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


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][2][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][5][6]. Ennantioselectively defined β-amino acids are applied in drug development, molecular recognition, bimolecular structure and functional studies [3][4][5][6][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 carboncarbon, 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(O 2 CCH 3 ) 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].
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]. 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].
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].
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].
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].
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].
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][22][23].
Another way to easy synthesis of S and R β-amino acids were preparedand reported by Soloshonok  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.
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.
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  The same group reported the proline catalyzed reaction of N-BOCimines with acetaldehyde (Scheme19) [32].
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].
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].
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].
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].
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].
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].
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].
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.
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 esterification the product was transformed into the N-BOC-protected β²-amino ester under basic conditions [46].
Homonuclear Ni 2 -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 NaBH 4 /NiCl 2 , which was transformed to the corresponding acid [47].
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].
Kobayashi et al. have also studied the asymmetric Mannichreaction (Scheme 35). The adducts with yield 84% are obtained by the reaction of β-dimethyl silylenol ethers with protected aromatic imines [49].
Feringa et al. obtained adducts of Et 2 Zn, Me 2 Zn and Bu 2 Zn 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. 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].
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 oxidation of the alcohol to the carboxylic acid after deprotection of the benzyl-protecting group re-protection using BOC 2 O [55].
A demonstration of the organocatalytic 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 in situ 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].
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].
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].
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].
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].
The polar solvents accelerate the hydrogenation of (Z)-βaminoacrylate 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].
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].
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].
Cis-and trans-cyclohexane based β-amino acids, have also been prepared from the Diels-Alder adduct tetrahydroanthranilic anhydride (Scheme 56) [84][85][86][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].
Enantiomerically pure cis β-amino acid was synthesised from diester (Scheme 57). Thisester was region specifically hydrolysed using pig liver esterase to give the monoester [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].
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].
A versatile method to synthesize cis or trans β-amino acids utilises a RCM approach using Grubb's 1 st and 2 nd generation ruthenium catalysts (Scheme 64). Allylation at the β 2 position gave the trans-diene, necessary for cyclization using Grubb's catalyst [101].
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].
Similar asymmetric synthesis of β-amino esters involved by the addition of silylenol ether to chiral imine generated in situ from the other β-lactam enantiomer, which could then be hydrolysed nonenzymatically (Scheme 58) [92].
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].
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].
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]. 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 MgSO 4 to remove the water [105].
The conjugate addition of hydrazoic acid (HN 3 ) 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].
When aromatic aldehydes added to sylamide and methylacrylate in the presence of nucleophilic quinuclidine alkaloid derived catalyst in combination with Ti(O i Pr) 4 as Lewis acid,a good yield with moderate enantioselectivities were obtained (Scheme 72) [111].
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-βlactam with high yield [112]. Brønstedacid (R 3 OH) 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].
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].
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].
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 NaBH 4 as hydride. A similar method using NaCNBH 3 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].
The enantioselective addition of lithium enolate to imine based on a ternary complex reagent was reported by Tomioka  amine or lithium dicyclohexyl amine as the additives with the highest enantioselectivity (Scheme 80) [121,122].

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.