Cyclopeptides functionalized

SCHEME 11.4 Postulated mechanism for inactivation of DPP IV by a functionalized cyclopeptide 11.32... 

Wakselman, M. Xie, J. Mazaleyrat, J.-P. Boggetto, N. Vilain, A. C. Montagne, J.-J. Reboud-Ravaux, M. New mechanism-based inactivators of trypsin-like proteinases. Selective inactivation of urokinase by functionalized cyclopeptides incorporating a sulfoniomethyl-substituted mera-aminobenzoic acid residue. J. Med. Chem. 1993, 36, 1539-1547. 

The synthesis of jS-hydoxy-a-amino acids is important since these compounds are incorporated into the backbone of a wide range of antibiotics and cyclopeptides such as vancomycins. These highly functional compounds are also subject to dynamic kinetic resolution (DKR) processes, as the stereocenter already present in the substrate epimerizes under the reaction conditions and hence total conversions into single enantiomers are possible. These transformations can be iy -selective ° for N-protected derivatives as shown in Figure 1.27 when using a mthenium-BlNAP catalyzed system and anfi-selective when the jS-keto-a-amino acid hydrochloride salts are reduced by the iridium-MeOBlPHEP catalyst as shown in Figure 1.28. One drawback is that both these reductions use 100 atm hydrogen pressure. 

In summary, our approach of using cyclopeptides with natural amino acids and 3-aminobenzoic acid subunits for the development of macrocydic receptors has afforded remarkably efficient hosts. The cation affinity of 4b, for example, exceeds that of many calixarene derivatives. Even more interesting is the high anion affinity of 5 in aqueous solution. By introdudng additional functional groups such as car-boxylates to the periphery of the cavity, we recently also obtained cydopeptides that interact with neutral substrates, for example, carbohydrates [25]. Our peptides therefore represent a versatile dass of artificial receptor that should prove useful in supramolecular and bioorganic chemistry. 

Cyclopeptide alkaloids are prepared in good yield by catalytic hydrogenation of pentafluorophenyl esters of (o-(Z)-aminocarbocyxlic acids. The slow release of the amino function under these conditions minimizes dimerization. ... 

A novel steroidal cyclopeptide (Figure 38) has been synthesized by Albert and Feigel from a steroidal amino acid [55]. Since a variety of amino acids can be incorporated into the macrocycle, this strategy offers attractive possibilities for the construction of functionalized macrocycles for catalyst design. 

In this section, we wish to discuss the results of recent studies on cyclopeptides carried out by our group [97-99]. Cyclopeptides as molecular receptors have been immobilized on different sensor surfaces, and can be prepared in high diversity by parallel solid-phase peptide synthesis (SPPS) [100], However, functional groups for the attachment to the surface must be available. On the other hand, the interaction with the analyte should be as specific as possible, and for this reason appropriate side chains must be selected. 

The phthalimide functional group has absorption and ET properties which make it very attractive in terms of PET processes in which it is the oxidizing species. The application of phthalimide derivatives in carbon-carbon bond forming processes with electron-donating groups such as ethers, thioethers, amines, arenes, carboxylates, etc., has been reviewed. A PET decarboxylation-cycliz-ation sequence has been used for the synthesis of medium-sized (8-16) heterocyclic ring systems (15) from AT-phthaloylanthranilic amides coupled to ca-aminoacids (14). The same PET protocol has been used to convert di-, tri-, and tetrapeptides into cyclopeptides with a minimum of protection and activation... 

Taunton and co-workers have reported a one-step racemization free organolithium-mediated diversification of peptide thiazoles. A mild procedure for the C5 lithiation of 2,4-disubstituted thiazoles has been described in this report, and an example is shown below. The method is compatible with A-Boc, A-trityl, carboxylic ester, and carboxamide protecting groups and has been used to functionalize directly the thiazole ring of cyclopeptide natural products. 

We will turn our attention toward the synthesis of macrocyclic lactones, macrocyclic lactams, cyclopeptides, and macrocarbocycles, which are abundant in nature. Retrosynthetic cleavage of the lactone function, lactam function, and cycloalkanes provides an co-hydroxy-acid, an oo-amino-acid, and an open-chain hydrocarbon deriv-... 

The total synthesis of (— )-nummularine-F (163), a 4(14)-amphibine-F-type cyclopeptide alkaloid, from D-serine was accomplished in 25 steps and an overall yield of 0.48%. This approach includes a stereoselective synthesis of a cw-2-(hydroxymethyl)-3-pyrrolidinol derivative, the inversion of the cjs-3-hydroxyl function to the desired... 

Besides the peptide C=0 and NH groups along the ring, many cyclopeptides contain functional groups in the amino acid side chains that are also available for substrate binding, hnanishi et al. showed, for example, that... 

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