Amino acids optically active centers

Asymmetric Peptide Synthesis. The reagent activates amino acids through 1,3-Dicyclohexylcarbodiimide (DCC) coupling to the N-hydroximide for subsequent coupling with chiral amino acids. The asymmetric center induces preferential reaction with L-amino acids and high optical purities of L-L-dipeptides can be achieved (eq 2). Enantioselectivity is improved if the 5-methyl group is replaced by isobutyl. ... 

Among the amino acids, threonine, hydroxylysine, cystine, isoleucine, the two hydroxyprolines, and others possess two optically active centers. Therefore, the synthetic compounds are mixtures of four diastereoisomers the l- and d- forms, and the L-allo- and D-allo- forms, respectively. For example, threonine can have these four forms L-threonine (XLI), D-threonine (XLII), L-allothreonine (XLIII), and D-allothreonine (XLIV). 

The asterisk signifies an asymmetric carbon. AH of the amino acids, except glycine, have two optically active isomers designated D- or L-. Isoleucine and threonine also have centers of asymmetry at their P-carbon atoms (1,10). Protein amino acids are of the L-a-form (1,10) as illustrated in Table 1. 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

The naturally occurring form of the amino acid cysteine (Problem 9.48) has the S configuration at its chirality center. On treatment with a mild oxidizing agent, two cysteines join to give cystine, a disulfide. Assuming that the chirality center is not affected by the reaction, is cystine optically active ... 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

Serine hydroxymethyl transferase catalyzes the decarboxylation reaction of a-amino-a-methylmalonic acid to give (J )-a-aminopropionic acid with retention of configuration [1]. The reaction of methylmalonyl-CoA catalyzed by malonyl-coenzyme A decarboxylase also proceeds with perfect retention of configuration, but the notation of the absolute configuration is reversed in accordance with the CIP-priority rule [2]. Of course, water is a good proton source and, if it comes in contact with these reactants, the product of decarboxylation should be a one-to-one mixture of the two enantiomers. Thus, the stereoselectivity of the reaction indicates that the reaction environment is highly hydro-phobic, so that no free water molecule attacks the intermediate. Even if some water molecules are present in the active site of the enzyme, they are entirely under the control of the enzyme. If this type of reaction can be realized using synthetic substrates, a new method will be developed for the preparation of optically active carboxylic acids that have a chiral center at the a-position. 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

Takemoto and his co-workers developed asymmetric allylic alkylation of allylic phosphates with (diphenyl-iminolglycinates as carbon-centered nucleophiles (Equation (56))/" " In this reaction system, use of optically active bidentate phosphites 142 bearing an (ethylthio)ethyl group as chiral ligands promotes the allylic alkylation, and chiral /3-substituted a-amino acids are obtained with an excellent enantioslectivity. 

For the synthesis of optically active sugars, a number of natural compounds has been successfully employed. The rather obvious prerequisite of such syntheses is the retention of configuration of chiral centers during all operations that are involved in conversion of the substrate into the desired sugar. Some readily available, natural products as, for the example, tartaric and amino acids have particularly often been used for that purpose. 

The a-carbon of each amino acid is attached to four different chemi cal groups and is, therefore, a chiral or optically active carbon atom. Glycine is the exception because its a-carbon has two hydro gen substituents and, therefore, is optically inactive. [Note Amino acids that have an asymmetric center at the a-carbon can exist in two forms, designated D and L, that are mirror images of each other (Figure 1.8). The two forms in each pair are termed stereoisomers, optical isomers, or enantiomers.] All amino acids found in proteins are of the L-configuration. However, D-amino acids are found in some antibiotics and in bacterial cell walls. (See p. 250 for a discus sion of D-amino acid metabolism.)... 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

Once an organism dies and its biochemicals are released into the environment, their chiral purity (and optical activity) may or may not persist depending on the relative chemical stability of the bonds in the vicinity of the chiral center. Various natural chemical processes can lead to racemization, the formation of mixtures of the two enantiomers. While racemization may result in loss or corruption of a biological signature, the rate at which it happens can also have a practical application. The best known example is the dating of fossil organic matter on the basis of the degree of amino acid racemization. 

All proteins are composed of amino acids linked into a linear sequence by peptide bonds between the amino group of one amino acid and the carboxyl group of the preceding amino acid. The amino acids found in proteins are all a-amino acids i.e., the amino and carboxyl groups are both attached to the same carbon atom (the a-carbon atom Fig. 3-1). The a-carbon atom is a potential chiral center, and except when the —R group (or side chain) is H, amino acids display optical activity. All amino acids found in proteins are of the l configuration, as indicated in Fig. 3-1. 

The synthesis of amino acid esters can be carried out enantioselectively when optically active EBTHI zirconaaziridines are used. After diastereomeric zir-conaaziridines are generated and allowed to equilibrate (recall Scheme 3), the stereochemistry of the chiral carbon center in the insertion product is determined by competition between the rate constants kSSR and ksss for the epimerization of zirconaaziridine diastereomers and the rate constants [EC] and ks[EC] for ethylene carbonate (EC) insertion (Eq. 31) [43]. When kR[EC] and ks[EC] are much greater than kSSR and ksss> the product ratio reflects the equilibrium ratio as shown in Eq. 32. However, the opposite limit, where epimerization is much faster than insertion, is a Curtin-Hammett kinetic situation [65] where the product ratio is given by Eq. 33. 

R,R-diphenyl ethylene carbonate CR,R-DPEC)) with a racemic zirconaaziridine. (C2-symmetric, cyclic carbonates are attractive as optically active synthons for C02 because optically active diols are readily available through Sharpless asymmetric dihydroxylations [67].) Reaction through diastereomeric transition states affords the two diastereomers of the spirocyclic insertion product protonolysis and Zr-mediated transesterification in methanol yield a-amino acid esters. As above, the stereochemistry of the new chiral center is determined by the competition between the rate of interconversion of the zirconaaziridine enantiomers and the rate of insertion of the carbonate. As the ratio of zirconaaziridine enantiomers (S)-2/(R)-2 is initially 1 1, a kinetic quench of their equilibrium will result in no selectivity (see Eq. 32). Maximum diastereoselec-tivity (and, therefore, maximum enantioselectivity for the preparation of the... 

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