l ch cina em Ashfaq et al. di is Med chem 2015, 5:7 e tr M y Medicinal chemistry DOI: 10.4172/2161-0444.1000278 ISSN: 2161-0444 Review Article Open Access 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 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, auxiliaries and catalysts in 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 Phosphoramidite ligand was used to obtain adducts in high yields with up to 94% by Fillion et al. through conjugate addition of dialkylzinc Introduction reagents to 2-aryl acrylate (Scheme 3). Deprotection of adduct, followed Enantionselective synthesis of β-amino acids has gained significant by a Curtius rearrangement of the succinic acid derivative resulted in importance because of their interesting pharmacological applications the formation of β-amino acid derivative [14]. as hypoglycaemic and antiketogenic properties, antibacterial and Sibi et al. reported an enantioselective rhodium catalysed enolate antifungal activities, antihelminthic as well potent insecticidal properties protonation method for the synthesis of β²-amino acid (Scheme 4). activities [1-3]. β-amino acids are fundamental building blocks for the Rh(acac)(ethylene)2 and difluorophos used to form a complex which preparation of pharmaceutical and agrochemical target molecules. They catalyzed the conjugate addition of aryl boronic acids to β-acrylates. have displayed a high tendency towards the formation of β-peptides The intermediate oxa-β-allyl-Rh resulted in good yields using one stable secondary structures (turns, sheets, and helices) and they are equivalent of phthalimideas proton source [15]. extensively used as chiral starting materials, auxiliaries and catalysts O O R R in organic synthesis [4-6]. Ennantioselectively defined β-amino acids Rh(COD)BF4 are applied in drug development, molecular recognition, bimolecular Carbohydrate phosphite N N CO2Me structure and functional studies [3-7]. However, the synthesis of CO2Me 10-85 atm. H2 β-amino acids bearing various functional groups on the β-carbon with O O thiadiazole ring systems have been well studied due to having variety of biological activities, including antifungal, antitubercular, antibacterial, Scheme 2: Rh-catalyzed hydrogenation of phthalimide protected acrylates. anticancer, and analgesic properties [8,9]. O O O O Different methodologies have been tried out for their synthesis to Pd/C,H2 NCO R Zn 2 CO2X EtOAC,rt O CO2X O XO2C maintain desired chirality is a big challenge. Several different catalytic Ar Cu(OTf) ,DME dppa, toluene R 2 Ar asymmetric approaches to synthesize β-amino acids involving carbon– O Ar Phosphoramidite O R carbon, carbon–nitrogen, and carbon–hydrogen bond forming Scheme 3: Cu-catalyzed dialkylzinc to 2-aryl-acrylates to form quaternary reactions have been developed [10]. As per literature evidences, the stereo centers. enantioslective derivative of β-amino acid like N-acyl-β-(amino) acrylates was prepared by using Ru(O2CCH3)2 as catalyst [1]. Similarly O O Ru and Rh chiral mono- and bi-dentate phosphorous homogeneous RB(OH)2 ,complex t Rh(acac)(ethylene) t BuCO 2 catalysts were used for their synthesis through hydrogenation 2 N BuCO2 o N Phthalimide,dioxane,50 C standard procedure. The hydrogenation of Z( )-enamines catalysed by O R bisphosphepine ligand was proceeded by Zhang et al. (Scheme 1) with O O 90% high yield. On the contrary, using the same catalyst system, (E)- Scheme 4: Enantioselective rhodium catalyzed conjugate addition and enamines give only low yield [11]. protonation. High enantioselectivity in Rh-catalyzed hydrogenations can also be obtained by phosphite and other phosphorous ligands [12]. When phthalimide protected acrylates are hydrogenated using carbohydrate- *Corresponding author: Muhammad Ashfaq, Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan, Tel: +92 300 6829307, phosphite β²- amino acid derivatives are formed with 99% yield +92 62 9255473; Fax: +92 62 9255563, E-mail: [email protected] (Scheme 2) [13]. Received May 05, 2015; Accepted July 15, 2015; Published July 27, 2015 Citation: Ashfaq M, Tabassum R, Ahmad MM, Hassan NA, Oku H, et al. (2015) NHAc NHAc Enantioselective Synthesis of β-amino acids: A Review. Med chem 5: 295-309. doi: Rh(biphosphepine)(nbd)SbF 6 10.4172/2161-0444.1000278 CO2Me CO Me THF, 20 psi H 2 Ar 2 Ar 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 Scheme 1: Rhodium-bis phosphepine catalyzed hydrogenation of (Z)- use, distribution, and reproduction in any medium, provided the original author and enamines. source are credited. Med chem Volume 5(7): 295-309 (2015) - 295 ISSN: 2161-0444 Med chem, an open access journal 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 A dipeptide antibiotic TAN-1057 A,B was synthesized (58% yield) yield are obtained from aromatic amines substituted with electron via tri-N-Cbz-L-arginine and diazoketone in 1:1 molar ratio while donating or withdrawing groups (Scheme 8) [19]. the tert-butyl alcohol/water is used as solvent. The overall chemical In 2007, a diphenylamine-tethered bisoxazoline Zn(II) complex was reaction is given in Scheme 5 [16]. used to add methoxyfuran to aromatic nitro olefins in an asymmetric On the other hand enantioselective β-amino acids were synthesized Friedel-Crafts alkylation of 2-methoxyfuran with nitroalkenes with yield in good yield from N-protected amino acids via reduction of carboxyl upto 96% (Scheme 9). The furan ring oxidatively give an intermediate function, β-amino alcohol into corresponding β-amino iodide and which is then treated with diazomethane to form the β-nitro ester from cyanides (Scheme 6) [17]. which the corresponding β²-amino acids are obtained [20]. The conjugate addition of cyanide to α, β-unsaturated imides using In the following scheme 10, Candida antarctica lipase A and B aluminium-salen catalyst was reported by Jacobsen et al. (Scheme enzymes played a vital role in synthesis of enantiomeric (S and R) 7). The basic hydrolysis of the imide to the corresponding carboxylic β-amino acids, because lipase can achieve resolution of a racemic acid resulted in the formation of adducts which were transformed into substrate [21-23]. β-amino acids, under acidic conditions the β-amino acids are converted to corresponding carboxylic acid followed by Curtius rearrangement Another way to easy synthesis of S and R β-amino acids were with diphenylphosphorylazide (dppa) and hydrolysis of the nitrile preparedand reported by Soloshonok et al. The N-phenylacetyland group [18]. malonic acid was taken as reactants in the presence of ammonium acetate. Penicillin acylase enzyme in aqueous media used to produce 2,2´-bis(diphenylphosphino)-1,1´-binaphtyl (BINAP) in its enantiomers. The scheme 11 describes the key steps of their synthesis [24]. 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 Ar O O NH O O NH CH2N2 NH ArNH ,THF ClCO Et/NMM 2 CO2H 2 R N NHCbz N R N NHCbz N CO2H O Cat.PhCO2Ag ,Pd catalyst O Cbz CbzHN in H2O/t-BuOH Cbz CbzHN (A) Me S configuration.TAN 1057A Scheme 8: Enantioselective aromatic amines to α-β unsaturated imides NH R configuration.TAN 1057B catalysed palladium. N (A) NH2 NH NH O NH2 O O N NH NH2 R Scheme 5: Arndt–Eistert reaction in the total synthesis of TAN-1057A, and NO2 Zn(OTf)2, Xylene NO2 TAN-1057B. + R O MeO O diphenylamine MeO tethered bisoxazoline (A) R O H RuCl3 - NalO4 H2N N-Protection H OH P N Reduction P N NO2 OH (A) OH CCl ,MeCN,H O CO2Me R 4 2 R CH N R 2 2 1 (Boc, Cbz, Fmoc) i Scheme 9: Zn-catalyzed Friedel-Crafts reaction of 2-methoxyfuran with nitroalkenes. H H Fmoc N Cbz ,Boc N I I R O R (A) Kanerva et al. ii ii NH2 O NH2 O Pr NH O H Lipase H H Fmoc N Cb N R OEt R OEt R OEt z Boc N iii I PrCOOR I I 1 rac (S) or (R) (R) or (S) R R R iv v vi (B) Gotor et al. O H H H Fmoc N Cbz N Boc N CO Me NH O H C NH O CO2Me CO2Me 2 NH2 O 2 3 Lipase R R R OEt OEt OEt CH3COOEt + - o i-.PDI-imidazole, CH2Cl2, reflux 1h; ii. Et3N CN , CH2Cl2, reflux 4h; iii.30%TFA in CH2Cl2, 0 C, 0.5 h, then FmocOsu, 10% Aq Na2CO3, rac (S) or (R) (R) or (S) o THF, room temp. 1h; iv.excess con, HCl/MeOH, Et2O, 4 C 12h; v.as iv without Et2O, room temp.