136030-52-9Relevant academic research and scientific papers
Exploring the scope of an α/β-aminomutase for the amination of cinnamate epoxides to arylserines and arylisoserines
Shee, Prakash K.,Ratnayake, Nishanka Dilini,Walter, Tyler,Goethe, Olivia,Onyeozili, Edith Ndubuaku,Walker, Kevin D.
, p. 7418 - 7430 (2019/08/20)
Biocatalytic process-development continues to advance toward discovering alternative transformation reactions to synthesize fine chemicals. Here, a 5-methylidene-3,5-dihydro-4H-imidazol-4-one (MIO)-dependent phenylalanine aminomutase from Taxus canadensis (TcPAM) was repurposed to irreversibly biocatalyze an intermolecular amine transfer reaction that converted ring-substituted trans-cinnamate epoxide racemates to their corresponding arylserines. From among 12 substrates, the aminomutase ring-opened 3′-Cl-cinnamate epoxide to 3′-Cl-phenylserine 140 times faster than it opened the 4′-Cl-isomer, which was turned over slowest among all epoxides tested. GC/MS analysis of chiral auxiliary derivatives of the biocatalyzed phenylserine analogues showed that the TcPAM-transamination reaction opened the epoxides enantio- A nd diastereoselectively. Each product mixture contained (2S)+(2R)-anti (erythro) and (2S)+(2R)-syn (threo) pairs with the anti-isomers predominating (-90:10 dr). Integrating the vicinal proton signals in the 1H NMR spectrum of the enzyme-catalyzed phenylserines and calculating the chemical shift difference (?"?) between the anti and syn proton signals confirmed the diastereomeric ratios and relative stereochemistries. Application of a (2S)-threonine aldolase from E. coli further established the absolute stereochemistry of the chiral derivatives of the diastereomeric enzymatically derived products. The 2R:2S ratio for the biocatalyzed anti-isomers was highest (88:12) for 3′-NO2-phenylserine and lowest (66:34) for 4′-F-phenylserine. This showed that the stereospecificity of TcPAM is in part directed by the substituent-type on the cinnamate epoxide analogue. The catalyst also converted each cinnamate epoxide analogue to its corresponding isoserine, highlighting a biocatalytic route to arylisoserines, which play a key role in building the pharmacophore seen in anticancer and protease inhibitor drugs.
Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids
Davies, Stephen G.,Fletcher, Ai M.,Greenaway, Catherine J.,Kennedy, Matthew S.,Mayer, Christoph,Roberts, Paul M.,Thomson, James E.
, p. 5049 - 5061 (2018/05/08)
A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.
A new d-threonine aldolase as a promising biocatalyst for highly stereoselective preparation of chiral aromatic β-hydroxy-α-amino acids
Chen, Qijia,Chen, Xi,Cui, Yunfeng,Ren, Jie,Lu, Wei,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
, p. 5964 - 5973 (2017/12/26)
d-Threonine aldolase is an enzyme belonging to the glycine-dependent aldolases, and it catalyzes the reversible aldol reaction of glycine and acetaldehyde to give d-threonine and/or d-allo-threonine. In this study, a putative d-threonine aldolase gene from Delftia sp. RIT313 was cloned and expressed in Escherichia coli BL21 (DE3). The purified enzyme (DrDTA, 47 KDa) exhibited 21.3 U mg-1 activity for the aldol addition of glycine and acetaldehyde in MES-NaOH buffer (pH 6.0) at 50 °C. Both pyridoxal 5′-phosphate and metal ions were needed for the reaction, and the existence of the metal ions enhanced the stability of the enzyme. It was found that the conversion and Cβ-stereoselectivity were dramatically influenced by the reaction temperature, co-solvent, amount of enzyme and reaction time, and it is possible to enable the reaction under kinetic control to retain suitable conversion and high stereoselectivity at the β-carbon, thus tackling the "Cβ-stereoselectivity problem". DrDTA showed high activity toward aromatic aldehydes with electron-withdrawing substituents. Under the optimized reaction conditions, phenylserines with a 2′-fluoro- or 3′-nitro-substituent were obtained with >90% conversion and >90% de. In addition, dl-threo-phenylserine and dl-threo-4-(methylsulfonyl)phenylserine were efficiently resolved with an excellent enantiomeric excess value (ee, >99%) using a whole cell biocatalyst in a two-phase system at 1.0 M and 0.3 M, respectively, the highest substrate concentration reported so far. These results suggested that DrDTA might be a promising biocatalyst for producing chiral aromatic β-hydroxy-α-amino acids.
HOMOCHIRAL HETEROORGANIC ANALOGS OF NATURAL COMPOUNDS. III. BIOCATALYTIC METHOD OF OBTAINING HOMOCHIRAL FLUORINE-CONTAINING (R)- AND (S)-PHENYLALANINES AND (S,R)- AND (R,S)-PHENYLSERINES
Soloshonok, V. A.,Shvyadas, V. K.,Kukhar, V. P.,Galaev, I. Yu.,Kozlova, E. V.,Svistunova, N. Yu.
, p. 236 - 240 (2007/10/02)
A convenient biocatalytic method of obtaining homochiral (S)- and (R)-threo-β-(4-fluorophenyl)serine and -2-, -3-, and 4-fluoro- and -2,3,4,5,6-pentafluorophenylalanines by the enantioselective hydrolysis of their racemic N-phenylacetyl derivatives under the action of Escherichia coli penicillin acylase is proposed.
General Method for the Synthesis of Enantiomerically Pure β-Hydroxy-α-amino Acids, containing Fluorine Atoms in the Side Chains. Case of Stereochemical Distinction between Methyl and Trifluoromethyl Groups. X-Ray Crystal and Molecular Structure of the Nickel(II) Complex of ...
Soloshonok, Vadim A.,Kukhar, Valeri P.,Galushko, Sergei V.,Svistunova, Nataly Yu.,Avilov, Dimitri V.,et al.
, p. 3143 - 3156 (2007/10/02)
The chiral NiII complex 1 of a Schiff's base derived from (S)-o-benzophenone (BPB) and glycine was treated with fluoro-substituted aldehydes (aliphatic and aromatic) in MeOH or CHCl3.The addition proceeds with high diastereoselectivity to give, if catalysed by MeONa in MeOH, the corresponding complexes of syn-(2R)-3-fluorophenylserines (84-100percent) d.e.) and syn-(2S)-fluoroalkylserines (90percent d.e.), and, if catalysed by NEt3 or DABCO (MeOH or CHCl3), the corresponding complexes of syn-(2S)-, and anti-(2S)-3-fluorophenylserines and fluoroalkylserines.The second-order asymmetric transformation may be successfully employed to obtain diastereoisomerically pure complexes of anti-(2R)-3-fluorophenylserines.Condensation of trifluoroacetone with complex 1, catalysed by MeONa, gave predominantly (at least >95percent d.e.) the diastereoisomeric complex, containing (2S,3S)-β-(trifluoromethyl)threonine, as shown by an X-ray diffraction structural study.Diastereoisomerically and enantiomerically pure fluorine-containing 3-phenyl- and 3-alkyl-serines were obtained from the corresponding diastereomerically pure complexes, separated by chromatography or crystallization.The initial chiral auxiliary BPB was recovered (80-98percent).The influence of the reaction's conditions and the nature of the corresponding fluoro-substituted aldehydes on the diastereoselectivity of the reactions is discussed.
ASYMMETRIC SYNTHESIS OF HETEROORGANIC ANALOGS OF NATURAL COMPOUNDS. 3. GENERAL PREPARATIVE METHOD OF DIASTEREO- AND ENANTIOSELECTIVE SYNTHESIS OF FLUORINE-CONTAINING 2(R),3(S)-β-PHENYLSERINES
Soloshonok, V. A.,Kukhar, V. P.,Galushko, S. V.,Kolycheva, M. T.,Rozhenko, A. B.,Belokon, Yu. N.
, p. 1046 - 1054 (2007/10/02)
The diastereo- and enantioselective synthesis of the previously unknown 2(R),3(S)-β-phenylserines containing fluorine atoms, the O-CHF2-, O-CF3-, and CF3 groups in the benzene ring, was carried out by alkylation of a Ni(II) complex of a Schiff base of glycine with (S)-2-N-(N'-benzylprolyl)aminobenzophenone by fluorine-substituted benzaldehydes.The factors influencing the stereochemical result of the reactions studied are not the steric characteristics of the substituents in benzaldehydes, but their electronic nature.
