Hydrogen Peroxide → (S)-3,7-dimethyloct-6-en-1-yl methanesulfonate

To S-(−)-citronellol (42.8 g, 0.274 mol) and triethylamine (91 mL, 0.657 mol) in CH2Cl2 (800 mL) at 0° C. was added methanesulphonyl chloride (26 mL, 0.329 mol) in CH2Cl2 (200 mL). After 2 hours at 0° C. the solution was washed with 1N HCl then brine. The organic phase was dried (MgSO4) and concentrated to afford the titled compound an oil (60.5 g, 94%) which was used without further purification. MS, m/z (relative intensity): 139 [100%], 143 [100%]. 1H NMR (400 MHz; CDCl3) δ 5.05 (1H, m), 4.2 (2H, m), 2.95 (3H, s), 1.98 (2H, m), 1.75 (1H, m), 1.6 (3H,s), 1.5 (4H, m), 1.35 (2H, m), 1.2 (1H, m), 0.91 (3H, d, J=6.5 Hz). (R)-2,6-Dimethyl-oct-2-ene. To methanesulfonic acid (S)-3,7-dimethyl-oct-6-enyl ester (60 g, 0.256 mol) in THF (1 L) at 0° C. was added lithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours, a further 3.8 g of lithium aluminum hydride was added and the solution warmed to room temperature. After 18 hours, a further 3.8 g of lithium aluminum hydride was added. After a further 21 hours, the reaction was carefully quenched with 1N citric acid and the solution diluted further with brine. The resultant two phases were separated and the organic phase was dried (MgSO4) and concentrated to afford the titled compound as an oil which was used without further purification. MS, m/z (relative intensity): 139 [M+H, 100%]. (R)-4-Methyl-hexanoic acid. A procedure similar to the synthesis of (R)-4-methyl-heptanoic acid was utilized giving the acid as an oil (9.3 g, 56%). IR (film) 2963, 2931, 2877, 2675, 1107, 1461, 1414 cm−1; MS, m/z (relative intensity): 129 [M−H, 100%]; 1H NMR (400 MHz; CDCl3) δ2.35 (m, 2H), 1.66 (m, 1H), 1.37 (m, 4H), 1.29 (m, 1H), 0.86 (m, 6H); 13C NMR (100 MHz; CDCl3) δ 181.02, 34.09, 32.12, 31.39, 29.29, 18.94, 11.44. (4R,5S)-4Methyl-3-((R)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one. A procedure similar to the synthesis of (4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one was utilized giving the titled compound as an oil (35.7 g, 95%). MS, m/z (relative intensity): 290 [M+H, 100%]; 1H NMR (400 MHz; CDCl3) § 7.4-7.25 (m, 5H), 5.6 (d, J=7.32 Hz, 1H), 4.75 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H), 1.68 (m, 1H), 1.43 (m, 2H), 1.12 (m, 2H), 0.87 (m, 9H); 13C NMR (100 MHz; CDCl3) δ 173.71, 153.24, 133.56, 128.94, 128.90, 125.83, 79.14, 54.95, 34.22, 33.72, 31.07, 29.45, 27.20, 26.52, 19.19, 19.15, 14.77, 14.53, 11.54. (3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-methanoyl]-heptanoic acid tert-butyl ester. A procedure similar to the preparation of (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-arbonyl)-octanoic acid tert-butyl ester was followed giving the titled compound as an oil (7.48 g; 31%). IR (film) 2967, 2934, 1770, 1716, 1696, 1344, 1148, 1121, 1068, 1037, 947 cm−1; MS, m/z (relative intensity): 178 [100%],169 [100%]; [α]D=+21.6 (c 1 in CHCl3). (S)-2-((R)-2-Methyl-butyl)-succinic acid 4-tert-butyl ester. (3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-methanoyl]-heptanoic acid tert-butyl ester (7.26 g, 0.018 mol) in H2O (53 mL) and THF (176 mL) at 0° C. was added a premixed solution of LiOH (37 mL of a 0.8 M solution) and H2O2 (10.57 mL of a 30% solution) and the solution warmed to room temperature. After 2 hours sodium bisulfite (7 g), sodium sulfite (13 g), and water (60 mL) was added and the two layers were separated and the aqueous layer extracted with ether. The combined organic phases were concentrated to an oil that was dissolved in heptane (200 mL). The resultant solid was filtered off and the filtrate dried (MgSO4) and concentrated to afford the titled compound as an oil (4.4 g) that was used without further purification. MS, m/z (relative intensity): 243 [100%]; 1H NMR (400 MHz; CDCl3) δ2.88 (m, 1H), 2.59 (m, 1H), 2.36 (m, 1H), 1.65 (m, 1H), 1.41 (s, 9H), 1.20 (m, 4H), 0.84 (m, 6H) (3S,5R)-3-Benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester-This compound was prepared as described above starting with (S)-2-((R)-2-methyl-butyl) succinic acid, 4-tert-butyl ester to give (3S, 5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester as an oil (73.3% yield). 1H NMR (400 MHz; CDCl3) δ 0.84(t, 3H, J=7.33 Hz), 0.89(d, 3H, J=6.60 Hz), 1.12-1.38 (m, 4H), 1.41 (s, 9H), 1.43-1.59 (m, 2H), 2.42 (m, 2H), 4.05 (m, 1H), 5.07 (t, 2H J=12.95 Hz), and 7.28-7.34 (m, 5H). (3S,5R)-Amino-5-methyl-heptanoic acid, tert-butyl ester—This compound was prepared as described above starting with (3S,5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester instead of (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester to give the titled compound. 1H NMR (400 MHz; CDCl3) δ 0.84 (overlapping t and d, 6H), 1.08-1.16(m, 2H), 1.27-1.30(m, 2H), 1.42(s, 9H), 1.62 (br s, 2H), 2.15 (dd, 1H, J=8.54 and 15.62 Hz), 2.29(dd, 1H, J=4.15 and 15.37 Hz), and 3.20(br s, 2H). (3S, 5R)-Amino-5-methyl-heptanoic acid hydrochloride-A slurry of (3S, 5R)-amino-5-methyl-heptanoic acid, tert-butyl ester (1.44 g, 6.69 mmol) in 3N HCl was heated at reflux for 3 hours, filtered hot over Celite, and concentrated to dryness. Trituration of the resulting solid in ethyl ether provided (3S,5R)-3-amino-5-methyl-heptanoic acid hydrochloride, (0.95 g, 85%) mp 126.3-128.3° C. 1H NMR (400 MHz; CD3OD) δ 0.92 (t, 3H, J=7.32 Hz), 0.92 (d, 3H, J=6.35 Hz), 1.15-1.24 (m, 1H), 1.33-1.43 (m, 2H), 1.44-1.52 (m, 1H), 1.60-1.67 (m, 1H), 2.57 (ddd, 1H, J=7.32 17.67 and 5.12 Hz), 2.69 (ddd, 1H, J=0.97, 4.88 and 17.32 Hz), and 3.28 (m, 1H). Anal. Calc'd for C6H17NO2.HCl.0.1H2O: C, 48.65; H, 9.29, N, 7.09, Cl: 17.95. Found: C, 48.61; H, 9.10, N, 7.27, Cl: 17.87MS: M+1: 160.2.

1. customthe two layers were separated
2. extractionthe aqueous layer extracted with ether
3. concentrationThe combined organic phases were concentrated to an oil that
4. dissolutionwas dissolved in heptane (200 mL)
5. filtrationThe resultant solid was filtered off
6. dry with materialthe filtrate dried (MgSO4)
7. concentrationconcentrated

ORD record

ord-5028d8477880422d984038ad6a0ea5c5

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07517909B2