Solid-Phase Synthesis of Triostin A Using a Symmetrical Bis(diphenylmethyl) Linker System

Abstract

Triostin A is a symmetric bicyclic depsipeptide with very potent antitumoral activity because of its bisintercalation into DNA. In this study, we report a new synthetic strategy that exploits a structural symmetry of triostin A. First, we prepared a novel symmetric linker molecule that is labile under mildly acidic conditions and suitable for a solidphase synthesis procedure. Two Cys units were attached to a linker-resin conjugate via their free thiol groups, and double deprotection and double coupling reactions were then applied to synthesize linear tetradepsipeptides. Subsequently, the key biscyclization of the tetradepsipeptides was performed on the resin, and the resulting cyclic octapeptide was detached from the linker-resin conjugate to give a peptide with two free thiols. Finally, triostin A was obtained by oxidizing the free thiols in solution to produce a disulfide. The yield was improved through exploration of two different solid-phase synthetic approaches under similar strategy. Mainly, this strategy was developed to enable the ease and rapid preparation of libraries of symmetric bicyclic depsipeptides. It also addresses several synthetic problems with our synthesis, including diketopiperazine (DKP) formation, poor cyclization yields and preparation of noncommercial N-methyl amino acids in good yields.

Design, Synthesis, and Conformation–Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents

“…However, cyclization of the H-shaped intermediate was expected to form two isomers, 24 and 24a , possessing theta- and manacle-shaped rings, respectively . It has previously been reported that both theta- and manacle-shaped isomers of TA were obtained by a double cyclization of an H-shaped intermediate in a solid phase procedure . In the study, double cyclization between N -Me-Cys and N -Me-Val afforded an unnatural conformer of TA.…”

Total Synthesis of Echinomycin and Its Analogues

“…The structural characteristic of 1 is the thioacetal bridge within the macrocycle, and the total chemical synthesis of 1 has not yet been accomplished presumably because the difficulty in the chemical synthesis of 1 may lie with constructing the thioacetal moiety. Accordingly, synthetic studies have mainly been focused on 2 . − Here, we describe the first total synthesis of 1 .…”

“…Under these conditions, the diastereomer of 1 was also obtained in a yield of 4%; hence, the substitution of the chloro group by the methylthio group proceeded in a stereoselective manner. Triostin A ( 2 ) is a synthetically more accessible compound, and several total syntheses have been reported. − Direct conversion of the disulfide moiety of 2 to the corresponding sulfide leading to 4 by treatment of 2 with P­(NEt 2 ) 3 with various temperatures and solvents was also investigated . However, these efforts were unsuccessful and 4 was not obtained at all.…”

Recent Progress in Solid‐Phase Total Synthesis of Naturally Occurring Small Peptides

“…have potent activity in inhibiting the platelet-derived growth factor (PDGF) signaling pathway as well as an anti-biofilm activity. The synthesis skyllamycins AÀ C began with anchoring the linear peptide precursor onto a Sieber amide resin (104). Notably, the β-OHÀ Leu, β-OHÀ Phe, and β-OHÀ O-MeÀ Tyr were protected as oxazolidines to facilitate the macrocyclization.…”

“…The synthesis of triostin A was achieved via anchoring the sulfur atoms of two N ‐Me‐Cys residues onto a symmetrical bis(diphenylmethyl) linker ( 181 ) (Scheme 27). [104] Then the chain was symmetrically elongated toward both of the two N ‐termini before biscyclization to give the resin‐bound bis‐macrocycle 183 . Finally, cleavage from the resin followed by oxidative disulfide bond formation generated triostin A ( 185 ).…”