Resolution of α-cyclohexyl-mandelic acid enantiomers by two-phase (O/W) recognition chiral extraction

This paper presents a new chiral separation technology: two-phase (O/W) recognition chiral extraction. Distribution behavior of α-cyclohexyl-mandelic acid enantiomers was studied in the extraction system with D(L)-isobutyl tartrate in 1,2-dichloroethane organic phase and β-CD derivatives in aqueous phase, and the influence of the kind and concentration of extractant and pH on extraction performance was investigated. The experimental results indicate that two-phase (O/W) recognition chiral extraction is of strong chiral separation ability. HP-β-CD, HE-β-CD and Me-β-CD have higher recognition ability for S-CHMA than that for R-CHMA, among which HP-β-CD has the strongest ability; whereas, D-isobutyl tartrate has reversed recognition ability for them. In the extraction system containing HP-β-CD and D-isobutyl tartrate, e.e.% of S-CHMA in aqueous phase reached 27.6% by one stage extraction, and the distribution ratio for R-CHMA(kR) and for S-CHMA(kS) and separation factor (α) are 2.44, 0.89 and 2.49, respectively. Meanwhile, pH and concentration of extractant have great effects on chiral separation ability. Two-phase (O/W) recognition chiral extraction has great significance for preparative separation of racemic compounds.     

Stereoselective Synthesis of α-Aminonitril on Glucose Templates

Both proteinogenic and non proteinogenic α-amino acids are of particular interest as constituents of peptide factors, peptidomimetics and antibiotics for the construction of modern selective drugs. [1] Furthemore, α-amino acid derivatives are interesting building units for chiral-pool syntheses of enantiomerically pure natural products. [2] Numerous efforts in modern organic synthesis are centered on the synthesis of enantiomerically pure α-amino acids. [3] During the past three decades efficient methods of asymmetric synthesis of α-amino acids have been developed; most of them are based on electrophilic transformations of organometallic intermediates. [4] Using the concept that the chirality of the carbohydrates can be exploited for diastereoselective reactions, Kunz and his cooperator had developed a Strecker synthesis with glycosyl amines as chiral auxiliaries. [5]     

Enantioselective trapping of oxonium ylide intermediates by N-benzhydryl-α-imino ester:Synthesis of β-tetrasubstituted α-amino acids

A synergistic rhodium(Ⅱ)/phosphoric acid catalyzed three component reaction of 3-diazooxindoles,alcohols and N-benzhydryl-α-imino ester is developed for the efficient construction of chiral β-alkoxy C~β-tetrasubstituted α-amino acid derivatives in good yields and with excellent diastereoselectivities and high enantioselectivities.The synthetic application of the resulting products was illustrated by reducing with Pd/C under H_2 atmosphere followed reacting with CSCl_2 at room temperature to rapid afford 3-spirocyclic oxindole in a good yield with a chirality retainment.The three-component reaction is proposed to proceed through an electrophilic trapping of the oxonium ylides by N-benzhydryl-α-imino ester.     

Extensive Studies on the AlEt3/THF-Promoted Diastereoselec-tive Tandem Rearrangement/Reduction of a-Hydroxy (Amino) Heterocyclopropane: An Efficient Approach to 2-Quaternary 1,3-Diheteroatom Units

Introduction Diastereoselective construction of 1,3-diheteroatom units, especially 1,3-amino alcohols and 1,3-diols, has always been in high demands in synthetic organic chemistry, as they are widely present in many natural products and potent drugs, such as nucleoside antibiot-ics and the HIV protease inhibitors.1,2 They have also been used as chiral ligands for asymmetric catalysts and as synthetic intermediates.3 Although several methods for the construction of 1,3-amino alcohols have been…     

Silicon-mediated enantioselective synthesis of structurally diverseα-amino acid derivatives

The catalytic asymmetric synthesis of novel and chiral amino acid derivatives with unconventional chemo-, diastereo-, and enantio-selectivity remains a paramount challenge. Herein we reported a novel protocol for the use of highly enantioselective copper-catalyzed cycloaddition of α,β-unsaturated acylsilanes as a springboard reaction for the facile synthesis of structurally diversified pyrrolidines and complicated α-amino esters by desilylation. The newly developed process could provide a wide range of synthetically useful acylsilane-substituted pyrrolidines(ASiP) in high yields and excellent diastereo-and enantioselectivities with Cu/(R)-XylBINAP complex as the catalyst. And the downstream desilylation transformation enables to expand the potntial applications of 1,3-dipolar cycloaddition in the construction of structurally unique amino acid derivatives, in which an unprecedented and concerted fluoride anion-promoted C–X(X=H, Si, N, C) bond cleavage occurred to the enantioselective construction of aldehyde-substituted pyrrolidines, linear cinnamaldehyde or alkene-substituted amino esters in high ee values.     

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 of α-fluoro-β-amino acids via the Reformatsky reaction of chiral N-tert-butylsulfinylimines with ethyl bromofluoroacetate

Treatment of chiral N-tert-butyl sulfinylimines with ethyl bromofluoroacetate in the presence of activated Zn dust in THF afforded the α-fluoro- β-amino acid derivatives in good yields(70-86%) and moderate diastereoselectivity(66:34-92:8).     

Synthesis of novel chiral stationary phases for high-performance liquid chromatography

Three novel chiral selectors 4a-c were synthesized from(S)-amino acids and(R)-1-phenyl-2-(4-methylphenyl)ethylamine.4a-cwere connected to 3-aminopropylsilanized silica gel to be used as the chiral stationary phase for HPLC.Five amino acid derivativesand two pyrethroid insecticides were fairly resolved on these three new chiral stationary phases under normal phase condition.     

Free amino group-directed C(sp2)–H arylation of α-amino-β-aryl esters by palladium catalysis

Native amino-directed palladium-catalyzed C(sp³)–H activation/functionalization has been developed for modification of α-amino acids and peptides. Herein a palladium(Ⅱ)-catalyzed C(sp²)–H arylation of α-amino-β-aryl esters has been disclosed, using the native amino as the directing group. A variety of chiralα-amino-β-aryl esters can be functionalized to give the corresponding ortho-substituted mono-and diarylated products.     

Soluble Polymer-Supported Synthesis of α-Amino Acid Derivatives

Due to the central role played by α-amino acid in chemistry and biology, the development of versatile and new methodology for the synthesis of natural and unnatural α-amino acid has emerged as an important and challenging synthetic endeavour for organic chemists.[1] Among the various methodologies reported for α-amino acid synthesis, [2,3] the solid-phase organic synthesis (SPOS) has served as an important approach. [4] However, inherent prob lems on solid supports are reactive site accessibility, site-site interaction and monitoring of the reaction.     

Synthesis of chiral α-amino acids

A novel method for the synthesis of chiral α-amino acids has been developed where the acid functionality was constructed by oxidizing a hydroxymethyl group introduced by Evans’ method in the α-position of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.     

Stereoselective synthesis of chiral β-disubstituted-β-amino acid derivatives using Pd/In transmetallation cascade processes

A new, highly efficient synthesis of chiral β^2,3-disubstituted-β-amino acid derivatives has been developed, based on an allylation procedure employing allene and a catalytic Pd/In bimetallic process.     

New chiral building blocks of β-peptoid analogs

The synthesis of chiral functionalized β-amino esters via the hydride reductive amination of chiral allenes was explored. These compounds can be regarded as β-peptoids building blocks bearing a chiral side chain at the nitrogen and at the same time retaining the β-amino acid side chain. β-Enamino esters were obtained from the nucleophilic addition of α-amino esters (l-Ala, d-Ala, l-Phe, l-Leu, l-Trp and d-Trp methyl esters) to 2,3-allenoates bearing a chiral auxiliary, which determines the stereochemistry outcome of the subsequent reduction reaction. It was also demonstrated that in the reduction of β-enamino esters derived from l-Pro and d-Pro methyl esters the chirality of the new chiral center is controlled by the α-amino ester moiety.     

Poly(α-amino acid)-immobilized polymer adsorbents for optical resolution. IV. Elucidation of chiral recognition mechanism of poly(N5-benzyl-L-glutamine)-immobilized resin

Various investigations have been carried out in order to further elucidate the chiral recognition mechanism of immobilized poly(N⁵-benzyl-L -glutamine) (PBLGN) for optical resolution. The shape and dimension of the chiral recognition site are determined by resolution of hydantoin derivatives, with substituents of varied bulkiness at the chiral center. The site of the hydrogen bonding association of the enantiomers responsible for chiral recognition is also elucidated. Several adsorbents with electron-donating/withdrawing substituents incorporated into the PBLGN side chain phenyl are synthesized and evaluated for the resolution of (RS)-5-isopropylhydantoin in order to elucidate the association site of PBLGN. Based on the experimental evidences obtained, a most plausible mechanism of chiral recognition is proposed. Additionally, adsorbents with several other poly(α-amino acid)s are also synthesized, and the effect of poly(α-amino acid) side chain length is discussed.     

Synthesis and chiral recognition properties of two novel chiral calix[4]arene tartaric ester derivatives

Two new chiral calix[4]arene derivatives containing tartaric acid ester moieties were synthesized. The chiral calix[4]arenes are in a ‘cone’ conformation according to NMR spectroscopy. The chiral recognition capabilities of 1–4 toward the guests, 1,2-propanediol and serine methyl ester hydrochloride (SerOMe), were investigated (¹H NMR spectroscopy). The extraction properties of compounds 1 and 2 toward selected α-amino acid methyl esters were also studied.     

手性助剂诱导催化不对称Strecker反应研究进展

亚胺的不对称Strecker反应是合成α-氨基酸化合物的重要途径之一,一般在手性助剂的诱导下进行.近年来,用于诱导不对称Strecker反应的各类手性助剂的研究受到广泛关注.本文综述了α-苯乙胺、α-氨基酸、α-氨基酸衍生的酰胺、α-苯甘氨醇、亚磺酰基亚胺、糖胺、肼等七类化合物作为手性助剂在不对称Strecker反应中的应用研究现状,就该研究领域存在的问题进行了分析,并对其前景进行了展望.     

Multi-functionalized chiral crown ethers as enzyme models for the synthesis of peptides. Multiple chiral recognition in the enzyme model

A novel approach to the enzyme model for the synthesis of peptides has been established by using multi-functionalized chiral crown ethers as hosts. The new strategy consists of three key steps as follows. (1) Guest assembly: the host having one free thiol and one thioester withN-protected-amino acid or peptide proceeds via rapid intra-complex thiolysis of-amino acid ester salts to form the dithioester, and assembles two guests. (2) Amide formation: the intramolecular aminolysis occurs between the bound guests to form the amide bond. (3) Peptide chain elongation: as the thiol reactive group is regenerated, the above two reactions are repeated to elongate the peptide chain. In the present paper, we describe the multiple chiral recognition that could be achieved by the chiral crown ether in both the intra-complex thiolysis and the intramolecular aminolysis. For explanation of the chiral recognition, we propose a likely structure for the intermediate of the aminolysis.     

Comparison of enantiomer separation on two chiral stationary phases derived from (+)-18-crown-6-2,3,11,12-tetracarboxylic acid of the same chiral selector

Liquid chromatographic comparisons for enantiomer resolution of α-amino acids and chiral primary amino compounds were made using chiral stationary phases (CSPs) prepared by covalently bonding (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA) of the same chiral selector. The resolution of all α-amino acids on CSP 1 developed in our group was found to be better than that on CSP 2 reported by Machida et al. All α-amino acids examined in this study were well enantioseparated on CSP 1 (α=1.22–2.47), while four analytes were not resolved or all the other analytes were poorly resolved on CSP 2 than on CSP 1. However, in resolving the primary amino compounds without a carbonyl group, CSP 1 was comparable with CSP 2. Although (+)-18-C-6-TA of the same chiral selector was used to prepare CSP 1 and CSP 2, this study showed that different connecting methods for the CSPs might influence their ability to resolve the analytes depending on their structures related to the chiral recognition mechanism.     

Solvent directed chemically divergent synthesis of β-lactams and α-amino acid derivatives with chiral isothiourea

A protocol for the chemically divergent synthesis of β-lactams and α-amino acid derivatives with isothiourea (ITU) catalysis by switching solvents was developed. The stereospecific Mannich reaction occurring between imine and C(1)-ammonium enolate generated zwitterionic intermediates, which underwent intramolecular lactamization and afforded β-lactam derivatives when DCM and CH₃CN were used as solvents. However, when EtOH was used as the solvent, the intermediates underwent an intermolecular esterification reaction, and α-amino acid derivatives were produced. Detailed mechanistic experiments were conducted to prove that these two kinds of products came from the same intermediates. Furthermore, chemically diversified transformations of β-lactam and α-amino acid derivatives were achieved.

A protocol for the solvent directed chemically divergent synthesis of β-lactam and α-amino acid derivatives with chiral isothiourea was reported.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.