Synthesis of novel cyclopeptides containing heterocyclic skeletons

Abstract

Cyclopeptides can be considered as naturally biologically active compounds. Over the last several decades, many attempts have been made to synthesize complex naturally occurring cyclopeptides, and great progress has been achieved to advance the field of total synthesis. Moreover, cyclopeptides containing heterocyclic skeletons have been recently developed into powerful reactions and approaches. This review aims to highlight recent advances in the synthesis of cyclopeptides containing heterocyclic skeletons such as triazole, oxazole, thiazole, and tetrazole.

Fig. 1. Structures of some synthetic cyclopeptides.

Scheme 1. Synthesis of 1,4- and 1,5-disubstituted 1,2,3-triazoles by heat, CuAAc, and RuAAC.

Scheme 2. Schematic examples of the synthesis of triazole peptides.

Scheme 3. Azide-alkyne cycloadditions in the synthesis of peptide macrocycles. (a) A click-mediated macrocyclization of Tyr-Pro-Val-Pro. (b) Synthesis of a cyclic peptide nanotube through either a high-yielding tandem dimerization-macrocyclization approach by two tandem click reactions of an azido-dipeptide alkyne (top) or through a less efficient conventional macrolactamization approach (bottom). (c) The synthesis of triazole-modified analogues of the cyclic tetrapeptide apicidin. Top: ruthenium-catalyzed formation of a 1,5-disubstituted 1,2,3-triazole on a solid phase is followed by macrolactamization to yield an analogue resembling the biologically active conformation of apicidin. Bottom: a Cu(i)-catalyzed intramolecular azide–alkyne cycloaddition to yield an analogue of apicidin resembling its predominant conformation in solution.

Scheme 4. Synthesis of a cyclic tetrapeptide analogue containing a 1,5-disubstituted 1,2,3-triazole through intramolecular cyclative cleavage of a solid-support-bound azidopeptidylphosphorane. HATU, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; NMP, N-methyl-2-pyrrolidone; TBTA, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl] amine.

Scheme 5. Application of click chemistry to the macrocyclization of peptidomimetics and the synthesis of cyclopeptides containing triazole skeletons.

Fig. 2. Examples of cyclopeptides and their triazolo-analogues synthesized by Bock.

Fig. 3. Examples of a cyclopeptide and its triazolo-analogue synthesized by Davis and co-workers.

Fig. 4. Examples of a cyclopeptide and a triazole-containing peptide synthesized by Horne and co-workers.

Fig. 5. Examples of a cyclopeptide and a triazole-containing peptide synthesized by Liu and co-workers.

Fig. 6. Examples of a cyclopeptide and a triazole-containing peptide synthesized by Tischler and co-workers.

Scheme 6. Application of click chemistry to the macrocyclization of peptidomimetics.

Scheme 7. Preparation of cyclodimeric peptides using click chemistry.

Scheme 8. Application of click chemistry to construct triazole bridges in peptides.

Scheme 9. Strategies employed in the solid-phase synthesis of N^αAc-[Xaa¹³(&¹), Yaa¹⁷(&²)] hPTHrP (11–19)NH₂]-[(&¹(CH₂)4-1,4-[1,2,3]triazolyl-CH₂&²)]^a. The & sign indicates the positions of the side-chain-to-side-chain cyclization.^a Pathway A: stepwise assembly of the fully protected resin-bound peptide in which the ε-NH₂ groups of the two lysine residues are differently protected to allow selective deprotection and subsequent diazo-transfer reaction in the on-resin transformation of Lys into Nle (ε-N₃). Pathway B: stepwise on-resin assembly of the fully protected peptide 59 incorporating Fmoc-Nle (ε-N₃)–OH as a building block. Cleavage and deprotection of 59 obtained by either pathway generated the linear precursor 61, which was then cyclized by CuI-catalyzed azide-alkyne 1,3-dipolar cycloaddition to yield the cyclic (1,2,3) triazolyl-containing peptide 62.

Scheme 10. Sequential Ugi ligation/Huisgen 1,3-dipolar reactions to construct cyclopeptides containing triazole moieties.

Scheme 11. Sequential Ugi ligation/Huisgen 1,3-dipolar reactions to construct cyclopeptides containing triazole moieties.

Fig. 7. Lissoclinum cyclopeptides and their imidazole analogues.

Scheme 12. Synthesis of cyclopeptides 86a–c and 87a–c containing imidazole moieties. Reagents and conditions: (i) isobutyl chloroformate, NMM, THF, −20 °C, 85%; (ii) MeNH₂, AcOH, xylenes, reflux, 70%; (iii) 2 M NaOH, MeOH/dioxane, rt, 95%; (iv) HCl/AcOEt, rt, quant.; (v) DPPA, iPr₂NEt, CH₃CN, rt, 25% to 35% for 86a–c, 5% to 10% for 87a, 87b.

Scheme 13. Synthesis of cyclopeptide 87a containing imidazole moieties. Reagents and conditions: (i) HCl/AcOEt, rt, quant.; (ii) 2 M NaOH, MeOH/dioxane, rt, 95%; (iii) DPPA, iPr₂NEt, CH₃CN, rt, 70%; (iv) 2 M NaOH, MeOH/dioxane, rt, 95%; (v) HCl/AcOEt, rt, quant.; (vi) FDPP, iPr₂NEt, CH₃CN, rt, 40%.

Scheme 14. Synthetic strategy for the macrocycle synthesis.

Scheme 15. Cyclization of histidine-containing peptides.

Scheme 16. Synthesis of receptor 109. Reagents and conditions: (i) FDPP, iPr₂NEt, CH₃CN, r.t., 41%; (ii) 2N NaOH, MeOH/dioxane, 0 °C → rt, quant.; (iii) TFA, CH₂Cl₂, 0 °C → rt, quant.; (iv) FDPP, iPr₂NEt, CH₃CN, rt, 52%.

Scheme 17. Synthesis of indole-imidazole linkage cyclic peptidomimetics by an oxidative coupling reaction.

Fig. 8. Left: dipeptide with a cis amide bond. Right: Dipeptide with a cis amide bond replaced by the tetrazole surrogate (Ψ[CN₄]). In this study, R′ = benzyl and R′′ = methyl.

Scheme 18. A synthetic strategy for Trunkamide A.

Scheme 19. Synthesis of the cyclopeptide Trunkamide A. Reagents: (i) Cd : Pb, 1 M NH₄OAc : THF (1 : 1), 98%; (ii) TBAH, THF, 0 °C; (iii) DPPA, DIPEA, DMF, 35% (two steps); (iv) DAST, CH₂Cl₂; (v) H₂S, Et₃N, MeOH.

Scheme 20. Synthesis of nostocyclamide.

Scheme 21. Synthesis of nostocyclamide and related cyclic peptides by metal-templated assembly.

Scheme 22. Synthesis of dendroamide A.

Scheme 23. Synthesis of the cyclopeptide promothiocin A.

Scheme 24. Synthesis of the cyclopeptide telomestatin.

Scheme 25. Synthesis of the cyclopeptide YM-216391.

Scheme 26. Structure of diazonamide A and general retrosynthetic analysis.

Scheme 27. Synthesis of ulongamide A.

Scheme 28. Different approaches for the synthesis of halipeptin A.

Scheme 29. Retro-synthetic analysis of IB-01211.

Scheme 30. Two synthetic approaches: (A) solution phase retrosynthesis of Ustat A and (B) solid phase synthesis of Ustat A.

Scheme 31. Retrosynthetic analysis of ceratospongamide.

Scheme 32. Retrosynthetic analysis of lyngbyabellin A.

Scheme 33. Synthesis of griseoviridin.

Scheme 34. Cyclization of apratoxin A.

Fig. 9. Structures of apratoxins A–C and an oxazoline analogue of apratoxin A.

Scheme 35. Synthesis of an oxazoline analogue of apratoxin A.

Fig. 10. Structure of micrococcin P (222) and its analogue.

Scheme 36. Solid-phase synthesis of oxazole- and thiazole-based peptides from threonine-containing dipeptides.

Scheme 37. Solid-phase synthesis of 1,3-oxazole-based peptides from serine-containing dipeptides.

Scheme 38. Solid-phase synthesis of thiazole-based peptides.

Scheme 39. Solid-phase synthesis of imidazole-based peptides.

Scheme 40. Solid-phase synthesis of azole-containing tripeptides.

Fatima Hamdan

Fatemeh Tahoori

Saeed Balalaie