Efficient Enantioselective Synthesis of (ϩ)-(R,Z)-5-Muscenone and (Ϫ)-(R)-Muscone
FULL PAPER
mol), KOH (25.3 g, 0.45 mol, 0.95 equiv.) and EtOH (1 l) was
heated at reflux for 16 h. The reaction mixture was cooled to room
temperature, poured into 5% HCl, extracted with pentane, washed
(d, J ϭ 14 Hz, 2 H) ppm. 13C NMR: δ ϭ 143.8 (s), 135.5 (s), 131.9
(s) (2 s are not visible), 129.3 (2 d), 128.4 (2 d), 36.9 (t), 32.8 (t),
31.8 (t), 27.7 (d), 26.7 (t), 26.1Ϫ25.2 (5 t), 24.7 (t), 23.9 (t), 21.6
(2 ϫ H2O, then satd. NaCl), dried (Na2SO4), concentrated (115.8 g) (q), 21.3 (q) ppm.
and distilled (100 °C/ 0.07 Torr) to afford (Ϯ)-5 (104.9 g, 95%) as
(؊)-(R)-3-Methyl-5-cyclopentadecyn-1-one [(؊)-(R)-10]: Peracetic
a colorless viscous oil which crystallizes upon standing. M.p.
acid (40%; 5.07 mL, 5.70 g, 30.1 mmol) and water (3.8 mL) were
added whilst stirring to a solution of (S)-9 (4.02 g, 10.0 mmol) in
toluene (102 mL). The two-phase system was warmed to 30 °C and
vigorously stirred for 6 h. Stirring was continued at 25 °C for 15 h.
The phases were separated and the aqueous phase was extracted
with diethyl ether. The organic phases were successively washed
with 10% aq. Na2SO3, water and satd. NaCl, dried (Na2SO4), con-
centrated (2.49 g) and bulb-to-bulb distilled from CaCO3 (1%) at
100 °C/0.06 Torr to afford 1.98 g of (R)-10 (83%, 97% ee) contain-
ing 1% of (S)-5. The ee was determined by reduction of (R)-10 to
the corresponding alcohol diastereomers (LiAlH4, diethyl ether)
1
39Ϫ42 °C. H NMR: δ ϭ 1.05 (d, J ϭ 7 Hz, 3 H), 1.10Ϫ1.80 (m,
14 H), 1.95Ϫ2.20 (m, 3 H), 2.30Ϫ2.60 (m, 6 H) ppm. 13C NMR:
δ ϭ 197.8 (s), 157.1 (s), 136.9 (s), 47.2 (t), 38.8 (t), 32.8 (t), 30.7
(d), 27.4 (t), 27.2 (t), 26.9 (t), 26.3 (t), 26.0 (t), 25.9 (t), 25.4 (t),
24.4 (t), 21.6 (q) ppm. MS: m/z (%) ϭ 234 (31) [Mϩ], 219 (8), 191
(37), 177 (100), 163 (28), 121 (16), 107 (23), 91 (20), 79 (25), 67
(22), 55 (26), 41 (40).
(؉)-(S)-14-Methylbicyclo[9.4.0]pentadec-1(11)-en-12-one [(؉)-(S)-5]
and (؊)-(12R,14R)-14-Methylbicyclo[9.4.0]pentadec-1(11)-en-12-ol
[(؊)-7]: Over a period of 5 h, BH3·SMe2 (11.94 g (14.93 mL),
157.2 mmol) in THF (200 mL) was added at 25Ϫ27 °C to a stirred and injection onto the chiral GC column (good separation of the
solution of (Ϯ)-5 (92.6 g, 396 mmol) and the (S)-oxazaborolidine 6
minor diastereomer). [α]2D0 ϭ Ϫ29.6 (c ϭ 0.05, MeOH). M.p. 38Ϫ39
1
(50 mL, 0.396 , 19.8 mmol) in THF (700 mL).[17] The reaction °C. H NMR: δ ϭ 0.94 (d, J ϭ 7 Hz, 3 H), 1.15Ϫ1.55 (m, 12 H),
was quenched by addition of 5% NaOH (40 mL). After stirring for
1 h, the product was extracted (2 ϫ Et2O), washed (2 ϫ satd.
1.62 (m, 1 H), 1.80 (m, 1 H), 1.97 (m, 1 H), 2.15Ϫ2.50 (m, 7 H),
2.93 (dd, J ϭ 17, 4 Hz, 1 H) ppm. 13C NMR: δ ϭ 211.7 (s), 81.8
NaCl), dried (Na2SO4), concentrated (98.3 g) and distilled (simple (s), 78.6 (s), 49.2 (t), 41.6 (t), 28.2 (d), 28.0 (t), 27.3 (t), 26.8 (t),
distillation; 120 °C/0.15 Torr): 90.0 g of distillate [7 (ϩ 8)/5, 64:36; 26.5 (t), 26.3 (t), 26.1 (t), 25.7 (t), 24.7 (t), 20.1 (q), 18.4 (t) ppm.
383 mmol). A solution of the distillate in CH2Cl2 (800 mL) was MS: 234 m/z ϭ(16) [Mϩ], 219 (20), 177 (20), 149 (17), 135 (32), 121
treated with diisopropylethylamine (96.2 g (126.5 mL), 750 mmol),
succinic anhydride (48.5 g, 485 mmol) and 4-dimethylaminopyrid-
ine (DMAP; 4.4 g, 36.1 mmol). The resulting solution was stirred
at room temperature for 20 h [disappearance of 7 (ϩ 8)], cooled to
0 °C and treated with an excess of 5% aq. NaOH. The organic
phase was separated and the aqueous phase was extracted with
EtOAc (2 ϫ). The combined organic phases were washed with satd.
NaHCO3, H2O (2 ϫ) and satd. NaCl, dried (Na2SO4) and the sol-
vents evaporated (35.8 g). Bulb-to-bulb distillation (100 °C/
0.06 Torr) afforded 33.85 g of (S)-5 (GC: 92% pure; 35% yield; 97%
ee). The aqueous phase was acidified (concd. HCl, ice), and the
acidic parts extracted (2 ϫ Et2O), washed (satd. aq. NaCl), dried
(Na2SO4) and the solvents evaporated (77.4 g). The alcohols (Ϫ)-7
؉8 could be liberated by hydride reduction (LiAlH4, Et2O).
Alternatively, pure (S)-5 (31%) and (Ϫ)-7 (45%; 70% ee) could be
isolated by column chromatography (SiO2; cyclohexane/EtOAc,
97:3). Yield of (Ϫ)-7 after crystallization (heptane, 0 °C): 26% (98%
ee) (chiral GC).
(39), 107 (41), 93 (61), 79 (94), 55 (68), 41 (100).
(؉)-(R,Z)-3-Methyl-5-cyclopentadecen-1-one [(R,Z)-5-Muscenone,
(R)-1]: A solution of (R)-10 (3.38 g, 14.4 mmol) in EtOH (30 mL)
was hydrogenated using 600 mg of Lindlar’s catalyst. After 1 h, the
reaction was complete and the hydrogenation stopped immediately
(sometimes additional catalyst was necessary). Filtration through
Celite, concentration and bulb-to-bulb distillation (80 °C/0.06 Torr)
afforded 3.23 g (95%, 97% ee) of (R)-1 containing 2% of muscone.
[α]2D0 (99 ee from another experiment) ϭ ϩ11.7 (c ϭ 2.45, MeOH).
The ee was determined by reduction of (R)-1 to the corresponding
alcohol diastereomers (LiAlH4, ether) and injection onto the chiral
GC column (excellent separation of the major diastereomer).The
spectroscopic data are in agreement with those reported for (Ϯ)-
1.[1]
(؊)-(R,E)-3-Methyl-5-cyclopentadecen-1-one [(R,E)-5-Muscenone,
(R)-2]: Under argon, a vigorously stirred, cooled (Ϫ30 °C) solution
of (Ϫ)-10 (1.20 g, 5.10 mmol), 1,3-diaminopropane (3.04 g,
3.40 mL, 41.0 mmol) and THF (10 mL) was treated with small
pieces of lithium (287 mg, 41.0 mmol). Stirring was continued for
2.5 h. The reaction mixture became progressively dark blue. The
liquid was decanted from the remaining lithium and poured into
(؉)-(S)-5: [α]2D0 (98% ee from another experiment) ϭ ϩ90.1 (c ϭ
2.7, MeOH). M.p. 51Ϫ52 °C.
(؊)-7 (98% ee): [α]2D0 ϭ Ϫ77.2 (c ϭ 1.4, CHCl3). M.p. 75Ϫ76 °C.
1H NMR: δ ϭ 0.97 (d, J ϭ 7 Hz, 3 H), 1.10Ϫ1.80 (m, 18 H), 1.88 ice/10% HCl whilst the lithium was decomposed with EtOH. The
(m, 1 H), 2.05Ϫ2.20 (m, 2 H), 2.29 (m, 1 H), 2.40Ϫ2.55 (m, 2 H),
muscenones [(E)/(Z) ϭ 11:1] and corresponding alcohols (29% by
4.30 (broad m, 1 H) ppm. 13C NMR: δ ϭ 135.5 (s), 132.7 (s), 69.3 GC) were isolated by extraction with diethyl ether (2 ϫ), followed
(d), 42.3 (t), 37.6 (t), 32.0 (t), 27.4 (d), 26.9Ϫ24.9 (6t), 24.1 (t), 23.3 by washing (satd. NaHCO3, then H2O, then satd. NaCl), drying
(t), 21.9 (q) ppm. MS: m/z (5) ϭ 236 (100) [Mϩ], 221 (78), 218 (35), (Na2SO4) and concentration (1.20 g). The oil was dissolved in ace-
137 (81), 124 (69), 109 (60), 105 (66), 91 (65), 55 (51), 41 (66).
tone (15 mL) and treated at 0 °C with Jones reagent (2.5 ;
0.61 mL). The green reaction mixture was poured onto ice and ex-
tracted as above. The crude oil (1.12 g) was bulb-to-bulb-distilled
(80 °C/0.08 Torr). Yield: 1.04 g (86%) of (R)-2, containing 5% of
(ϩ)-1. [α]2D0 (97 ee) ϭ Ϫ3.3 (c ϭ 0.06, MeOH). The spectroscopic
data are in agreement with those reported for (Ϯ)-2.[1]
(؉)-(S)-14-Methylbicyclo[9.4.0]pentadec-1(11)-en-12-one p-Tolu-
enesulfonylhydrazone [(؉)-(S)-9]: mixture of (S)-5 (23.4 g,
A
100 mmol), tosylhydrazine (20.5 g, 110 mmol), MeOH (200 mL)
and AcOH (3 drops) was heated at reflux for 5 h, stored at 25 °C
overnight (formation of a precipitate), heated again at reflux for
3 h, cooled to 0 °C and filtered. Yield of (S)-9: 35.1 g (87%). [α]2D0
(99% ee from another experiment) ϭ ϩ79.9 (c ϭ 2.1, CHCl3). M.p.
(؊)-(R)-Muscone [(؊)-(R)-3] from (؊)-(R)-10: (Ϫ)-(R)-10 (250 mg,
1.07 mmol) was dissolved in EtOAc (5 mL) and hydrogenated with
(dec.) 157Ϫ159 °C (other sample with 80% ee). 1H NMR: δ ϭ 0.97 Raney-Ni [500 mg of suspension (not optimized), washed success-
(d, J ϭ 7 Hz, 3 H), 1.13Ϫ1.85 (m, 19 H), 2.15 (d, J ϭ 14 Hz, 1 H),
2.25Ϫ2.60 (m, 4 H), 2.41 (s, 3 H), 7.28 (d, J ϭ 14 Hz, 2 H), 7.85
ively with H2O, EtOH and EtOAc] (1 h). Filtration, concentration
and bulb-to-bulb distillation (80 °C/0.08 Torr) afforded (Ϫ)-(R)-3
Eur. J. Org. Chem. 2004, 1953Ϫ1957
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1955