Method for the conversion of Abienol to Sclarediol

Abstract

A method of selective conversion of Abienol, represented by formula 1, to Sclareodiol, represented by formula 2 ##STR00001##
by ozonolysis and subsequent reduction. The ozonolysis is carried out at temperatures above 60 C., preferably in nonhalogenated solvents. R is selected from H, acetals, aminals, optionally substituted alkyl groups, such as benzyl group, carboxylates such as acetates or formates, carbonates such as methyl or ethyl carbonates, carbamates, and any protecting group which can be attached to 1 and cleaved from 2, R is selected from CHCH.sub.2, an alkyl moiety with C2-C20, e.g. CH.sub.2CH.sub.3, or a cycloalkyl or polycycloalkyl moiety with C3-C20, e.g. cyclopropyl, optionally alkylated, respectively, and the wavy bond is depicting an unspecified configuration of the adjacent double bond between C2 and C3.

Claims

1. A method of selective conversion of a compound of formula 1 to a compound of formula 2 ##STR00010## by an ozonolysis carried out at temperatures above 60 C. and a subsequent reduction, wherein: R is selected from H, acetals, aminals, alkyl groups, carboxylates, carbonates, carbamates, and any protecting group which can be attached to the compound of formula 1 or cleaved from the compound of formula 2, R is selected from CHCH.sub.2, a C.sub.2-C.sub.20 alkyl moiety, a C.sub.3-C.sub.20 cycloalkyl moiety which may be alkylated, and a C.sub.3-C.sub.20 polycycloalkyl moiety which may be alkylated, wherein in formula 1, the wavy bond depicts an unspecified configuration of the adjacent double bond between C2 and C3.

2. The method of claim 1 wherein the ozonolysis is carried out at a temperature above 20 C.

3. The method of claim 1 wherein the ozonolysis and/or the reduction takes place in a flow reactor.

4. The method of claim 1, wherein the ozonolysis and/or reduction takes place in a non-halogenated solvent or a mixture of non-halogenated solvents.

5. The method of claim 4 wherein the non-halogenated solvent is an alcoholic solvent comprising one or more OH moieties.

6. The method of claim 4 wherein the non-halogenated solvent is ethanol.

7. The method of claim 1 wherein the ozonolysis takes place in a solvent, and the reduction takes place in the same solvent.

8. The method of claim 1, wherein a borohydride reducing agent is used in the reduction.

9. The method of claim 8 wherein NaBH4 is used as reducing agent in a concentration of 0.5-5 mol equiv.

10. The method of claim 1 which yields a compound of formula 2 ##STR00011## wherein: R is selected from acetals, aminals, alkyl groups, carboxylates, acetates or formates, carbonates, carbamates, and any protecting group which can be cleaved from the compound of formula 2 to yield a compound of formula 2a ##STR00012##

11. A method of preparing a compound of formula 3 by the steps of: a) performing a selective conversion of a compound of formula 1 to a compound of formula 2 according to the steps of claim 1, b) subsequently performing a cyclization of the compound of formula 2 to yield a compound of formula 3 ##STR00013##

12. The method of claim 11, wherein the compound of formula 1 is protected on the OH-function and yields the corresponding compound of formula 2 protected on the OH-function.

13. The method of claim 12, wherein the compound of formula 2 protected on the OH-function is directly cyclized to the compound of formula 3.

14. The method of claim 12, wherein the compound of formula 2 protected on the OH-function, is deprotected and subsequently cyclized to the compound of formula 3.

15. A compound of formula 1d ##STR00014## wherein the wavy bond depicts an unspecified configuration of the adjacent double bond between C2 and C3.

Description

EXAMPLE 1

Ozonolysis of Z-(1R,2R,4aS,8aS)-2,5,5,8a-tetramethyl-1-(3-methyl-penta-2,4-dien-1-yl)decahydronaphthalen-2-ol 1a at 15 C. Followed by Immediate Reduction of the Ozonide to (1R,2R,4aS,8aS)-1-(2-hydroxyethyl)-2,5,5,8a-tetramethyldeca-hydronaphthalen-2-ol 2a

(1) Ozone (4% in oxygen, 0.25 m.sup.3/h) is introduced at 20 C. to 15 C. and under stirring to a yellow cloudy solution of Z-(+)-Abienol 55% 1a (10 g, 19 mmol) in ethanol (100 ml) under strong external cooling. After 30 min (and complete conversion of 1a according to TLC) the ozone feed is stopped, and the reaction flask purged with oxygen for 10 min. The colorless cloudy solution of ozonide in ethanol is added to a suspension of sodium borohydride (2.13 g, 56 mmol) in ethanol (20 ml) between 20 C. and 5 C. under strong external cooling and stirring. After complete addition (and a negative peroxide test) the bright yellow reaction mixture is allowed to warm-up to room temperature and the solvent is partially removed by evaporation. The residue is mixed with ice and water (75 ml) under strong stirring. The resulting milky suspension is extracted with tert-butyl methylether (250 ml). The combined organic layers are washed with water (250 ml) and conc. NaCl (225 ml), dried over MgSO.sub.4, filtered and evaporated giving 7.6 g of a light yellow solid which is chromatographed over silicagel (300 g) using a hexane/ethylacetate 66/33 to 100% ethyl acetate gradient giving 0.5 g of (+)-Sclareolide 4 (11%) and 4.15 g (88%) of ()-Sclareodiol 2a as colorless solids.

(2) The analytical data of (+)-Sclareolide 4 were identical to the ones described for the commercially available compound. The analytical data of ()-Sclareodiol 2a were identical to the ones described for this compound, e.g. by L. E. Overman et al. J. Am. Chem. Soc. 135, 15342 (2013).

EXAMPLE 2 (COMPARATIVE)

Ozonolysis of Z-(+)-Abienol 1a Followed by Conversion of the Ozonide to (+)-Sclareolide 4 and Sclareacetal 5 at Ambient Temperatures

(3) Ozone (4% in oxygen, 0.25 m.sup.3/h) is introduced at 20 C. to 15 C. and under stirring to a yellow cloudy solution of Z-(+)-Abienol 55% (10 g, 19 mmol) and internal standard dodecane (0.5 g, 2.9 mmol) in ethanol (100 ml) under strong external cooling. After 30 min (and complete conversion of Z-(+)-Abienol 1a according to TLC) the ozone feed is stopped and the reaction flask purged with oxygen for 10 min. The reaction mixture is allowed to warm-up to room temperature. GC-analysis after 67 h at room temperature shows (+)-Sclareolide 4 (25% according to internal standard [istd]). The colorless cloudy solution of ozonide in ethanol is added to a suspension of sodium borohydride (2.13 g, 56 mmol) in ethanol (20 ml) between 20 C. and 5 C. under strong external cooling and stirring. GC-analysis shows (+)-Sclareolide 4 (17% according to istd) and ()-Sclareodiol 2a (34% according to istd). After a negative peroxide test the bright yellow reaction mixture is mixed with ice and water (75 ml) under strong stirring. The resulting milky suspension is extracted with tert-butyl methylether (250 ml). The combined organic layers were washed with water (50 ml) und conc. NaCl (25 ml), dried over MgSO.sub.4, filtered and evaporated giving 8.1 g of a yellow oil. The crude product is flash-chromatographed over silicagel (300 g) using a hexane/ethylacetate 66:33 to 100% ethylacetate gradient giving 1.9 g of O-ethyl sclaracetal 5 (19%), 1.25 g (13%) of (+)-Sclareolide 4 and 0.5 g (5%) of ()-Sclareodiol 2a as colorless solids.

(4) The NMR-data of Sclaracetal 5 (REt, 2 isomers, ratio 72:28) were identical to the ones described by K. Awano et al. in F&F Journal 20, 18-21 (2005). MS of 5 (EI): 280 (3%, [M].sup.+), 266 (17%), 265 (66%), 201 (10%), 195 (19%), 191 (30%), 178 (11%), 177 (76%), 175 (10%), 150 (18%), 138 (10%), 137 (54%), 136 (24%), 135 (18%), 125 (51%), 123 (68%), 121 (40%), 119 (14%), 99 (11%), 97 (23%), 96 (23%), 95 (92%), 94 (13%), 93 (36%), 91 (26%), 85 (30%), 83 (23%), 82 (60%), 81 (77%), 80 (11%), 79 (16%), 77 (16%), 71 (20%), 69 (95%), 68 (40%), 67 (57%), 57 (22%), 55 (63%), 53 (18%), 43 (100%), 41 (82%), 29 (78%), 27 (21%). IR (film): 2923 (m), 2867 (m), 1457 (m), 1377 (m), 1330 (w), 1224 (w), 1180 (w), 1115 (m), 1096 (m), 1041 (m), 987 (w), 969 (s), 942 (m), 912 (m), 896 (w), 865 (w), 843 (w).

EXAMPLE 3

Ozonolysis of Z-(+)-Abienol 1a at 60 C. Followed by Quench of the Ozonide Upon NaBH4

(5) Ozone (4% in oxygen, 0.25 m.sup.3/h) is introduced at 70 C. to 60 C. and under stirring to a yellow cloudy solution of Z-(+)-Abienol 55% (10 g, 19 mmol) and istd dodecane (0.5 g, 2.9 mmol) in ethanol (100 ml) under strong external cooling. After 30 min (and complete conversion of Z-(+)-Abienol 1a according to TLC) the ozone feed is stopped and the reaction flask purged with oxygen for 10 min. The colorless cloudy solution of ozonide in ethanol is added portionwise to a suspension of sodium borohydride (2.13 g, 56 mmol) in ethanol (20 ml) between 20 C. and 5 C. under strong external cooling and stirring. After a negative peroxide test the bright yellow reaction mixture is mixed with ice and water (75 ml) under strong stirring. The resulting milky suspension is extracted with tert-butyl methyl ether (250 ml). The combined organic layers were washed with water (50 ml) und conc. NaCl (25 ml), dried over MgSO.sub.4, filtered and evaporated giving 7.75 g of a light yellow semi-solid. The crude product is flash-chromatographed over silicagel (300 g) using a hexane/ethylacetate 66:33 to 100% ethylacetate gradient giving 4 g of ()-Sclareodiol 2a (84%) and 0.2 g (4%) of (+)-Sclareolide 4 as colorless solids.

EXAMPLE 4

Ozonolysis and Reduction of Z-4,5-Dihydroabienol 1b

Z-(1R,2R,4aS,8aS)-2,5,5,8a-tetramethyl-1-(3-methylpenta-2,4-dien-1-yl)decahydronaphthalen-2-ol) 1b

(6) ##STR00007##

(7) 30% H.sub.2O.sub.2 in water (186 g, 1.64 mol) is added dropwise to a stirred mixture of Z-(+)-Abienol 55% (1a, 50 g, 95 mmol) and hydrazine hydrate (116 g, 2.43 mol) in ethanol (500 ml) at 5-10 C. within 3.5 h. After another hour at this temperature the mixture is poured onto water and ice (500 ml). Extraction with tert-butyl methyl ether (2250 ml), washing of the combined organic layers with H.sub.2O (100 ml), conc. FeSO.sub.4 (350 ml) and brine (50 ml), drying of the organic phase over MgSO.sub.4, filtration and evaporation of the solvents give 44 g of a brown oil which is purified by flash chromatography over silicagel (600 g) using a hexane/tert-butyl methyl ether gradient of 20:1 to 2:1 to give 28.3 g (81-94% corr) of 4,5-dihydroabienol 1b with 77-90% purity.

(8) Analytical data of 1b: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.2 (t, 1H), 2.2 (m, 1H), 2.0-2.2 (3H), 1.85 (1H), 1.7 (s, 3H), 1.5-1.7 (2H), 1.2-1.5 (7H), 1.2 (s, 3H), 1.1-1.2 (m, 1H), 1.0 (t, 3H), 0.9-1.0 (2H), 0.9 (s, 3H), 0.82 (s, 3H), 0.8 (s, 3H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 136.4 (s, alkene), 126.8 (d, alkene), 74.4 (s), 61.8 (d), 56.1 (d), 43.7 (t), 42.0 (t), 40.0 (t), 38.8 (s), 33.5 (q), 33.3 (s), 24.9 (t), 24.7 (q), 23.6 (t), 23.2 (q), 21.6 (q), 20.6 (t), 18.6 (t), 15.7 (q), 12.8 (q) ppm. MS (EI): 274 (4%, [M-18].sup.+), 259 (3%, [M-18-15].sup.+), 217 (2%), 191 (10%), 178 (8%), 177 (8%), 163 (7%), 150 (8%), 149 (10%), 137 (20%), 136 (100%), 135 (11%), 123 (13%), 121 (29%), 109 (24%), 108 (11%), 107 (78%), 95 (23%), 93 (14%), 91 (10%), 83 (15%), 82 (10%), 81 (17%), 79 (11%), 69 (18%), 68 (13%), 67 (11%), 55 (28%), 43 (17%), 41 (18%). IR (film): 3441 (br), 2961 (w), 2923 (s), 2868 (m), 1458 (m), 1386 (m), 1339 (m), 1190 (w), 1156 (w), 1124 (m), 1083 (m), 1067 (w), 1031 (w), 1012 (w), 995 (w), 970 (w), 936 (s), 909 (w), 824 (w). The IR data were congruent to the ones described by P. F. Vlad et al. J. Gen. Chem. USSR 42, 1839-1854 (1972). Anal. calcd. for C.sub.20H.sub.36O: C, 82.13; H, 12.04. Found: C, 82.15; H, 12.51.

(9) Ozonolysis and reduction of 4,5-Dihydroabienol 1b: as described in example 1 using 4,5-dihydroabienol 1b (5 g, 14 mmol) and sodium borohydride (1.94 g, 51 mmol). Standard work-up and flash chromatography as described gave 2.92 g (82%) of ()-Sclareodiol 2a, 0.12 g (3%) of (+)-Sclareolide 4 and 0.12 g (3%) of Sclareacetal 5 as white solids.

EXAMPLE 5

Ozonolysis and Reduction of Abienol Acetate 1c

Z-(1R,2R,4aS,8aS)-1-(2-hydroxyethyl)-2,5,5,8a-tetra methyldecahydro-naphthalen-2-yl acetate) 1c

(10) ##STR00008##

(11) Under nitrogen atmosphere N,N-dimethylaniline (10.4 g, 86 mmol) is added dropwise to Z-(+)-Abienol 55% (1a, 10 g, 19 mmol) at 50 C. followed by dropwise addition of acetyl chloride (6.8 g, 86 mmol) at 25-35 C. After 2 h at 50 C. the reaction mixture is poured upon 20% aqueous H.sub.2SO.sub.4. Extraction with t-butyl methyl ether, washing of the organic phase with conc. aqueous NaCl, drying over MgSO.sub.4, filtration and evaporation of the solvent gives 9.6 g of a crude which is purified by flash chromatography over 400 g of silicagel using hexane/t-butyl methyl ether 9:1 as eluent, giving 3.75 g of Abienol acetate 1c (41%) with a purity of 69% according to standardized NMR.

(12) Analytical data of 1c: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 6.8-6.9 (m, 1H), 5.4 (m, 1H), 5.0-5.2 (2H), 2.55 (m, 1H), 2.3-2.4 (1H), 2.1-2.2 (1H), 1.87 (s, 3H), 1.8 (s, 3H), 1.8-1.9 (2H), 1.5-1.7 (4H), 1.47 (s, 3H), 0.9-1.45 (5H), 0.85 (s, 6H), 0.8 (s, 3H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 170.2 (s, OAc), 134.0 (d, alkene), 133.9 (d, alkene), 129.8 (s, alkene), 112.9 (t, alkene), 87.4 (s), 58.5 (d), 55.5 (d), 41.8 (t), 39.9 (t), 39.3 (s), 38.6 (t), 33.4 (q), 33.1 (s), 23.5 (t), 22.9 (q), 23.2 21.5 (q), 20.9 (q), 20.0 (t), 19.9 (q), 18.4 (t), 15.7 (q) ppm. MS (EI): 272 (10%, [M-HOAc].sup.+), 257 (5%, [M-HOAc-15].sup.+), 191 (17%), 178 (18%), 163 (9%), 148 (17%), 135 (21%), 134 (100%), 133 (14%), 121 (15%), 119 (73%), 109 (18%), 107 (17%), 105 (20%), 95 (24%), 93 (19%), 91 (16%), 81 (30%), 79 (17%), 69 (19%), 67 (11%), 55 (20%), 43 (43%), 41 (24%). IR (film): 2925 (m), 2870 (w), 1726 (s), 1643 (w), 1459 (w), 1441 (w), 1387 (m), 1367 (m), 1245 (s), 1188 (w), 1154 (w), 1126 (m), 1081 (w), 1066 (w), 1020 (m), 987 (w), 971 (w), 931 (w), 898 (m), 865 (w). The IR data are congruent to the ones described for this compound by P. F. Vlad et al. in J. Gen. Chem. USSR 39, 451 (1969).

(13) Ozonolysis and reduction of abienol acetate 1c: as described in example 1 using abienol acetate 1c (2.5 g, 5.2 mmol) in ethanol (50 ml) and sodium borohydride (0.85 g, 22 mmol) in ethanol (10 ml). Standard work-up and flash chromatography over silicagel (70 g) using a hexane/ethyl acetate 5:1 to 2:1 gradient gave 1.5 g (10%) of sclaral acetate 6 and 1.13 g (73%) of sclareodiol acetate 2c ((1R,2R,4aS,8aS)-1-(2-hydroxyethyl)-2,5,5,8a-tetramethyldeca-hydronaphthalen-2-yl acetate) as white solids.

(14) The analytical data of sclaral acetate 6 (NMR, IR, MS) and sclareodiol acetate 2c (NMR, IR) are identical to the ones described in the literature, e.g. in Synth. Comm. 34, 3631 (2004) and Australian J. Chem. 25, 1767-1778 (1972). MS (EI) of 2c: 236 (34%, [M-HOAc].sup.+), 221 (50%, [M-HOAc-15].sup.+), 195 (9%), 192 (19%), 191 (35%), 177 (39%), 166 (9%), 165 (15%), 163 (13%), 151 (63%), 149 (17%), 138 (10%), 137 (44%), 136 (52%), 125 (20%), 124 (38%), 123 (63%), 121 (34%), 112 (56%), 110 (12%), 109 (95%), 107 (34%), 105 (13%), 97 (23%), 95 (100%), 93 (32%), 91 (16%), 85 (36%), 83 (29%), 82 (29%), 81 (69%), 79 (24%), 71 (26%), 69 (66%), 67 (33%), 60 ([HOAc.sup.+], 4%), 57 (11%), 55 (38%), 43 (84%), 41 (43%).

EXAMPLE 6

Cyclization of Sclareodiol Acetate 2c to ()-Ambrox 3

(15) A mixture of dimethylcarbonate (0.12 g, 1.3 mmol) and NaOMe 30% in MeOH (0.25 g, 1.4 mmol) is added dropwise within 10 min to sclareodiol acetate 2c (0.25 g, 0.85 mmol) in water-free THF (5 ml) at reflux (65 C.). Another 10 ml THF are added to the white slurry. GC-analysis after 2 h at reflux shows complete conversion. After cooling to 25 C. the white suspension is poured onto water (25 ml) and is extracted with t-butyl methyl ether (225 ml). The organic layers are washed with water (25 ml), dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue (237 mg) is purified by flash chromatography over silicagel using hexane/ethyl acetate 5:1 as eluent to give after evaporation of the solvents 133 mg (67%) of ()-Ambrox 3 and Sclareodiol 2a (4%) as white solids.

(16) The analytical data of ()-Ambrox 3 were identical to the ones known from the commercially available compound.

EXAMPLE 7

Ozonolysis and Reduction of -Abienol 1d

Z-(1R,2R,4aS,8aS)-1-(3-cyclopropylbut-2-en-1-yl)-2,5,5,8a-tetramethyl-decahydro-naphthalen-2-ol) 1d

(17) ##STR00009##

(18) Pd(acac).sub.2 (57 mg, 0.2 mmol, 0.5%) is added at 0 C. to a stirred mixture of Z-(+)-Abienol 55% (20 g, 37 mmol) in toluene (50 ml) and 40% aqueous KOH (30 ml). N-Nitroso-dimethylurethane 1.5 M in toluene (52 ml, 74 mmol) is added at 0-5 C. over 2 h. After 18 h at room temperature GC-analysis shows a 54% conversion to -Abienol 1d. Phase separation and extraction with toluene (150 ml) gives an organic phase which is washed with 10% HOAc (100 ml), water (300 ml), 10% NaOH (100 ml) and brine (200 ml). Drying over MgSO.sub.4, filtration and evaporation of the solvent under reduced pressure gives 21.6 g of a viscous brown oil which is dissolved in hexane/t-butyl methyl ether and filtered over a Buchner funnel loaded with 100 g of silicagel using a 100% hexane to hexane/t-butyl methyl ether 2:1 gradient as eluent, giving after evaporation of the solvents 13.7 g of a clear yellow oil which is subjected a second time to the same cyclopropanation procedure, giving after complete conversion (GC) and work-up 12.6 g of a clear yellow oil. Flash chromatography purification through 500 g SiO.sub.2 using a hexane/t-butyl methyl ethyl 10:1.fwdarw.1:1 gradient gives 9.9 g -Abienol 1d (58%) as colorless oil with a purity of 67% according to GC and istd NMR.

(19) Analytical data of 1d: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.4 (m, 1H), 2.45 (m, 1H), 2.15 (m, 1H), 1.1-1.9 (10H), 1.4 (s, 3H), 1.23 (s, 3H), 0.8-1.0 (4H), 0.88 (s, 3H), 0.85 (s, 3H), 0.82 (3H), 0.5-0.65 (5H, ) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 133.9 (s, alkene), 128.2 (d, alkene), 71.8 (s), 61.8 (d), 56.1 (d), 43.6 (t), 41.9 (t), 37.6 (s), 33.5 (q), 33.3 (s), 24.6 (q), 23.1 (t), 21.6 (q), 20.1 (t), 18.8 (q), 18.7 (t), 15.4 (q), 12.3 (d), 2.3 (2 C, t) ppm. GCMS (EI): 286 (8%, [M-18].sup.+), 271 (4%), 191 (17%), 149 (15%), 148 (66%), 147 (12%), 135 (14%), 133 (45%), 123 (15%), 121 (25%), 119 (30%), 109 (29%), 108 (13%), 107 (33%), 105 (22%), 95 (100%), 94 (20%), 93 (44%), 92 (19%), 91 (27%), 83 (15%), 81 (30%), 79 (28%), 77 (16%), 71 (10%), 69 (41%), 67 (38%), 55 (34%), 43 (30%), 41 (34%). IR (film): 3454 (br), 3083 (w), 2922 (s), 2867 (m), 1648 (w), 1458 (m), 1442 (m), 1386 (m), 1364 (w), 1336 (w), 1317 (w), 1274 (w), 1188 (w), 1156 (w), 1125 (m), 1083 (m), 1066 (w), 1033 (m), 1015 (w), 997 (w), 972 (w), 936 (m), 924 (w), 909 (w), 883 (w), 847 (w), 817 (m), 722 (w).

(20) Ozonolysis and reduction of -Abienol 1d: as described in example 1 using -Abienol 1d (2.5 g, 54 mmol) in ethanol (60 ml) and sodium borohydride (0.93 g, 24.6 mmol) in ethanol (10 ml). Standard work-up and flash chromatography through silicagel (70 g) using a hexane/ethyl acetate 2:1 to 100% ethyl acetate gradient gave 40 mg of (+)-Sclareolide 4 (3%) and 1.31 g (94%) of ()-Sclareodiol 2a as white solids.