Amino acids nonnatural

Non-proteinogenic amino acids, nonnatural amino acids, amino acids not occurring in natural peptides and proteins. In eukaryotes, the introduction of these amino acid building blocks into proteins cannot be conducted by the natural ribo-somal machinery. However, in prokaryotes biologically active peptides are synthesized by the non-ribosomal peptide synthesis (NRPS). 

A subclass of lyases, involved in amino acid metabolism, utilizes pyridoxal 5-phosphate (PLP, 3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinecarbaldehyde) as a cofactor for imine/ enamine-type activation. These enzymes are not only an alternative to standard fermentation technology, but also offer a potential entry to nonnatural amino acids. Serine hydroxymethyl-tansferase (SHMT EC 2.1.2.1.) combines glycine as the donor with (tetrahydrofolate activated) formaldehyde to L-serine in an economic yield40, but will also accept a range of other aldehydes to provide /i-hydroxy-a-amino acids with a high degree of both absolute and relative stereochemical control in favor of the L-erythro isomers41. 

SYNTHESIS OF N-( -BUTOXYCARBONYL)-P-IODOALANINE METHYL ESTER A USEFUL BUILDING BLOCK IN THE SYNTHESIS OF NONNATURAL a-AMINO ACIDS VIA PALLADIUM CATALYZED CROSS COUPLING REACTIONS... 

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

Reactions of methyl nitroacetate with aldehydes are induced by TiCl4 in pyridine. They afford nitroalkenyl-esters,64 which are used in the preparation of various nonnatural amino acids (Eq. 3.39).65... 

Summary N-Silylation is a crucial prerequisite for the synthesis of interesting nonnatural amino acids via cycloaddition reactions of unsaturated amines. 

Since most synthetic applications require enzymes catalyzing nonnatural substrates, their properties often have to be improved. One way to achieve this is to optimize reaction conditions such as pH, temperature, solvents, additives, etc. [6-9]. Another way is to modulate the substrates without compromising the synthetic efficiency of the overall reaction [10]. In most cases for commercial manufacturing, however, the protein sequences have to be altered to enhance reactivity, stereoselectivity and stability. It was estimated that over 30 commercial enzymes worldwide have been engineered for industrial applications [11]. Precise prediction of which amino acids to mutate is difficult to achieve. Since the mid 1990s, directed evolution... 

May O., Verseck, S., Bommarius, A. and Drauz, K. (2002) Development of dynamic kinetic resolution processes for biocatalytic production of natural and nonnatural L-amino acids. Organic Process Research Development, 6 (4), 452-457. 

Chapter 10 covers reductive enzymes with an emphasis on transaminase enzymes, which are enjoying widespread application in the synthesis of nonnatural amino acids which are key building blocks for several products of industrial importance. 

A number of nonnatural amino acids were resolved into individual enantiomers on 0-9-(2,6-diisopropylphenylcarbamoyl)quinine-based CSPby Peter and coworkers [48,90,113,114] after derivatization with Sanger s reagent, chloroformates (DNZ-Cl, FMOC-Cl, Z-Cl), Boc-anhydride, or acyl chlorides (DNB-Cl, Ac-Cl, Bz-Cl). For example, the four stereoisomers of P-methylphenylalanine, P-methyltyrosine, P-methyltryptophan, and P-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid could be conveniently resolved as various A-derivatives [113]. The applicability spectrum of cinchonan carbamate CSPs comprises also P-amino carboxylic acid derivatives, which were, for example, investigated by Peter et al. [114]. A common trend in terms of elution order of DNP-derivatized P-amino acids was obeyed in the latter study On the utilized quinine carbamate-based CSP, the elution order was S before R for 2-aminobutyric acid, while it was R before S for the 3-amino acids having branched R substituents such as wo-butyl, iec-butyl, tert-butyl, cyclohexyl, or phenyl residues. 

Parmar et al have developed a method for resolving racemic mixtures of a variety of natural and nonnatural amino acids using the ethyl ester of the amino acid protected at the amino position hy the formation of a Schiff base with an aromatic aldehyde such as /)-chlorobenzaldehyde. Both chymotrypsin and Lip such as porcine Lip gave good yields of the L-amino acid which precipitates out of solution as the amino acid ester released from the imine is cleaved by the hydrolase. 

R Synthesis of N-(tert-Butoxycarbonyl)-3-lodoalanine Methyl Ester A Useful Building Block in the Synthesis of Nonnatural a-Amino Acids via Palladium Catalyzed Cross Coupling Reactions. 

Scheme 6.90 Chiral N-benzoyl-protected a-amino acid allyl esters obtained from 64- and 78-catalyzed asymmetric DKR of racemic azlactones derived from racemic natural nonnatural a-amino acids.

Scheme 1. Structures of the native amino acids and their nonnatural a-substituted analogs. a-Trifluoromethyl phenylalanine as well as a-trifluoromethyl alanine have been used as racemic mixtures.

The lipidated a-amino acids (e.g., 2) are nonnatural a-amino acids with long aliphatic side chains covalently attached to the Ca-carbon. 130 The side chains are saturated or unsaturated, and vary in the total number of carbon atoms (8 to 24), as shown with a few examples in Scheme 11. These amino adds possess the peculiar dual nature of amphiphiles,... 

In principle every compound with an amino and a carboxy group can be used for such purpose ranging from simple co-amino acids [e.g., 5-aminopentanoic acid (6-aminovaleric acid) (1, n = 3)]1541 or 6-aminohexanoic acid (e-aminocaproic acid) (1, n = 4)]135,57,4 791 and related derivatives of 3-aminobenzoic acid 14801 or more sophisticated structures. A few examples (1-6) are shown in Scheme 28. Numerous cyclic turn mimetics have been developed in the past years and for details on this subject the reader is directed to Vol. E 22c, Section 12. To explore the rigidification introduced by nonnatural amino acids or equivalent structures into cyclic peptides, a careful NMR conformational analysis is required, since frequently the so-called p-turn mimetics do not enable such turns to be established, conversely other secondary structure elements may be induced.14811... 

The incorporation of these artificial structural elements as well as the subsequent cycliza-tions are generally performed according to standard procedures e.g. in the case of 5-aminopentanoic acid (1, n = 3) and 6-aminohexanoic add (1, n=4) the cyclization proceeds in good yields without particular difficulties. 35 Conversely, real turn mimetics may increase cyclization yields as a result of the anticipated rearrangement of the linear precursors. t28-87-481-482 in most cases, the nonnatural amino adds or equivalent building blocks are used in the synthetic steps in complete analogy to natural amino acids. 

Stabilization of a P-hairpin structure can be achieved in two ways, promoting a stable (or restricted) turn structure (as done with mimetics) or linking the two arms either chemically, or, more naturally, by hydrophobic interactions. In an approach to utilizing both methods, a D-Pro-Gly linkage was used to stabilize a left-handed turn (type I or II ) and various charged and hydrophobic residues were used to stabilize the molecule and enhance the interaction between arms. I252"254 Examples of these peptides studied in nonaqueous solution by IR, VCD and NMR spectroscopy exhibit characteristics of well-formed hairpins. 255 Alternatively, in aqueous solution, IR, VCD, and ECD results for related peptides agree with the NMR interpretation of conformations characterized as hairpins stabilized at the turn and frayed at the ends. 256 These latter results also have a qualitative match with theoretical simulations. Recently, examples of hydrophobically stabilized hairpins studied by NMR spectroscopy have avoided use of a nonnatural amino acid. 257,258 ... 

Consensus IFN (IFN-conl) is a synthetic nonnaturally occurring IFN-a hybrid designed by assigning each of the most frequently observed amino acids in the Hu-IFN-a subtypes. For the most part it is a... 

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