Amino acids stereospecific synthesis

In many cases only the racemic mixtures of a-amino acids can be obtained through chemical synthesis. Therefore, optical resolution (42) is indispensable to get the optically active L- or D-forms in the production of expensive or uncommon amino acids. The optical resolution of amino acids can be done in two general ways physical or chemical methods which apply the stereospecific properties of amino acids, and biological or enzymatic methods which are based on the characteristic behavior of amino acids in living cells in the presence of enzymes. 

Asano et al. have developed an approach for the synthesis of D-amino acids through DKR using a two-enzyme system [55]. They had previously reported the discovery of new D-stereospecific hydrolases that can be applied to KR of racemic amino acid amides to yield D-amino acids. Combination of a D-stereospedfic hydrolase with an amino acid amide racemase allows performing DKR of i-amino acid amides yielding enantiomerically pure D-amino acids in excellent yields (Figure 4.29). 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

Another example of the ability of proteinogenic amino acids, small peptides, and amines to catalyse the formation of new C-C bonds has been demonstrated by Weber and Pizzarello they were able to carry out model reactions for the stereospecific synthesis of sugars (tetroses) using homochiral L-dipeptides. The authors achieved a D-enantiomeric excess (ee) of more than 80% using L-Val-L-Val as the peptide catalyst in sugar synthesis (in particular D-erythrose) via self-condensation of glycol aldehyde. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Virtually all biological reactions are stereospecific. This generalization applies not only to the enzyme-catalyzed reactions of intermediary metabolism, but also to the processes of nucleic acid synthesis and to the process of translation, in which the amino acids are linked in specific sequence to form the peptide chains of the enzymes. This review will be restricted mainly to some of the more elementary aspects of the stereospecificity of enzyme reactions, particularly to those features of chirality which have been worked out with the help of isotopes. 

The carba-analogue of Plm-Dhc(Plm)2-OH was also synthesized. 95100 The four possible diastereoisomers were all obtained by stereospecific synthesis via the construction of didehydro-amino acids using the phosphonoglycinate method and subsequent enantio- or diastereoselective hydrogenation. 

K. Yonaha u. K. Soda, Ad v. Biochem. Eng./Biotcchnol. 33,95 -130 (1986) . .Applications of Stereoselectivity of Enzymes Synthesis of Optically Active Amino Acids and a-Hydroxy Adds and Stereospecific Isotope Labeling of Amino Acids, Amines, and Coenzymes". 

A very interesting modification of method B was applied to the stereospecific synthesis of ( )-pseudoheliotridane.27 Condensation of ethyl bromoacetate with l-methyl-2-ethyl-4,5-dihydropyrrole (42) afforded the quaternary salt 43, which was reduced, without isolation, with formic acid to give ethyl /3-(Ar-methyl-2-pyrrolidyl)butyrate (44). The amino alcohol (45), obtained by reduction of 44 with lithium... 

The optically active N-aminoindoline (265) has been applied to the asymmetric synthesis of a variety of a-amino acids (70JA2476, 2488). Starting from TV-benzoyl-1,2,3,4-tetrahy-droquinaldine (257), the chloro amide (258) was prepared by von Braun cleavage. Thermolysis converted (258) to the rrans-unsaturated amide (259) which was epoxidized. On base treatment the epoxide (260) underwent intramolecular nucleophilic displacement and amide hydrolysis to afford indoline (261) stereospecifically. Resolution of (261) was accomplished via the brucine salt of the N-o-carboxybenzoyl derivative (262). Alkaline hydrolysis, N-nitrosation and reduction yielded the levorotatory 1-aminoindoline (265). Reaction of... 

A less common approach to the synthesis of phosphinates is the reaction of electrophilic phosphonates with carbon nucleophiles such as Grignard reagents or lithium enolates. For example, the phosphinic acid analogue 71 of the amino acid statine was synthesized by displacement of tert-butyl lithioacetate on a 5-phenyl phosphonothioate 70 (Scheme 23)d104l The racemic diastereomers of the 5-phenyl phosphonothioate were obtained in pure form, and the displacement of the phenylsulfanyl moiety was found to be stereospecific, although the stereocenter at phosphorus would later be lost on hydrolysis of the ester. A similar displacement reaction has been described using the p h osp h on och I ori d ate.1711... 

Stereospecific synthesis of succinyl derivatives is now commonly carried out as shown in Scheme 7. The tert-butyl ester of the succinyl amino acid methylamides 16 was treated with TFA to deprotect the carboxy group, which was then activated by isobutyl chloroformate and reacted with H2NOTMS.[18] The OTMS protection was removed during the isolation and purification of the hydroxamic acid 17. 

Since the stereochemical changes in each reaction of the sequence are known, a particular amino acid starting material (R or S) will give a particular configuration in the product. In this strategy of asymmetric synthesis, all or part of die final molecular skeleton is derived from the chiral precursor. While simple, diis strategy is limited by the size of the chiral pool and by the types of reactions which occur stereospecifically at tetrahedral centers. 

The alternative approach to the determination of the stereochemistry of hydroxylation )3 to the nitrogen occurring in the biosynthesis of haemanthamine involved the synthesis of stereospecifically labeled tyrosine. Catalytic hydrogenation of suitable acylaminocinnamic acids labeled with isotopic hydrogen in fi position proceeds stereoselectively to furnish an equimolecular mixture of L-(/3i -3H]-and D-[j8 -3H]tyrosine (419) and (420). Enzymic resolution of the racemic amino acid yielded the L and d isomers. The two optically active forms of tyrosine were... 

Katagiri, T. Uneyama, K. Stereospecific substitution at a-carbon to trifluoromethyl group application to optically active fluorinated amino acid synthesis. Chirality 2003, 35, 4-9. 

As a whole, such high stereospecificity is difficult to attain by chemical catalysis, although asymmetric synthesis has developed markedly in recent years.80) Stereospecificity has been applied to the production of optically active compounds such as amino acids, and also to the synthesis of stereospecifically isotope-labeled compounds, the synthesis of which is not easily achieved by a chemical method (Table I. 3).75)... 

A stereospecific synthesis of (S)-(—)-cathinone that utilizes the Friedel-Crafts reaction has been described (3/7). Reaction of the acid chloride obtained from /V-(methoxycarbonyl)-L-alanine (10) in benzene by A1C13 catalysis provided the N-protected a-amino ketone 11 with retention of chiralty 11 was deprotected by hydrolysis with potassium hydroxide. A more recently published method (408)... 

Finally, a pyridoxal transamination converts the two keto-acids stereospecifically to the corresponding amino acids, valine (R = Me) and isoleucine (R = Et). The donor amino acid is probably glutamate—-it usually is in amino acid synthesis. 

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