Synthesis of honokiol
Disclosed herein are improved methods for the synthesis of honokiol, as well as methods for the synthesis of 3,3′-di-tert-butyl-5,5′-dimethyl-[1,1′-biphenyl]-2,4′-diol, 3′,5-dimethyl-[1,1′-biphenyl]-2,4′-diol, and 2,4′-dimethoxy-3′,5-dimethyl-1,1′-biphenyl, 3,3′,5,5′-tetra-tert-butyl-[1,1′-biphenyl]-2,4′-diol, and certain tetrasubstituted bisphenols, and uses therefor.
1. A method of making honokiol comprising the reaction of 2-tert-butyl-6-methylphenol with 2-tert-butyl-4-methylphenol to yield 3,3′-di-tert-butyl-5,5′-dimethyl-[1,1′-biphenyl]-2,4′-diol (Compound I):
the dealkylation of Compound I to yield Compound II:
the methylation of Compound II to yield Compound III:
the benzylic halogenation of Compound III to yield Compound IV, wherein X is bromine, chlorine, or iodine:
the coupling of a vinylmetallic agent with Compound IV to yield di-allyl compound V:
the demethylation of Compound V to yield honokiol:
and the isolation of the honokiol from the reaction mixture.
2. The method of claim 1 , wherein the reaction comprises the use of a metal catalyst.
3. The method of claim 2 , wherein the metal catalyst comprises the metal atom in complex with an acetylacetonate scaffold or an amine or imine scaffold.
4. The method of claim 1 , wherein the reaction further comprises an oxidant, optionally, wherein the oxidant is oxygen.
5. The method of claim 1 , wherein the cross-coupling reaction and the dealkylation reaction occurs in the same reaction vessel without isolation of the intermediate Compound I.
6. The method of claim 1 , wherein the cross-coupling reaction, the dealkylation reaction, and the methylation reaction occurs in the same reaction vessel without isolation of the intermediate Compounds I and II.
7. The method of claim 1 , wherein X is bromine.
8. Compound IV, wherein X is selected from bromine, chlorine or iodine.
9. A method of making honokiol comprising the reaction of 2,6-di-tert -butyl-6-phenol with 2,4-di-tert-butyl-4-phenol to yield 3,3′,5,5′-tetra-tert-butyl-5,5′-[1,1′-biphenyl]-2,4′-diol (Compound VI):
the dealkylation of Compound VI to yield Compound VII:
the methylation of Compound VII to yield Compound VIII:
the electrophilic aromatic halogenation of Compound VIII to yield Compound IX, wherein X is bromine, chlorine or iodine:
the coupling of an allyl reagent with Compound IX to yield di-allyl compound V:
the demethylation of Compound V to yield honokiol, and the isolation of the honokiol from the reaction mixture.
10. The method of claim 9 , wherein the reaction comprises the use of a metal catalyst.
11. The method of claim 10 , wherein the metal catalyst comprises the metal atom in complex with an acetylacetonate scaffold or an amine or imine scaffold.
12. The method of claim 9 , wherein the reaction further comprises an oxidant.
13. The method of claim 12 , wherein the reaction further comprises a metal catalyst which is a chromium-Salen complex and wherein the oxidant is oxygen.
14. The method of claim 12 , wherein reaction further comprises a solvent which is toluene or chlorobenzene.
15. The method of claim 9 , wherein the cross-coupling reaction and the dealkylation reaction occurs in the same reaction vessel without isolation of the intermediate Compound VI.
16. The method of claim 9 , wherein the cross-coupling reaction, the dealkylation reaction, and the methylation reaction occurs in the same reaction vessel without isolation of the intermediate Compounds VI and VII.
17. The method of claim 9 , wherein X is bromine.