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

• Published in: Journal of organic chemistry Vol. 80; no. 15; pp. 7486 - 7494
• Main Authors: Sable, Ganesh A, Lim, Dongyeol
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.08.2015; Amer Chemical Soc
• Subjects: amino acids; Chemistry; Chemistry, Organic; Cyclization; depsipeptides; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; diketopiperazines; DNA; DNA - chemistry; organic chemistry; Oxidation-Reduction; Physical Sciences; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Science & Technology; Solid-Phase Synthesis Techniques; Solutions; Sulfhydryl Compounds - chemistry; synthesis; thiols; ORGANIC-SYNTHESIS; CYCLIC PEPTIDE; SEQUENCE SPECIFICITY; N-TETRAMETHYLTRIOSTIN-A; MARINE MICROMONOSPORA; BIFUNCTIONAL INTERCALATION; BISINTERCALATOR NATURAL-PRODUCTS; QUINOXALINE ANTIBIOTICS; ANTITUMOR-ACTIVITY; PEPTIDE-SYNTHESIS
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/acs.joc.5b01055

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 solid-phase 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.