Amino acids unnatural cyclic

Unusual amino acids include a class of unnatural a-amino acids such as phenylalanine, tyrosine, alanine, tryptophan, and glycine analogs, and f)-amino acid analogs containing 1,2,3,4-tetrahydroisoquinoline, tetraline, l,2,3,4-tetrahydro-2-carboline, cyclopentane, cyclohexane, cyclohexene, bicyclo[2.2.1]heptane or heptene skeletons. Different selectors were exploited for the separation of unusual amino acids, most of the production being made by Peter and coworkers teicoplanin [41, 56, 84, 90, 93, 124, 141-144], ristocetin A [33, 94, 145, 146], and TAG [56, 147]. Enantiomeric and diastereomeric separations of cyclic -substituted a-amino acids were reported by other authors on a teicoplanin CSP [88, 89], Ester and amide derivatives of tryptophan and phenylalanine were recently analyzed on a Me-TAG CSP [58],... 

Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified in Step B, a process such as an alanine scan is used to identify which of the amino acids are important for bioactivity in Step C, individual amino acids have their configuration changed from the naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make the peptide less naturally peptidic ) in Step D, individual amino acids are replaced with atypical unnatural amino acids and amino acid mimics in Step E the peptide is cychzed to constrain it con-formationally finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in an attempt to make a non-peptidic organic molecule.

This process was developed in order to synthesize unnatural a-amino acids. Naturally occurring, enantiomerically pure amino acids, as well as achiral glycine, have been used as starting materials in order to enantioselectively introduce a-substituents1 14. The resulting cyclic esters and amides have been alkylated and subjected to aldol reactions1-14. 

Takeo Kawabata of the Institute for Chemical Research associated with Kyoto University reports (J. Am. Chem. Soc. 125 13012,2003) that unnatural amino acids can also be used to assemble four-, five-, six-, and seven-membered cyclic amines having quaternary stereogenic centers. Given the conventional wisdom that ester enolates are sp -hybridized, this memory effect is remarkable. 

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° (< >) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205... 

While cyclic peptides have proven to be problematic, we beheve that amino acids are ideal candidates for derivatization of our macrocyclic scaffolds. Mary natural and unnatural amino acids with appropriately protected side chains are commercially available or can be readily prepared providing facile access.22 The a-amino- and a-carboxy- groups common to all of these will provide constant sites for attachment to a macrocyclic scaffold core. Side chains varying in aromatic, aliphatic, polar and ionic characters should provide sufficient chemical diversity. Finally, amino acids may be combined in many ways to form short acyclic peptides, allowing access to more diverse chemical properties not found in individual amino acids. 

Boulton, L. T. Stock, H. T. Raphy, J. Horwell, D. C. Generation of unnatural a,a-disubsti-tuted amino acid derivatives from cyclic sulf-amidates./. Chem. Soc. Perkin Trans. 3 1999, 1421-1429. 

Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening. 

Our BNCT research has focused on radiolabeling BP A find on the creation of boron analogues of an unnatural cyclic a-amino acid, 1-aminocydobutanecarboxylic acid (ACBC), as a carrier molecule, Figure 3. This unnatural amino acid is known to be preferentially retained in intracerebral tumors. In fact, carbon-11 labeled ACBC, 3, is used for imaging brain tumors at the University of Tennessee Medical Center.6 Recently, we reported the syntheses of a m-carboranyl containing ACBC derivatives which were lipophilic in nature.7... 

However, some other depsipeptides require additional tools. Many depsipep-tides of natural origin possess complex architectures such a cyclic or a bicyclic skeleton and may include unnatural or N-methylated amino acids in their structure. In these cases, a manual synthesis combined with careful optimization of each step is required. In this regard, syntheses of callipeltin B [171] and oxathio-coraline [172] have recently been described. 

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

A new application of the Schmidt rearrangement is to give unnatural aminoacids <91BMC125>. Treatment of the optically active cyclic -ketoester (266) with hydrazoic acid gives the optically active azepinone (267) which upon selective reduction with diborane furnishes the novel cyclic amino acid ester (268) (Scheme 36). 

A two-step stereoselective strategy for converting glycine-derived aminoesters into unnatural cyclic amino acids has been reported. The process involves a palladium-catalysed tandem allylic amination/[2,3]-Stevens rearrangement followed by a ruthenium-catalysed ring-closing metathesis (Scheme 175). " ... 

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