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.     

Synthesis,Characterization and Structure of Chiral Amino Acids and Their Corresponding Amino Alcohols with Camphoric Backbone

1 INTRODUCTION Chiral amino acids and their versatile derivatives are very useful compounds in many fields[1]. In com- parison with well-documented chiral α and β amino acids and amino alcohols, the studies of chiral γ, δ… ω amino acids and amino alcohols deserve more attention. For example, there have been numerous reports on versatile functions of γ aminobutyric acid (GABA) produced from L-glutamic acid in the presence of L-glutamate decarboxylase (GAD)[2]. However, the stereo…     

Chiral Ferrocenyl Amino Alcohols：Preparation and Application as Catalysts in the Enantioselective Reduction of Ketones Using NaBH4／I2

Five novel chiral ferrocenyl amino alcohols were prepared from natural amino acids and used as catalysts in the asymmetric reduction of prochiral ketones with NaBH4/I2 combination.The incorporation of the ferrocenyl moiety into the molecule of the chiral amino alcohols greatly improved their enantioselectivity in the catalysis.The optically active secondary alcohols were obt5ained in moderate to good enantiomeric excesses and high chemical yields.     

Synthesis and Catalytic Asymmetric Reaction of Chiral Pyridine Prolinol Derivatives

The enantioselective reduction of prochiral ketones with borane in the presence of a chiral ligand leading to enantiomerically pure secondary alcohols has received considerable attention in recent years. [1] Enantiomerically pure secondary alcohols are important intermediates for the synthesis of various other organic compounds such as halides, esters, ethers, ketones and amines. To the best of our knowledge, the use of pyridine prolinol derivatives in the reduction of ketones has not been reported so far. Thus, it should be of interest to investigate the catalytic a bility of such ligands. We have an ongoing project in the synthesis and application of chiral pyridine derivatives in chiral molecular recognition[2] and we want to evaluate the effect resulting from the introduction of a pyridinyl moiety onto the catalysts. We expect that the cooperation of pyridine unit and chiral prolinol unit in new ligands may result in unique properties for catalytic reaction.     

Conformer Pair Contributions to Optical Rotations in a Series of Chiral Linear Aliphatic Alcohols

The chain length effect of four chiral aliphatic alcohols,(S)-2-butanol,(S)-2-pentanol,(S)-2-hexanol and (S)-2-heptanol,on their specific optical rotations(OR)was studied experimentally and theoretically via quantum theory.Many conformations of each chiral alcohol exist as conformer pairs in solution.The OR sum from these pairs of conformers has much smaller contributions to OR values than that contributed by the most stable conformation. These four alcohols'OR values were also investigated using the matrix model,which employs each substituent's comprehensive mass,radii,electronegativity and symmetry number as the elements in the matrix.These are all particle properties.This matrix determinant is proportional to its OR values within a closely related structural series of chiral compounds.The experimental OR values and the matrix determinants of these four alcohols were compared with the predicted OR values obtained from quantum theory wave functions.The ORs predicted by the matrix method, which is based on particle function statistics,agreed with the results from quantum theory.The agreement between OR predictions by the matrix method and DFT calculations illustrates the wave-particle duality of polarized light that is operating in these predictions.     

Diboron-mediated palladium-catalyzed asymmetric transfer hydrogenation using the proton of alcohols as hydrogen source

The developments of hydrogen sources stand at the forefront of asymmetric reduction. In contrast to the well-studied alcohols as hydrogen sources via β-hydride elimination, the direct utilization of the proton of alcohols as a hydrogen source for activatormediated asymmetric reduction is rarely explored. Herein we report the proton of alcohols as a hydrogen source in diboronmediated palladium-catalyzed asymmetric transfer hydrogenation of 1,3-diketones and indoles, providing a series of chiral β-hydroxy ketones and indolines with excellent yields and enantioselectivities. This strategy would be useful for the synthesis of chiral deuterium-labelled compounds due to the ready availability of deuterium-labelled alcohols. Mechanistic investigations and DFT calculations revealed that active chiral Pd-H species was generated from the proton of alcohols by activating of tetrahydroxydiboron, hydrogen transfer was the rate-determining step, and the reaction preferred Pd(0)-catalyzed mechanism.     

Enthalpy-entropy compensation effect in gas chromatographic enantiomeric separation

In this paper, the enthalpy-entropy compensation effect in the enantiomeric separation by modified cyclodextrins (CD) and diamide chiral stationary phase (CSP) gas chromatography was investigated using the method of plotting △(△H) versus △(△G) rhm combined with t-test statistic analysis. The investigated racemates cover α-phenylethylamine and its analogs, 2-alkylamines, chiral acyclic alcohols, halogenated arylethanediol-1, 2-diperfluoropropionates, amino acid and its analogs, and two series of compounds containing chloro and bromo substituents. From the compensation analysis results, the effects of the diluent composition in the investigated chiral stationary phases, the size and the modified groups on investigated cyclodextrins, the derivatization methods and the groups attached to the stereocenters on enantiomeric separation mechanisms were all discussed.     

Highly Enantioselective Phenylacetylene Addition to Benzaldehyde Catalyzed by Chiral Tridentate Ligand

Development of new or improved methods for the asymmetric preparation of chiral propargylic alcohols has gained considerable significance during the past years because they are useful building blocks for the synthesis of many biologically active compounds and natural products.[1] A series of chiral tridentate ligands were conveniently synthesized from amino acids with good yields (Scheme 1).[2] A preliminary study of the enantioselective alkynylation of benzaldehyde catalyzed by this chiral tridentate ligand was carried out and up to 83% ee of chiral propargyl alcohols was obtained (Table 1 ). A further investigation of the tridentate ligand is currently underway.     

Synthesis of Novel Derivatives of （R）-Cysteine and Their Application in Asymmetric Reduction of Prochiral Ketones

ovel chiral β-amino alcohols containing sulfide or sulfonyl groups were synthesized from （R）-cysteine. Their chiral induction in the asymmetric borane reduction of prochiral ketones was investigated. Optically active secondary alcohols with moderate or high e. e. values were obtained, and the causes of different enantioselectivities between these two sulfur-containing chiral β-amino alcohols were researched.     

Optically Active Chiral Auxiliary Benzyloxyphenylglycinol for Preparation of Oxazolidine and Its Derivatives

To investigate the recovery of amino alcohols as chiral auxiliaries, optically active p-benzyloxyphenylglycinol and its corresponding oxazolidine of 1-naphthylcarboxaldehyde were prepared. Grignard additions to the oxazolidine followed by electrophilic quench and acidic hydrolysis afforded an aldehyde( compound 8) (later it was reduced to an alcohol, compound 9) in an excellent enantiomeric excess and a good recovery of the chlral amino alcohol. This research provides a model study of chiral amino alcohols in solid phase asymmetric synthesis.     

N-磺化手性β-氨基醇修饰的钛试剂催化下的酮的不对称炔基化反应研究

The easily prepared and recoverable chiral N-sulfonylated fl-amino alcohol 2 in combination with Ti（OPr-i）4 was found to be an effective chiral catalyst for the enantioselective addition of alkynylzinc to ketones, which gave the useful products, i.e. chiral tertiary propargyl alcohols, with the ee up to 92%.     

The Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by 2-Methylquinoline Derived Chiral Ligands

One of the most important and fundamental synthetic procedures for the establishment of a carbon-carbon bond stereoselectively is the enantioselective addition of organometallic reagents to aldehydes affording chiral secondary alcohols1. In this process, a frequently used method is to perform the reaction in the presence of a chiral ligand such as amino alcohol2. Here, we first report that two new chiral ligands3, which were readily available by the reaction of chiral ketone with lithiated 2-m…     

An Efficient Method for Catalytic Asymmetric Reduction of Diketones and Application of Synthesis to Chiral 2,5- Diphenylpyrrolidine and 2,5-Diphenylthiolane

Asymmetric reduction of diketones with borane reagents generated in situ using cheap and available NaBH_4 andSnCl_2 in the presence of(S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol was successfully achieved to yield the corre-sponding chiral diols with excellent stereoselectivity and enantioselectivity.And the chiral diol was transformedinto optically pure C_2-symmetricl chiral amine or thioether.     

手性氨基醇催化的苯乙炔与酮的对映选择性加成

(S)-(1-Benzylpyrrolidin-2-yl)diphenylmethanol and cinchonine were evaluated as promotors in the asymmetricadditions of phenylacetylene to ketones,in order to prepare chiral propargylic alcohols.Good yields(up to 89%)and moderate enantioselectivities(up to 77.9% ee)were achieved.Addition of Ti(OPr-i)_4 can significantly improvethe enantioselectivity of the reaction.     

Enantioselective Alkynylation of Benzaldehyde Catalyzed by New Chiral Lewis Acid Ligand: Zinc-Amide Complex

The enantioselective alkynylzinc addition to aldehydes is very useful for the synthesis of chiral propargyl alcohols which are important versatile building blocks of many biologically active compounds and natural products1. A series of chiral oxazolidines were conveniently synthesized from amino acids in three steps with good yields. The use of chiral Lewis acid ligand: zinc-amide complex in situ generated from this oxazolidine with alkylzinc as chiral catalysts for the enantioselective alkyny…     

Novel Chiral PNNP-Ru Complexes:Synthesis and Application in Asymmetric Transfer Hydrogenation of Ketones

The efficient catalytic systems generated in situ from RuCl2(PPh3)3 and chiral ligands N,N-bis[2-(di-o- tolylphosphino)-benzyl]cyclohexane-1,2-diamine(2) were employed for asymmetric transfer hydrogenation of aromatic ketones, giving the corresponding optically active alcohols with high activities(up to 99% conversion) and excellent enantioselectivities(up to 96% e.e.) under mild conditions. The chiral ruthenium(Ⅱ) complex (R,R)-3 has been prepared and characterized by NMR and X-ray crystallography.     

Asymmetric reduction of representative ketones with a bis-chiral oxazaborolidine system

In recent years, many optically active β-amino alcohols, mostly derived from naturally occurring α-amino acids, have been incorporated into the asymmetric synthesis as chiral auxiliaries or ligands.1 An effective asymmetric catalysts, the oxazaborolidine-borane reagents, which were originally pioneered by Itsuno and Corey,2 were generally prepared from chiral β-amino alcohols by the reaction with boric acid or formed in situ in the presence of borane. These reagents provide excellent enanti…     

Synthesis of novel chiral tetraaza ligands and their application in enantioselective transfer hydrogenation of ketones

Novel chiral tetraaza ligands(R)-N,N′-bis[2-(piperidin-1-yl)benzylidene]propane-l,2-diamine 6 and(S)-N-[2-(piperidin-l- yl)benzylidene]-3-{[2-(piperidin-1-yl)benzylidene]amino}-alanine sodium salt 7 have been synthesized and fully characterized by NMR,IR,MS and CD spectra.The catalytic property of the ligands was investigated in Ir-catalyzed enantioselective transfer hydrogenation of ketones.The corresponding optical active alcohols were obtained with high yields and moderate ees under mild reaction conditions.     

Chiral separation abilities of homogeneously synthesized cellulose 3,5-dimethylphenylcarbamates: Influences of degree of substitution and molecular weight

A series of cellulose 3,5-dimethylphenylcarbamates(CDMPCs) with different degrees of substitution(DS) and degrees of polymerization(DP) were homogeneously synthesized in 1-allyl-3-methylimidazolium chloride(Amim Cl). Then, the CDMPCs were coated on silica gel and used as chiral stationary phases(CSPs), and their chiral recognition abilities for seven racemates were evaluated by high performance liquid chromatography. The results showed that DS and DP of CDMPCs had a great influence on chiral recognition abilities of the CSPs. The CSPs with the DS ≈ 1 gives a low chiral recognition to most racemates. On the contrast, the CSPs with the DS ? 2 exhibited high chiral separation abilities. For example, six racemates could be separated on the CSP with CDMPC of DS ≈ 2(CSP-2). Especially, for the enantioseparation of 1-(2-naphthyl) ethanol and Tr?ger's base, CSP-2 gave the highest separation ability in all of CSPs. On the other hand, when the DP of cellulose was in a range from 39 to 220, the chiral separation abilities of CDMPCs increased as the DP increased. This work demonstrates that the structure of cellulose esters such as DS and DP has important effect on their chiral separation ability, and therefore provides a practical method to design and prepare desirable CSPs for different racemates.     

醇和N,N-二甲基乙酰胺分子间相互作用的FTIR光谱研究

The association between alcohols and N,N-dimethylacetamide in carbon tetrachloride was investigated using FTIR spectroscopy at 298 K.The formation constants for 1∶1 and 1∶2 complexes were calculated using the method of Whetsel and Kagarise.The observed 1∶1 complex values were also verified using the method of Nash.The rate of change in C=O bond moment on complexing with alcohols increased with increasing acidity of alcohols.The formation constant and values of free energy change increased with the increase in carbon chain length of alcohols,which suggested that the degree of complex formation varied with the length of the carbon chain of alcohols.