Method for the synthesis of khusimone

Abstract

A novel method for synthesis of khusimone, by bringing zizanal into contact with an oxidizing reagent in the presence of a base and an organic solvent.

Claims

1. Khusimone synthesis method by bringing together zizanal and an oxidizing reagent.

2. Method of claim 1, wherein zizanal is brought together with an oxidizing reagent in the presence of a base.

3. Method of claim 1, wherein zizanal is brought together with an oxidizing reagent in the presence of an organic solvent.

4. Method of claim 1, wherein zizanal is brought together with an oxidizing reagent in the presence of a base and an organic solvent.

5. Method of claim 1, wherein said oxidizing reagent is a peracid or peroxide, or a mixture.

6. Method of claim 1, wherein said oxidizing reagent can be selected from hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, dicumyl peroxide, tert-butyl cumyl peroxide, dibenzoyl peroxide, dilauryl, di-(2,4-dichlorobenzoyl), tert-butyl hydroperoxide, cumyl, 1-phenylethyl, performic acid, peracetic acid, perpropionic acid, m-chloroperbenzoic acid, monoperphthalic acid, monopermaleic acid or trifluoroperacetic acid.

7. Method of claim 1, wherein the molar ratio [(OR)/(Z)] between the oxidizing reagent (OR) and zizanal (Z) is between 0.1 and 50.

8. Method of claim 1, wherein the molar ratio [(OR)/(Z)] between the oxidizing reagent (OR) and zizanal (Z) is between 0.5 and 25.

9. Method of claim 1, wherein the molar ratio [(OR)/(Z)] between the oxidizing reagent (OR) and zizanal (Z) is between 1 and 10.

10. Method of claim 1, wherein the molar ratio [(OR)/(Z)] between the oxidizing reagent (OR) and zizanal (Z) is equal to 6.

11. Method of claim 2, wherein said base can be selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methanolate (MeNaO), calcium hydroxide (Ca(OH)2), lithium hydroxide (LiOH).

12. Method of claim 2, wherein the molar ratio [(B)/(Z)] between the base (B) and zizanal (Z) is between 0.1 and 50.

13. Method of claim 2, wherein the molar ratio [(B)/(Z)] between the base (B) and zizanal (Z) is between 0.5 and 25.

14. Method of claim 2, wherein the molar ratio [(B)/(Z)] between the base (B) and zizanal (Z) is between 1 and 10.

15. Method of claim 2, wherein the molar ratio [(B)/(Z)] between the base (B) and zizanal (Z) is equal to 3.

16. Method of claim 3, wherein said solvent is selected from water, methanol, ethanol, 5 propanol, isopropanol, n-butanol, secbutanol, isobutanol, tert-butanol, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), diethyl ether (Et.sub.2O), glyme, diglyme, dichloromethane (CH.sub.2Cl.sub.2), chloroform (CHCl.sub.3), dimethylsulfoxide (DMSO), acetonitrile, ethyl acetate, isopropyl acetate, or mixtures in any proportions of these solvents.

17. Method of claim 1, wherein the zizanal concentration in the reaction mixture is between 0.01 and 4.5M.

18. Method of claim 1, wherein the zizanal concentration in the reaction mixture is between 0.02 and 0.07M.

19. Method of claim 1, wherein the zizanal concentration in the reaction mixture is 0.2M.

20. Method of claim 1, wherein the reaction is carried out at a temperature between 25 C. (13 F.) and the solvent reflux temperature.

21. Method of claim 1, wherein an oxidation step of an 12-norzizaenol (IV)/khusimone (I) mixture obtained after the decarbonylation reaction in an oxidizing medium is involved.

22. Method of claim 21, wherein the oxidizing step of the 12-norzizaenol (IV)/khusimone (I) mixture is carried out in the presence of an oxidizing medium (0) and an organic solvent.

23. Method of claim 22, wherein the oxidizing medium (0) is selected from tetrapropylammonium perruthenate, manganese oxide, pyridinium chlorochromate, ceric ammonium nitrate (CAN), pyridinium dichromate, Collins reagent, chromium trioxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), 2,4,6-trichloro-1,3,5-triazine, DMSO, a mixture of DMSO and oxalyl chloride, a mixture of mixture of DMSO and pyridine sulfur trioxide, a mixture of DMSO and trifluoroacetic anhydride, a mixture of DMSO and acetic anhydride, a mixture of DMSO and phosphorus oxide (P.sub.2O.sub.5), a mixture of dimethyl sulfide and N-chlorosuccinimide (Me.sub.2S/NCS Corey-Kim Oxidation), a mixture of H.sub.2O.sub.2 and potassium bicarbonate (KHCO.sub.3) (Fleming Oxidation), Dess-Martin periodinane or acetoxyiodine oxide, 2-iodoxybenzoic acid, aluminum isopropoxide, an oxidizing system containing TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl), or tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide and, optionally, a co-oxidant.

24. Method of claim 22, wherein the oxidizing medium (O) is N-methylmorpholine N-oxide (NMO).

25. Method of claim 22, wherein the organic solvent is selected from dichloromethane (DCM), diethyl ether, DMSO, toluene, tetrahydrofuran (THF), or acetone, acetonitrile, water, or a mixture in all proportions of the listed solvents, or a mixture in all proportions of the listed solvents.

Description

EXAMPLES

Example 1

Synthesis of Khusimone from Zizanal in the Presence of Hydrogen Peroxide (H202)

(1) In a flask, 1 equivalent of zizanal is mixed with 6 equivalents of hydrogen peroxide (35% w/w in water) and 3 equivalents of potassium hydroxide (6N in water) until a final zizanal concentration of 0.2 mol/L was reached in the reaction mixture, which further contains a 1:1 mixture of MeOH/DMSO, at the reflux temperature (76 C. [169 F.]) for 4 hours.

(2) The progress of the reaction can be monitored by analyzing samples of the reaction medium. Once the desired conversion is reached, a saturated of sodium bicarbonate (NaHCO.sub.3) solution was added to the reaction medium. Next, an equivalent amount of diethyl ether was added. The organic phase is recovered. Hydrochloric acid (HCl), 2M, is added to the aqueous phase in order to reach an acidic pH (almost 0); next, this acidified aqueous phase is re-extracted 3 times with diethyl ether. Once combined, the organic phases are washed with brine and then dried with magnesium sulfate, and finally filtered for evaporation.

(3) The result of this reaction is shown in the FIGURE, in which we can see the monitoring chromatogram for this reaction. The total disappearance of the starting material was observed (Zizanal), as well as the presence of 12-norzizaenol [peaks (6) and (7)] and khusimone [peak (5)], which are quantified using two internal references, anisole (peak 3) and hexadecane (peak 4). The chromatogram revealed the peak of an unknown product (1), a peak corresponding to dimethyl sulfone (peak 2) and 2 peaks [(8 and (9)] corresponding respectively to zizanal dimethyl acetal (peak 8) and zizanoic acid (peak 9).

(4) These results were also confirmed by product purification by passage through a silica column.

(5) The resulting mixture is composed of 6% khusimone, 75% of 12-norzizaenols, and 1% zizanal dimethyl acetal

Example 2

Synthesis of Khusimone from the Khusimone/Zizaenol Mixture Obtained in Example 1

(6) In a flask, 1 equivalent of the zizaenol/khusimone mixture obtained in Example 1 is mixed with 0.01 equivalent of tetrapropylammonium perruthenate (TPAP) and 0.7 equivalents of N-methylmorpholine N-oxide (NMO) in dichloromethane (DCM) (to have a mixture concentration of 0.35 mol/L) at room temperature for 30 minutes. The reaction medium is filtered through silica, with ether and then evaporated. In this way, khusimone is obtained with a 94% yield.