Chiral Β-amino Alcohols Research Articles

β-amino alcohols as promising inhibitory candidates against the SARS-CoV-2, A theoretical design based on MD simulation and DFT insights

Nelfinavir, as a compound with a Chiral β-amino alcohol unit, is a well-known inhibitor against HIV-protease, studying. The role of heterocyclic derivatives of Nelfinavir as inhibitors against the Main-Protease of COVID-19 is the main purpose of this study. To reach a deep understanding, different theoretical approaches including molecular docking, Molecular Dynamic (MD) simulations, and DFT insights are applied in the studies. Investigation of the ligand bioactivity reveals that smaller HOMO/LUMO band gaps and lower chemical hardness (η), mean stronger interaction with the active site of the Main-Protease for the corresponding β-amino alcohols. Analyzing the efficient interactions in binding energy shows that among the studied Chiral β-amino alcohols, formed Van der Waals interactions via π and alkyl parts of ligands have more remarkable roles in inhibitory effects than hydrogen bonding. Accordingly, molecular mechanics (MM) and polar interactions have the highest contributions to the total energy of residues. Finally, it has been concluded that among the studied derivatives those that contain Dihydroisoquinoline (4b), and Perhydroisoquinoline (4d) heterocyclic rings can be considered as more potent candidates against Main-Protease of COVID-19.

Brønsted-Acid-Catalyzed Enantioselective Desymmetrization of 1,3-Diols: Access to Chiral β-Amino Alcohol Derivatives.

Herein, we describe a Brønsted-acid-catalyzed enantioselective desymmetrization of 1,3-diols with alkynes through a hydroalkoxylation/hydrolysis process. The reaction leads to the atom-economical synthesis of valuable chiral β-amino alcohols under mild reaction conditions. Further synthetic transformations based on the β-amino alcohol moiety provide divergent approaches toward chiral N-containing heterocycles.

Cr-Catalyzed Asymmetric Cross Aza-Pinacol Couplings for β-Amino Alcohol Synthesis.

Chiral β-amino alcohols are crucial structural motifs found in pharmaceuticals, natural products, and chiral ligands in asymmetric catalysis. Despite previous advances, the development of catalytic approaches to access β-amino alcohols bearing vicinal stereocenters from readily available chemicals remains a prominent challenge. Herein, we describe the Cr-catalyzed asymmetric cross aza-pinacol coupling of aldehydes and N-sulfonyl imines. This protocol proceeds in a radical-polar crossover manner from the intermediacy of an α-amino radical instead of a ketyl radical. Key to the success is using a chiral chromium catalyst, which plays a triple role in the chemoselective single-electron reduction of the imine, fast radical interception to inhibit radical addition to imines, and chemo- and stereoselective addition to aldehydes instead of imines. This method provides a modular and efficient approach to accessing diverse β-amino alcohols bearing vicinal stereocenters.

O-Allylhydroxyamine: A Bifunctional Olefin for Construction of Axially and Centrally Chiral Amino Alcohols via Asymmetric Carboamidation.

Difunctionalization of olefins offers an attractive approach to access complex chiral structures. Reported herein is the design of N-protected O-allylhydroxyamines as bifunctional olefins that undergo catalytic asymmetric 1,2-carboamidation with three classes of (hetero)arenes to afford chiral amino alcohols via C-H activation. The C═C bond in O-allylhydroxyamine is activated by the intramolecular electrophilic amidating moiety as well as a migrating directing group. The asymmetric carboamidation reaction pattern depends on the nature of the (hetero)arene reagent. Simple achiral (hetero)arenes reacted to give centrally chiral β-amino alcohols in excellent enantioselectivity. The employment of axially prochiral or axially racemic heteroarenes afforded amino alcohols with both axial and central chirality in excellent enantio- and diastereoselectivity. In the case of axially racemic heteroarenes, the coupling follows a kinetic resolution pattern with an s-factor of up to >600. A nitrene-based reaction mechanism has been suggested based on experimental studies, and a unique mode of induction of enantio- and diastereoselectivity has been proposed. Applications of the amino alcohol products have been demonstrated.

Expeditious preparation of β-sec-alkyl vicinal amino alcohols used for chiral ligand synthesis.

An economical route providing quick access to chiral β-amino alcohols bearing one β-sec-alkyl group was developed. This protocol starts with commercially available and cheap chiral sources such as derivatives of L-serine and L-threonine. A series of vicinal amino alcohols with high optical purity were prepared in good yields through 4 or 6 operationally simple steps. Two different strategies (three routes) were designed for the synthesis of amino alcohols bearing β-sec-alkyl groups with various steric hindrance.

Parallel kinetic resolution of aziridines via chiral phosphoric acid-catalyzed apparent hydrolytic ring-opening

An intriguing chiral phosphoric acid-catalyzed asymmetric hydrolytic ring-opening of racemic aziridines via regiodivergent PKR is presented, providing an efficient approach for the construction of chiral β-amino alcohols.

Asymmetric Henry Reaction of Nitromethane with Substituted Aldehydes Catalyzed by Novel In Situ Generated Chiral Bis(β-Amino Alcohol-Cu(OAc)2·H2O Complex

Novel chiral thiophene-2,5-bis(β-amino alcohol) ligands (L1–L5) were designed and synthesized from thiophene-2,5-dicarbaldehyde (3) with chiral β-amino alcohols (4a–e) in 4 steps with overall 23% yields. An in situ generated L-Cu(OAc)2·H2O catalyst system was found to be highly capable catalyst for the asymmetric Henry reaction of nitromethane (7) with various substituted aromatic aldehydes (6a–m) producing chiral nitroaldols product (8a–m) with excellent enantiomeric purity (up to 94.6% ee) and up to >99% chemical yields. 20 mol% of L4-Cu(OAc)2 catalyst complex in EtOH was effective for the asymmetric Henry transformation in 24 h, at ambient temperature. Ease of ligand synthesis, use of green solvent, base free reaction, mild reaction conditions, high yields and excellent enantioselectivity are all key factors that make this catalytic system robust and highly desirable for the access of versatile building block β-nitro alcohol in practical catalytic usage via asymmetric Henry reaction.

Enantioselective Conjugate Addition of Catalytically Generated Zinc Homoenolate

We report herein an enantioselective conjugate addition reaction of a zinc homoenolate, catalytically generated via ring opening of a cyclopropanol, to an α,β-unsaturated ketone. The reaction is promoted by a zinc aminoalkoxide catalyst generated from Et2Zn and a chiral β-amino alcohol to afford 1,6-diketones, which undergo, upon heating, intramolecular aldol condensation to furnish highly substituted cyclopentene derivatives with good to high enantioselectivities. The reaction has proved applicable to various 1-substituted cyclopropanols as well as chalcones and related enones. The chiral amino alcohol has proved to enable ligand-accelerated catalysis of the homoenolate generation and its conjugate addition. Positive nonlinear effects and lower reactivity of a racemic catalyst have been observed, which can be attributed to a stable and inactive heterochiral zinc aminoalkoxide dimer.

Catalytic enantioselective synthesis of β-amino alcohols by nitrene insertion

Chiral β-amino alcohols are important building blocks for the synthesis of drugs, natural products, chiral auxiliaries, chiral ligands and chiral organocatalysts. The catalytic asymmetric β-amination of alcohols offers a direct strategy to access this class of molecules. Herein, we report a general intramolecular C(sp3)–H nitrene insertion method for the synthesis of chiral oxazolidin-2-ones as precursors of chiral β-amino alcohols. Specifically, the ring-closing C(sp3)–H amination of N -benzoyloxycarbamates with 2 mol% of a chiral ruthenium catalyst provides cyclic carbamates in up to 99% yield and with up to 99% ee. The method is applicable to benzylic, allylic, and propargylic C–H bonds and can even be applied to completely non-activated C(sp3)–H bonds, although with somewhat reduced yields and stereoselectivities. The obtained cyclic carbamates can subsequently be hydrolyzed to obtain chiral β-amino alcohols. The method is very practical as the catalyst can be easily synthesized on a gram scale and can be recycled after the reaction for further use. The synthetic value of the new method is demonstrated with the asymmetric synthesis of a chiral oxazolidin-2-one as intermediate for the synthesis of the natural product aurantioclavine and chiral β-amino alcohols that are intermediates for the synthesis of chiral amino acids, indane-derived chiral Box-ligands, and the natural products dihydrohamacanthin A and dragmacidin A.

Cascade Biocatalysis for Regio- and Stereoselective Aminohydroxylation of Styrenyl Olefins to Enantiopure Arylglycinols

Chiral β-amino alcohols are privileged scaffolds frequently found in pharmaceutically active molecules and natural products. Aminohydroxylation of olefins is one of the most powerful strategies to access chiral vicinal amino alcohols. However, the direct regio- and stereoselective aminohydroxylation of olefins to unprotected enantioenriched β-amino alcohols remains a long-standing challenge. Herein, we report that a novel one-pot four-enzyme [styrene monooxygenase (SMO)/epoxide hydrolase (EH)/alcohol dehydrogenase (ADH)/ω-transaminase (TA)] biocatalytic cascade efficiently catalyzes the direct transformation of readily available styrenyl olefins into unprotected 2-amino-2-phenyl ethanols in good yields and excellent enantioselectivity. In vitro cascade biocatalysis aminohydroxylation of styrenyl olefins was first investigated by the combined four enzymes (SMO/EH/ADH/TA) with a trace amount of NADH (0.02 mM) and pyridoxal-5′-phosphate (0.1 mM), affording both enantiomers of β-amino alcohols 5a–j in 13.9–98.7% conversions and 86–99% ee. Whole-cell-based cascade biocatalysis was achieved by using the constructed recombinant Escherichia coli pairwise combinations and single tailor-made whole-cell biocatalyst without an additional NADH cofactor; (R)- and (S)-β-amino alcohols 5a–j could be obtained in 14.6–99.7% conversions and 86–99% ee. Moreover, the preparative experiments of this new cascade biocatalysis were demonstrated by the single tailor-made whole-cell biocatalyst [E. coli (CGS-DEM) and E. coli (CGS-DEB)] with the substrates 1a–b and 1h in an aqueous-organic two-phase system, affording chiral β-amino alcohols [(R)- or (S)-5a–b, h] in good yields (50.9–64.3%) and excellent ee (>99%).

Synthesis, Absolute Configuration, Antibacterial, and Antifungal Activities of Novel Benzofuryl β-Amino Alcohols.

A series of new benzofuryl α-azole ketones was synthesized and reduced by asymmetric transfer hydrogenation (ATH). Novel benzofuryl β-amino alcohols bearing an imidazolyl and triazolyl substituents were obtained with excellent enantioselectivity (96–99%). The absolute configuration (R) of the products was confirmed by means of electronic circular dichroism (ECD) spectroscopy supported by theoretical calculations. Selected benzofuryl α-azole ketones were also successfully asymmetrically bioreduced by fungi of Saccharomyces cerevisiae and Aureobasidium pullulans species. Racemic and chiral β-amino alcohols, as well as benzofuryl α-amino and α-bromo ketones were evaluated for their antibacterial and antifungal activities. From among the synthesized β-amino alcohols, the highest antimicrobial activity was found for (R)-1-(3,5-dimethylbenzofuran-2-yl)-2-(1H-imidazol-1-yl)ethan-1-ol against S. aureus ATCC 25923 (MIC = 64, MBC = 96 μg mL−1) and (R)-1-(3,5-dimethylbenzofuran-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-ol against yeasts of M. furfur DSM 6170 (MIC = MBC = 64 μg mL−1). In turn, from among the tested ketones, 1-(benzofuran-2-yl)-2-bromoethanones (1–4) were found to be the most active against M. furfur DSM 6170 (MIC = MBC = 1.5 μg mL−1) (MIC—minimal inhibitory concentration, MBC—minimal biocidal concentration).

Enantioselective radical C-H amination for the synthesis of β-amino alcohols.

Asymmetric, radical C–H functionalizations are rare, yet powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regio-selective C–H amination of alcohols to access medicinally valuable, chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol is transiently converted to an imidate radical that undergoes intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C–H amination enables broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl, and propargyl C–H bonds. Mechanistic experiments reveal triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity – enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C–H amination.

Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral β-Amino Alcohols with 2-Pyridyl and 6-(2,2'-Bipyridyl) Moieties.

In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45–82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc)2 under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN3 to form the corresponding azido amines as single regio- and diastereomers in 90–97% yield. Different results were obtained for 1,2-disubstituted and 1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted configurations, compared to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same configuration as the starting β-amino alcohols. To obtain a complete series of diastereomeric vic-diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium azide in SN2 reaction (25–58% overall yield). The azides obtained either way underwent the Staudinger reduction, giving a series of six new chiral vic-diamines of defined stereochemistries.

Copper-Catalyzed Enantioselective Reductive Cross-Coupling of Aldehydes and Imines.

A copper-catalyzed enantioselective reductive cross-coupling using aromatic aldehydes and imines, producing chiral β-amino alcohols, is described. The catalytic formation of enantioenriched chiral α-alkoxyalkylcopper(I) species from aromatic aldehydes and the subsequent reaction with imine electrophiles are attractive features of this protocol.

Pd-Catalyzed Asymmetric Hydroalkylation of 1,3-Dienes: Access to Unnatural α-Amino Acid Derivatives Containing Vicinal Quaternary and Tertiary Stereogenic Centers.

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

Multi-Catalytic Route for the Synthesis of (S)-Tembamide

Enantiopure β-amino alcohols constitute one of the most significant building blocks for the synthesis of active pharmaceutical ingredients. Despite the availability of a range of chiral β-amino alcohols from a chiral pool, there is a growing demand for new enantioselective synthetic routes to vicinal amino alcohols and their derivatives. In the present study, an asymmetric 2-step catalytic route that converts 4-anisaldehyde into a β-amino alcohol derivative, (S)-tembamide, with excellent enantiopurity (98% enantiomeric excess) has been developed. The recently published initial step consists in a concurrent biocatalytic cascade for the synthesis of (S)-4-methoxymandelonitrile benzoate. The O-benzoyl cyanohydrin is then converted to (S)-tembamide in a hydrogenation reaction catalyzed by Raney Ni. To achieve hydrogenation of the nitrile moiety with highest chemoselectivity and enantioretention, various parameters such as nature of the catalyst, reaction temperature and hydrogen pressure were studied. The reported strategy might be transferrable to the synthesis of other N-acyl-β-amino alcohols.

(±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction

Bis(NHC) ligand precursors, L1, based on trans-1,2-diaminocyclohexane were designed and synthesized. To introduce chirality at the hydroxyamide side arm on the NHC of L1, a chiral β-amino alcohol, such as enantiopure leucinol, was used. Cu-catalyzed asymmetric conjugate addition reactions of cyclic and acyclic enones with Et2Zn were selected to evaluate the performance of L1 as a chiral ligand. For the reaction of cyclic enone, a combination of [bis(trimethylsilyl)acetylene]-(hexafluoroacetylacetonato)copper(I) (Cu(hfacac)(btmsa)) with a (±)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (rac; S,S)-L1, which was prepared from (S)-leucinol, was the most effective. Thus, treating 2-cyclohexen-1-one (3) with Et2Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (rac; S,S)-L1 afforded (R)-3-ethylcyclohexanone ((R)-4) with 97% ee. Similarly, use of (rac; R,R)-L1, which was prepared from (R)-leucinol, produced (S)-4 with 97% ee. Conversely, for the asymmetric 1,4-addition reaction of the acyclic enone, optically pure (−)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (R,R; S,S)-L1, worked efficiently. For example, 3-nonen-2-one (5) was reacted with Et2Zn using the CuOAc/(R,R; S,S)-L1 catalytic system to afford (R)-4-ethylnonan-2-one ((R)-6) with 90% ee. Furthermore, initially changing the counterion of the Cu precatalyst between an OAc and a ClO4 ligand on the metal reversed the facial selectivity of the approach of the substrates. Thus, the conjugate addition reaction of 5 with Et2Zn using the Cu(ClO4)2/(R,R; S,S)-L1 catalytic system, afforded (S)-6 with 75% ee.

Enantioselective synthesis of enantiopure β-amino alcohols via kinetic resolution and asymmetric reductive amination by a robust transaminase from Mycobacterium vanbaalenii

Chiral β-amino alcohols are very important chiral building block for preparing bioactive compounds for use in pharmaceutical and fine chemical industries. Synthesis of chiral β-amino alcohols by transaminase is big challenging due to the strict substrate specificities and very low activity of the enzyme. In this work, a (R)-selective ω-transaminase (MVTA) from Mycobacterium vanbaalenii was employed as a biocatalyst for the first time for the synthesis of chiral β-amino alcohol via kinetic resolution and asymmetric reductive amination. The enzyme was purified and characterized. Kinetic resolution of a set of racemic β-amino alcohols including two cyclic β-amino alcohols by MVTA was demonstrated, affording (R)-β-amino alcohols, (1S, 2S)-trans-2-aminocyclopentanol and (1R, 2S)-cis-1-amino-2-indanols in >99% ee and 50–62% conversion. Asymmetric reductive amination of three α-hydroxy ketones (10–300 mM) by MVTA was conducted, (S)-β-amino alcohols were obtained with >99% ee and 80–99% conversion. Preparation experiment for the reductive amination of 200 mM 2-hydroxyacetophenone by the resting cells of recombinant E. coli (MVTA) was proceeded smoothly and product (S)-2-amino-2-phenylethanol was obtained with 71% isolated yield, >99% ee and 68.6 g/L/d volumetric productivity. The current research proved that the MVTA is a robust enzyme for the preparation of chiral β-amino alcohol with high volumetric productivity.

Catalytic Asymmetric Amination of meso-Epoxide Using Soy Polysaccharide (Soyafibe S-DN)

Abstract The asymmetric amination of epoxides is an effective method to synthesize chiral β-aminoalcohols and their components as pharmaceuticals. We have developed a new catalyst system for the asymmetric amination of 1,2-epoxycyclohexane with cyclopropylamine. We have also found that water-soluble soy polysaccharide (Soyafibe S-DN) functions as a catalyst. This catalytic reaction proceeded under mild conditions in hydrous toluene at 37–40 °C. (1R,2R)-2-(cyclopropylamino)cyclohexan-1-ol was obtained at 64% enantiomeric excess (ee) by the asymmetric amination of 1,2-epoxycyclohexane with cyclopropylamine using this catalyst system; it was also made at >99% ee by purification as the fumarate salt. The catalytic activity of this soluble soy polysaccharide remained unchanged, even when treated with a protease, but its activity disappeared when treated with a sugar chain degrading enzyme. These results indicate that the polysaccharide rather than the protein acts as the catalyst for this reaction. Thus, we have discovered for the first time that polysaccharides can act as asymmetric catalysts for the amination of 1,2-epoxycyclohexane.

Exploitation of differential electronic densities for the stereoselective reduction of ketones bearing a masked amino surrogate

A tethered ruthenium-TsDPEN catalyst is employed for the facile catalytic asymmetric reduction of α-phthalimyl-α′-ketoethers under mild conditions. Leveraging exclusively on the contrasting electronic densities on the heteroatoms, a series of enantioenriched phthalimyl ether alcohols can be obtained in generally good stereoselectivities from this challenging class of substrate. Subsequent transformation into highly valuable chiral β-amino alcohols is demonstrated to take place without significant losses in yield and optical purity.