Chiral Β-amino Alcohols Research Articles

New functional chiral P-based ligands and application in ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral β-amino alcohols were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium catalytic systems generated from [Ru(arene)(μ-Cl)Cl]2 complexes and chiral phosphinite ligands based on amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(η6-benzene)ruthenium(II)] acts an excellent catalyst in the reduction of α-naphthyl methyl ketone, giving the corresponding alcohol with up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation is characterized by low reversibility under these conditions.

Synthesis and crystal structure of a chiral lactam and three amino alcohols as potential protein tyrosine phosphates 1B inhibitors

Chiral lactam 2 and three chiral β-amino alcohols 3–5 have been synthesized and characterized by spectroscopic techniques. Regioselective ring opening reaction of chiral styrene oxide by an amine nucleophile was confirmed by X-ray diffraction data. Ligand 2–4 crystallizes in the tetragonal, orthorhombic and tetragonal crystal lattice system respectively. Ligands 2–6 have been used as potential inhibitors for protein tyrosine phosphatase 1B enzyme (PTP1B). The potential inhibitor effect of these molecules to the target protein was investigated by Dock and molecular dynamics calculations. Dock score analysis and Lipinski parameters suggested that ligands 1, 2, 4–6 are potential inhibitors towards PTP1B, thus indicating that the residues Arg24, Arg254 and Met258, Asp29 in the second active site of PTP1B are essential for the high selectivity of inhibitors. The results indicate that the polar hydrogen bonding interacts with Asp29, Gln102, and the amino acid residues of PTP1B are responsible for governing inhibitory potency of ligands 1–6.

Inversions in asymmetric conjugate addition reaction of cyclic enones catalyzed by the Cu/NHC-AgX system: Factors affecting the stereoselective formation of both enantiomers

A switchable enantioselectivity was achieved in a Cu-catalyzed asymmetric conjugate addition (ACA) reaction. The ethylene-bridged, hydroxyamide-functionalized NHC-AgI complex, readily accessible from a chiral β-amino alcohol, was found to be a versatile chiral ligand precursor for dual enantioselective control. The stereocontrol of the catalytic ACA reaction depended on the order of addition of the substrates. To a THF solution containing CuOTf (6 mol %), NHC-AgI complex (1b, R1 = Et, R2 = Bn, 4 mol %), and 2-cyclohexen-1-one (3) was added Et2Zn to yield (R)-3-ethylcyclohexanone ((R)-4) in 74% enantioselectivity (method A). In stark contrast, when 3 was added as a last component to a mixture of CuOTf (4 mol %), 1b (10 mol %), and Et2Zn in THF (method B), the ACA reaction afforded (S)-4 with 87% ee. In order to obtain an insight into various aspects of the present ACA reaction, the chiral NHC ligand precursors, substrates, and NHC skeletons were fully evaluated. A study of the relationship between the catalyst ee (eecat) and the product ee (eepro) revealed a chiral amplification phenomenon. Moreover, it was found that the ACA reaction using method A was not affected by the halide ion on the NHC-AgX complex, whereas the halide ion on the silver complex showed a significant influence on the enantiocontrol of the ACA reaction using method B. In particular, a Cu/NHC/I catalytic ratio of 1/1/2 was needed for a successful ACA reaction using method B. According to these factors affecting the reversal of enantioselectivity in the ACA reaction, a possible reaction pathway was proposed.

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β-Amino Alcohol.

The development of a flow chemistry process for asymmetric propargylation using allene gas as a reagent is reported. The connected continuous process of allene dissolution, lithiation, Li-Zn transmetallation, and asymmetric propargylation provides homopropargyl β-amino alcohol 1 with high regio- and diastereoselectivity in high yield. This flow process enables practical use of an unstable allenyllithium intermediate. The process uses the commercially available and recyclable (1S,2R)-N-pyrrolidinyl norephedrine as a ligand to promote the highly diastereoselective (32:1) propargylation. Judicious selection of mixers based on the chemistry requirement and real-time monitoring of the process using process analytical technology (PAT) enabled stable and scalable flow chemistry runs.

ChemInform Abstract: Green Regio‐ and Enantioselective Aminolysis Catalyzed by Graphite and Graphene Oxide under Solvent‐Free Conditions.

The ring-opening reactions of epoxides with amines were efficiently and regioselectively catalyzed by high-surface-area graphite and graphene oxide under metal-free and solvent-free conditions. For epoxides without aryl groups, catalytic activity was observed only for graphene oxide, and hence, the activity must have been due to its acidic groups. For styrene oxide, instead, graphite and graphene oxide exhibited rather similar catalytic activities, and hence, the activity was mainly due to activation of the electrophilic epoxide by π-stacking interactions with the graphitic π system. The described aminolysis procedure is green and cheap because the catalyst can be recovered and recycled without loss of efficiency. Moreover, these heterogeneous catalysts exert high stereoselective control in the presence of nonracemic epoxides and provide chiral β-amino alcohols with enantiomeric excess values up to 99 %.

ChemInform Abstract: Rhodium‐Catalyzed Asymmetric Hydrogenation of α‐Dehydroamino Ketones: A General Approach to Chiral α‐Amino Ketones.

AbstractEfficient asymmetric hydrogenation of α‐dehydroamino ketones is achieved in excellent enantioselectivity using a Rh‐DuanPhos catalyst.

ChemInform Abstract: Designing New Readily Available Sugar‐Based Ligands for Asymmetric Transfer Hydrogenation of Ketones. In the Quest to Expand the Substrate Scope

AbstractReview: [20 refs.

ChemInform Abstract: Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides.

Synthesis of enantiomerically enriched α-hydroxy amides and β-amino alcohols has been accomplished by enantioselective reduction of α-keto amides with hydrosilanes. A series of α-keto amides were reduced in the presence of chiral Cu(II)/(S)-DTBM-SEGPHOS catalyst to give the corresponding optically active α-hydroxy amides with excellent enantioselectivities by using (EtO)3SiH as a reducing agent. Furthermore, a one-pot complete reduction of both ketone and amide groups of α-keto amides has been achieved using the same chiral copper catalyst followed by tetra-n-butylammonium fluoride (TBAF) catalyst in presence of (EtO)3SiH to afford the corresponding chiral β-amino alcohol derivatives.

Copper-Catalyzed Synthesis of Chiral α-Hydroxy Amides and β-Amino Alcohols

Copper-Catalyzed Synthesis of Chiral α-Hydroxy Amides and β-Amino Alcohols

Chiral Co(iii)–salen complex supported over highly ordered functionalized mesoporous silica for enantioselective aminolysis of racemic epoxides

New mesoporous chiral Co(iii)-catalyst has been synthesed and used in the synthesis of chiral β-amino alcohols with excellent yield and enantioselectivity (ee > 99%) under neat conditions at RT.

A new recyclable functionalized mesoporous SBA-15 catalyst grafted with chiral Fe(iii) sites for the enantioselective aminolysis of racemic epoxides under solvent free conditions

A mesoporous SBA-15 supported chiral Fe(iii)-catalyst was prepared and used for the synthesis of chiral β-amino alcohols with very good yields and enantioselectivities (ee upto 98%) under neat conditions at RT.

Enantioselective Synthesis of α-Hydroxy Amides and β-Amino Alcohols from α-Keto Amides.

Synthesis of enantiomerically enriched α-hydroxy amides and β-amino alcohols has been accomplished by enantioselective reduction of α-keto amides with hydrosilanes. A series of α-keto amides were reduced in the presence of chiral Cu(II)/(S)-DTBM-SEGPHOS catalyst to give the corresponding optically active α-hydroxy amides with excellent enantioselectivities by using (EtO)3SiH as a reducing agent. Furthermore, a one-pot complete reduction of both ketone and amide groups of α-keto amides has been achieved using the same chiral copper catalyst followed by tetra-n-butylammonium fluoride (TBAF) catalyst in presence of (EtO)3SiH to afford the corresponding chiral β-amino alcohol derivatives.

Rhodium-catalyzed Asymmetric Hydrogenation of α-Dehydroamino Ketones: A General Approach to Chiral α-amino Ketones.

Rhodium/DuanPhos-catalyzed asymmetric hydrogenation of aliphatic α-dehydroamino ketones has been achieved and afforded chiral α-amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β-amino alcohols by LiAlH(tBuO)3 with good yields. This protocol provides a readily accessible route for the synthesis of chiral α-amino ketones and chiral β-amino alcohols.

ChemInform Abstract: Asymmetric Reduction of α‐Amino Ketones with a KBH4 Solution Catalyzed by Chiral Lewis Acids.

An efficient enantioselective reduction of α-amino ketones with potassium borohydride solution catalyzed by chiral N,N'-dioxide-metal complex catalysts was accomplished under mild reaction conditions for the first time. It provided a simple, convenient, and practical approaches for obtaining synthetically important chiral β-amino alcohols in good to excellent yields (up to 98%) and enantioselectivities (up to 97% ee).

Enantioselective addition of dialkylzinc to aromatic aldimines mediated by camphor-derived chiral β-amino alcohols.

The enantioselective addition of diethylzinc or dimethylzinc to N-(diphenylphosphinoyl)imines mediated by 1 or 2 could be achieved in high yields (70-97 %) and enantioselectivities (85-98 % ee). The catalytic loading of 1 or 2 a could be reduced to 10 mol % for methylation or ethylation of imines in high yields and enantioselectivities (79-96 %) when the reaction was conducted in the presence of 1.8 equiv of methanol. N-Monosubstituted amino alcohols induced higher enantioselectivity than their N,N-disubstituted congener in our catalytic system.

ChemInform Abstract: Efficient Asymmetric Addition of Diethylzinc to Aldehydes Using C2‐Novel Chiral Pyridine β‐Amino Alcohols as Chiral Ligands.

A series of novel C2-symmetric chiral pyridine β-amino alcohol ligands have been synthesized from 2,6-pyridine dicarboxaldehyde, m-phthalaldehyde and chiral β-amino alcohols through a two-step reaction. All their structures were characterized by 1H NMR, 13C NMR and IR. Their enantioselective induction behaviors were examined under different conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2′R)-2,2′-((pyridine-2,6-diylbis(methylene))bisazanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was used in toluene at room temperature. The ligand 3g (2S,2′R)-2,2′-((1,3-phenylenebis(methylene))bis(azanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was prepared in which the pyridine ring was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the asymmetric induction reaction. Copyright © 2014 John Wiley & Sons, Ltd.

ChemInform Abstract: Magnetic Nano Fe3O4 Catalyzed Solvent‐Free Stereo‐ and Regioselective Aminolysis of Epoxides by Amines; a Green Method for the Synthesis of β‐Amino Alcohols.

AbstractThe magnetic nano‐Fe3O4 catalyst can be easily recovered and reused.

Asymmetric Reduction of α‐Amino Ketones with a KBH4 Solution Catalyzed by Chiral Lewis Acids

An efficient enantioselective reduction of α-amino ketones with potassium borohydride solution catalyzed by chiral N,N'-dioxide-metal complex catalysts was accomplished under mild reaction conditions for the first time. It provided a simple, convenient, and practical approaches for obtaining synthetically important chiral β-amino alcohols in good to excellent yields (up to 98%) and enantioselectivities (up to 97% ee).

Enantioselective Synthesis of Chiral 1,2-Amino Alcohols via Asymmetric Hydrogenation of α-Amino Ketones with Chiral Spiro Iridium Catalysts

A highly efficient iridium-catalyzed asymmetric hydrogenation of α-amino ketones for the synthesis of chiral 1,2-amino alcohols is described. With chiral spiro iridium catalyst Ir-(<i>R</i>)-<b>1c</b>, a series of α-amino ketones were hydrogenated to chiral β-amino alcohols in excellent enantioselectivities (up to 99.9% ee) with TON up to 100 000. In addition, with this highly efficient method the chiral drugs (<i>R</i>)-clorpenaline and (<i>R</i>)-phenylephrine were prepared in very high efficiency.

Inside Cover: Design of Peptidyl Thiourea Derivatives as Organocatalysts for the Asymmetric Ring Opening ofmeso-Stilbene Oxides (Asian J. Org. Chem. 6/2014)

Organocatalysis Organocatalytic asymmetric ring opening of epoxides with aliphatic amines has always been a challenge. In their Communication on page 700 ff., Swapandeep Singh Chimni report the design and synthesis of chiral peptidyl thiourea organocatalysts for the asymmetric ring opening of epoxides with N-phenylpiperazines. A tripeptide scaffold with a β-turn nucleating element provides favorable stereochemistry by positioning the nucleophile close to the epoxide. Chiral β-amino alcohols were obtained with up to 95% ee after crystallization. The configuration at the N-terminal residue of the catalyst affects the stereochemical outcome of the reaction.