Facile Total Synthesis of Thailandepsins D–F: Novel Bicyclic Depsipeptide Histone Deacetylase Inhibitors Isolated from a Microorganism

Abstract

The naturally occurring bicyclic depsipeptide histone deacetylase inhibitors thailandepsins D–F were efficiently synthesized for the first time in 49–61% overall yield over five steps, starting from known amine and carboxylic acid segments. The synthesis includes the condensation of the two known starting materials to directly assemble the corresponding seco-acids, which are the key precursors for macrolactonization. The seco-acids are then macrolactonized using the Shiina method to construct the requisite 15-member macrocycles.

Automated Solid‐Phase Oligo(disulfide) Synthesis

“…Linker 6 was then coupled to a resin‐bound T 15 ‐oligonucleotide, synthesized using standard oligonucleotide synthesis conditions. The oxidation of the phosphite triester was performed using the mild oxidant, camphorsulfonyloxaziridine (CSO), given that iodine oxidized the MMTr‐protected thiol as reported [35] . Afterwards, 1 to 5 oligo(disulfide) synthesis cycles (deblock, wash, couple, wash) were performed using monomer 5 a followed by a single cycle with linker 7 and a deblocking step of the DMTr protecting group (Figures 3a and 4).…”

“…The oxidation of the phosphite triester was performed using the mild oxidant, camphorsulfonyloxaziridine (CSO), given that iodine oxidized the MMTrprotected thiol as reported. [35] Afterwards, 1 to 5 oligo(disulfide) synthesis cycles (deblock, wash, couple, wash) were performed using monomer 5 a followed by a single cycle with linker 7 and a deblocking step of the DMTr protecting group (Figures 3a and 4). Cleavage was performed using 50 mM K 2 CO 3 in MeOH and the crude mixture was subjected to HPLC analysis (Figure 3b).…”

A Concise Approach for Producing Optically Pure Carboxylic Acid Segments for the Synthesis of Bicyclic Depsipeptide Histone Deacetylase Inhibitors

“…18 By utilizing the synthetic samples of 34c (R = CH 2 CH 2 SMe) and 34d (R = n-Bu) as the key carboxylic acid segments, the syntheses of thailandepsins D-F (9, 11, and 12) were efficiently achieved for the first time, which is the subject of our next study. 19 All reactions involving air-and moisture-sensitive reagents were carried out using oven dried glassware and standard syringe-septum cap techniques. Routine monitoring of the reaction was carried out using glass-supported Merck silica gel 60 F254 TLC plates.…”