

A novel PdII -catalyzed enantioselective oxycarbonylation of alkenes has been established. The ligand with an ethyl group at the C-6 position of Pyox plays a significant role in the intermolecular oxypalladation process, leading to high reactivity and excellent enantioselective control. Compared to the conventional methods, the reaction itself features alkenes as easily prepared starting materials, mild and operationally simple reaction conditions, and insensitivities to air and water. Moreover, this method allows for broad alkene substrate scope, excellent regio- and enantioselectivities, scalabilities and a wide array of applications, and provides a useful route for the convenient and straightforward synthesis of chiral β-hydroxy alkylcarboxylic acids/esters.

A chemo-enzymatic oxidation/aldol sequential process directly converts arylbenzyl alcohols and cyclohexanol into chiral β-hydroxy carbonyls

An integrated laccase and prolines as a co-catalyst system enables an efficient oxidation/Aldol process to direct access chiral β-hydroxy carbonyls by using alcohols instead of environmentally unfriendly aldehydes and ketones.

Biphasic Bioelectrocatalytic Synthesis of Chiral β-Hydroxy Nitriles

Two obstacles limit the application of oxidoreductase-based asymmetric synthesis. One is the consumption of high stoichiometric amounts of reduced equivalent. The other is the low solubility of organic substrates, intermediates, and products in the aqueous phase. In order to address the two obstacles of oxidoreductase-based asymmetric synthesis, a biphasic bioelectrocatalytic system was constructed and applied.. In this study, the preparation of chiral β-hydroxy nitriles catalyzed by alcohol dehydrogenase (AdhS) and halohydrin dehalogenase (HHDH) was investigated as a high-value organic product. Diaphorase (DH) was immobilized by cobaltocene-modified poly(allylamine) redox polymer on the electrode surface (DH/Cc-PAA bioelectrode) to realize the effective bioelectrocatalytic NADH regeneration. AdhS is a NAD-dependent dehydrogenase, so the diaphorase modified biocathode was used to regenerate NADH to support the conversion from ethyl 4-chloroacetoacetate (COBE) to ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE) catalyzed by AdhS. The addition of methyl tert-butyl ether (MTBE) as organic phase not only increased the uploading of COBE, but also prevented the spontaneous hydrolysis of COBE and extended the lifetime of DH/Cc-PAA bioelectrode, and finally increased the Faradaic efficiency and the concentration of generated (R)-ethyl-4-cyano-3-hydroxybutyrate ((R)-CHCN). After 10 hours of reaction, the highest concentration of (R)-CHCN in biphasic bioelectrocatalytic system achieve 25.5 mM with 81.2% enantiomeric excess (ee p). The conversion ratio of COBE achieved 85%, which was 8.8 times higher than that of single phase system. Besides COBE, the other two substrates with aromatic ring structures were also used in this biphasic bioelectrocatalytic system to prepare corresponding chiral β-hydroxy nitriles. The results indicate that the biphasic bioelectrocatalytic system has the potential to produce a variety of β-hydroxy nitriles with different structures.

Biphasic Bioelectrocatalytic Synthesis of Chiral β-Hydroxy Nitriles.

Two obstacles limit the application of oxidoreductase-based asymmetric synthesis. One is the consumption of high stoichiometric amounts of reduced cofactor. The other is the low solubility of organic substrates, intermediates, and products in the aqueous phase. In order to address these two obstacles to oxidoreductase-based asymmetric synthesis, a biphasic bioelectrocatalytic system was constructed and applied. In this study, the preparation of chiral β-hydroxy nitriles catalyzed by alcohol dehydrogenase (AdhS) and halohydrin dehalogenase (HHDH) was investigated as a model bioelectrosynthesis, since they are high-value intermediates in statin synthesis. Diaphorase (DH) was immobilized by a cobaltocene-modified poly(allylamine) redox polymer on the electrode surface (DH/Cc-PAA bioelectrode) to achieve effective bioelectrocatalytic NADH regeneration. Since AdhS is a NAD-dependent dehydrogenase, the diaphorase-modified biocathode was used to regenerate NADH to support the conversion from ethyl 4-chloroacetoacetate (COBE) to ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE) catalyzed by AdhS. The addition of methyl tert-butyl ether (MTBE) as an organic phase not only increased the uploading of COBE but also prevented the spontaneous hydrolysis of COBE, extended the lifetime of DH/Cc-PAA bioelectrode, and increased the Faradaic efficiency and the concentration of generated (R)-ethyl-4-cyano-3-hydroxybutyrate ((R)-CHCN). After 10 h of reaction, the highest concentration of (R)-CHCN in the biphasic bioelectrocatalytic system was 25.5 mM with 81.2% enantiomeric excess (eep). The conversion ratio of COBE achieved 85%, which was 8.8 times higher than that achieved with the single-phase system. Besides COBE, two other substrates with aromatic ring structures were also used in this biphasic bioelectrocatalytic system to prepare the corresponding chiral β-hydroxy nitriles. The results indicate that the biphasic bioelectrocatalytic system has the potential to produce a variety of β-hydroxy nitriles with different structures.

Biocatalytic asymmetric ring-opening of dihydroisoxazoles: a cyanide-free route to complementary enantiomers of β-hydroxy nitriles from olefins

From alkenes and nitromethane, a cyanide-free pathway to synthesize chiral β-hydroxy nitriles via the enantioselective ring-opening of 5-sub-4,5-dihydroisoxazoles catalyzed by aldoxime dehydratases has been developed.

Identification and application of threonine aldolase for synthesis of valuable α-amino, β-hydroxy-building blocks

Chiral β-hydroxy α-amino acid structural motifs are interesting and common synthons present in multiple APIs and drug candidates. To access these chiral building blocks either multistep chemical syntheses are required or the application of threonine aldolases, which catalyze aldol reactions between an aldehyde and glycine. Bioinformatics tools have been utilized to identify the gene encoding threonine aldolase from Vanrija humicola and subsequent preparation of its recombinant version from E. coli fermentation. We planned to implement this enzyme as a key step to access the synthesis of our target API. Beyond this specific application, the aldolase was purified, characterized and the substrate scope of this enzyme further investigated. A number of enzymatic reactions were scaled-up and the products recovered to assess the diastereoselectivity and scalability of this asymmetric synthetic approach towards β-hydroxy α-amino acid chiral building blocks.

Enantioselective Carbonyl 1,2- or 1,4-Addition Reactions of Nucleophilic Silyl and Diazo Compounds Catalyzed by the Chiral Oxazaborolidinium Ion.

Boron Lewis acid catalysis has a long history and has become one of the most powerful methods for organic synthesis. In addition to achiral boron catalysts such as BX3 (X = F, Cl, Br) and B(C6F5)3, chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al. in 2002( Corey et al. J. Am. Chem. Soc. 2002 , 124 , 3808 ), the chiral oxazaborolidinium ion (COBI), an activated form of proline-derived oxazaborolidine, has been used as a strong Lewis acid catalyst. Although the early examples of asymmetric synthesis through COBI-catalyzed nucleophilic 1,2- or 1,4-carbonyl additions were reported in 2004-2006, Diels-Alder and cycloaddition reactions of various carbonyl compounds were mostly developed over the next several years to afford enantioenriched cyclized products. The power of COBI in catalyzing carbonyl 1,2- or 1,4-addition reactions triggered our interest in developing asymmetric synthetic methodologies to generate versatile enantiomerically enriched compounds. In this Account, we summarize our recent studies on COBI-catalyzed asymmetric nucleophilic carbonyl addition and tandem reactions. Logical mechanistic explanations of asymmetric COBI catalysis are also discussed. The proton-activated COBI catalyst, which can activate various carbonyl compounds such as aldehydes, ketones, acroleins, and enones through Lewis acid-base interactions and synergistic hydrogen bonds, facilitates asymmetric 1,2- or 1,4-carbonyl additions of nucleophiles. Nucleophiles bearing trialkylsilyl groups successfully reacted with aromatic, aliphatic, and α,β-unsaturated aldehydes through 1,2-addition reactions resulting in chiral β-hydroxy esters. In addition, efficient asymmetric hydrosilylation of ketones was achieved with a TfOH-activated COBI catalyst. Optically active β-keto esters and all-carbon quaternary aldehydes were synthesized successfully through asymmetric 1,2-addition of diazo compounds and tandem H- or C-migration, respectively. In some cases, epoxide products were obtained as side products via the Darzens reaction pathway. Solvent and π-π interactions played important roles in favoring C-migration over H-migration. Nucleophilic 1,4-addition of diazo compounds and chemoselective ring-closure afforded an efficient approach to cyclopropanes, and their tandem rearrangements provided four- and seven-membered cyclic compounds with excellent stereoselectivity. After a Michael addition of diazo compounds, the selective β-hydride shift pathway afforded the β-substituted cyclic enones with high diastereo- and enantioselectivity. The presence of π-bond(s) in the substituents at the α-position of the diazo compound hindered the β-hydride shift pathway and, as a result, favored the cyclopropanation pathway. While there still remain challenges to be overcome, these results further understanding of COBI catalysis and open a window for future development of new asymmetric synthetic methods using carbonyl addition and tandem reactions.

Ru-Catalyzed Chemo- and Enantioselective Hydrogenation of β-Diketones Assisted by the Neighboring Heteroatoms.

A highly chemo- and enantioselective hydrogenation of β-diketones was achieved by using [Ru(benzene)(S)-SunPhosCl]Cl for consistency in THF. The neighboring heteroatoms played important roles in guaranteeing the reactivity and controlling the chemoselectivity. These results suggested a potential approach for the clean and facile synthesis of functionalized chiral β-hydroxy ketones, which could otherwise be prepared through much less step-economic transformations.

Efficient synthesis of chiral β-hydroxy sulfones via iridium-catalyzed hydrogenation.

A highly efficient Ir/f-Amphol-catalyzed asymmetric hydrogenation of prochiral β-keto sulfones was successfully developed to prepare a series of chiral β-hydroxy sulfones with good to excellent results (62%->99% conversions, 35%-99% yields and 86%->99% ee). Our Ir/f-Amphol L4 catalytic system exhibited very high activity; the gram-scale asymmetric hydrogenation was performed well with just 0.005 mol% catalyst loading (S/C = 20 000) to afford the desired product 2a with >99% conversion, 99% yield and 93% ee.

Efficient biocatalytic stereoselective reduction of methyl acetoacetate catalyzed by whole cells of engineered E. coli.

Asymmetric synthesis of chiral β-hydroxy esters, the key building blocks for many functional materials, is currently of great interest. In this study, the biocatalytic anti-Prelog reduction of methyl acetoacetate (MAA) to methyl-(R)-3-hydroxybutyrate ((R)-HBME) was successfully carried out with high enantioselectivity using the whole cell of engineered E. coli, which harbored an AcCR (carbonyl reductase) gene from Acetobacter sp. CCTCC M209061 and a GDH (glucose dehydrogenase) gene from Bacillus subtilis 168 for the in situ regeneration of the coenzyme. Compared with the corresponding wild strain, the engineered E. coli cells were proved to be more effective for the bio-reduction of MAA, and afforded much higher productivity. Under the optimized conditions, the product e.e. was >99.9% and the maximum yield was 85.3% after a reaction time of 10 h, which were much higher than those reported previously. In addition, the production of (R)-HBME increased significantly by using a fed-batch strategy of tuning pH, with a space-time yield of approximately 265 g L−1 d−1, thus the issue in previous research of relatively low substrate concentrations appears to be solved. Besides, the established bio-catalytic system was proved to be feasible up to a 150 mL scale with a large-scale relatively high substrate concentration and selectivity. For further industrial application, these results open a way to use of whole cells of engineered E. coli for challenging higher substrate concentrations of β-ketone esters enantioselective reduction reactions.