Total Synthesis of Spiruchostatin A via Chemoselective Macrocyclization using an Accessible Enantiomerically Pure Latent Thioester

Abstract

HDAC inhibitor Spiruchostatin A was synthesized via a route that differs significantly from previously reported routes. The key step involves a latent thioester that initiates a chemoselective transformation similar to native chemical ligation to form the macrocyclic alanine-cysteine amide bond. The easily prepared latent thioester--the first such moiety reported in enantiomerically pure form--is designed with a pendant carboxylic acid to serve as a solid-phase linker for the synthesis of cyclic, cysteine-containing, peptidic materials.

Unmasking latent thioesters under hydrophobic‐compatible conditions

“…The latent thioester in Figure 1 meets all of the desired criteria: compatibility with Fmoc SPPS and both aqueous and organic unmasking conditions. We have already demonstrated its suitability for Fmoc/t-Bu SPPS and subsequent aqueous ligation; 23,24 here, we establish that our latent thioester also functions under conditions compatible with hydrophobic materials, in addition to the previously reported aqueous conditions. As seen below, these organic reaction conditions can be employed to convert protected latent thioesters into thioesters or to enter directly into chemoselective ligations, if desired.…”

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

“… A) Total synthesis of spiruchostatin A by Miller and co‐workers . Reagents and conditions: a) KOH, O 2 , MeOH, RT, 48 h; b) t BuMeSiOTf, lutidine, −60 °C to RT, THF; c) BrCH 2 CO 2 H, NaH, THF, 0 °C to RT, 22 h; d) 2‐methoxyethylamine, 2‐(1 H ‐benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium tetrafluoroborate (TBTU), i Pr 2 NEt, CH 2 Cl 2 , RT, 30 min; e) Bu 4 NF, THF, RT, 3 h; f) Fmoc‐ d ‐Ala‐OH, EDC ⋅ HCl, DMAP, CH 2 Cl 2 , RT, 16 h; g) 20 % piperidine, DMF, RT, 10 min; h) 83 , EDC ⋅ HCl, CH 2 Cl 2 , RT, 30 min; i) 112 , DMAP, 2,4,6‐trichlorobenzoyl chloride, RT, 15.5 h; j) Bu 4 NF, THF, RT, 4.5 h; k) TFA, i Pr 3 SiH, CH 2 Cl 2 , RT, 2.5 h; l) 10 % MeCN in 0.2 m aq.…”

Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

“…One total synthesis of FR901375 (4) has been reported by Wentworth, Janda et al [14] in 2003. In addition, three total syntheses of spiruchostatin A (1) have been reported by Ganesan et al [15] in 2004, Doi, Takahashi et al [16] in 2006 and Miller et al [17] in 2009. However, the total synthesis of spiruchostatin B (2) has not been mentioned in the literature, and the stereochemistry at C5'' (spiruchostatin numbering) of 2 has not been clearly assigned.…”