ABSTRACT
Methods for the synthesis of tocoflexols of Formula (I) and (II) and a number of related tocol analogs are provided herein. The methods are economical and amenable to large scale production and can be performed using either pure of partially purified tocotrienols as the starting material.
CLAIMS
1. A method of making tocoflexols of Formula (I) or (II) comprising the steps of:(a) introducing a protective group to the phenolic hydroxyl group of a pure or partially purified tocotrienol of formula (X) to form the product of formula (XI); wherein the solvent used is an aprotic solvent, the reaction temperature is between −20° C. to 120° C. and the reaction time can range from 5 minutes in 24 hours: wherein R1, R2, and R3, are the same or different and are each selected from hydrogen and methyl and P is hydroxyl protective group; and(b) cleaving by oxidation the double bonds in products from step (a) in the formula (XI) to afford an aldehyde intermediate in the formula (XII); wherein the oxidation is performed using OsO4/NaIO4 or ozonolysis: wherein R1, R2, R3, and P are the same as described in step (a);(c) reacting the aldehyde of the formula (XII) from step (b) with trialkyl 2-phosphonopionate (XIII); wherein the reaction is a Homer-Wadsworth-Emmons reaction; wherein the phosphonopionate (XIII) is initially treated with a base selected from the group consisting of sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, butyl lithium, lithium diisopropylamide, lithium diethylamide, sodium amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide: wherein R4 is independently methyl, ethyl, propyl, isopropyl, or benzyl to afford products of the formula (XIV):(d) reducing the compounds obtained from step (c) to form compounds of formula (XV) using diisobutylaluminum hydride, lithium borohydride, lithium triethyl borohydride, borate, lithium aluminium hydride, lithium trimethoxide aluminium hydride, aluminium hydride, lithium aluminium hydride mixed with aluminium chloride, and sodium borohydride mixed with lithium chloride or calcium chloride:(e) converting the hydroxyl group in the compounds from step (d) to a leaving group to form compounds of the formula (XVI): wherein Z is OTs, OMs, OTf, Cl, or Br;(f) performing a coupling reaction between the compounds obtained in step (e) and a Grignard reagent or an organozinc reagent in the formula (XVII), wherein the reaction is catalyzed by a transition metal with or without a ligand: wherein X′ is chloro, bromo, or iodo; and M is Mg or Zn, to form compound (XVIII) or (XIX);(g) removing the protective group in compounds in the formula (XVIII) and (XIX) from step (f) to afford the final product in the formula (I) and (II):