Chiral Amino Alcohols Research Articles

ChemInform Abstract: Dinuclear Zinc Catalyzed Asymmetric Spirannulation Reaction: An Umpolung Strategy for Formation of α‐Alkylated‐α‐hydroxyoxindoles.

AbstractTreatment of oxindoles of type (I) with α,β‐unsaturated esters in the presence of ZnEt2 and the chiral amino alcohol results in efficient, highly diastereo‐ and enantioselective formation of spirocyclic oxindoles.

Chemical resolution and chiral recognition of an inherently chiral biscalix[4]arene cone–partial cone conformer

An inherently chiral biscalix[4]arene carboxylic acid cone–partial cone conformer was optically resolved into individual enantiomers by chemical resolution method using (S)-BINOL as a chiral auxiliary. The partial cone calix[4]arene component plays a crucial role in optical resolution. The title compound may interact enantiodiscriminantly with chiral aminoalcohols, especially 2-phenylglycinol.

Synthesis and Structure of 2-Cyclohexylamino-3-methyl-1,1-diphenyl-butan-1-ol (d-N-Cyclohexyl-diphenylvalinol), an Amino Alcohol Ligand Useful in Asymmetric Catalysis

Amino alcohols are important ligands for the asymmetric catalytic hydroamination of aminoallenes to form chiral pyrrolidines. The amino alcohol d-N-cyclohexyl-diphenylvalinol was synthesized and crystallized by slow evaporation from a 7:1 ether:ethanol mixture. The molecule crystallizes in the monoclinic space group P2 1 with unit cell parameters a = 8.0724(8) A, b = 14.4327(14) A, c = 8.6752(9) A and β = 107.098(2)° and contains one molecule in the asymmetric unit with all constituent atoms being on general positions. Close inspection of the solid-state structure revealed a strong intramolecular hydrogen bond between the hydrogen atom of the hydroxyl group and the amine nitrogen. Herein we report the solid state structure of the chiral amino alcohol D-N-cyclohexyl-diphenylvalinol, a molecule which can serve as a ligand for transition metal complexes that function as asymmetric hydroamination catalysts .

Functionalized organolithium reagents in the synthesis of chiral ligands for catalytic enantioselective addition of diethylzinc to aldehydes

Series of functionalized organolithium compounds were prepared and added to chiral bicyclic ketones (1R-(+)-camphor analogue 2 and 1R-(−)-fenchone 3), resulting in the preparation of a small “library” of chiral aminoalcohols able to serve as ligands in metal mediated asymmetric synthesis. The configuration of the chiral ligands was approved by applying advanced NMR experiments. The absolute configurations of 1,2-disubstituted planar chiral ferrocene-based aminoalcohols 15, 18 and 19 were determined by means of NMR experiments and confirmed by X-ray crystallography. The new chiral ligands were tested as pre-catalysts for the addition of diethyl zinc to benzaldehyde. The reactions proceeded with excellent conversions and a moderate degree of enantioselectivity.

Threonine aldolase immobilization on different supports for engineering of productive, cost-efficient enzymatic microreactors

This paper consists of two parts – a detailed experimental investigation on the activity of supported threonine aldolase for use in a microreactor/flow reactor and a generic, explorative outline on potential productivity of enzymatic microreactors; with the need to use data from other enzymes here as well. Threonine aldolase was immobilized on different supports foreseen to be coated or packed within the micro- and millichannels of flow reactors. As enzyme supports, an innovative high-surface area and high-porosity silica (Nanosprings), the commercial Eupergit CM, and polymer membrane materials were used. For Eupergit CM, the share of chemically fixed enzymes and active enzymes were within the reported literature performance for enzyme immobilization. The values of immobilized enzymes on Nanosprings were somewhat lower. However, this is overcompensated by the larger specific surface area of Nanosprings and the availability of a new, second generation flow reactor concept, which involves a tight packing of stacked Nanosprings disks. For the investigated membranes, the density of immobilized enzymes was close to the reported value of capacity. From these experimental results, calculations on (maximally achievable) productivity of microreactors were made. This was combined with results of glucose oxidase immobilization on Nanosprings. The objective was to achieve high enzyme loadings to obtain reasonable space–time yields to ensure cost-effectiveness of the derived chemical reaction processes. These productivities were benchmarked to industrial production needs for two processes – a high-value pharmaceutical intermediate synthesis (towards chiral amino alcohols, using threonine aldolase) and a large-volumefine-chemical synthesis (the gluconic acid synthesis, using glucose oxidase), including suggestions for reactor scale-up. This shows that the present loading performance suffices in the case of high-value products, such as pharmaceuticals, but not for larger-volume, low-cost chemicals; at least under best-performance assumptions such as the avoidance of mass-transfer limitations.

A Ni(OAc)2·4H2O-Catalysed Sonogashira-Type Coupling Reaction of Aryl Iodides and Terminal Alkynes in the Presence of CuI

An effective and promising Ni/Cu catalytic system for the coupling of aryl iodides with various terminal alkynes has been developed. For the first time the readily available chiral amino alcohol has been employed as the ligand for the Pd-free Sonogashira coupling reaction.

A Chiral Porous Metal–Organic Framework for Highly Sensitive and Enantioselective Fluorescence Sensing of Amino Alcohols

A highly porous and fluorescent metal-organic framework (MOF), 1, was built from a chiral tetracarboxylate bridging ligand derived from 1,1'-bi-2-naphthol (BINOL) and a cadmium carboxylate infinite-chain secondary building unit. The fluorescence of 1 can be effectively quenched by amino alcohols via H-bonding with the binaphthol moieties decorating the MOF, leading to a remarkable chiral sensor for amino alcohols with greatly enhanced sensitivity and enantioselectivity over BINOL-based homogeneous systems. The higher detection sensitivity of 1 is due to a preconcentration effect by which the analytes are absorbed and concentrated inside the MOF channels, whereas the higher enantioselectivity of 1 is believed to result from enhanced chiral discrimination owing to the cavity confinement effect and the conformational rigidity of the BINOL groups in the framework. 1 was quenched by four chiral amino alcohols with unprecedentedly high Stern-Volmer constants of 490-31200 M(-1) and enantioselectivity ratios of 1.17-3.12.

Enantioselective sensing of chiral amino alcohols with a stereodynamic arylacetylene-based probe

Enantioselective induced circular dichroism analysis of amino alcohols has been accomplished using a conformationally flexible arylacetylene-based probe exhibiting two terminal aldehyde groups. The chirality of the amino alcohol substrates is imprinted on the stereodynamic receptor upon [1 + 2] condensation, which ultimately generates a strong chiroptical response. The distinct induced circular dichroism effects of the diimines obtained can be used for enantioselective sensing and enantiomeric excess determination of a wide range of substrates.

Titanium complexes of chiral amino alcohol derived Schiff bases as efficient catalysts in asymmetric oxidation of prochiral sulfides with hydrogen peroxide as an oxidant

An efficient asymmetric oxidation of prochiral sulfides catalyzed by a series of simple in situ generated complexes based on chiral amino alcohol derived Schiff bases with Ti(Oi-Pr)4 was carried out in presence of cheap and environmentally benign oxidant H2O2 at 0°C. Prochiral sulfides were converted to respective chiral sulfoxides efficiently (conversion, 93%; up to ee, 98%) with this system in 10h at 0°C. The present study demonstrated a significant role of steric influence of the substituent attached on both aryl and alkyl moiety on the enantioselectivity. Kinetic studies of the catalytic reaction showed first order dependence on substrate and catalyst whereas it is zero for the oxidant. Kinetic studies in combination with UV–vis. spectral studies were used to propose a catalytic cycle for the sulfoxidation reaction.

Self assembly and chirality transfer in D-Alaninol on the Cu(100) surface

Chirality expression modifications occurring for a simple chiral amino-alcohol, d-Alaninol, adsorbed on Cu(100), when passing from low to high molecular coverage, are studied by means of scanning tunneling microscopy (STM) and theoretical modeling. At low coverage, d-Alaninol molecules organize in tetramers that are aligned to Cu(100) unit vectors whereas, increasing the molecular amount on the surface, the interplay of supramolecularity and chirality induces a rotation of the tetramers of 14° with respect to the substrate lattice vectors. This behaviour is analyzed by means of a theoretical approach that combines classical molecular dynamics (MD) and density functional theory (DFT). The force field adopted in MD calculations is parametrized by fitting it to results obtained at DFT level on a single adsorbed alaninol molecule on the Cu(100) surface. The configurations of isolated and surrounded tetramers most sampled by MD are extracted by Principal Component Analysis. Further DFT relaxation with semiempirical dispersion correction (DFT-D) and considering also the possible dehydrogenation of both functional groups of alaninol, give rise to a few structures that are discussed in terms of their energetics and by comparing the resulting simulated STM images with the experimental ones.

Asymmetric Organocatalytic Efficiency of Synthesized Chiral β-Amino Alcohols in Ring-Opening of Glycidol with Phenols

A series of novel chiral β-amino alcohols 3–5 and 7–10 were synthesized by regioselective ring opening of epoxides and chiral amines with a straightforward method in high yields (up to 99 %). Kinetic resolution of racemic glycidol with phenols was achieved by using chiral amino alcohols as organocatalysts. Amino alcohols 5, 8 and 10 exhibited the highest enantioselectivities with p-cresol, phenol, and p-methoxyphenol by 63, 65, 58 % ee, respectively. The moderate enantioselectivities were observed with catalyst 9b towards all the nucleophiles (34–48 % ee). The ee values of the desired 3-aryloxy-1,2-diols were determined by HPLC. This study presents an attractive tool for the synthesis of β-blockers and structurally complex molecules.

Sterically encumbered chiral amino alcohols for the titanium catalyzed asymmetric alkylation of benzaldehyde

Sterically encumbered chiral l-amino alcohols with secondary amines and tertiary alcohols catalyze the enantioselective alkylation of benzaldehyde with diethyl zinc. Using 2mol% of amino alcohol catalyst predominantly gave (R)-1-phenylpropanol with enantiomeric excesses of up to 61%. Using the in situ prepared titanium complex at 2mol% as catalyst also favored the (R)-enantiomer with enantiomeric excesses of up to 73%. In almost all cases, the addition catalyzed by the titanium complex exhibited higher enantioselectivity than that of the amino alcohol ligand alone.

The synthesis of phosphine oxide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

The phosphine oxide-linked bis(oxazoline) ligands were designed and synthesized in two ways. One is the coupling of Grignard reagent derived from 2-(2-bromophenyl)oxazoline with phenylphosphonic dichloride, another route is the condensation of bis(2-formylphenyl)(phenyl)phosphine oxide with chiral amino alcohols followed by NBS oxidation. These new bis(oxazoline) ligands were applied in Pd-catalyzed asymmetric allylic alkylation reactions and good yields and enantioselectivities were obtained with diphenyl substituted ligand (up to 95% ee).

Synthesis of new acetal aza-cage compounds via ozonolysis of bis-endo-diol- and diacylnorbornene derivatives

We synthesized acetal aza-cage compounds directly via ozonolysis of 2,3-bis-endo-diol- and diacylnorbornenes in dichloromethane at −78 °C. Ozonolysis of the diols followed by addition of amines gave the aza-cage compounds in high yields. The reaction mechanism for the formation of this type of aza-cage compounds is proposed to proceed via the hydroperoxide intermediate. Ozonolysis of the diacetyl norbornene followed by addition of (1) primary amines gave monoaza-cages and diaza-cage, (2) tert-butylamine gave hydroxyl lactone and diaza-cages, and (3) amino acid ester gave optically active aza-cages, in which one compound was converted into chiral aminoalcohol and structure of another was proven by X-ray analysis. A mechanism via the final ozonide and the imine intermediates is proposed for the formation of this type of aza-cages.

ChemInform Abstract: Asymmetric Henry Reaction Catalyzed by a Zn‐Amino Alcohol System.

AbstractAromatic as well as aliphatic aldehydes undergo the Henry reaction with nitromethane under catalysis of an in situ generated chiral amino alcohol—Zn complex to give the corresponding β‐nitroalcohols in moderate to good enantioselectivity.

Preparation of Axially Chiral Biphenyls by Configuration Transformation Based on Chiral Amino Alcohols

Axially chiral biphenyls (P, S)-3a and (M, R)-3b were obtained from (M/P)-4,4'-dimethoxy- 5,6,5',6'-bis(methylenedioxy)-2-carboxylester-2'-carboxamide biphenyls via configuration transformation of the biphenyls with (S)-alaninol or (R)-alaninol chiral-arm. Crystal structure of (P, S)-3a was determined. The crystal of (P, S)-3a belongs to monoclinic, space group P2(1), a=12.122(2) A, b=8.9911(18) A, c= 12.779(3) A, β=112.38(3)°. There are two kinds of hydrogen-bonding in the (P, S)-3a crystal. The first is hydrogen-bonding between the hydroxyl group of the amino alcohol arm and the amide oxygen of a neighboring molecule. The second is hydrogen-bonding between the amide hydrogen atom and the amide oxygen of a neighboring molecule. Each molecule is linked to its two adjacent molecules by four intermo- lecular H-bonds. The configuration of (M, R)-3b was assigned based on the CD spectra. In addition, from (P, S)-3a, (P)-2,2'-dihydroxymethyl-4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-biphenyl (6a) was synthe-

Isolation of Microorganisms for Asymmetric Reduction of Prochiral α -aminoacetophenone and Optimization of Reaction Conditions

Optically active amino alcohols are important building blocks for the synthesis of many chiral pharmaceuticals.A straightforward approach to the synthesis of these chiral amino alcohols is the biocatalytic asymmetric reduction of the corresponding prochiral ketones.Two strains were isolated from soil samples by screening using α-aminoacetophenone as the substrate,and named as 1403 and 4802.Strains 1403 and 4802 reduced α-aminoacetophenone to(R)-and(S)-αaminophenethanol with enantiomeric excess(e.e.) of 99% and 70%,and were identified as Fusarium sp.and Galactomyces sp.,respectively.The conditions for cultivation and biotransformation were optimized.The optimal cultivation time of both strains were 24 h;the optimized concentrations of substrate and resting cell were 5 g/L and 20 g/L for strain 1403(Fusarium sp.),3 g/L and 80 g/L for strain 4802(Galactomyces sp.),respectively.Two strains could also convert α-chloroacetophenone,α-bromoacetophenone,and acetophenone to the corresponding alcohols of(R)-and(S)-configuration.Moreover,when α-hydroxyacetophenone was served as substrate(S)-hydroxyphenylethanol was obtained with e.e.of 99% for both strains.

Large-Scale Synthesis of Singh’s Catalyst in a One-Pot Procedure Starting from Proline

A practical one-pot procedure for the preparation of Singh’s catalyst from either l-/d-proline or Boc-proline is described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the corresponding amino acid ester. Moreover, a procedure for tert-butoxycarbonyl (Boc) group removal using concentrated HCl in MeOH–DCM was developed and utilized for the multigram-scale synthesis of Singh’s catalyst.

Synthesis of novel chiral Schiff base and amino alcohol derivatives of calix[4]arene and chiral recognition properties

Abstract In the present study, the synthesis and liquid phase extraction properties towards some amino acid methylesters and amino alcohols of Schiff base and amino alcohol substituted calix[4]arene are reported. The Schiff base substituted calix[4]arene 5 has been synthesized via condensation reaction involving 5,17-diformyl-11,23-di-tert-butyl-25,27-di[3-(4-formylphenoxy)propoxy]-26,28 dihydroxycalix[4]arene 4 and (R)-(−)-2-phenylglycine methyl ester in CHCl3:MeOH. To give the amino alcohol substituted calix[4]arene 6, the synthesized chiral compound 5 was reduced by LiAlH4. The new chiral Schiff base and amino alcohol derivatives of calix[4]arene have been characterized by a combination of FT-IR, 1H NMR, 13C NMR, FAB-MS and elemental analysis. Also, the extraction behaviors of 5 and 6 towards some selected amino acid methylesters and amino alcohols have been studied by liquid–liquid extraction.

고성능 액체 크로마토그래피에 의한 다당 유도체를 기초로 한 흡착되거나 공유결합된 키랄 고정상에서 키랄 아미노 알코올의 안트르알디민 유도체의 광학분리

The convenient derivatization method of chiral amino alcohols as 9-anthraldimine Schiff base derivatives for chiral resolution was developed and the liquid chromatographic enantiomer separation of chiral amino alcohols as 9-anthraldimine derivatives was investigated on several coated and covalently bonded polysaccharide-derived chiral stationary phases (CSPs). In general, the performance of Chiralcel OD-H (or Chiralcel OD) (α = 1.24-2.89), the coated CSP derived from cellulose derivative was superior to the other CSPs for resolution of 9-anthraldimine derivatives of several amino alcohols. The results of enantioseparation depending on the structure of 9-anthraldimine analytes like the steric bulky group and the polar moiety etc were discussed. The analytical method was applied to measure the enantiomeric purity of commercially available chiral amino alcohols. It is expected that the convenient analytical method will be very efficient for determination of enantiomeric purity of amino alcohols as 9-anthraldimine Schiff base derivatives with strong UV absorption.