Synthesis of (R)-(−)-Muscone from (R)-5-Bromo-4-methylpentanoate: A Chiron Approach
25
forded ketone 13 (0.53 g, 76%) as a colorless oil. [α]D
aqueous phase extracted with EtOAc for three times.
1
+2.9 (c 2.0, CHCl3); H NMR (CDCl3, 300 MHz) δ:
The combined organic layers were washed with sturated
aqueous NaHCO3 solution and brine, dried over Na2SO4,
and concentrated in vacuo. Distillation under reduced
pressure (45 ℃/10 mmHg) provided alkene 10 (880 mg,
5.75-5.86 (m, 1H), 4.90-5.03 (m, 2H), 4.61 (s, 2H),
3.50 (t, J=6.6 Hz, 2H), 3.36 (s, 3H), 2.33-2.42 (m,
3H), 2.18-2.25 (m, 1H), 1.98-2.06 (m, 3H), 1.50-
1.64 (m, 4H), 1.27-1.35 (m, 12H), 0.88 (d, J=6.9 Hz,
3H); IR (KBr) ν: 2929, 2856, 1714, 1112, 1047 cm−1;
EIMS (70 eV) m/z (%): 281 (M+−31, 100). Anal. calcd
for C19H36O3: C 73.03, H 11.61; found C 73.04, H
11.23.
25
73%) as a colorless liquid. [α]D +3.19 (c 0.94, MeOH,
lit. +2.94, c 0.9, MeOH); 1H NMR (CDCl3, 300 MHz)
δ: 5.77-5.87 (m, 2H), 4.93-5.04 (m, 4H), 2.30-2.36
(m, 3H), 2.18-2.24 (m, 1H), 1.97-2.05 (m, 4H), 1.54
-1.62 (m, 3H), 1.24-1.37 (m, 12H), 0.88 (d, J=6.3
Hz, 3H); IR (KBr) ν: 3076, 2926, 2854, 1713, 909 cm−1;
EIMS (70 eV) m/z (%): 264 (M+, 100).
(R)-4-Methyl-6-oxohexadec-15-enal (14)
A solution of ketone 13 (3.2 g, 12.1 mmol) in MeOH
was added concentrated HCl (0.50 mL) and heated to
reflux for 6 h. The solvent was removed and the residue
was dissolved in EtOAc (200 mL), washed with satu-
rated aqueous NaHCO3 solution and brine, dried over
Na2SO4, and concentrated in vacuo. Flash column
chromatography on silica gel afforded alcohol (2.7 g,
98%) as a colorless oil, which was directly used in the
(R)-3-Methylcyclopentadec-6-en-1-one (16)
To a solution of diene 10 (60 mg, 0.23 mmol) in dry
benzene (60 mL) at ambient temperature under argon
was added bis(tricyclohexylphosphine)benzylidene ru-
thenium(IV) dichloride (15, 19 mg, 0.02 mmol) in ben-
zene (10 mL). The mixture was heated to reflux for 36 h
before filtered through a pad of Florisil/silica. The pad
was washed with CH2Cl2, and the solvent was removed
by evaporation. The residue was purified by flash col-
umn chromatography on silica gel to yield 16 (40 mg,
74%) as a colorless oil, along with a dimer (10 mg,
25
next step. [α]D +3.8 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ: 5.77-5.86 (m, 1H), 4.90-5.03 (m, 2H),
3.64 (br s, 2H), 2.34-2.44 (m, 3H), 2.20-2.27 (m, 1H),
1.98-2.06 (m, 3H), 1.50-1.58 (m, 4H), 1.23-1.38 (m,
12H), 0.89 (d, J=6.6 Hz, 3H); IR (KBr) ν: 3407, 2929,
2856, 1712 cm−1; ESIMS (m/z): 269 ([M+H]+). Anal.
calcd for C17H32O2: C 75.54, H 11.89; found C 75.55, H
12.06.
To a solution of oxalyl chloride (0.24 mL, 2.7 mmol)
in CH2Cl2 (10 mL) cooled at −78 ℃ was added drop-
wise a solution of dimethylsulfoxide (DMSO 0.4 mL,
5.6 mmol) in CH2Cl2 (5 mL). After 1 h, a solution of
alcohol (0.5 g, 1.9 mmol) in CH2Cl2 (5 mL) was added.
The reaction mixture was then stirred for 1 h at −78 ℃
and triethylamine (2 mL) was added in one portion. Af-
ter 15 min at −78 ℃, the mixture was allowed to warm
to room temperature over 3 h, and quenched with water.
The mixture was diluted with CH2Cl2, washed with wa-
ter and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. Flash
column chromatography on silica gel gave aldehyde 14
1
19%). H NMR (CDCl3, 300 MHz) δ: 5.32-5.40 (m,
2H), 2.34-2.45 (m, 3H), 2.02-2.20 (m, 6H), 1.54-
1.63 (m, 1H), 1.25-1.38 (m, 13H), 0.91 (d, J=6.6 Hz,
3H); IR (KBr) ν: 2928, 2855, 1710, 1459, 971 cm−1;
+
1
EIMS m/z (%): 237 (M +1, 100). For dimer: H NMR
(CDCl3, 300 MHz) δ: 5.37-2.43 (m, 4H), 2.36-2.43
(m, 6H), 1.96-2.23 (m, 12H), 1.54-1.62 (m, 2H),
1.20-1.38 (m, 26H), 0.86-0.94 (m, 6H); IR (KBr) ν:
2926, 2852, 1706, 1467, 1407, 1375, 973 cm−1; ESIMS
(m/z): 495([M+H]+).
(R)-3-Methylcyclopentadecan-1-one (1, muscone)
A reaction flask containing alkene 16 (30 mg, 0.13
mmol), Pd/C (10%, 5 mg), and MeOH (10 mL) was
evacuated and back-filled with hydrogen (1 atm). The
reaction mixture was stirred at 40 ℃ under hydrogen
for 5 h and then filtered over a plug of silica gel topped
with Celite (MeOH eluent). The filtrate was concen-
trated and purified by flash column chromatography on
silica gel to give muscone (1, 28 mg, 93%) as a color-
25
(0.46 g, 92%) as a colorless liquid. [α]D +4.6 (c 0.87,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ: 5.79-5.89 (m,
1H), 4.95-5.02 (m, 2H), 2.22-2.50 (m, 6H), 1.98-
2.04 (m, 3H), 1.27-1.57 (m, 14H), 0.89 (d, J=6.9 Hz,
3H); IR (KBr) ν: 2929, 2856, 1713, 1460, 1412 cm−1;
ESIMS (m/z): 267 ([M+H]+). Anal. calcd for C17H30O2:
C 76.64, H 11.35; found C 76.20, H 11.12.
25
less oil. [α]D −12.4 (c 0.92, MeOH, lit. −12.7, c 0.9,
MeOH); 1H NMR (CDCl3, 300 MHz) δ: 2.38-2.46 (m,
3H), 2.18 (dd, J=5.1, 15.0 Hz, 1H), 1.97-2.11 (m, 1H),
1.57-1.68 (m, 2H), 1.15-1.40 (br, 20H), 0.92 (d, J=
6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 21.0, 23.0,
25.0, 26.1, 26.2, 26.52, 26.57, 26.6, 26.7, 27.1, 27.5,
29.0, 35.5, 42.0, 50.4, 212.0; IR (KBr) ν: 2962, 2929,
2858, 1714, 1461, 1261, 1093, 1021 cm−1; EIMS m/z
(%): 238 (M+, 100); HRMS-EI M+ calcd for C16H30O:
238.2297, found 238.2308.
(R)-5-Methylheptadeca-1,16-dien-7-one (10)
To a suspension of methyltriphenylphosponium io-
dide (2.0 g, 5.0 mmol) in dry THF (20 mL) at ambient
temperature under argon was added n-BuLi (2.4 mL of
2.0 mol/L solution in hexanes, 4.8 mmol). The mixture
was stirred for 1 h, cooled to −78 ℃, and a solution of
the aldehyde 14 (1.2 g, 4.5 mmol) in THF (10 mL) was
added. The mixture was allowed to warm to room tem-
perature for 24 h and quenched with a saturated aqueous
solution of NH4Cl. The phases were separated, and the
Results and Discussion
Our group’s efforts in developing new degradation
methods of steroidal sapogenins allowed us to collect
Chin. J. Chem. 2015, 33, 683—687
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
685