Cyclopeptides synthesis

Walzel B, Riederer B, Keller U. Mechanism of alkaloid cyclopeptide synthesis in the ergot fungus Claviceps purpurea. Chem Biol 4 223-230, 1997. 

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

Wakselman, M. Mazaleyrat, J.-P. Lin, R. C. Xie, J. Vigier, B. Vilain, A. C. Fesquet, S. Boggetto, N. Reboud-Ravaux, M. Design, synthesis and study of a selective cyclopeptidic mechanism-based inhibitor of human thrombin. In Peptides Chemistry, Structure... 

Zhu and co-workers used S Ar reactions to create the biaryl ether bond in their synthesis of cyclopeptide alkaloids [55-57] (Scheme 5). The electrophile in this case is an aryl fluoride, often additionally activated by an electron-withdrawing group such as a nitro group. The necessity of such an activation auxiliary obviously has a negative impact on general applicability of this method. 

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

A multicomponent reaction/cyclization strategy was employed to synthesize simplified cyclopeptide alkaloid analogues 82. The enamide double bond found in many natural derivatives is missing, but biologically active cyclopeptide alkaloids with a hydrated enamide double bond (like sanjoi-nine G1 [55, 56]) are known. The synthesis is considerably simplified by omitting this unsaturation, obviously not required for biological activity. 

Cristau P, Vors JP, Zhu JP (2006) Rapid synthesis of cyclopeptide alkaloid-like para-cyclophanes by combined use of Ugi-4CR and intramolecular SNAr reaction. Qsar Comb Sci 25 519-526... 

Scheme 11 Synthesis of confonnationally restricted cyclopeptides and cyclic peptidomimetics by the Ugi4CR/RCM strategy...

The Joullie, Zhu, and Wessjohann groups reported the synthesis of different M-alkyl ansa-cyclopeptides and the corresponding ansa-cyclopeptoids. These are inspired by natural cyclopeptide alkaloids. The first approaches to combine the Ugi reaction with a macrocyclization toward cyclopeptide alkaloids was done by Joullie and coworkers [73-75]. 

A rapid synthesis of cyclodepsipeptides containing sugar moieties was reported by Zhu and coworkers (Scheme 20) [88]. A three-component reaction of a sugar amino acid derivative 20a, an aldehyde b, and a dipeptide isocyanide c, followed by saponification and trifluoroacetic acid-promoted macrocyclization was employed to afford the cyclic amino sugar cyclopeptides d. This approach allows to systematically modify the amino acids and the carbohydrate residue, as well as the size of the macrocycle. Again, the only reagents used to mediate the formation of the... 

However, this strategy failed when applied to the synthesis of the cyclopeptide lissoclinamide 7. Here, the serine-derived oxazoline moiety could not be selectively thiolyzed in the presence of the threonine-derived oxazoline in the cyclopeptide 334. " The authors attributed this lack of chemoselectivity to the increased stability and thus reduced reactivity, of the serine-derived oxazoline in the macrocyclic scaffold. AU three oxazoline moieties reacted under the prolonged reaction conditions to give the trithio cyclopeptide 335 (Scheme 8.102). The structure of 335 was confirmed by conversion to the tristhiazoline cyclopeptide 336. 

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. 

Enzymatic Synthesis of Fungal A/-Methylated Cyclopeptides and Depsipeptides... 

This is also a traditional peptide synthesis procedure. Joullie and coworkers [79] used it in the synthesis of the cyclopeptide alkaloid dihydromauritine A (142). As shown in Scheme 47, the linear precursor 140 was treated with p-nitrophenyl trifluoroacetate in pyridine to give the p-nitrophenyl ester. After cleavage of the Boc group, the amino ester was subjected to cyclization in dilute DMF in the presence of hydroxybenztriazole (HOBt) and diisopropylethylamine at 25 °C for 5 days. The cyclic product 141 v/as obtained in 10% yield only. 

Schmidt and coworkers [80] developed the pentafluorophenyl ester method for synthesizing cyclopeptides, particularly applicable for 13- and 14-membered ansa peptides. This procedure is superior to the p-nitrophenyl ester method in respect to short reaction time and easy separation of products. Evans and Ellman [81] applied this method to the synthesis of the cyclic tripeptide K-13 146). As shown in Scheme 48, the reaction of the linear precursor 143 with pentafluorophenol and DCC afforded pentafluorophenyl ester 144 in 87-93% yield. Then, under catalytic hydrogenation condition in the presence of a mild base and ethanol, 144 was cyclized to 145 in up to 70% yield. There are more applications of the pentafluorophenyl ester procedure in recent literature [82]. 

Nonapeptides are constructed using DCC and N-hydroxybenzodiazole, this method is also used in the synthesis of prothimosin o (pro Ta), a polypeptide consisting of 109 amino acids. In the latter reaction the coupling is conducted using DMSO as solvent. Similarly, glycoproteins are synthesized, but in this case piperidine/DMF is used as solvent. " The synthesis of cyclosporin, a cyclopeptide formed from 11 amino acids also uses DCC in the formation of the heptapeptide intermediate. ... 

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