Evolution of Concise and Flexible Synthetic Strategies for Trichostatic Acid and the Potent Histone Deacetylase Inhibitor Trichostatin A. Issue 1 (20th November 2012)

• Record Type: Journal Article
• Authors: Cosner, Casey C.; Bhaskara Reddy Iska, Vijaya; Chatterjee, Anamitra; Markiewicz, John T.; Corden, Steven J.; Löfstedt, Joakim; Ankner, Tobias; Richer, Joshua; Hulett, Tyler; Schauer, Douglas J.; Wiest, Olaf; Helquist, Paul
• Is Part Of: European journal of organic chemistry. Issue 1(2013)
• Page Start: 162
• Page End: 172
• Publication Date: 2012-11-20
• Subjects: Medicinal chemistry -- Natural products -- Synthetic methods -- Asymmetric synthesis -- Enzyme inhibitors -- Histone deacetylase inhibitor; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201201233
• Languages: English
• ISSNs: 1434-193X

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. Abstract : Three synthetic strategies have been developed for trichostatic acid and trichostatin A. Each strategy has a different key bond‐forming step; a vinylogous Horner–Wadsworth–Emmons condensation, a Marshall propargylation, and coupling of a ketone enolate with various alkenyl halides. Two of the syntheses were efficient and able to produce analogues. Two of the syntheses were enantioselective.