Evolution of Concise and Flexible Synthetic Strategies for Trichostatic Acid and the Potent Histone Deacetylase Inhibitor Trichostatin A

Abstract

Abstract(R)‐(+)‐Trichostatic acid and (R)‐(+)‐trichostatin A (TSA) are natural products that have attracted considerable attention in the field of epigenetic therapies. TSA in particular is a naturally occurring hydroxamic acid having potent activity as a histone deacetylase inhibitor (HDACi) and having significant potential for treatment of a myriad of genetically based diseases. Development of TSA and other trichostatic acid derivatives into useful small‐molecule therapies has been hindered by the low natural abundance and high cost associated with these compounds. We report herein our collective efforts towards the development of concise and scalable routes for the synthesis of trichostatic acid and TSA in both racemic and enantioenriched forms. Three independent synthetic pathways were developed with varying degrees of efficiency and convergency. In the first synthesis, the key step was a vinylogous Horner–Wadsworth–Emmons condensation. A Marshall propargylation reaction was used as the key step in the second synthesis, and Pd‐catalyzed α‐alkenylation of a ketone zinc enolate by using various functionalized alkenyl or dienyl halides was developed for the third synthesis. The second pathway proved to be readily amenable to an enantioselective modification, and both the second and third pathways were straightforwardly adapted for the facile preparation of new analogues of trichostatic acid and TSA.

Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes

“…To further illustrate the utility of the Cu-catalyzed aalkenylation reaction, the method was applied for the formal synthesis of (AE)-trichostatin A (Scheme 3). [11] The addition reaction of substrate 1 o to the TIPS-protected propynol 2 o (TIPS = triisopropylsilyl) gave the product 6 a in a 52 % yield and with a Z/E ratio of 4.3:1. Pd-catalyzed Negishi coupling of 6 a with MeZnCl installed the methyl group at the g position, giving product 6 b in an 86 % yield.…”

Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis

“…92,93 The major carbon-carbon bond forming reaction in this synthetic sequence was the palladium-catalyzed coupling of ketone 107 with vinyl bromide 108 (Scheme 30). The removal of the PMB group from the ester followed by coupling of the newly formed carboxylic acid with a hydroxylamine equivalent provided trichostatin A ( 111 ) in excellent yield.…”

Recent Applications of Phosphane-based Palladium Catalysts in Suzuki-Miyaura Reactions Involved in Total Syntheses of Natural Products

“…[110 ]More recently, Helquist and co-workers accomplished an enantioselective synthesis on a gram scale of the potent histone deacetylase inhibitor (R)-trichostatin A (35a). [111] The synthetic intermediate C29 was synthesized by Pd(PPh3)4-catalyzed coupling of methyl (E)-3-bromopropenoate (B32) with the organoboron compound A29 followed by saponification (entry 33, Table 2). Compound A29 was in turn prepared by treatment of alkyne 118 ( Figure 6) with (-)-Ipc2BH in THF at 0 °C.…”

“…Compound A29 was in turn prepared by treatment of alkyne 118 ( Figure 6) with (-)-Ipc2BH in THF at 0 °C. [111] Figure 6. Structure of alkyne 118…”

“…Compound C29 was then treated with DDQ to give (R)trichostatic acid (35b), which was converted to (R)trichostatin (35a) by conversion to a mixed anhydride followed by reaction with O-t-butyldimethylsilyl (TBS) hydroxylamine and subsequent O-desilylation (Scheme 30). [111 ] Scheme 30. Synthesis of (R)-trichostatic acid (35b) and (R)-trichostatin A (35a) It should be noted that trichostatic acid of unknown absolute configuration is a natural product first isolated from Streptomyces sioyaensis, which was found to induce differentiation of leukemia cells.…”