Asymmetric Synthesis Of α-Amino Acids Research Articles

ChemInform Abstract: Asymmetric Synthesis of α-Amino Acids Based on Carbon Radical Addition to Glyoxylic Oxime Ether.

ChemInform Abstract: Asymmetric Synthesis of α-Amino Acids Based on Carbon Radical Addition to Glyoxylic Oxime Ether.

ChemInform Abstract: Asymmetric Syntheses of Unnatural Amino Acids and Hydroxyethylene Peptide Isosteres

Unnatural and naturally occurring nonproteinogenic α-amino acids have become important building blocks for the synthesis of biologically active peptides and peptidomimetic drug molecules. The asymmetric synthesis of α-amino acids has therefore become quite important as an indispensable research tool in academic, government, and industrial laboratories, and methodologies have been reviewed extensively. The established methods for the asymmetric synthesis of amino acids can be divided into roughly six categories (1). (1) The highly stereoselective hydrogenation of chiral, nonracemic dehydro amino acid derivatives or the asymmetric hydrogenation of prochiral dehydro amino acid derivatives. Chiral glycine equivalents serve as useful α-amino acid templates undergoing homologation via carbon-carbon bond formation at the α-position through nucleophilic carbanion alkylation (2) or electrophilic carbocation substitution (3). In addition both nucleophilic amination (4) and electrophilic amination (5) of optically active carbonyl derivatives has very recently been developed. (6) Enzymatic and whole-cell-based syntheses have recently become more attractive in terms of substrate versatility, cost, and scale. All of these methods have their relative strengths and weaknesses; the optimum method for each individual application must still be considered on a case-by-case basis with respect to functionality, quantity desired, cost, and time. The focus of this chapter will illustrate the utility of chiral, nonracemic glycinates which are commercially available and can be manipulated in a variety of ways to access structurally diverse classes of α-amino acids.

Catalytic Asymmetric Syntheses of α-Amino and α-Hydroxyl Acid Derivatives

Herein we report the first room temperature Heck reaction of aryl bromides and CH(2)=C(NHP)CO(2)Me (P = Boc or CBz) to form ArCH=C(NHP)CO(2)Me, which are then used for the asymmetric syntheses of alpha-amino acids. We also report the first syntheses of ArCH=C(OCOAr(1))CO(2)Me (Ar(1) = Ph, 4-Cl-Ph) from ArBr and CH(2)=C(OCOAr(1))CO(2)Me by the Heck reaction and subsequent successful asymmetric hydrogenation to afford alpha-hydroxyl esters in excellent chemical yields and good-to-excellent enantioselectivities.

Asymmetric Synthesis of α-Amino Acids: Preparation and Alkylation of Monocyclic Iminolactones Derived from α-Methyl trans-Cinnamaldehyde

Two novel chiral monocyclic iminolactones 14a and 14b have been prepared. The chiral auxiliary 12 was obtained from alpha-methyl-trans-cinnamaldehyde through reduction, methylation, Sharpless asymmetric dihydroxylation, and oxidation in 87% overall yield. Esterification of compound 12 with the respective protected amino acids followed by deprotection and cyclization provided the corresponding iminolactones, each in 82% overall yield. Alkylation of the iminolactone 14a afforded the alpha-methyl-alpha,alpha-disubstituted products 15 and 16 in good yields (78-99%) and excellent diastereoselectivity (de >98%). Alkylations of the iminolactone 14b furnished the alpha-benzyl-alpha,alpha-disubstituted products 15a, 16b, 17, and 18 in good yields (51-86%) but moderate diastereoselectivities (43-56%). When HMPA or DMPU was used as a cosolvent, the rate of alkylation of the iminolactone 14b was accelerated with improved yields (56-99%) and diastereoselectivities (50-83%). Hydrolysis of the dialkylated iminolactones yielded the alpha,alpha-disubstituted alpha-amino acids in good yields (80-98%) and high enantiomeric excesses (98-99%) with good recovery of compound 12 (83-92%).

Catalytic Asymmetric Synthesis of α-Amino Acids

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCatalytic Asymmetric Synthesis of α-Amino AcidsCarmen Nájera and José M. SansanoView Author Information Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080-Alicante, Spain Cite this: Chem. Rev. 2007, 107, 11, 4584–4671Publication Date (Web):October 4, 2007Publication History Received29 November 2006Published online4 October 2007Published inissue 1 November 2007https://doi.org/10.1021/cr050580oCopyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views11698Altmetric-Citations613LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (3 MB) Get e-AlertsSUBJECTS:Catalysts,Ligands,Organic compounds,Reaction products,Stereoselectivity Get e-Alerts

Asymmetric synthesis of novel α-amino acids with β-branched side chains

An asymmetric synthesis of α-amino acids with novel β-branched side chains has been implemented. The syntheses feature a p-toluenesulfinylimine induced chiral Strecker approach and were found to be applicable to the introduction of both aliphatic and aromatic β-branched sidechains for preparation of previously unknown α-amino acids.

Organoboron Reagents in the Preparation of Functionalized ?-Amino Acids

Over the past decade, major advances in the preparation and utilization of organoboron reagents have been applied to virtually all areas of organic synthesis. The present review collates recent examples of the use of organoboron reagents in the synthesis of α-amino acids and their derivatives. Aryl- and alkenylboronic acids have been used in the asymmetric synthesis of α-amino acids through conjugate addition to unsaturated amino acids and the Petasis three-component coupling reaction. Additionally, α-amino acid derivatives with organoboron functionality on the side-chain have been prepared and used in metal-catalyzed cross-coupling reactions to prepare cross-linked amino acids and complex cyclic peptide natural products.

Improved conditions for the asymmetric synthesis of α-amino acids using Cinchona-derived anthracenylmethyl ammonium salts as chiral phase-transfer organocatalysts

Cinchonidine and cinchonine-derived monomeric anthracenylmethyl ammonium salts bearing different counter-anions are used as chiral organocatalysts in the enantioselective alkylation of a benzophenone-imine tert-butyl glycinate under phase-transfer conditions. Generally, an improvement of the enantioselectivity is observed when the counterions are tetrafluoroborate and hexafluorophosphate using 50% aqueous KOH as the base and toluene/chloroform as the solvent. The enantioselectivities achieved are comparable and frequently higher, even working under simpler and less-strict reaction conditions and with lower organocatalyst loading, than those reported previously.

Efficient enantioselective synthesis of orthogonally protected ( R)-α-alkylserines compatible with the solid phase peptide synthesis

The Schöllkopf methodology for the asymmetric synthesis of α-amino acids, which was previously not applicable to the construction of quaternary α-amino acids, has been rendered not only suitable but also practical for this purpose and applied to a highly efficient enantioselective synthesis of orthogonally protected ( R)-α-alkylserines suitable for the solid phase synthesis.

Improved Schöllkopf construction of quaternary α-amino acids: efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377

The Schöllkopf methodology for the asymmetric synthesis of α-amino acids which was previously not applicable to the construction of α,α-dialkylated (quaternary) α-amino acids, has been rendered practical for this purpose and applied in a highly efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377.

Regio‐ and Stereocontrolled Palladium‐ or Iridium‐Catalyzed Allylation

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regio- and Stereocontrolled Palladium- or Iridium-Catalyzed Allylation

We studied palladium- or iridium-catalyzed allylation as an effective method for the asymmetric synthesis of α-amino acids, hydroxylamines, oximes, and amines. The stereochemistry of the palladium-catalyzed allylic alkylation of a prochiral diphenylimino glycinate was controlled by chiral PTC, and gave chiral amino acids. In contrast, iridium-catalyzed allylic substitution of diphenylimino glycinate proceeded with good enantio- and diastereoselectivities with a new bidentate chiral ligand to give a novel method for preparing two branched diastereoisomers by simply switching the base. For the synthesis of α,α-disubstituted amino acids, the palladium-catalyzed tandem reaction of dehydroamino acids was developed based on radical chemistry. Next, the viability of oximes and hydroxylamines as oxygen atom nucleophiles in transition metal-catalyzed allylic substitutions was examined. Regioand enantioselective allylic substitution of oximes and hydroxylamines was achieved by using the iridium complex of chiral pybox ligand. Sequential allylic amination gave a novel method for preparing azacycles. Finally, umpolung allylation with aldehyde or imine was studied by using palladium catalyst and indium iodide. The palladium-indium iodide-mediated reaction of chiral 2-vinylaziridines with aldehydride proceeded with excellent diastereoselectivity. The role of water in directing the diastereo- or regioselectivities was investigated in the allylation and propargylation of chiral oxime ether. The allylation of oxime ether with monosubstituted allylic reagents afforded either γ-adduct or α-adduct depending on the reaction conditions.

Contrast performance in catalytic ability—new cinchona phase transfer catalysts for asymmetric synthesis of α-amino acids

Two new cinchona phase transfer catalysts are prepared from dihydrocinchonidine using 13-picenylmethyl bromide and 1-pyrenylmethyl bromide, respectively. A total contrast in catalytic efficiency is observed during the asymmetric alkylation of glycinate esters; with one catalyst, the reaction is either incomplete or the enantioselectivity is very poor (15% ee) while the other catalyst afforded high selectivity up to 94% ee.

The counterion effect in the phase-transfer catalyzed asymmetric synthesis of α-amino acids promoted by anthryl-derived dimeric Cinchona ammonium salts

Dimeric ammonium salts derived from cinchonidine or cinchonine and a bridging (anthracen-9,10-yl)dimethyl moiety bearing different counter-anions are used as chiral phase-transfer catalysts in the asymmetric alkylation reaction of a benzophenone-imine tert-butyl glycinate. The counterion generally has a great influence on the final enantioselectivity, the tetrafluoroborate or hexafluorophosphate anion giving place to higher ee’s compared to the chloride or bromide anions. The more noticeable differences are generally observed when the hexafluorophosphate salts of O-allylated dimeric catalysts are employed.

Asymmetric Synthesis of N‐Protected Amino Acids by the Addition of Organolithium Carboxyl Synthons to ROPHy/SOPHy‐Derived Aldoximes and Ketoximes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Carbon-Carbon Bond Construction Based on Radical Addition to C=N Bond

We have studied the carbon radical addition to imine derivatives as an effective carbon-carbon bond forming method for the synthesis of a variety of amines. The reaction of oxime ethers proceeded smoothly in the presence of BF3·OEt2 to give the alkylated products in high yields via the free radical-mediated carbon-carbon bond forming process. Intermolecular radical addition to oxime ethers was effectively improved by using alkyl iodides and triethylborane, which acts multiply as a Lewis acid, a radical initiator and a terminator. The asymmetric synthesis of α-amino acids based on a diastereoselective radical addition to glyoxylic imine derivatives was achieved. Highly diastereoselective alkyl radical addition to Oppolzer’s camphorsultam derivatives of oxime ether provided a convenient method for preparing the enantiomerically pure α,β-dialkyl-β-amino acids. We have demonstrated that imine derivatives such as oxime ethers, hydrazones, and nitrones are excellent radical acceptors for the radical reactions in aqueous medium. The radical addition to imine derivatives in aqueous medium was also studied by using indium or zinc as a single-electron transfer radical initiator. We have found that triethylborane can be applied to solid-phase radical reactions. The solid-phase tandem carbon-carbon bond forming reaction of oxime ethers connected with an α,β-unsaturated carbonyl group proceeded effectively to give the azacycles or chiral oxacycles after cleavage from the resin.

Zinc-mediated radical reaction of glyoxylic oxime ether and hydrazone in aqueous media: asymmetric synthesis of α-amino acids

Alkyl radical addition to glyoxylic oxime ether and hydrazone in aqueous media was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities, which could be converted into enantiomerically pure α-amino acids.

Improved synthesis of proline-derived Ni(II) complexes of glycine: versatile chiral equivalents of nucleophilic glycine for general asymmetric synthesis of alpha-amino acids.

A synthetically practical and operationally convenient method for preparing (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPBP) and hitherto unknown (S)-2-[N-(N'-benzylprolyl)amino]-4-methylbenzophenone (4-Me-BPBP), (S)-2-[N-(N'-benzylprolyl)amino]-5-nitrobenzophenone (5-NO(2)-BPBP), and their corresponding Ni(II) complexes with glycine [GlyNi(II)BPBP], a widely used chiral equivalent of nucleophilic glycine, and new analogues [GlyNi(II)-4-Me-BPBP] and [GlyNi(II)-5- NO(2)-BPBP] is described. The key step of the method is the synthetically efficient amid bond formation between the corresponding o-aminobenzophenones, featuring significant steric shielding and low nucleophilicity of the amino functionality as well as sterically constrained (S)-N-benzylproline (BP).

Novel Intermolecular Carbon Radical Addition to a Nitrone: Asymmetric Synthesis of α‐Amino Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

From α‐Amino Acids to Peptides: All You Need for the Journey.

AbstractFor Abstract see ChemInform Abstract in Full Text.