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Enantioselective Synthesis of andbeta;-amino acids: A Review | OMICS International
ISSN: 2161-0444
Medicinal Chemistry

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Enantioselective Synthesis of β-amino acids: A Review

Muhammad Ashfaq1*, RukhsanaTabassum1, Muhammad Mahboob Ahmad2, Nagina Ali Hassan1, Hiroyuki Oku3 and Gildardo Rivera4

1Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

2Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan

3Department of Chemistry & Chemical Biology, Gunma University Kiryu, Gunma 376-8515, Japan

4Centro de Biotecnología, Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México

*Corresponding Author:
Muhammad Ashfaq
Department of Chemistry
The Islamia University of Bahawalpur
Bahawalpur, Pakistan
Tel: +92 300 6829307 +92 62 9255473
Fax: +92 62 9255563
E-mail: [email protected]

Received date: May 05, 2015; Accepted date: July 15, 2015; Published date: July 27, 2015

Citation: Ashfaq M, Tabassum R, Ahmad MM, Hassan NA, Oku H, et al. (2015) Enantioselective Synthesis of β-amino acids: A Review. Med chem 5:295-309. doi: 10.4172/2161-0444.1000278

Copyright: © 2015 Ashfaq M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The synthesis of enantioselective β-amino acids is being reported in this review on account of their significant properties as proteinogenic, non-proteinogenic role such as neurotransmitter, biosynthesizer and nutritional supplementing materials etc. They are extensively used as chiral starting materials, auxiliariesand catalystsin organic synthesis. According to literature evidences, extensive research has been carried out to develop the methodologies for the synthesis of stereoselective β-amino acids. In this review, we describe recent advances in synthetic routes of enantioselective β-amino acids derivatives with chemical reactions during the last decades and to provide the most suitable route of their synthesis to compete the future challenges.

Keywords

β-amino acids; Enantioselective; Synthesis

Introduction

Enantionselective synthesis of β-amino acids has gained significant importance because of their interesting pharmacological applications as hypoglycaemic and antiketogenic properties, antibacterial and antifungal activities, antihelminthic as well potent insecticidal properties activities [1-3]. β-amino acids are fundamental building blocks for the preparation of pharmaceutical and agrochemical target molecules. They have displayed a high tendency towards the formation of β-peptides stable secondary structures (turns, sheets, and helices) and they are extensively used as chiral starting materials, auxiliaries and catalysts in organic synthesis [4-6]. Ennantioselectively defined β-amino acids are applied in drug development, molecular recognition, bimolecular structure and functional studies [3-7]. However, the synthesis of β-amino acids bearing various functional groups on the β-carbon with thiadiazole ring systems have been well studied due to having variety of biological activities, including antifungal, antitubercular, antibacterial, anticancer, and analgesic properties [8,9].

Different methodologies have been tried out for their synthesis to maintain desired chirality is a big challenge. Several different catalytic asymmetric approaches to synthesize β-amino acids involving carbon– carbon, carbon–nitrogen, and carbon–hydrogen bond forming reactions have been developed [10]. As per literature evidences, the enantioslective derivative of β-amino acid like N-acyl-β-(amino) acrylates was prepared by using Ru(O2CCH3)2 as catalyst [1]. Similarly Ru and Rh chiral mono- and bi-dentate phosphorous homogeneous catalysts were used for their synthesis through hydrogenation standard procedure. The hydrogenation of (Z)-enamines catalysed by bisphosphepine ligand was proceeded by Zhang et al. (Scheme 1) with 90% high yield. On the contrary, using the same catalyst system, (E)- enamines give only low yield [11].

medicinal-chemistry-Rhodium-bis-phosphepine

Scheme 1: Rhodium-bis phosphepine catalyzed hydrogenation of (Z)- enamines.

High enantioselectivity in Rh-catalyzed hydrogenations can also be obtained by phosphite and other phosphorous ligands [12]. When phthalimide protected acrylates are hydrogenated using carbohydratephosphite β2- amino acid derivatives are formed with 99% yield (Scheme 2) [13].

medicinal-chemistry-phthalimide-protected

Scheme 2: Rh-catalyzed hydrogenation of phthalimide protected acrylates.

Phosphoramidite ligand was used to obtain adducts in high yields with up to 94% by Fillion et al. through conjugate addition of dialkylzinc reagents to 2-aryl acrylate (Scheme 3). Deprotection of adduct, followed by a Curtius rearrangement of the succinic acid derivative resulted in the formation of β-amino acid derivative [14].

medicinal-chemistry-quaternary-stereo

Scheme 3: Cu-catalyzed dialkylzinc to 2-aryl-acrylates to form quaternary stereo centers.

Sibi et al. reported an enantioselective rhodium catalysed enolate protonation method for the synthesis of β2-amino acid (Scheme 4). Rh(acac)(ethylene)2 and difluorophos used to form a complex which catalyzed the conjugate addition of aryl boronic acids to β-acrylates. The intermediate oxa-β-allyl-Rh resulted in good yields using one equivalent of phthalimideas proton source [15].

medicinal-chemistry-catalyzed-conjugate

Scheme 4: Enantioselective rhodium catalyzed conjugate addition and protonation.

A dipeptide antibiotic TAN-1057 A,B was synthesized (58% yield) via tri-N-Cbz-L-arginine and diazoketone in 1:1 molar ratio while the tert-butyl alcohol/water is used as solvent. The overall chemical reaction is given in Scheme 5 [16].

medicinal-chemistry-Eistert-reaction

Scheme 5: Arndt–Eistert reaction in the total synthesis of TAN-1057A, and TAN-1057B.

On the other hand enantioselective β-amino acids were synthesized in good yield from N-protected amino acids via reduction of carboxyl function, β-amino alcohol into corresponding β-amino iodide and cyanides (Scheme 6) [17].

medicinal-chemistry-amino-acid

Scheme 6: Synthesis of β-amino acid by reduction of N-protected α-amino acid.

The conjugate addition of cyanide to α, β-unsaturated imides using aluminium-salen catalyst was reported by Jacobsen et al. (Scheme 7). The basic hydrolysis of the imide to the corresponding carboxylic acid resulted in the formation of adducts which were transformed into β-amino acids, under acidic conditions the β-amino acids are converted to corresponding carboxylic acid followed by Curtius rearrangement with diphenylphosphorylazide (dppa) and hydrolysis of the nitrile group [18].

medicinal-chemistry-Aluminium-salen

Scheme 7: Aluminium-salen catalyzed addition of cyanide to α-β unsaturated imides.

2,2´-bis(diphenylphosphino)-1,1´-binaphtyl (BINAP) in its dimeric form used to derive cationic catalyst which was employed by Sodeoka et al. in the synthesis of β-amino acids. The adducts in high yield are obtained from aromatic amines substituted with electron donating or withdrawing groups (Scheme 8) [19].

medicinal-chemistry-aromatic-amines

Scheme 8: Enantioselective aromatic amines to α-β unsaturated imides catalysed palladium.

In 2007, a diphenylamine-tethered bisoxazoline Zn(II) complex was used to add methoxyfuran to aromatic nitro olefins in an asymmetric Friedel-Crafts alkylation of 2-methoxyfuran with nitroalkenes with yield upto 96% (Scheme 9). The furan ring oxidatively give an intermediate which is then treated with diazomethane to form the β-nitro ester from which the corresponding β2-amino acids are obtained [20].

medicinal-chemistry-Friedel-Crafts

Scheme 9: Zn-catalyzed Friedel-Crafts reaction of 2-methoxyfuran with nitroalkenes.

In the following scheme 10, Candida antarctica lipase A and B enzymes played a vital role in synthesis of enantiomeric (S and R) β-amino acids, because lipase can achieve resolution of a racemic substrate [21-23].

medicinal-chemistry-Catalytic-kinetic

Scheme 10: Catalytic kinetic resolution of aliphatic β-substituted β-amino esters.

Another way to easy synthesis of S and R β-amino acids were preparedand reported by Soloshonok et al. The N-phenylacetyland malonic acid was taken as reactants in the presence of ammonium acetate. Penicillin acylase enzyme in aqueous media used to produce enantiomers. The scheme 11 describes the key steps of their synthesis [24].

medicinal-chemistry-aromatic-aldehydes

Scheme 11: Condensation of aromatic aldehydes and malonic acid.

A rhodium-catalyzed C-H insertion of aromaticdiazoacetates into N-Boc-N-benzyl-N-methylamine was also used in the synthesis of β2-amino acids (Scheme 12) [25]. Benzylaminewhich will give up to 96% yieldis used for insertion of various aromatic, heteroaromatic andalkenyldiazoacetates.

medicinal-chemistry-activation-synthesis

Scheme 12: Rh-catalyzed C-H-activation for the synthesis of β2-amino acids.

Aromatic β3-aminoacid derivatives were obtained with up to 98% yield in the reaction ofsilylenol etherswith N-BOC-aldimines having thiourea as a catalyst (Scheme 13) [26]. Comparable enantioselectivities were given by the catalyst i.e. thiourea due to variations in the amine part.

medicinal-chemistry-Thiourea-catalyzed

Scheme 13: Thiourea catalyzed asymmetric Mannich reaction.

Amulti-step procedure for the synthesis of β-unsaturated β2-amino acid derivatives was described by Walsh et al. (Scheme 14). First, enantioselectivevinylzinc addition to aldehydes yield allylic alcohol, followed by Overman’s 3,3-sigmatropicimidate rearrangement by one-pot deprotection-oxidation sequence. The hydroboration of terminal alkyne with dicyclohexylborane and transmetalation of the vinylborane with diethylzinc generated vinylzinc reagents. The addition of the vinylzincreagent to aromatic and aliphatic aldehydes was catalyzed by ligands in high yield 99% using the trichloroacetonitrile in 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to synthesize trichloroacetimidate and heated to reflux yielding the rearranged product. One-pot deprotection of the tritylalcohol and oxidation of the free hydroxyl group gaveN-protected amino acid using chromium trioxide in sulphuric acid [27].

medicinal-chemistry-vinylzinc-reagent

Scheme 14: Enantioselective addition of vinylzinc reagent for synthesis of β-amino acids.

In another reaction, synthesis of N-BOC imines were catalysed by Cinchona alkaloid given in scheme 15 are moderate enantioselective amino acids [28].

medicinal-chemistry-Cinchona-alkaloid

Scheme 15: Cinchona alkaloid catalyzed asymmetric Mannich reaction.

Lavielle and co-workersused sultam-β-alaninate-derived Schiff base for the synthesis of α-substituted β-amino acid derivatives. Lithium enolate was produced as a bi-product which is trapped with electrophiles. The reaction is given in scheme 16 [29].

medicinal-chemistry-acid-derivatives

Scheme 16: Synthesis of α-substituted β-amino acid derivatives.

The synthesis of protected aminotetroses and syn-β-hydroxy- β-amino acids was successfully described by Córdova et al. using glycol aldehydes (Scheme 17a, b). They are enantioselective and diastereoselective in nature [30,31].

medicinal-chemistry-Proline-catalyzed

Scheme 17: Proline-catalyzed asymmetric synthesis of α-hydroxy β- amino aldehydes.

The proline catalysed addition of aldehydes to aromatic N-BOC-protected imines gave syn-adduct (Scheme 18) with excellent diastereoselectivities and enantioselectivities. This was reported by List et al. [32].

medicinal-chemistry-asymmetric-reaction

Scheme 18: Proline catalyzed asymmetric reaction of N-BOC-imines.

The same group reported the proline catalyzed reaction of N-BOCimines with acetaldehyde (Scheme 19) [32].

medicinal-chemistry-catalyzed-reaction

Scheme 19: Proline-catalyzed reaction of acetaldehyde.

Versatile asymmetric syn-α-alkyl-β-amino estersmay be generated in good yield and with excellent stereocontrol. Several examples illustrate these products may be debenzylated and hydrolysed to afford homo chiral syn-α-alkyl-β-amino acids (Scheme 20) [33,34].

medicinal-chemistry-Stereoselective

Scheme 20: Stereoselective β-amino acids synthesis.

In the following scheme 21, Saito et al. produced isoxazolidinones which were converted to β-amino acids by reductive cleavage of the N–O bond by double diastereo induction of chiral methyl benzylhydroxylamine to chiral esters [35].

medicinal-chemistry-Double-diastereo

Scheme 21: Double diastereo induction to produce amino acids.

Thiourea was used as a catalyst for the conjugate addition of O-substituted hydroxylamines to pyrazolecrotonates by Sibi et al. (Scheme 22). The yield of adducts is higher with aliphatic α, β-unsaturated compounds as compared to the phenyl substituted substrates [36].

medicinal-chemistry-hydroxylamines

Scheme 22: Thiourea catalysed aza Michael addition of hydroxylamines.

The synthesis of β-amino acids was also characterized by a new biocatalyst which was named as β-transaminase (Scheme 23). The lipase from Candida rugosa catalyzes the hydrolysis of β-keto acid being the substrate for the transamination. The final product obtained was β-phenylalanine while the racemic β-alanine was used as nitrogen source [37].

medicinal-chemistry-catalyzed-synthesis

Scheme 23: Transaminase catalyzed synthesis of β-phenylalanine.

Aromatic and heteroaromatic β-amino acids were employed to synthesize the corresponding β-amino acids. Phenylalanine amino mutase (PAM) has been used to synthesize β-Styryl- and β-aryl-β- alanine derivatives (Scheme 24) [38].

medicinal-chemistry-PAM-catalyzed

Scheme 24: PAM catalyzed synthesis of β-amino acids from α-amino acids.

PAM was used by Janssen and Feringa et al. in a synthetic procedure for β-amino acids to catalyze the amination of cinnamic acid derivatives (Scheme 25). A mixture of α- and β-amino acids which remained unisolated or un-separated was obtained. By the substitution of electron donating groups in para-position of the aromatic ring corresponding β-amino acids are obtained [39].

medicinal-chemistry-cinnamic-acid

Scheme 25: PAM catalyzed synthesis of β-amino acids from cinnamic acid derivatives.

β-amino acids were synthesized by transformation of enantioselective β-lactams. In this method, the di-substituted symmetric or asymmetric ketenes react with imines effectively to produce β-lactams which is preceded further to get enantioselective of high purity β amino acids (Scheme 26) [40].

medicinal-chemistry-transformation

Scheme 26: Synthesis of β-amino acids by transformation of β-lactams

High enantiomeric and diastereomeric purity N-benzoyl α- hydroxy β-amino acids was prepared by excellent chiral starting material cyanohydrin [(-)-(R,E)p-2-hydroxy-3-pentenenitrile] which was prepared by R-oxynitrilase catalytic addition of HCN to 2-butenal, reaction is described in the scheme 27 [41].

medicinal-chemistry-amino-acids

Scheme 27: Synthesis of N-benzoyl α- hydroxy β-amino acids.

The use of chiralferrocenylphosphine ligand in the hydrogenation of (Z)-enamine esters with an unprotected amine group in trifluoroethanol (TFE) as solvent to yield the corresponding amino esters with excellent yield98% (Scheme 28) [42].

medicinal-chemistry-unprotected-enamines

Scheme 28: Rhodium-ferrocenylphosphinecatalyzed hydrogenation of unprotected enamines.

MalPhoscatalyzed(E)-enamines with 99% yield and of the corresponding (Z)-enamines with 90% yield is reported (Scheme 29). In a similar reaction, Me-DuPhos gave also high yields with these (E)- enamines, but (Z)-enamines gave correspondingly lower yields [43].

medicinal-chemistry-catalyzed-hydrogenation

Scheme 29: Rhodium catalyzed hydrogenation of (E)- and (Z)-enamines.

The mixed ligand approach has been employed in the synthesis of β-amino acid catalyzed by rhodium-phosphoramidite complexes in order to further enhance the enantioselectivity. The combination of chiral phosphoramidite with achiral tris-o-tolyl-phosphine using the unprotected carboxylic acid was used for the synthesis of β2-amino acids (Scheme 30) [44].

medicinal-chemistry-Mixed-ligand

Scheme 30: Mixed ligand approach towards β-amino acids.

In 2005, the addition of β-ketoesters to various imines catalyzed by a chiral cationic palladium complex was described by Sodeoka et al. (Scheme 31) [45]. The catalyzed addition of β ketoesters to α-imino esters gave the corresponding β-amino acids.

medicinal-chemistry-keto-esters

Scheme 31: Pd-catalyzed addition of β keto esters to α-imino esters.

Shibasaki et al.in the direct asymmetric reaction of trichloromethyl ketones and pyridyl- orthienylsulfonyl-protected imines studied La(III)-i Pr-pybox (Scheme 32). The trend of the reaction was to use the aliphatic, aromatic and heteroaromatic imines as substrates. Using esterificationthe product was transformed into the N-BOC-protected β2-amino ester under basic conditions [46].

medicinal-chemistry-ketones-imines

Scheme 32: La-catalyzed addition of trichloromethyl ketones to imines.

Homonuclear Ni2-Schiff base complex was also reported by Shibasaki et al. for the synthesis of tetra substituted anti-α, β-diamino acids (Scheme 33). The corresponding adducts were obtained with high yields from BOC-protected aromatic and aliphatic imines with nitroacetate. The nitro group was reduced to give α, β-diamino ester using NaBH4/NiCl2, which was transformed to the corresponding acid [47].

medicinal-chemistry-nitroacetate

Scheme 33: Ni-catalyzed addition of nitroacetate to imines.

`Simple aromatic and enolizable aliphatic aldehydes, secondary amines and glycine derivatives are used as starting materials producing protected α, β-diamino esters using Me-Duphos as ligand by Kobayashi (Scheme 34) [48].

medicinal-chemistry-catalyzed-Mannich

Scheme 34: Cu-catalyzed Mannich reaction of glycine derivative with aldehyde and amine.

Kobayashi et al. have also studied the asymmetric Mannich reaction (Scheme 35). The adducts with yield 84% are obtained by the reaction of β-dimethyl silylenol ethers with protected aromatic imines [49].

medicinal-chemistry-silylenol-ethers

Scheme 35: Fe-catalyzed addition of silylenol ethers to aromatic imines.

Feringa et al. obtained adducts of Et2Zn, Me2Zn and Bu2Zn with high yield by the addition of dialkyl zinc reagents to acetal-substituted nitropropenoates (Scheme 36) [50]. Raney-Nickel reduction of the nitroalkane, followed by BOC-protection of the amine group and oxidation of the acetal under acidic conditions to the corresponding carboxylic acid gavethe corresponding N-BOC protected β2-amino acids.

medicinal-chemistry-Raney-catalysts

Scheme 36: Synthesis of N-BOC protected β²-amino acids using Cu- and Raney Ni catalysts.

Hii et al. investigated cationic palladiumbinap complex using aniline and crotonyloxazolidinone, to get enantioselective addition of primary aromatic amines to α, β unsaturated oxazolidinones (Scheme 37a) [51]. Similarly high yield 98% obtained when cationic palladium complex was investigated in addition to aromaticamines to N-alkenoylcarbamates (Scheme 37b) using various aliphatic substrates (R = Me, Et, Pr). By the hydrolysis of the imide under basic conditions, the products were converted to N-aryl-β3-aminoacids [52].

medicinal-chemistry-aromatic-amines

Scheme 37: Pd-catalyzed addition of aromatic amines to α-β unsaturated imides.

The synthesis of β2-amino acids was reported by Gellman et al. by the enantioselective aminomethylation of aldehydes (Scheme 38a). The β-amino aldehydes were reduced to the corresponding alcohols by reaction with Proline derivative. For the synthesis of β2-amino acids, the amino alcohol was recrystallized as hydrochloride salt to increase the yield, the protecting groups removed by hydrogenation followed by BOC-protection, and the alcohol oxidized to the corresponding carboxylic acid [53,54]. High yields up to 98% were obtained by Córdova et al. by using LiBr (Scheme 38b). The corresponding β2-amino acid was synthesized by oxidationof the alcohol to the carboxylic acid after deprotection of the benzyl-protecting group re-protection using BOC2O [55].

medicinal-chemistry-Synthesis

Scheme 38: Synthesis of β²-amino acids

A demonstration of the organo catalytic amine addition and the accompanying products is presented in the one pot conversion of simple aldehydes to enantio enriched β-amino acids. The 2-hexenal reacts with asymmetric amination conditions followed by I Pinnick oxidation provided the corresponding β-amino acids with excellent enantioselective (92%). N-O bond removal can be accomplished under mild reduced conditions (Zn/AcOH) (Scheme 39) [56].

medicinal-chemistry-catalyticaza-Michael

Scheme 39: Organo catalyticaza-Michael addition.

Similarly, in another report by Córdova et al. the α, β-unsaturated aldehydes were obtained by the reaction of proline-derived chiral amine with N-Cbz-methoxylamine as a nucleophile (Scheme 40a) [57]. The β-amino aldehydes obtained in high yield up to 99% undergo oxidation to the corresponding carboxylic acid and deprotection of the amine provided β3-amino acids. When carbamate-protected hydroxylamines were used as nucleophile, the cyclic 5-hydroxy-isooxazolidinones were obtained with high yield up to 98% (Scheme 40b). The corresponding β3 amino acids were obtained by subsequent cleavage by hydrogenolysis with high yield up to 97% [58].

medicinal-chemistry-Organo-catalytic

Scheme 40: Organo catalytic aza Michael addition.

The derivatives of β-amino acid were obtained with high yields through 1,3-asymmetric induction through radical mediated 1,5-hydrogen atom transfer and trapped by electrophilic olefins (Scheme 41) [59].

medicinal-chemistry-Synthesis-amino-derivatives

Scheme 41: Synthesis of β-amino acids derivatives through 1, 3-asymmetric induction.

The preparation of syn-α-hydroxy β-amino acids was reported in two steps by Cardillo and Gentilucci. The key stepof this synthesis was the formation of transoxazoline (Scheme 42).The PGA catalyzed kinetic resolution gave 3-amino-3-phenylpropanoic acid [60].

medicinal-chemistry-Preparation-hydroxy-amino

Scheme 42: Preparation of syn-α-hydroxy β-amino acids.

The enantioselective (R)-(+)-β-phenylalanine and (S)-(+)-ethyl- β-amino-3-pyridinepropanoate have been prepared elsewhere in literature (Scheme 43). The reaction was completed by the addition of sodium enolate to chiral sulfinimine [61,62]. The sulfinyl group activated the carbon–nitrogen double bond, and therefore facilitates the additionof various nucleophiles. In similar methodology titanium enolate was added to tertbutanesulfinylimine by Ellman and Tang for the construction of β, β disubstituted and α, β disubstituted β-amino acids [63].

medicinal-chemistry-sulfoxides-chiral-auxiliaries

Scheme 43: The use of sulfoxides as chiral auxiliaries in asymmetric synthesis of β-amino acids.

In another approach α-methyl-β-substituted β-amino esters were prepared by Badia et al., utilizing readily available (S, S)-(+)- pseudoephedrine as chiral auxiliary (Scheme 44a) [64]. An asymmetric preparation of β-substituted β-aminoacids were explored by reactions of imines and chiral enolates (Scheme 44b) [65,66].

medicinal-chemistry-Asymmetric-preparation-substituted

Scheme 44: Asymmetric preparation of β-substituted β-amino acids.

TMS-SAMP as anucleophile was used by Enders et al. to synthesis N-silylated β-hydrazino- estersin as aza analogous Michael addition process [67]. In a Tandem aza Michael addition intramolecular cyclization, the same reaction sequence was also applied to the synthesis of cyclic β-amino acids and heterocyclic β-amino acids [68]. Sibi et al. reported β-amino acid derivatives with 97% yield (Scheme 45) [69].

medicinal-chemistry-Synthesis-amino-derivatives

Scheme 45: Synthesis of β-amino acid derivatives.

Lavielle et al. reported the asymmetric synthesis of the N-BOC protected derivative of (S)-3-Amino-2-phenyl propanoic acid featuring acylation of metallated phenylacetonitrile as the key step [70]. Another approach involved base catalyzed addition of (R)-pantolactone to N-phthaloyl ketene following an entirely different strategy was later described by Calmes and Escale (Scheme 46) [71].

medicinal-chemistry-catalyzed-addition-amino

Scheme 46: A base catalyzed addition of β-amino acids

Prashad et al. reported the first enantioselective cyclic β-amino acid (+)-methylphenidate hydrochloride, which is a mild nervous system stimulant used for the treatment of attention deficit hyperactivity disorder (Scheme 47) [72,73].

medicinal-chemistry-Enantioselective-synthesis-amino

Scheme 47: Enantioselective synthesis of β-amino acid.

Β3-amino esters were obtained by Börner et al. using 1, 3-diphenyl- 1,3-bis(diphenylphosphino) propanein the hydrogenation of (E)- enamines (Scheme 48). The esters were then converted to the corresponding β3-amino acids [74].

medicinal-chemistry-Rhodium-diphenylphosphino-propane

Scheme 48: Rhodium-diphenylphosphino-propane catalyzed hydrogenation of (E)-enamines.

Kim, Park and Beak recently synthesized β-phenyl amino acidsfrom N-BOC-N-(p-methoxy- phenyl) benzylamine via (-)-sparteine/BuLi catalysed diastereoselective alkylation with substituted vinyl bromide, and subsequent oxidation with ozone, followed by Jones reagent (Scheme 49) [75].

medicinal-chemistry-Synthesis-phenyl-benzylamine

Scheme 49: Synthesis of β-phenyl amino acid from N BOC- N-(pmethoxyphenyl) benzylamine.

Berkessel et al. studied thiourea catalyst for the kinetic resolution of racemic oxazinones (Scheme 50). The N-benzoyl-β-amino acid was isolated with 97% yield using hydrolytic environment [76].

medicinal-chemistry-Organo-catalytic-oxazinones

Scheme 50: Organo catalytic resolution of oxazinones.

The α-amino acid derived amide was reduced with imines with trichlorosilane which are in equilibrium with the corresponding enamines (Scheme 51). The β–amino esters obtained were converted to the corresponding β–aminoacids [77].

medicinal-chemistry-enamines-amino-derivatives

Scheme 51: Resolution of enamines towards β-amino acid derivatives.

The polar solvents accelerate the hydrogenation of (Z)-β- aminoacrylate in the presence of Et-DuPHOS-Rh as a catalysts reported by Heller and co-workers. The corresponding β-amino acids were obtained from the E and Z isomers which were hydrogenated to give β-amino esters (Scheme 52) [78].

medicinal-chemistry-hydrogenation-aminoacrylate-synthesis

Scheme 52: The hydrogenation of (Z)-β-aminoacrylate towards β-amino acid synthesis.

Various aminomutases have been used for the conversion of aliphatic and aromatic α-amino acids to the corresponding β-isomers [39]. Various aromatic (S)-β amino acids can be obtained by using phenylalanine aminomutase (PAM) in tandem with phenylalanine ammonialyase (PAL).The stereoselective hydrolysis of racemic phenyldihydrouracil to D- and L-N-carbamoyl-β-phenylalanine on further hydrolyse to corresponding β-amino acid [79].

Transaminases (also known as aminotransferases) possess a great potential for the synthesis of optically pure-amino acids [80]. Transaminases can be applied either for the kinetic resolution of racemic compounds or the asymmetric synthesis starting from a prochiral substrate. The catalytic ring-expansive carbonylation of oxazolines, easily derived from α-amino acids, to yield β-amino acid derivatives is described in Scheme 53 [81].

medicinal-chemistry-catalytic-ring-expansive

Scheme 53: The catalytic ring-expansive carbonylation of oxazolines.

copper-catalyzedenantioselective 1,4-reduction of β-(acylamino) acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yield 99% (Scheme 54) [82].

medicinal-chemistry-copper-catalyzed-enantioselective

Scheme 54: The copper-catalyzed enantioselective 1, 4-reduction.

The chlorosulfonylisocyanate was reacted with cycloalkene to give fused β-lactams. The ring opening of the lactams was easily carried out with hydrochloric acid (Scheme 55) [83].

medicinal-chemistry-Synthesis-amino-cycloaddition

Scheme 55: Synthesis of β-amino acids through 1,2 cycloaddition.

Cis- and trans- cyclohexane based β-amino acids, have also been prepared from the Diels-Alder adduct tetrahydroanthranilic anhydride (Scheme 56) [84-87]. The cis-isomer was prepared by ring-opening of this cyclic anhydride with aqueous ammonia to give the monoamide. Hoffman degradation of the resulting amide with hypobromite (or hypochlorite if a double bond was present) gave the β-amino acid. The synthesis of trans-cyclohexane required three additional steps. Esterification of anhydride gave the cis-diester and this was epimerised with sodium methoxide to give the trans-diester. Dehydration of this ester afforded the transanhydride, which was reacted to give the amine in two steps [88].

medicinal-chemistry-Racemic-synthesis-trans

Scheme 56: Racemic synthesis of cis and trans ACHC.

Enantiomerically pure cis β-amino acid was synthesised from diester (Scheme 57). Thisester was region specifically hydrolysed using pig liver esterase to give the mono ester [89, 90]. Reaction of this ester with sodium azide afforded the azide intermediate. A subsequent Curtius rearrangement of the azide gave the enantiomerically pure cis β-amino acid. In a related synthesis, epimerisation of the methyl ester to the trans-analogue gave the enantiomerically pure trans-β-amino acid [91].

medicinal-chemistry-Enantiomeric-synthesis-enzymatic

Scheme 57: Enantiomeric synthesis of cis-ACHC using enzymatic resolution.

A general enzymatically-catalysed synthesis of cyclic β-amino acids was reported by Forro et al. The β-lactam (±) was enantioselectively hydrolysed with alipase B enzyme, giving cis β-amino acid. This resolved the other β-lactam enantiomer, which could then be hydrolysed nonenzymatically (Scheme 58) [92].

medicinal-chemistry-Enzyme-catalysed-racemic

Scheme 58: Enzyme catalysed resolution of a racemic β-lactam.

Another sequence which includes an enzymatic resolution involves the enantioselective acylation of β-amino acid (±), to give the amide and resolving the other enantiomer(Scheme 59) [93,94].

medicinal-chemistry-enantioselective-acylation-amino

Scheme 59: The enantioselective acylation of β-amino acid

The use of chiral auxiliaries to introduce stereocentres into achiral molecules has proven very successful in the synthesis of β-amino acids. The racemic ketone (±) was reacted with chiral α-methyl benzylamine, to give the enantiomerically pure β-enamino ester intermediate was reduced by using sodium borohydride (Scheme 60) [95]. An alternative reduction at the more hindered face of enaminoester with sodium cyanoborohydride gave the corresponding trans β-amino acid [96,97].

medicinal-chemistry-Diastereoselective-reduction-enaminoester

Scheme 60: Diastereoselective reduction of a β-enaminoester to give a β-amino acid.

Davies et al. synthesized enantiomerically pure cyclic β-amino acids in 98% diastereomeric excess via conjugate addition of a chiral amine to cyclic α, β-unsaturated esters (Scheme 61) [ 98,99]. Stereoselective addition of the chiral amine, followed by aqueous quenching of the lithium enolate gave the cis as major isomer. The chiral amine moiety was hydrogenated with Pd(OH)2 to give the cyclopentane-based trans β-amino acid. This versatile general method was also used to synthesize novel heterocyclic β-amino acids [100].

medicinal-chemistry-Diastereomeric-synthesis-pentacin

Scheme 61: Diastereomeric synthesis of cis pentacin and trans ACPC.

Enders et al. synthesised cycloheptane based β-amino acids using a conjugate addition/alkylation reaction of α,β-unsaturated ester (Scheme 62). This gave the cyclic chiral intermediate in >96% yield was cleaved to β-amino acid [67,68].

medicinal-chemistry-enantioselective-synthesis-cycloheptane

Scheme 62: The enantioselective synthesis of trans-2-amino-cycloheptane-1-carboxylic acid.

Enantioselective hydrogenation of the β-unsaturated ester using a ruthenium catalyst gave the β-amino ester, in up to 99% yield (Scheme 63). This reaction proved efficient for the synthesis of cyclopentane and cyclohexane. However, hydrogenation of seven- and eight-membered cycles gave lower diastereoselectivity [100].

medicinal-chemistry-Ruthenium-catalyzed-enantioselective

Scheme 63: Ruthenium-catalyzed enantioselective hydrogenation.

A versatile method to synthesize cis or trans β-amino acids utilises a RCM approach using Grubb’s 1st,and 2nd generation ruthenium catalysts (Scheme 64). Allylation at the β2 position gave the trans-diene, necessary for cyclization using Grubb’s catalyst [101].

medicinal-chemistry-Synthesis-amino-acids

Scheme 64: Synthesis of cyclic β-amino acids via RCM.

The stereoselective alkylation of oxazolidin 2-one-4-acetic acid derivative with inversions of stereochemistry is the main step for the synthesis of diastereomer of α, β-disubstituted β-amino acid derivatives (Scheme 65) [102,103].

medicinal-chemistry-Stereoselective-alkylation-diastereomers

Scheme 65: Stereoselective alkylation of diastereomers of the α, β-disubstituted β-amino acid.

Such type of synthesis of stereoselective preparation of iturinic acid and 2-methyl-3-aminopropanoic acid also reported via alkylation mechanism is being described in scheme 66 [104].

medicinal-chemistry-Stereoselective-preparation-iturinic

Scheme 66: Stereoselective preparation of iturinic acid and 2 methyl-3- aminopropanoic acid.

Similar asymmetric synthesis of β-amino esters involved by the addition of silylenol ether to chiral imine generated in situ from aldehydes and (S)-valine methyl ester described in scheme 67.All reactions were carried out at room temperature in Yb(OTf)3 catalyst to activate the imine and anhydrous MgSO4 to remove the water [105].

medicinal-chemistry-Asymmetric-synthesis-amino

Scheme 67: Asymmetric synthesis of β-amino esters.

The synthesis of anti-α-substituted-β-amino esters based on diastereoselective conjugate addition of BnNH2 was reported by Perlmutter and Tabone scheme 68 (a) [106]. In another recent report, Costa et al. were also able to add BnNH2 to choral esterin 90% yield scheme 68 (b) [107].

medicinal-chemistry-diastereoselective-conjugate-addition

Scheme 68: The diastereoselective conjugate addition of BnNH2.

The conjugate addition of hydrazoic acid (HN3) to α,β-unsaturated imide scatalyzed by Chiral (salen)Al(III) complex was also described by Jacobsen et al. (Scheme 69).This procedure provided access to a variety of enantiopure β-alkyl-β-azido compounds. However, the addition to cinnamate was inefficient and reaction was incomplete [108].

medicinal-chemistry-conjugate-addition-hydrazoic

Scheme 69: The conjugate addition of hydrazoic acid (HN3) to α,β-unsaturated imide.

Enantioselective hydrogenation of α, β-unsaturated nitriles and their methyl esters bearing β-phthalimidomethyl substituents were reported by Jackson et al. (Scheme 70a,b).Surprisingly, only up to 48% yield was observed for Rh-DuPhos mediated hydrogenation of phthalimido nitriles. An improved selectivity (84%) was achieved in the hydrogenation of phthalimido ester (R=H) using Ru-BINAP as the catalyst. However, the β-substituent phthalimido ester (R=Me) resulted in a drastic decrease in yield (only 10%) [109].

medicinal-chemistry-Enantioselective-hydrogenation-unsaturated

Scheme 70: Enantioselective hydrogenation of α, β-unsaturated nitriles (a) and methyl (b) esters.

Juhl and Jørgensen reported anovel method to synthesize α-hydroxy β-amino esters via asymmetric α-amination and 2-keto esters (Scheme 71). Dibenzylazodicarboxylate was acted as electrophilic nitrogen source. When THF gave higher % yields with excellent levels of enantio selectivities [110].

medicinal-chemistry-asymmetric-amination-reaction

Scheme 71: The asymmetric α-amination reaction of 2-keto esters.

When aromatic aldehydes added to sylamide and methylacrylate in the presence of nucleophilic quinuclidine alkaloid derived catalyst in combination with Ti(OiPr)4 as Lewis acid,a good yield with moderate enantioselectivities were obtained (Scheme 72) [111].

medicinal-chemistry-Catalytic-asymmetric-Hillman

Scheme 72: Catalytic asymmetric Baylis-Hillman reaction.

Lectka et al. used bifunctional asymmetric catalyst and synthesized β-lactams from acyl chlorides and imine (Scheme 73). A combination of In(OTf)3 and quinidine derivative was used to obtain the syn-β- lactam with high yield [112].

medicinal-chemistry-symmetric-lactams-quinidine

Scheme 73: A symmetric formation of β-lactams in quinidine catalyst.

Chiral Brønsted acid which was proposed to activate imine through hydrogen bonding was studied by Yamamoto et al. An achiral Brønstedacid (R3OH) protonates the amine moiety of the intermediate to give adducts in good yields. The addition of silylenolethers to aromatic aldimines was also catalyzed by Taddol-derived phosphoric acid with good yield as well (Scheme 74) [113,114].

medicinal-chemistry-Catalyst-catalysed-Mannich

Scheme 74: Catalyst/H2 Brønsted acid catalysed Mannich reactions synthesize β2,2,3-amino acids.

N-protected β-amino esters have been synthesized in good yield by Jørgensen et al. using the [1,3]-sigmatropic rearrangement of O-allylictrichloroacetimidates catalyzed by dihydroquinidine (DHQD)2PHAL (Scheme 75) [115].

medicinal-chemistry-Sigmatropic-rearrangement-esters

Scheme 75: [1,3]-Sigmatropic rearrangement for the synthesis of β-amino esters.

The addition of nitrosobenzene to α, β-unsaturated aldehydes was catalyzed by N-Heterocyclic carbine. This transformation gives isooxazolidinone intermediates which were hydrolyzed under acidic conditions to the corresponding methyl ester (Scheme 76) [116].

medicinal-chemistry-Addition-unsaturated-aldehydes

Scheme 76: Addition of α,β-unsaturated aldehydes to nitrosobenzene.

Waldmann et al. developed that imines while reacting with N, N-phthaloyl protected amino acid chloride lead to the N-acyliminium intermediate, which was then subjected to nucleophilic attack (Scheme 77). It is interesting to note that excellent results were obtained if the aromatic groups of the imine carried an orthosubstituent [117].

medicinal-chemistry-Synthesis-asymmetric-Mannich

Scheme 77: Synthesis of β-amino acid via asymmetric Mannich reaction.

The synthesis of α, α-difluoro-β-amino acid was reported by Quirion et al. using ethyl bromodifluoroacetate with chiral 1, 3-oxazolidines (Scheme 78a) [118]. Buttero et al. used a similar procedure in the addition of bromo esters to imines attached to atricarbonyl (η6 arene) chromium(0) complex (Scheme 78b) [119]. Shankar et al. synthesized β-lactams which were analogs of cholesterol absorption inhibitor SCH 48461 using chiral bromoacetate and imines(Scheme 78c) [120].

medicinal-chemistry-Synthesis-amino-acids

Scheme 78: Synthesis of β-amino acids.

A large-scale asymmetric synthesis of cis-2 amino-1-cyclohexane carboxylate was reported by Xu et al. (Scheme 79a) [95]. Highest selectivity was obtained when the reaction was carried out in isobutyric acid and NaBH4 as hydride. A similar method using NaCNBH3 as the reducing agent to prepare β-peptide building blocks (b) and (c) has also been explored by Gellmans’ group (Scheme 79b,c) [96,97].

medicinal-chemistry-Asymmetric-synthesis-amino

Scheme 79: Asymmetric synthesis of β-amino acids.

The enantioselective addition of lithium enolate to imine based on a ternary complex reagent was reported by Tomioka et al. β-Lactams were produced directly by the use of lithium cyclohexylisopropyl amine or lithium dicyclohexyl amine as the additives with the highest enantioselectivity (Scheme 80) [121,122].

medicinal-chemistry-asymmetric-preparation-lactams

Scheme 80: The asymmetric preparation of β-lactams.

A novel biomimetic preparation of β-fluoroalkyl-β-amino acids is given in scheme 81. The process involved two consecutive base catalyzed 1,3-proton shift of enamine to aldimine, which was hydrolyzed to β-amino acids in 6N HCl [123-125].

medicinal-chemistry-biomimetic-fluoroalkyl-amino

Scheme 81: A novel biomimetic preparation of β-fluoroalkyl-β-amino acids.

Conclusions

A tremendous progress has been made in the past decades forthe enantiopure synthesis of β-amino acids and derivatives on account of bearing varieties of biological activities including antifungal, antitubercular, antibacterial and anticancer. They are also used in the treatment of many diseases and health issues.Therefore, enantioselective β-amino acids have potential therapeutic values and are a great challenge for chiral synthesis.Therefore, β-amino acids with various substitution patterns are now available. Each approach has itsown advantages and limitations while more than 80 numbers of different approaches have been discussed here but the organo-Rh based and heterogeneous catalyzed approach is found to be more effective (Scheme 1, 2, 4,11, 12, 13, 28, 29) and (Scheme 8, 9, 33, 34, 35, 36, 37, 45, 54, 63). Other approaches can also be considered to synthesize enantioselective amino acids (Scheme 11, 13, 15, 40, 45, 50, 61, 62, 68, 70, 74). No doubt, the growing interest in enantioselective β-amino acids will stimulate new and improved methods for their synthesis in near future.

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