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Synthesis of complex head-to-side-chain cyclodepsipeptides

Nature Protocols volume 11, pages 1924–1947 (2016)Cite this article

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Abstract

Cyclodepsipeptides are cyclic peptides in which at least one amide link on the backbone is replaced with an ester link. These natural products present a high structural diversity that corresponds to a broad range of biological activities. Therefore, they are very promising pharmaceutical candidates. Most of the cyclodepsipeptides have been isolated from marine organisms, but they can also originate from terrestrial sources. Within the family of cyclodepsipeptides, 'head-to-side-chain' cyclodepsipeptides have, in addition to the macrocyclic core closed by the ester bond, an arm terminated with a polyketide moiety or a branched amino acid, which makes their synthesis a challenge. This protocol provides guidelines for the synthesis of 'head-to-side-chain cyclodepsipeptides' and includes—as an example—a detailed procedure for preparing pipecolidepsin A. Pipecolidepsin was chosen because it is a very complex 'head-to-side-chain cyclodepsipeptide' of marine origin that shows cytotoxicity in several human cancer cell lines. The procedure begins with the synthesis of the noncommercial protected amino acids (2R,3R,4R)-2-{[(9H-fluoren-9-yl)methoxy]carbonylamino}-3-hydroxy-4,5-dimethylhexanoic acid (Fmoc-AHDMHA-OH), Alloc-pipecolic-OH, (4R,5R)-5-((((9H-fluoren-9-yl)methoxy)carbonylamino)-4-oxo-4-(tritylamino)butyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (Fmoc-DADHOHA(acetonide, Trt))-OH and the pseudodipeptide (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid ((HTMHA)-D-Asp(OtBu)-OH). It details the assembly of the depsipeptidic skeleton using a fully solid-phase approach (typically on an amino polystyrene resin coupled to 3-(4-hydroxymethylphenoxy)propionic acid (AB linker)), including the key ester formation step. It concludes by describing the macrocyclization step performed on solid phase, and the global deprotection and cleavage of the cyclodepsipeptide from the resin using a trifluoroacetic acid–H2O–triisopropylsilane (TFA−H2O−TIS; 95:2.5:2.5) cocktail, as well as the final purification by semipreparative HPLC. The entire procedure takes ∼2 months to complete.

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Figure 1: Number of research articles on cyclodepsipeptides per year interval.
Figure 2
Figure 3
Figure 4: Key stages for the synthesis of 'head-to-side-chain' depsipeptides, as depicted for pipecolidepsin A, and diagrams showing the related steps in the procedure.
Figure 5
Figure 6
Figure 7: HPLC chromatograms of crude and pure pipecolidepsin.

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References

  1. Antonov, V.K., Shkrob, A.M. & Shemyakin, M.M. Cyclol formation in peptide systems. 3. Rearrangement of N-(beta-hydroxypropionyl)-piperidone into a 10-membered cyclodepsipeptide. Tetrahedron Lett. 4, 439–443 (1963).

    Google Scholar 

  2. Macdonald, C.G. & Shannon, J.S. The structure of the cyclodepsipeptide, angolide. Tetrahedron Lett. 5, 3113–3118 (1964).

    Google Scholar 

  3. Sarabia, F., Chammaa, S., Ruiz, A.S., Ortiz, L.M. & Herrera, F.J.L. Chemistry and biology of cyclic depsipeptides of medicinal and biological interest. Curr. Med. Chem. 11, 1309–1332 (2004).

    CAS  PubMed  Google Scholar 

  4. Andavan, G.S.B. & Lemmens-Gruber, R. Cyclodepsipeptides from marine sponges: natural agents for drug research. Mar. Drugs 8, 810–834 (2010).

    PubMed  PubMed Central  Google Scholar 

  5. Suarez-Jimenez, G.-M., Burgos-Hernandez, A. & Ezquerra-Brauer, J.-M. Bioactive peptides and depsipeptides with anticancer potential: sources from marine animals. Mar. Drugs 10, 963–986 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Newman, D.J. & Cragg, G.M. Marine-sourced anti-cancer and cancer pain control agents in clinical and late preclinical development. Mar. Drugs 12, 255–278 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Mehbub, M.F., Lei, J., Franco, C. & Zhang, W. Marine sponge derived natural products between 2001 and 2010: trends and opportunities for discovery of bioactives. Mar. Drugs 12, 4539–4577 (2014).

    PubMed  PubMed Central  Google Scholar 

  8. Sivanathan, S. & Scherkenbeck, J. Cyclodepsipeptides: a rich source of biologically active compounds for drug research. Molecules 19, 12368–12420 (2014).

    PubMed  PubMed Central  Google Scholar 

  9. Kitagaki, J., Shi, G.B., Miyauchi, S., Murakami, S. & Yang, Y.L. Cyclic depsipeptides as potential cancer therapeutics. Anticancer Drugs 26, 259–271 (2015).

    CAS  PubMed  Google Scholar 

  10. Grieco, P.A., Hon, Y.S. & Perezmedrano, A. A convergent, enantiospecific total synthesis of the novel cyclodepsipeptide (+)-jasplakinolide (Jaspamide). J. Am. Chem. Soc. 110, 1630–1631 (1988).

    CAS  Google Scholar 

  11. Boger, D.L., Keim, H., Oberhauser, B., Schreiner, E.P. & Foster, C.A. Total synthesis of HUN-7293. J. Am. Chem. Soc. 121, 6197–6205 (1999).

    CAS  Google Scholar 

  12. Pelay-Gimeno, M., Tulla-Puche, J. & Albericio, F. 'Head-to-side-chain' cyclodepsipeptides of marine origin. Mar. Drugs 11, 1693–1717 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Marcucci, E., Tulla-Puche, J. & Albericio, F. Solid-phase synthesis of NMe-IB-01212, a highly N-methylated cyclic peptide. Org. Lett. 14, 612–615 (2012).

    CAS  PubMed  Google Scholar 

  14. Tulla-Puche, J. et al. Enzyme-labile protecting groups for the synthesis of natural products: solid-phase synthesis of thiocoraline. Angew. Chem. Int. Ed. 52, 5726–5730 (2013).

    CAS  Google Scholar 

  15. Tsakos, M., Schaffert, E.S., Clement, L.L., Villadsena, N.L. & Poulsen, T.B. Ester coupling reactions–an enduring challenge in the chemical synthesis of bioactive natural products. Nat. Prod. Rep. 32, 605–632 (2015).

    CAS  PubMed  Google Scholar 

  16. Banker, R. & Carmeli, S. Inhibitors of serine proteases from a waterbloom of the cyanobacterium Microcystis sp. Tetrahedron 55, 10835–10844 (1999).

    CAS  Google Scholar 

  17. Gao, J. & Hamann, M.T. Chemistry and biology of kahalalides. Chem. Rev. 111, 3208–3235 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rinehart, K.L.J. et al. Didemnins: antiviral and antitumor depsipeptides from a Caribbean tunicate. Science 212, 933–935 (1981).

    CAS  PubMed  Google Scholar 

  19. Lee, J., Currano, J.N., Carroll, P.J. & Joullié, M.M. Didemnins, tamandarins and related natural products. Nat. Prod. Rep. 29, 404–424 (2012).

    CAS  PubMed  Google Scholar 

  20. Vervoort, H., Fenical, W. & Epifanio, R.A. Tamandarins A and B: new cytotoxic depsipeptides from a Brazilian ascidian of the family Didemnidae. J. Org. Chem. 65, 782–792 (2000).

    CAS  PubMed  Google Scholar 

  21. Matsunaga, S., Fusetani, N. & Konosu, S. Bioactive marine metabolites IV. Isolation and the amino acid composition of discodermin A, an antimicrobial peptide, from the marine sponge Discodermia kiiensis. J. Nat. Prod. 48, 236–241 (1985).

    CAS  PubMed  Google Scholar 

  22. Li, H., Matsunaga, S. & Fusetani, N. Halicylindramides A–C, antifungal and cytotoxic depsipeptides from the marine sponge Halichondria cylindrata. J. Med. Chem. 38, 338–343 (1995).

    CAS  PubMed  Google Scholar 

  23. Zampella, A. et al. Callipeltin A, an anti-HIV cyclic depsipeptide from the New Caledonian Lithistida sponge Callipelta sp. J. Am. Chem. Soc. 118, 6202–6209 (1996).

    CAS  Google Scholar 

  24. Tran, T.D. et al. Cytotoxic cyclic depsipeptides from the Australian marine sponge Neamphius huxleyi. J. Nat. Prod. 75, 2200–2208 (2012).

    CAS  PubMed  Google Scholar 

  25. Ford, P.W. et al. Papuamides A–D, HIV-inhibitory and cytotoxic depsipeptides from the sponges Theonella mirabilis and Theonella swinhoei collected in Papua New Guinea. J. Am. Chem. Soc. 121, 5899–5909 (1999).

    CAS  Google Scholar 

  26. Plaza, A. et al. Celebesides A-C and theopapuamides B-D, depsipeptides from an Indonesian sponge that inhibit HIV-1 entry. J. Org. Chem. 74, 504–512 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lu, Z. et al. Mirabamides E-H, HIV-inhibitory depsipeptides from the sponge Stelletta clavosa. J. Nat. Prod. 74, 185–193 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zampella, A. et al. Homophymines B-E and A1-E1, a family of bioactive cyclodepsipeptides from the sponge Homophymia sp. Org. Biomol. Chem. 7, 4037–4044 (2009).

    CAS  PubMed  Google Scholar 

  29. Rodriguez, R. et al., inventors. Stellatolide analogs as anticancer compounds. Int. Appl. Patent WO2010/007147; filed July 16, 2009; issued January 21, 2010.

  30. Martin, M.J. et al. Stellatolides, a New Cyclodepsipeptide Family from the sponge Ecionemia acervus: isolation, solid-phase total synthesis, and full tructural assignment of stellatolide A. J. Am. Chem. Soc. 136, 6754–6762 (2014).

    CAS  PubMed  Google Scholar 

  31. Coello Molinero, L., Fernández Rodríguez, R., Reyes Benítez, J.F., Francesch Solloso, A.M. & Cuevas Marchante, C. Anticancer Compounds. Int. Appl. Patent WO2010/070078 A1; filed December 18, 2009; issued June 24, 2010.

  32. Pelay Gimeno, M., García Ramos, Y., Tulla Puche, J., Albericio, F. & Martín López, M.J. Synthetic process for the manufacture of pipecolidepsin compounds. Int. Appl. Patent WO2014/108526; filed January 13, 2014; issued July 17, 2014.

  33. Pelay-Gimeno, M. et al. The first total synthesis of the cyclodepsipeptide pipecolidepsin A. Nat. Commun. 4, 2352 (2013).

    PubMed  Google Scholar 

  34. Medina, R.A. et al. Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp. J. Am. Chem. Soc. 130, 6324–6325 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Debono, M. et al. A21978C, a complex of new acidic peptide antibiotics: isolation, chemistry, and mass spectral structure elucidation. J. Antibiot. 40, 761–777 (1987).

    Google Scholar 

  36. Goodreid, J.D. et al. Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from Streptomyces hawaiiensis. J. Nat. Prod. 77, 2170–2181 (2014).

    CAS  PubMed  Google Scholar 

  37. Ling, L.L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015).

    CAS  Google Scholar 

  38. Xie, W., Ding, D., Zi, W., Li, G. & Ma, D. Total synthesis and structure assignment of papuamide B, a potent marine cyclodepsipeptide with anti-HIV properties. Angew. Chem. Int. Ed. 47, 2844–2848 (2008).

    CAS  Google Scholar 

  39. Mazur, S. & Jayalekshmy, P. Chemistry of polymer-bound o-benzyne. Frequency of encounter between substituents on cross-linked polystyrenes. J. Am. Chem. Soc. 101, 677–683 (1979).

    CAS  Google Scholar 

  40. Barlos, K. et al. Darstellung geschützter peptid-fragmente unter einsatz substituierter triphenylmethyl-harze. Tetrahedron Lett. 30, 3943–3946 (1989).

    CAS  Google Scholar 

  41. Callipeltin, B. et al. Solid-phase total synthesis and structure proof of callipeltin B. J. Am. Chem. Soc. 128, 15392–15393 (2006).

    Google Scholar 

  42. Stolze, S.C., Meltzer, M., Ehrmann, M. & Kaiser, M. Development of a solid-phase approach to the natural product class of Ahp-containing cyclodepsipeptides. Eur. J. Org. Chem. 2012, 1616–1625 (2012).

    CAS  Google Scholar 

  43. Tokairin, Y., Takeda, S., Kikuchi, M. & Konno, H. Synthetic studies on homophymine B: solid phase synthesis of a cyclic fragment. Tetrahedron Lett. 56, 2809–2812 (2015).

    CAS  Google Scholar 

  44. Albericio, F. & Barany, G. Improved approach for anchoring N-9- fluorenylmethyloxycarbonylamino acids as p-alkoxybenzyl esters in solid-phase peptide synthesis. Int. J. Peptide Protein Res. 26, 92–97 (1985).

    CAS  Google Scholar 

  45. Acevedo, C.M., Kogut, E.F. & Lipton, M.A. Synthesis and analysis of the sterically constrained L-glutamine analogues (3S,4R)-3,4-dimethyl-L-glutamine and (3S,4R)-3,4-dimethyl-L-pyroglutamic acid. Tetrahedron 57, 6353–6359 (2001).

    CAS  Google Scholar 

  46. Zampella, A. et al. Homophymine A, an anti-HIV cyclodepsipeptide from the sponge Homophymia sp. J. Org. Chem. 7, 5319–5327 (2008).

    Google Scholar 

  47. Carpino, L.A. 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J. Am. Chem. Soc. 115, 4397–4398 (1993).

    CAS  Google Scholar 

  48. Coste, J., Le-Nguyen, D. & Castro, B. PyBOP: A new peptide coupling reagent devoid of toxic by-product. Tetrahedron Lett. 31, 205–208 (1990).

    CAS  Google Scholar 

  49. Carpino, L.A., El-Faham, A., Minor, C.A. & Albericio, F. Advantageous applications of azabenzotriazole (triazolopyridine)-based coupling reagents to solid-phase peptide synthesis. J. Chem. Soc., Chem. Commun. 201–203 (1994).

  50. Albericio, F. et al. On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis. Tetrahedron Lett. 38, 4853–4856 (1997).

    CAS  Google Scholar 

  51. Gausepohl, H., Pieles, U. & Frank, R.W. Schiff base analog formation during in situ activation by HBTU and TBTU. In Peptides-Chemistry and Biology: Proceedings of the 12th American Peptide Symposium (eds. Smith, J.A., Rivier, J.E.) 523–524 (ESCOM, Science: Leiden, 1992).

  52. Story, S.C. & Aldrich, J.V. Side-product formation during cyclization with HBTU on a solid support. Int. J. Pept. Protein Res. 43, 292–296 (1994).

    CAS  PubMed  Google Scholar 

  53. Arttamangkul, S., Arbogast, B., Barofsky, D. & Aldrich, J.V. Characterization of synthetic peptide byproducts from cyclization reactions using online HPLC-ion spray and tandem mass spectrometry. Lett. Pept. Sci. 3, 357–370 (1997).

    CAS  Google Scholar 

  54. Albericio, F., Bofill, J.M., El-Faham, A. & Kates, S.A. Use of onium salt-based coupling reagents in peptide synthesis. J. Org. Chem. 63, 9678–9683 (1998).

    CAS  Google Scholar 

  55. Meienhofer, J. Major Methods of Peptide Bond Formation. In 'The Peptides, Analysis, Synthesis, Biology' (eds. Gross, E. & Meienhofer, J.) Vol. 1, 263 (Academic Press, New York, 1979).

  56. Izdebski, J., Orlowska, A., Anulewicz, R., Witkowska, E. & Fiertek, D. Reinvestigation of the reactions of carbodiimides with alkoxycarbonylamino acid symmetrical anhydrides. Isolation of two N-acylureas. Int. J. Pept. Protein Res. 43, 184–189 (1994).

    CAS  PubMed  Google Scholar 

  57. Steglich, W. & Höfle, G. 4-Dialkylaminopyridines as highly active acylation catalysts. Angew. Chem. Int. Ed. 8, 981 (1969).

    CAS  Google Scholar 

  58. Kaiser, E., Colescot, R.L., Bossinger, C.D. & Cook, P.I. Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal. Biochem. 34, 595–598 (1970).

    CAS  PubMed  Google Scholar 

  59. Gisin, B.F. & Merrifield, R.B. Carboxyl-catalyzed intramolecular aminolysis. Side reaction in solid-phase peptide synthesis. J. Am. Chem. Soc. 94, 3102–3106 (1972).

    CAS  PubMed  Google Scholar 

  60. Khosla, M.C., Smeby, R.R. & Bumpus, F. Failure sequence in solid-phase peptide synthesis due to the presence of an N-alkylamino acid. J. Am. Chem. Soc. 94, 4721–4724 (1972).

    CAS  PubMed  Google Scholar 

  61. Rothe, M. & Mazánek, J. Side-reactions arising on formation of cyclodipeptides in solid-phase peptide synthesis. Angew. Chem. Int. Ed. 11, 293 (1972).

    CAS  Google Scholar 

  62. Guibé, F. Allylic protecting groups and their use in a complex environment. Part II: allylic protecting groups and their removal through catalytic palladium π-allyl methodology. Tetrahedron 54, 2967–3042 (1998).

    Google Scholar 

  63. Carpino, L.A. et al. New family of base- and nucleophile-sensitive amino-protecting groups. A Michael-acceptor-based deblocking process. Practical utilization of the 1,1-dioxobenzo[b]thiophene-2-ylmethyloxycarbonyl (Bsmoc) group. J. Am. Chem. Soc. 119, 9915–9916 (1997).

    CAS  Google Scholar 

  64. Carpino, L.A. et al. The 1,1-dioxobenzo[b]thiophene-2-ylmethyloxycarbonyl (Bsmoc) amino-protecting group. J. Org. Chem. 64, 4324–4338 (1999).

    CAS  Google Scholar 

  65. Meldal, M., Juliano, M.A. & Jansson, A.M. Azido acids in a novel method of solid-phase peptide synthesis. Tetrahedron Lett. 38, 2531–2534 (1997).

    CAS  Google Scholar 

  66. Tornoe, C.W., Davis, P., Porreca, F. & Meldal, M. α-Azido acids for direct use in solid-phase peptide synthesis. J. Pept. Sci. 6, 594–602 (2000).

    CAS  PubMed  Google Scholar 

  67. Lundquist, J.T. IV. & Pelletier, J.C. Improved solid-phase peptide synthesis method utilizing α-azide-protected amino acids. Org. Lett. 3, 781–783 (2001).

    CAS  PubMed  Google Scholar 

  68. Alsina, J., Giralt, E. & Albericio, F. Use of N-tritylamino acids and PyAOP for the suppression of diketopiperazine formation in Fmoc/tBu solid-phase peptide synthesis using alkoxybenzyl ester anchoring linkages. Tetrahedron Lett. 37, 4195–4198 (1996).

    CAS  Google Scholar 

  69. Isidro-Llobet, A., Guasch-Camell, J., Álvarez, M. & Albericio, F. p-Nitrobenzyloxycarbonyl (pNZ) as a temporary Nα-protecting group in orthogonal solid-phase peptide synthesis – avoiding diketopiperazine and aspartimide formation. Eur. J. Org. Chem. 2005, 3031–3039 (2005).

    Google Scholar 

  70. Ueki, M. & Amemiya, M. Removal of 9-fluorenylmethyloxycarbonyl (Fmoc) group with tetrabutylammonium fluoride. Tetrahedron Lett. 28, 6617–6620 (1987).

    CAS  Google Scholar 

  71. Coin, I., Beerbaum, M., Schmieder, P., Bienert, M. & Beyermann, M. Solid-phase synthesis of a cyclodepsipeptide: cotransin. Org. Lett. 10, 3857–3860 (2008).

    CAS  PubMed  Google Scholar 

  72. Wade, J., Bedford, J., Sheppard, R. & Tregear, G. DBU as an N-deprotecting reagent for the fluorenylmethoxycarbonyl group in continuous flow solid-phase peptide synthesis. Pept. Res. 4, 194–199 (1991).

    CAS  PubMed  Google Scholar 

  73. Arndt, H.-D. et al. Divergent solid-phase synthesis of natural product-inspired bipartite cyclodepsipeptides: total synthesis of seragamide A. Chem. Eur. J. 21, 5311–5316 (2015).

    CAS  PubMed  Google Scholar 

  74. Tulla-Puche, J. et al. Solid-phase synthesis of oxathiocoraline by a key intermolecular disulfide dimer. J. Am. Chem. Soc. 129, 5322–5323 (2007).

    CAS  PubMed  Google Scholar 

  75. Sohma, Y. et al. The 'O-acyl isopeptide method' for the synthesis of difficult sequence-containing peptides: application to the synthesis of Alzheimer's disease-related amyloid β peptide (Aβ) 1–42. J. Peptide Sci. 11, 441–451 (2005).

    CAS  Google Scholar 

  76. Tulla-Puche, J., Marcucci, E., Fermin, M., Bayó-Puxan, N. & Albericio, F. Protection by conformationally restricted mobility: first solid-phase synthesis of triostin A. Chem. Eur. J. 14, 4475–4478 (2008).

    CAS  PubMed  Google Scholar 

  77. Dölling, R. et al. Piperidine-mediated side product formation for Asp(OBut)-containing peptides. J. Chem. Soc. Chem. Commun. 853–854 (1994).

  78. Subirós-Funosas, R., El-Faham, A. & Albericio, F. Use of oxyma as pH modulatory agent to be used in the prevention of base-driven side reactions and its effect on 2-chlorotrityl chloride resin. Biopolymers 98, 89–97 (2011).

    PubMed  Google Scholar 

  79. Michels, T., Dölling, R., Haberkorn, U. & Mier, W. Acid-mediated prevention of aspartimide formation in solid phase peptide synthesis. Org. Lett. 14, 5218–5221 (2012).

    CAS  PubMed  Google Scholar 

  80. Wade, J.D., Mathieu, M.N., Macris, M. & Tregear, G.W. Base-induced side reactions in Fmoc-solid phase peptide synthesis: minimization by use of piperazine as Nα-deprotection reagent. Lett. Pept. Sci. 7, 107–112 (2000).

    CAS  Google Scholar 

  81. Karlström, A. & Undén, A. A new protecting group for aspartic acid that minimizes piperidine-catalyzed aspartimide formation in fmoc solid phase peptide synthesis. Tetrahedron Lett. 37, 4243–4246 (1996).

    Google Scholar 

  82. Mergler, M., Dick, F., Sax, B., Weiler, P. & Vorherr, T. The aspartimide problem in Fmoc-based SPPS. Part I. J. Peptide Sci. 9, 36–46 (2003).

    CAS  Google Scholar 

  83. Mergler, M. & Dick, F. The aspartimide problem in Fmoc-based SPPS. Part III. J. Peptide Sci. 11, 650–657 (2005).

    CAS  Google Scholar 

  84. Chen, R. & Tolbert, T.J. Study of on-resin convergent synthesis of N-linked glycopeptides containing a large high mannose N-linked oligosaccharide. J. Am. Chem. Soc. 132, 3211–3216 (2010).

    CAS  PubMed  Google Scholar 

  85. Behrendt, R., Huber, S., Martí, R. & White, P. New t-butyl based aspartate protecting groups preventing aspartimide formation in Fmoc SPPS. J. Pept. Sci. 21, 680 (2015).

    CAS  PubMed  Google Scholar 

  86. Quibell, M., Owen, D., Packman, L.C. & Johnson, T. Suppression of piperidine-mediated side product formation for Asp(OBut)-containing peptides by the use of N-(2-hydroxy-4-methoxybenzyl) (Hmb) backbone amide protection. J. Chem. Soc. Chem. Commun. 2343–2344 (1994).

  87. Cardona, V. et al. Application of Dmb-dipeptides in the Fmoc SPPS of difficult and aspartimide-prone sequences. Int. J. Pept. Res. Ther. 14, 285–292 (2008).

    CAS  Google Scholar 

  88. Abdel-Aal, A-B.M., Papageorgiou, G., Quibell, M. & Offer, J. Automated synthesis of backbone protected peptides. Chem. Commun. 50, 8316–8319 (2014).

    CAS  Google Scholar 

  89. Isidro-Llobet, A., Just-Baringo, X., Álvarez, M. & Albericio, F. EDOTn and MIM, new peptide backbone protecting groups. Biopolymers 90, 444–449 (2008).

    CAS  PubMed  Google Scholar 

  90. López-Macià, A., Jiménez, J.-C., Royo, M., Giralt, E. & Albericio, F. Synthesis and structure determination of kahalalide F. J. Am. Chem. Soc. 123, 11398–11401 (2001).

    PubMed  Google Scholar 

  91. Carpino, L.A. & Han, G.Y. 9-Fluorenylmethoxycarbonyl amino-protecting group. J. Org. Chem. 37, 3404–3405 (1972).

    CAS  Google Scholar 

  92. Tessier, M. et al. Amino-acids condensations in the preparation of Nα-9-fluorenylmethyloxycarbonylamino-acids with 9-fluorenylmethylchloroformate. Int. J. Pept. Protein Res. 22, 125–128 (1983).

    CAS  PubMed  Google Scholar 

  93. Sigler, G.F., Fuller, W.D., Chaturvedi, N.C., Goodman, M. & Verlander, M. Formation of oligopeptides during the synthesis of 9-fluorenylmethyloxycarbonyl amino acid derivatives. Biopolymers 22, 2157–2162 (1983).

    CAS  Google Scholar 

  94. Albericio, F. Orthogonal protecting groups for Nα-amino and C-terminal carboxyl functions in solid-phase peptide synthesis. Biopolymers 55, 123–139 (2000).

    CAS  PubMed  Google Scholar 

  95. Cruz, L.J., Beteta, N.G., Ewenson, A. & Albericio, F. 'One-pot' preparation of N-carbamate protected amino acids via the azide. Org. Proc. Res. Dev. 8, 920–924 (2004).

    CAS  Google Scholar 

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Acknowledgements

This work was partially supported by CICYT (CTQ2015–68677-R to J.T.-P. and CTQ2012–30930 to F.A.) and the Generalitat de Catalunya (2014SGR 137 to F.A.). J.T.-P. acknowledges a Ramon y Cajal contract (MINECO).

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Authors and Affiliations

  1. Department of Inorganic and Organic Chemistry, Section of Organic Chemistry, University of Barcelona, Barcelona, Spain

    Marta Pelay-Gimeno, Fernando Albericio & Judit Tulla-Puche

  2. Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain

    Fernando Albericio

  3. School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa

    Fernando Albericio

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  1. Marta Pelay-Gimeno
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M.P.-G. carried out the experiments, as reported in the main paper; J.T.-P. tested the protocol and wrote the first draft of the article. All authors discussed the manuscript.

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Correspondence to Judit Tulla-Puche.

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Pelay-Gimeno, M., Albericio, F. & Tulla-Puche, J. Synthesis of complex head-to-side-chain cyclodepsipeptides. Nat Protoc 11, 1924–1947 (2016). https://doi.org/10.1038/nprot.2016.116

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  • DOI: https://doi.org/10.1038/nprot.2016.116

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