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Synthesis of complex head-to-side-chain cyclodepsipeptides

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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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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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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