Peptides asymmetric synthesis

There is increasing evidence13,7-191 demonstrating the important impact on bioactivity that (3-methylphenylalanines can have when incorporated into bioactive peptides. Asymmetric synthesis of these compounds with well-established chemistry and economic starting materials has become well developed. Among the reported syntheses, the chiral auxiliary assisted asymmetric pathway120-221 remains the most well-developed approach, while other pathways have only been briefly explored, because either too many steps were involved1231 or poor stereoselectivity was obtained.1241... 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

It is more difficult to prepare a chiral a,a-dialkylammo acid. Nevertheless, when such analogues are incorporated into the backbone of a peptide chain, analogues with modified properties are obtained. In this context, such residues have been evaluated as a new type of conformational constraint for the synthesis of enzyme-resistant agonists and antagonists of bioactive peptides. Here, the asymmetric synthesis or the resolution of the chiral quaternary amino acid is necessary and numerous procedures, which have recently been reviewed, were developed to produce the requisite amino acids in enantiomerically pure form. 

On the other hand, as synthetic equivalents of amino acids, unsaturated oxazolones are and will continue to be very important intermediates for the synthesis of new non-proteinogenic a-amino acids, particularly for the asymmetric synthesis of these compounds using diastereo- or enantioselective methodologies. In addition, the exocyclic double bond will continue as an important focus to build new constrained amino acids for the design of peptides with improved properties. 

Recent developments regarding the utility of chiral amino acids in asymmetric synthesis of natural products were reported. Examples of such syntheses are the preparation of carbohydrates from (S)-glutamic acid 257), (S)-alanine 258), or (S)-threonine 259), and syntheses of alkaloids 260), terpenes 26I), peptide 262) derivatives, and toxines 263>. 

The asymmetric synthesis of conformationally constrained a-amino acids and their incorporation into peptides are currently topics of great interest [47]. Much sought after are fused bicyclic a-amino acids having the N atom incorporated into a ring system [48]. Many of these amino acids display interesting pharmacological activities, and they have served as building blocks for the synthesis of pep-... 

The similarly constrained four isomers of 3,2, 6 -trimethylphenylalanine 33 have been prepared by asymmetric synthesis and incorporated into bioactive peptides. 39,401... 

C-H Insertion a to nitrogen is a useful process because it represents a direct method for the asymmetric synthesis of (3-amino esters. An especially attractive example of this is the reaction with N-Boc-protected amine 29 [26], Even though electronically functionalization at the benzylic position would be highly favored, this position is sterically too crowded and the reaction occurs cleanly at the N-methyl site. The resulting p-amino ester 30, formed in 96% ee, represents a potentially useful precursor to novel p-peptides. 

More recently, a Ti-TADDOLate catalyst was found useful for a similar asymmetric transformation, and this reaction has been successfully applied to the asymmetric synthesis of the potent, non-peptidic, NKl-selective, substance P antagonist RPR 107880 [59] (Eq. 8A.35). 

Small peptides - simple di- and tri-peptides with a primary amine at the N-terminus -catalyse the aqueous aldol between unmodified ketones and aldehydes with up to 86% ee.121 This is dramatically different from the corresponding amino acid-catalysed reaction, suggesting that peptide formation may have been significant in the evolution of asymmetric synthesis. Addition of a-cyclodextrin raised the ee further through the hydrophobic effect. 

Simple Amino Acids and Short-chain Peptides as Efficient Metal-free Catalysts in Asymmetric Synthesis... 

Asymmetric Synthesis Using Short-chain Peptide Catalysts 1183... 

Because of its bulky, inflexible, and hydrophobic side chain, terf-leucine (2-amino-3,3-dimethylbutanoic acid, Tie) is an important amino acid used as template or catalyst compound in asymmetric synthesis and in peptidic medicinal compounds. L-Tle has attracted much attention as a key component of newly emerged drugs or as building block of ligands, catalysts, and auxiliaries for asymmetric synthesis. It is synthesized in ton-scale by reductive amination of trimethylpyruvic acid by means of LeuDH from Bacillus stearothermophilus with very high yield and excellent optical purity [153]. NADH, which is consumed during the reaction, can be regenerated by FDH from C. boidinii (Fig. 35). 

Enantiomerically pure non-proteinogenic amino acids have attracted recent attention due to their antibiotic [1], antifungal [2], cytotoxic [3], and other important pharmacological properties [4]. Frequently, they also occur incorporated in natural products, such as peptides, depsipeptides, and other macrocyclic compounds. Other important applications are to serve as building blocks in asymmetric synthesis. A specifically prominent class of them are cyclic 3- and y-amino acids, the subject to which the present chapter is dedicated. 

Amino acids, peptides, and proteins Asymmetric synthesis and induction Beta-lactam antibiotics Carbohydrates (chemical aspects) Natural product synthesis New antibiotics... 

Enantiomerically pure 2-azetidinones are applied to the asymmetric synthesis of nonracemic 2-piperidones. This is a novel application of 2-azetidinones <03T6445>. Because 2-azetidinones are valued as antibacterials and chiral building blocks for amino acids, peptides and 2-pyrrolidinones, they are readily accessible for application to this transformation. 

General Considerations. In addition to its use in peptide chemistry, (S)-proline is often applied as a chiral precursor in the total syntheses of natural products, e.g. odorin, pumiliotoxin, petasinecine," or threonine. Some highly effective pharmaceuticals, such as optically pure ACE inhibitors, are prepared from L-proline. In the last two decades, (S)-proline has attracted much attention as an optically active auxiliary in asymmetric synthesis. 

Biomolecules, Asymmetric Synthesis of Biomolecules, Enzymatic Synthesis of Chemical Ligation Peptide Synthesis Organic Chemistry in Biology Peptide Combinatorial Synthesis Peptide Synthesis... 

Townsend, C. A., Nguyen, L. T. Improved asymmetric synthesis of (-)-3-aminonocardicinic acid and further observations of the Mitsunobu reaction for -lactam formation in seryl peptides. Tetrahedron Lett. 1982, 23,4859-4862. 

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