Synthesis of (2 R,8' S,3' E)-δ-tocodienol, a tocoflexol family member designed to have a superior pharmacokinetic profile compared to δ-tocotrienol

Abstract

A group of side chain partially saturated tocotrienol analogues, namely tocoflexols, have been previously designed in an effort to improve the pharmacokinetic properties of tocotrienols. (2R,8'S,3'E,11'E)-δ-Tocodienol (1) was predicted to be a high value tocoflexol for further pharmacological evaluation. We now report here an efficient 8-step synthetic route to compound 1 utilizing naturally-occurring δ-tocotrienol as a starting material (24% total yield). The key step in the synthesis is oxidative olefin cleavage of δ-tocotrienol to afford the chroman core of 1 with retention of chirality at the C-2 stereocenter.

Keywords: C-C coupling; Desulfonylation; Oxidative olefin cleavage; Tocodienol; Tocotrienol.

Figure 1

Structures of naturally occurring tocopherols and tocotrienols.

Figure 2

Structures of δ-tocotrienol and (2R,8′S,3′E,11′E)-δ-tocodienol (1) (left); and simulated docking of 1 in the binding cavity of α-TTP (right).

Scheme 1

Retrosynthetic approach to (2R,8′S,3′E,11′E)-δ-tocodienol (1).

Scheme 2

Synthesis of intermediates 7/8 and attempts for the formation of 10.

Scheme 3

Sulfone based coupling reaction for synthesis of compound 1.