Download Synthesis of ω-di-(monofluoromethyl)-δ-tocotrienol, a δ

Synthesis of ω-di-(monofluoromethyl)-δ-tocotrienol, a δ-tocotrienol analogues designed to have
improved metabolic stability
Xingui Liu, Satheesh Gujarathi, Xuan Zhang, Guangrong Zheng*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for
Medical Sciences, Little Rock, AR 72205, United States
Background and Objective: The low bioavailability and short plasma elimination half-life of δtocotrienol (DT3) is, at least in part, due to the rapid post-absorptive metabolism. The key step
of metabolism is ω-hydroxylation of the side chain mediated by CYP4F2. Accordingly, we
designed ω-di-(monofluoromethyl)-δ-tocotrienol (DT3-F2) in an attempt to block the ωhydroxylation. We reported herein the synthesis of DT3-F2.
Methods: Two synthetic routes have been developed for the synthesis of DT3-F2. Starting from
DT3, the first synthetic route is characterized by side chain cleavage and assembling. Using
NBS/water condition, the second method functionalizes the ∆11’ double bond selectively, which
facilitates the selective oxidative cleavage at the ∆11’ olefin.
Results: Using DT3 as the starting material, DT3-F2 was synthesized successfully through two
different synthetic routes with 12 and 9 steps, respectively. Both synthetic routes gave an
overall yield of ~10%.
Discussion and conclusion: Two synthetic routes have been developed for the synthesis of DT3F2. Although comparable yields were obtained for these two synthetic routes, the second
synthetic route was shorter, more atom economic, and no toxic and expensive chemical
reagents such as OsO4 and HMPA were used. Future studies will include the antioxidant activity,
CYP4F2 enzyme stability, and microsomal stability assays.
Acknowledgment: This work was supported by NIH under grant number P20 GM109005.