Solid-phase synthesis cyclic peptides

Abstract The utility of native chemical UgatiOTi (NCL) in the solution or solid phase synthesis of peptides, cyclic peptides, glycopeptides, and neoglycoconjugates is reviewed. In addition, the mechanistic details of inter- or intra-molecular NCLs are discussed from experimental and computational points of view. 

Dipyridyl disulfide and related compounds have also been used as a method for macrolide formation the addition of thio-philic metal cations and/or pyridine derivatives has been found to assist this process. This oxidation-reduction condensation, using 2,2 -dipyridyl disulfide, constitutes an excellent strategy for the solid-phase synthesis of peptides. This method does not affect amino acids sensitive to oxidation, proceeds under mild conditions without the requirement of basic or acid catalysts, and has the advantages of minimizing both racemization of carboxyl component and side-reactions of certain amino acids. Furthermore, it has been successfully applied to phosphorylation reactions, such as the synthesis of coenzyme A, oligothymidilates, and nucleotide cyclic phosphates, and nucleotides from G ,2 -cyclouridine. ... 

Enantioselective ring opening of epoxides was attained with (salen)Cr(III) complex (191) [68]. Cyclopentene derivatives (190) were converted with Me3SiN3 to azide-alcohols (192) in 80-90% yields up to 98% ee (Scheme 16.56). Kinetic resolution of racemic styrene oxide was performed in 98% ee. This reaction was applied to practical synthesis of enantiopure cyclic 1,2-aminoalcohols by reduction of the azide products by Pt02-catalyzed hydrogenation [69], to synthesis of cyclopentenone derivatives [70] to formal synthesis of bioactive compound Balanol [71], and to solid-phase synthesis of peptides [72]. 

Jensen KJ, Alsina J, Songster MF, Vagner J, Albericio F, Barany G. Backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal-modified and cyclic peptides. J Am Chem Soc 1998 120 5441— 5452. 

Alsina J, Chiva C, Ortiz M, Rabanal F. Active carbonate resins for solid-phase synthesis through the anchoring of a hydroxyl function. Synthesis of cyclic and alcohol peptides. Tetrahedron Lett 1997 38 883-886 and references cited therein. 

Annis, D. A. Helluin, 0. Jacobsen, E. N. (1998) Stereochemistry as a diversity element solid-phase synthesis of cyclic RGD peptide derivatives via asymmetric Catalysis., Chem., Int. Ed. Engl, 37, 1907-1909. 

The synthesis of amino acids in which a nonfunctionalized alkyl group is covalently connected to the a-nitrogen has been discussed vide supra). In this section the synthesis of N-substituted amino acids in which the alkyl chain bears a protected functional group is discussed. The resulting amino acids have the general formula /Va-(m-functionalized alkyl) amino acids 28 (Scheme 17). These amino acids were developed for the solid-phase synthesis of backbone cyclic peptides 70 (see also Vol. E 22b, Section 6.8.3.2.4) [in this case they were called building units (BU)], for the synthesis of PNA 71 and for the synthesis of peptoids. 72 (In this case they were called monomers.)... 

Other known oligonucleotide analogs include oligomers in which the heterocyclic bases have been modified [155] or replaced by other types of compound [156], Solid-phase syntheses of hybrids of DNA with peptides [157-163], with carbohydrates [164,165], and with PNA (peptide nucleic acids, see Section 16.4.1.2 [166-168]) have also been reported, and several strategies have been developed that enable the preparation of oligonucleotides with a modified 5 - or 3 -terminus [169-174] or of cyclic oligonucleotides [122,175], Various techniques for the parallel solid-phase synthesis of oligonucleotides have been developed for the preparation of compound libraries [176-181],... 

In the studies described below cyclic head-to-tail peptides were synthesized by standard solid-phase synthesis utilizing Boc chemistry 27 All syntheses were carried out with Boc-Pro-phenylacetamidomethyl resin. The use of Pro as the C-terminus residue was required so as to prevent racemization during the cyclization reaction (see Section 13.3.1.1). 

In this method, the cysteine-thioester cyclization generates a cyclic peptide 86a (see Scheme 23) with a Xaa-Cys bond whose thiol moiety is then used for tethering to the core through an S-alkylation reaction.191 The requirement for the cyclization reaction is a linear precursor 84 containing both an N-terminal Cys and a C-terminal thioester. Such a peptide precursor can be conveniently synthesized by a stepwise solid-phase synthesis on a thioester resin 81 using Boc chemistry (Scheme 22). Cleavage by HF after assembly of the peptide sequence will produce the desired precursor with an N-terminal Cys and a C-terminal thioester 84. The crude peptide is then purified by RP-HPLC and the purified unprotected peptide is then circularized in aqueous conditions buffered at pH > 7.0. 

Scheme 26. Solid-phase synthesis of cyclic peptides using hydroxyproline as a linking site.

Blackburn, C., and Kates, S. A. (1997) Solid-phase synthesis of cyclic homodetic peptides. Methods Enzymol. 289,175-198. 

Nefzi A, Ostresh JM, Meyer JP, Houghten RA, Solid phase synthesis of heterocyclic compounds from linear peptides cyclic ureas and thioureas, Tetrahedron Lett., 38 931-934, 1997. 

Kates, S. A., Sole, N. A., Johnson, C. R., Hudson, D., Barany, G., and Albericio, F. (1993) A novel, convenient, three-dimensional orthogonal strategy for solid-phase synthesis of cyclic peptides. Tetrahedron Lett. 34, 1549-1552. 

Tromelin, A., Fulachier, M.-H., Mourier, G., and Menez, A. (1992) Solid-phase synthesis of a cyclic peptide derived from a curaremimetic toxin. Tetrahedron Lett. 33, 5197-5200. 

Spatola, A. F., Darlak, K., and Romanovskis, P. (1996) An approach to cyclic peptide libraries reducing epimerization in medium sized rings during solid-phase synthesis. Tetrahedron Lett, yi, 591-594. 

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