Method for synthesizing a precursor of a single dairy-lactone isomer

Abstract

This disclosure provides a method for preparing a precursor of a single dairy-lactone isomer, methods of preparing a single dairy-lactone isomer, and to the organoleptic uses thereof.

Claims

1. A method for preparing a precursor molecule of formula (VI) of a single isomer of dairy-lactone, wherein R.sub.1 and R.sub.3 are alkyl groups and wherein the dashed lines represent a single or double carbon-carbon bond, the method comprising: preparing a glycidyl ester of formula (V) as a pure isomeric form only of R or S conformation, the glycidyl ester, of formula (V) having an epoxide group, said preparation of the glycidyl ester of formula (V) followed by opening the epoxide group of the glycidyl ester of formula (V) in the presence of hept-1-yne so as to form the molecule of formula (VI); wherein the glycidyl ester of formula (V) and the molecule of formal (VI) follows: ##STR00012##

2. The method according to claim 1, wherein the glycidyl ester of formula (V) is prepared from a lactone of formula (III) only of R or S conformation by a method comprising opening the lactone of formula (III), where the dashed line of the lactone of formula (III) represents a single or double carbon-carbon bond, so that said glycidyl ester and said precursor molecule of formula (VI) are in pure isomeric form only of R or S form, and that the dairy-lactone is a pure isomer only of R or S corresponding form: ##STR00013##

3. The method according to claim 2, wherein preparing said glycidyl ester consists of opening the lactone in molecule of formula (IV) and concerted elimination of an activated alcohol from a molecule of formula (IV), wherein R.sub.2 is selected from the group consisting of a tosyl group and a mesyl group, and wherein the dashed line of the molecule of formula (IV) represents a single or double carbon-carbon bond, wherein said molecule of formula (IV) is obtained by a process comprising activation of the alcohol of the lactone of formula (III): ##STR00014##

4. The method according to claim 2, wherein preparing said glycidyl ester consists of opening the lactone of formula (III) and concerted elimination of a halide of a molecule of formula (IV-BIS), wherein X is selected from the group consisting of Br, Cl, and I, and wherein the dashed line of the molecule of formula (IV-BIS) represents a single or double carbon-carbon bond, said molecule of formula (IV-BIS) being obtained by substituting halogen for the alcohol group in a lactone of formula (III): ##STR00015##

5. The method according to claim 3, wherein said molecule of formula (IV) is obtained by activating the alcohol group of a molecule of formula (III) by sulfonation.

6. The method according to claim 5, wherein the dashed line of said molecule of formula (III) represents a single carbon-carbon bond obtained by hydrogenating an ,-unsaturated lactone.

7. The method according to claim 5, wherein said molecule of formula (III) is obtained by oxidizing a dihydrolevoglucosenone in the presence of a peracid, followed by hydrolysis, said dihydrolevoglucosenone being obtained by hydrogenating a levoglucosenone.

8. The method according to claim 1, wherein the method further comprises lactonizing the molecule of formula (VI) to obtain a molecule of formula (VII), wherein the dashed line of formula (VII) represents a single or double carbon-carbon bond: ##STR00016##

9. The method according to claim 1, further comprising: incorporating a pure isomer of dairy-lactone obtained thereby into a food.

10. The method according to claim 1, further comprising: incorporating a pure isomer of dairy-lactone obtained thereby into a cosmetic product.

11. The method according to claim 9, wherein the food is a bakery product.

12. The method according to claim 9, wherein the food is a vegetable milk or animal milk substitute.

13. The method according to claim 1, wherein R.sub.1 and R.sub.3 are each independently selected from CH.sub.3 and C.sub.2H.sub.5.

14. A method for preparing a single isomer of dairy-lactone of formula (VIII), the method comprising the steps of: preparing a glycidyl ester of formula (V) having an epoxide group as a pure isomeric form only of R or S conformation, followed by opening of the epoxide group to obtain a molecule of formula (VI), a lactonization step of the molecule of formula (VI), wherein the dashed line thereof represents a single or double carbon-carbon bond to obtain a molecule of formula (VII), and a syn-hydrogenation step of the molecule of formula (VII) to form the single isomer of dairy-lactone of formula (VIII), wherein R.sub.1 and R.sub.3 are alkyl groups, and wherein the dashed lines represent a single or double carbon-carbon bond, and wherein the molecules of formula (V), (VI), (VII), and (VIII) have the following structures: ##STR00017##

15. The method according to claim 14, wherein R.sub.1 and R.sub.3 are each independently selected from CH.sub.3 and C.sub.2H.sub.5.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The disclosure will be better understood in light of non-limiting examples of the embodiment.

(2) FIG. 1 is a diagram of the various steps of the synthesis method of at least one precursor of an isomer of (Z,S)-dairy-lactone and an isomer of (Z,S)-dairy-lactone from the lactone (II).

(3) FIG. 2 is a diagram of the enzymatic synthesis of precursors of the dairy-lactone, (S)-furanone (molecule II) and of 4-hydroxymethylbutyrolactone (molecule III) and is described in Examples 1 and 2.

(4) FIG. 3 depicts an alternative synthesis route of 4-hydroxymethylbutyrolactone (molecule III) by chemical synthesis and is described in Example 2bis.

(5) FIG. 4 depicts an alternative synthesis route of at least one precursor of an isomer of (Z,S)-dairy-lactone and an isomer of the (Z,S)-dairy-lactone.

DETAILED DESCRIPTION

Example 1

Synthesis of (S)-furanone (HFO) of Formula (II) from a Specific Ketone, Levoglucosenone

(6) Any of the methods described in Patent Application Serial No. FR1453957 whose content is incorporated herein by this reference may be used.

(7) (S)-furanone or (S)-4-hydroxymethylbutenolide has the formula (II) below:

(8) ##STR00011##

(9) 4-hydroxymethylbutenolide of formula (II) is prepared from levoglucosenone (LGO), which is obtained by use of biomass, according to the particular implementation of the one-pot method.

(10) Oxidation

(11) In a reactor, an aqueous solution of hydrogen peroxide H.sub.2O.sub.2 at 30% (2.57 mmol, 0.26 mL, 1.2 eq. relative to the LGO) is added in one portion to an LGO suspension (270 mg, 2.14 mmol) and CAL-B lipase (NOVOZYM 435, 75 mg, 315 U/nmol LGO) in ethyl acetate (3 mL) with stirring at room temperature in a planar agitation incubator. For this example, as for all the examples described below, 1 g of NOVOZYM 435 corresponds to 9000 units of CAL-B lipase (activity measured after residence of the enzyme in ethyl acetate). The reaction mixture is stirred at 40 C. for 4 hours then evaporated to dryness.

(12) Acid Hydrolysis

(13) Concentrated hydrochloric acid (5 mmol, 0.4 mL) is added to a solution of this crude mixture in methanol (5 mL) at room temperature. The reaction mixture is heated under stirring for 8 to 16 hours, so as to convert the formate to the corresponding alcohol. The reaction mixture is evaporated to dryness with a silica gel. The crude product is purified by chromatography on silica gel (elution with 75%-100% ethyl acetate in cyclohexane) to obtain pure (S)-4-hydroxymethylbutenolide of formula (II) (175 mg, 72%).

(14) .sup.1H NMR (CDCl.sub.3): d 7.53 (dd, J=1.5 and 5.7 Hz, 1 H), 6.2 (dd, J=1.5 and 5.7 Hz, 1 H), 5.17 (m, 1 H), 4.0 (d, J=3.6 and 12.0 Hz, 1 H), 3.80 (dd, J=3.6 and 12.0 Hz, 1 H)

(15) .sup.13C NMR (CDCl.sub.3): d 173.5 (s), 154.0 (d), 122.8 (d), 84.3 (d), 62.2 (t)

(16) Alternatively, after of the LGO treatment step with the lipase, the latter is separated from the reaction medium before the dry evaporation step of the medium. The acid hydrolysis is then carried out as described above. Pure 4-hydroxymethylbutenolide is also obtained, with the same yield of 72%.

(17) In other variants of the method, the acid hydrolysis step is carried out directly on the reaction medium obtained after the oxidation step, without having previously performed an evaporation to dryness step. Whether or not the lipase is removed from the reaction medium by filtration, in such embodiments, the reaction yield is similar to that obtained for the implementation mode described above in detail, that is, about 72%.

Example 2

Synthesis of 4-hydroxymethylbutyrolactone of Formula (III) from (S)-furanone of Formula (II)

(18) (S)-4-hydroxymethylbutenolide or (S)-furanone of formula (II) obtained in Example 1 is subjected to catalytic hydrogenation, in the following manner.

(19) Pd/C (10% p/p, 250 mg) is added to a 4-hydroxymethylbutenolide solution (1.4 g, 12.3 mmol) in ethyl acetate (15 mL) at room temperature. The stirring suspension is degassed three times under nitrogen/vacuum. A hydrogen atmosphere at room temperature then hydrogenates the suspension for 4 hours. The crude mixture is filtered through a celite buffer and the filtrate is concentrated to dryness with a silica gel. The crude product is purified by chromatography on silica gel (elution with a gradient from 75% to 100% ethyl acetate in cyclohexane) to give a pure (S)-4-hydroxymethylbutyrolactone of formula (III) (1.19 g, 82%).

(20) .sup.1H NMR (CDCl.sub.3): d 4.64 (m, 1 H), 3.92 (dd, J=2.7 and 12.6 Hz, 1 H), 3.66 (dd, J=4.5 and 12.6 Hz, 1 H), 2.72-2.49 (m, 3 H), 2.35 to 2.09 (m, 2 H)

(21) .sup.13C NMR (CDCl.sub.3): d 177.7 (s), 80.8 (d), 64.1 (t), 28.7 (t), 23.1 (t)

(22) This synthetic route provides with high yields, the (S)-4-hydroxymethylbutyrolactone of formula (III) and S form, whose structure is confirmed by proton and carbon NMR, and polarimetry (optical rotation).

Example 2bis

Synthesis of (S)-4-hydroxymethylbutyrolactone of Formula (III) from dihydrolevoglucosenone

(23) This example is an alternative to Examples 1 and 2 above and is presented in FIG. 3.

(S)(+)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one (III)

(24) To a dihydrolevoglucosenone solution (5.0 g, 39 mmol) in water (30 mL) is added 32% peracetic acid (13 g, 55 mmol) over a period of 30 minutes while maintaining the mixture temperature between 25 C. and 35 C. The mixture is stirred at this temperature for 8 hours, then is neutralized by pouring it on the iron dust (1.0 g) and by stirring until no peroxides (iodine test paper, 5 minutes) and then for an additional 16-hour period. The mixture is then filtered through celite and concentrated under reduced pressure to give an oil-solid mixture. The latter is then suspended in ethyl acetate (50 mL) and filtered to remove the iron salts, which are then washed with ethyl acetate. The organic phases are then combined and concentrated under reduced pressure to provide a colorless oil (4.23 g, 80%, mixture of lactone III, its formate and its acetate). This oil is then taken up in ethanol (40 mL) and is then added IRP-69 (H+) (600 mg), and the mixture is refluxed for 1 hour before being cooled to ambient temperature. The ethanol is evaporated under reduced pressure and the residue is re-dissolved in dichloromethane (10 mL) and stirred for 16 hours. The mixture is then filtered and concentrated under reduced pressure to give (S)-4-hydroxymethylbutyrolactone as a colorless oil (75%).

Example 3

Synthesis of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate of Formula (IVa) from 4-hydroxymethylbutyrolactone of Formula (III)

(25) Tosyl chloride (1.55 g, 8.1 mmol) is added in one portion to a solution constituted by a mixture of 4-hydroxymethylbutyrolactone (0.9 g, 7.7 mmol) in DCM (5 mL)/pyridine (1.5 mL) at room temperature under nitrogen. The reaction mixture is stirred at room temperature for 4 hours. DCM (20 mL) is added and the reaction mixture is rinsed with a solution of HCl 3M, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dry product. This crude product is then triturated with diethyl ether (15 mL). The generated white precipitate is recovered by filtration and dried to obtain a pure product of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate formula (IVa) (1.3 g, 62%), which is then used as is, without further purification for the following synthesis.

(26) .sup.1H NMR (500 MHz): 7.8 ppm (2 H, d); 7.4 ppm (2 H, d); 4.7 ppm (1 H, m); 4.2 ppm (2 H, m); 2.6 ppm (2 H, m); 2.5 ppm (3 H, s); 2.4 ppm (1 H, m); 2.1 ppm (1 H, m)

Example 4

Synthesis of (S)-5-(iodomethyl)dihydrofuran-2(3H)-one (IV-bis-a)

(27) Triphenylphosphine (524 mg, 2 mmol) is added to a 4-hydroxymethylbutyrolactone solution (116 mg, 1 mmol), iodine (508 mg, 2 mmol) and imidazole (136 mg, 2 mmol) in acetonitrile (10 mL) at 0 C. The mixture is then refluxed overnight before being cooled to room temperature and then extracted with ether (320 mL). The organic phases are then combined, washed with water (20 mL), brine (20 mL) then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the crude product is purified by flash chromatography (3:1 hexane:ethyl acetate) on silica gel to give, after combination and evaporation of the pure fractions, the product of formula (IV-bis-a) as a colorless oil (160 mg, 71%).

Example 5

Synthesis of Glycidyl ester of Formula (Va) from the (S)-(5-oxotetrahydrofuran-2-yl) methyl 4-methylbenzenesulfonate of Formula (IVa)

(28) Sodium methoxide (0.7 g, 13 mmol) is added in one portion to a mixture of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate of formula (IVa) tosylated (3 g, 11 mmol) in methanol (20 mL) at 0 C. under nitrogen. The reaction mixture is stirred at room temperature for one hour. Ethyl acetate (100 mL) is added and the reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (50 mL). The phases are separated and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated by drying to obtain a glycidyl ester epoxide (0.9 g, 63%) as an oil. This crude product is used as is to synthesize the following desired product.

(29) .sup.1H NMR (500 MHz): 3.7 ppm (3 H, s); 3.0 ppm (1 H, m); 2.78 ppm (1 H, t) ppm 2.52 (1 H, dd); 2.48 ppm (2 H, t) 2.0 ppm (H, m) 1.8 ppm (1 H, m)

Example 6

Synthesis of Glycidyl ester of Formula (Va) from the (S)-5-(iodomethyl)dihydrofuran-2(3H)-one (IV-bis-a)

(30) Sodium methoxide (0.7 g, 13 mmol) is added in one portion to a mixture of (S)-5-(iodomethyl)dihydrofuran-2(3H)-one (IV-bis-a) (2.5 g, 11 mmol) in methanol (20 mL) at 0 C. under nitrogen. The reaction mixture is stirred at room temperature for one hour. Ethyl acetate (100 mL) is added and the reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (50 mL). The phases are separated and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated by drying to obtain an epoxide glycidyl ester (0.9 g, 63%) as an oil. This crude product is used as is to synthesize the following desired product.

(31) .sup.1H NMR (500 MHz): 3.7 ppm (3 H, s); 3.0 ppm (1 H, m); 2.78 ppm (1 H, t) 2.52 ppm (1 H, dd); 2.48 ppm (2 H, t) 2.0 ppm (1 H, m) 1.8 ppm (1 H, m)

Example 7

Synthesis of methyl (S)-4-hydroxyundec-5-ynoate of Formula (Via) from glycidyl ester of Formula (Va)

(32) N-BuLi (2.5 mol/L in hexane, 3 mL, 8.3 mmol) is added to a mixture of hept-1-yne (750 mg, 7.8 mmol) in dry THF (10 mL) at 78 C. under nitrogen. The reaction mixture is mixed at the same temperature for 20 minutes. BF.sub.3Et.sub.2O (1 mL, 8.3 mmol) is then added at 78 C. The reaction is continued at the same temperature for 20 minutes before incorporating the previously obtained pure glycidyl ester epoxide (1 g, 7.7 mmol). The reaction is continued for 2 hours at 78 C. The reaction mixture, back to 10 C., is then quenched with a saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (330 mL).

(33) The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated by drying. The crude product (absorbed on celite) is purified by flash chromatography (5% to 30% of EtOAc with cyclohexane as eluent) on silica gel to give, after combination and evaporation of the pure fractions, the PRODUCT 6 (700 mg, 40%) as a colorless oil.

Example 8

Synthesis of (S)-5-(oct-2-yn-1-yl)dihydrofuran-2(3H)-one of Formula (VIIa) from methyl (S)-4-hydroxyundec-5-ynoate of Formula (VIa)

(34) A mixture of methyl (S)-4-hydroxyundec-5-ynoate of formula (VIa) (600 mg, 2.6 mmol) in 5 mL of an aqueous solution of 80% acetic acid is heated with stirring at 50 C. for 18 hours. Ethyl acetate (20 mL) is added and the reaction mixture is rinsed with sodium bicarbonate-saturated aqueous solution, brine, then dried over anhydrous magnesium sulfate, filtered and then concentrated by drying. The crude product (absorbed on celite) is purified by flash chromatography (5% to 30% of EtOAc with cyclohexane as eluent) on silica gel to give, after combination and evaporation of the pure fractions, a lactone called (S)-5-(oct-2-yn-1-yl)dihydrofuran-2(3H)-one of formula (VIIa) (275 mg, 53%) as a colorless oil.

Example 9

Synthesis of (Z,S)-dairy-lactone from (S)-5-(oct-2-yn-1-yl)dihydrofuran-2(3H)-one of Formula (VIIa)

(35) A mixture of (S)-5-(oct-2-yn-1-yl)dihydrofuran-2(3H)-one of formula (VIIa) (270 mg, 1.39 mmol) in 10 mL of ethyl acetate is hydrogenated in a stream of dihydrogen stirred with Lindlar catalyst (50 mg) at room temperature for 6 hours. The reaction mixture is filtered through a celite filter and concentrated by drying to obtain the pure (Z)-dairy-lactone (270 mg, 90%) as a colorless oil. The obtained dairy-lactone is of the Z-S form.

(36) .sup.1H NMR (500 MHz): 5.6 ppm (1 H, m); 5.35 ppm (1 H, m); 2.55 ppm (3 H, m); 2.4 ppm (1 H, m); 2.3 ppm (1 H, m); 2.05 ppm (2 H, m); 1.9 ppm (1 H, m); 1.2-1.4 ppm (7 H, m), 0.9 ppm (3 H, t)