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

Dedicated to Professor Kiyoshi Tomioka, Doshisha Women’s College, Japan on his 70^th birthday

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.

Key words

thailandepsin - histone deacetylase inhibitor - natural products - bicyclic depsipeptide - total synthesis - macrocycles

• References

• 1 Wang C, Henkes LM, Doughty LB, He M, Wang D, Meyer-Almes FJ, Cheng Y.-Q. J. Nat. Prod. 2011; 74: 2031
• 2 Wang C, Flemming CJ, Cheng Y.-Q. Med. Chem. Commun. 2012; 3: 976
• 3 Biggins JB, Gleber CD, Brady SF. Org. Lett. 2011; 13: 1536
• 4 HDAC inhibitory data for thailandepsins A–F (1–6) along with reference compound FK228 have been reported,² and are as follows: FK228: IC₅₀ = 0.31 nM; 1: IC₅₀ = 0.28 nM; 2: IC₅₀ = 1.2 nM; 3: IC₅₀ = 0.20 nM; 4: IC₅₀ = 0.48 nM; 5: IC₅₀ = 0.94 nM; and 6: IC₅₀ = 2.6 nM.
• 5 Benelkebir H, Donlevy AM, Packham G, Ganesan A. Org. Lett. 2011; 13: 6334
• 6 Liu JY, Ma X, Liu Y, Wang Z, Kwong S, Ren Q, Tang S, Meng Y, Xu Z, Ye T. Synlett 2012; 23: 783
• 7 Fukui Y, Narita K, Dan S, Yamori T, Ito A, Yoshida M, Katoh T. Eur. J. Med. Chem. 2014; 76: 301
• 8 Cheng Y.-Q, Yang S, Wang P. (ChinAn PharmaTech Wuhan Co., Ltd., China) PCT WO 131355A1, 2015
• 9 Narita K, Katoh T. Chem. Pharm. Bull. 2016; 64: 913
• 10 Narita K, Sayar N, Saijo K, Ishioka C, Katoh T. Synthesis 2019;
• 11a Narita K, Kikuchi T, Watanabe K, Takizawa T, Yamori T, Yoshida M, Katoh T. Chem. Eur. J. 2009; 15: 11174
• 11b Takizawa T, Watanabe K, Narita K, Kudo K, Oguchi T, Abe H, Katoh T. Heterocycles 2008; 76: 275
• 12 Narita K, Fukui Y, Sano Y, Yamori T, Ito A, Yoshida M, Katoh T. Eur. J. Med. Chem. 2013; 60: 295
• 13 Shiina I, Katoh T, Nagai S, Hashizume M. Chem. Rec. 2009; 9: 305