Chemo-enzymatic synthesis of the HDAC inhibitor vorinostat

Thanks to its ability to chelate metal ions, hydroxamic acid is one of the most interesting functional groups in medicinal chemistry, especially in the context of metalloenzyme inhibition. Vorinostat, also known as suberoylaniline hydroxamic acid (SAHA), is a pan HDAC inhibitor approved by the FDA in 2006 for the treatment of relapsed/refractory cutaneous T cell NHL, inhibiting cell proliferation and selectively inducing apoptosis in hematologic and solid tumor malignancies. [1] Its large-scale preparation has been widely studied and essentially consists of the cyclic suberic anhydride opening by aniline, followed by acid activation with highly reactive chloroformates and condensation with hydroxylamine. Herein, we report the design of a new chemoenzymatic pathway for the synthesis of vorinostat. The preparation of the suberoylaniline acid was performed in water, in presence of Mycobacterium smegmatis acyl transferase (MsAcT), [2] and further functionalized with an O-protected hydroxylamine, via lipase-catalyzed condensation. Final deprotection in presence of acidic cationic resins afforded pure vorinostat in 60% total yield. In order to improve the productivity of the process, all the steps were performed testing several solvent mixtures, based on the most recent guidelines about solvent sustainability. In the best case, pure vorinostat was obtained in a 3-step-5-hour synthesis of in 79% overall yield. Finally, the entire procedure was further optimized and transferred to a continuous flow system, where the final product was obtained in a time-saving automated way, large scale, high yield and high purity, paving the way for a more sustainable preparation of pharmacologically active hydroxamic acid derivatives. References: [1] K. Xue, J.J. Gu, Q. Zhang, et al. J Cancer Res Clin Oncol 2006, 142, 379–387. [2] M.S. Christodoulou, M.L. Contente, S. Dallavalle, A. Pinto Green Chem 2022, 24, 4432.