J. Bergmann, C. Löfstedt, V. D. Ivanov, W. Francke
FULL PAPER
All syntheses were carried out under argon. Solvents were distilled
prior to use and dried according to standard procedures. For col-
umn chromatography, Merck silica gel (0.040Ϫ0.063 mm) was
sphane (2.63 g, 10 mmol), and 2-methylpentan-1-ol (815 mg,
8.0 mmol) yielded 1.04 g (78 %) of rac-9c. Ϫ 1H NMR (400.1 MHz,
3
2
CDCl3): δ ϭ 3.40 (dd, J1a,2 ϭ 5.1, J1a,1b ϭ 9.7 Hz, 1 H, H-1a),
3
2
used. Mass spectra were recorded by using a combination GC8008/ 3.32 (dd, J1b,2 ϭ 6.1, J1b,1a ϭ 9.7 Hz, 1 H, H-1b), 1.86Ϫ1.75 (m,
MD800 (Fisons) equipped with fused silica capillaries coated with
DB5 (30 m ϫ 0.25 mm ID; programmed from 60 to 300 °C at 5
1 H, H-2), 1.47Ϫ1.16 (m, 4 H, H-3,4), 1.01 (d, 3J2Ј,2 ϭ 6.6 Hz, 3 H,
H-2Ј), 0.91 (t, 3J5,4 ϭ 7.1 Hz, 3 H, H-5). Ϫ 13C NMR (100.6 MHz,
°C/min.) or 60% octakis-(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodex- CDCl3): δ ϭ 41.8 (Ϫ), 37.0 (Ϫ), 35.0 (ϩ), 20.0 (Ϫ), 18.8 (ϩ), 14.4
trin in OV1701 (25 m ϫ 0.25 mm ID; programmed from 40 to 120 (ϩ). Ϫ MS (70 eV): m/z ϭ 39 (23), 41 (58), 42 (20), 43 (100), 55
°C at 2 °C/min.). NMR spectra were recorded with a Bruker (11), 57 (6), 69 (5), 71, (9), 85 (55), 93 (1), 95 (1), 121 (1), 123 (1),
AMX400 using TMS as the internal standard. Optical rotatory
values were obtained with a PerkinϪElmer 341 in 10 cm cuvettes
at 20 °C.
164 (0.2) [Mϩ], 166 (0.2) [Mϩ].
rac-4,6-Dimethyl-3-nonanone (rac-4c): According to the procedure
described above for rac-4b, 2 (3.60 g, 28 mmol), and rac-9c (4.60 g,
28 mmol) were reacted and, after oxidative cleavage, yielded 1.68 g
(35 %) of rac-4c. Ϫ 1H NMR (400.1 MHz, CDCl3): δ ϭ 2.70Ϫ2.57
(m, 1 H, H-4), 2.54Ϫ2.37 (m, 2 H, H-2), 1.72Ϫ1.64 (m, 1 H, H-6),
1.47Ϫ1.19 (m, 6 H, H-5,7,8), 1.05 (d, J ϭ 7.1 Hz, 3 H, H-4Ј), 1.04
(d, J ϭ 6.1 Hz, 3 H, H-6Ј), 0.87 (t, J ϭ 7.6 Hz, 3 H), 0.86 (t, J ϭ
7.6 Hz, 3 H). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 215.6 (o),
43.9 (ϩ), 40.8 (Ϫ), 34.2 (Ϫ), 30.3 (ϩ), 20.0 (Ϫ), 19.9 (Ϫ), 17.4 (ϩ),
16.3 (ϩ), 14.3 (ϩ), 7.8 (ϩ). Ϫ MS (70 eV): m/z ϭ 41 (29), 43 (47),
55 (13), 57 (100), 69 (5), 71 (31), 86 (49), 87 (4), 99 (4), 113 (2), 127
(1), 141 (1), 155 (1), 170 (1) [Mϩ].
1-Bromo-2-methylbutane (rac-9b): Bromine (1.51 mL, 29 mmol)
was added slowly to a solution of triphenylphosphane (7.60 g,
29 mmol) in 25 mL dry dichloromethane at 0 °C. Subsequently, 2-
methylbutan-1-ol (8b; 3.11 mL, 29 mmol) was added dropwise at
the same temperature. After 1 h the mixture was allowed to warm
to room temperature, most of the dichloromethane was distilled
off, and 20 mL pentane was added. The solution was stored for
about 12 h in the refrigerator to allow the produced triphenylphos-
phane oxide to precipitate. The white precipitate was filtered off,
carefully washed with pentane, and the filtrate was concentrated.
The residue was distilled to yield 2.41 g (55 %) of a colorless liquid.
1
(S)-1-Bromo-2-methylbutane [(S)-9b]: The synthesis was essentially
the same as for rac-9b. Bromine (1.51 mL, 29 mmol), triphenylpho-
sphane (7.60 g, 29 mmol), and (S)-2-methylbutan-1-ol (8b; 3.11
mL, 29 mmol) yielded 2.41 g (55 %) of (S)-9b. Same NMR and MS
data as for rac-9b, [α]D ϭ ϩ3.8 (c ϭ 5.0, CHCl3) (ref.:[20] ϩ3.74).
bp760 ϭ 118 °C. Ϫ H NMR (400.1 MHz, CDCl3): δ ϭ 3.40 (dd,
J ϭ 9.7, J ϭ 5.1 Hz, H-1a), 3.34 (dd, J ϭ 9.7, J ϭ 6.1 Hz, H-1b),
1.76Ϫ1.67 (m, 1 H, H-2), 1.53Ϫ1.44 (m, 1 H, H-3), 1.34Ϫ1.23 (m,
1 H, H-3), 1.01 (d, J ϭ 6.6 Hz, 3 H, H-2Ј), 0.91 (t, J ϭ 7.6 Hz, 3
H, H-4). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 41.1 (Ϫ, C1), 36.8
(ϩ, C2), 27.6 (Ϫ, C3), 18.4 (ϩ), 11.3 (ϩ). Ϫ MS (70 eV): m/z ϭ 39
(25), 41 (63), 42 (19), 43 (49), 53 (6), 55 (36), 56 (10), 57 (35), 69
(4), 70 (4), 71 (100), 72 (5), 93 (3), 95 (3), 107 (2), 109 (2), 121 (6),
123 (6), 150 (3) [Mϩ].
(4S,6S)-4,6-Dimethyl-3-octanone [(4S,6S)-4b]: To a stirred solution
of diisopropylamine (1.30 mL, 9 mmol) in 50 mL dry diethyl ether
was added butyllithium (1.6 solution in hexane; 5.65 mL,
9 mmol) at 0 °C. After 15 min. of additional stirring, 3-pentanone-
SAMP-hydrazone (5; 1.76 g, 9 mmol) in 10 mL dry diethyl ether
was added dropwise. The mixture was stirred at 0 °C for 4 h, then
cooled to approx. Ϫ110 °C (pentane/liq. nitrogen), and (S)-9b
(1.40 g, 9 mmol) was added dropwise. The mixture was stirred for
about 12 h and allowed to warm to room temperature. It was then
poured into a mixture of 150 mL diethyl ether/30 mL water and
extracted three times with 20 mL portions of diethyl ether. The
combined organic extracts were washed with 30 mL water, dried
with anhydrous magnesium sulfate, and concentrated. The crude
product was dissolved in 40 mL dry dichloromethane, cooled to
Ϫ60 °C, and ozone was passed through the solution until it turned
green. It was then warmed to room temperature, and the solvent
was distilled off. The residue was chromatographed on silica (hex-
ane/ethyl acetate, 50:1) to yield 356 mg (26 %) of (4S,6S)-4b. Same
NMR and MS data as for rac-4b. Ϫ [α]D ϭ ϩ21.0 (c ϭ 1.3, hex-
ane), ee (chiral GC) ϭ 98 %. Ϫ HR-MS: calcd. 156.1514; found
156.1517.
rac-4,6-Dimethyl-3-octanone (rac-4b): To a stirred solution of diiso-
propylamine (1.16 mL, 8 mmol) in 100 mL dry tetrahydrofuran was
added butyllithium (1.6 solution in hexane; 5.00 mL, 8 mmol) at
0 °C and the mixture stirred for 15 min. Subsequently, 3-pen-
tanone-dimethylhydrazone (2; 1.03 g, 8 mmol) was added, and the
mixture was stirred for an additional 2 h at the same temperature.
The solution was then cooled to Ϫ78 °C and, rac-9b (1.20 g,
8 mmol) was added. This mixture was stirred for about 12 h and
then allowed to warm to room temperature. It was then poured
into a mixture of 150 mL water and 50 mL dichloromethane, and
the layers were separated. The aqueous layer was extracted three
times with 50 mL portions of dichloromethane. The combined or-
ganic layers were washed with brine, dried with anhydrous magnes-
ium sulfate, and concentrated. The residue was dissolved in 50 mL
of methanol and 10 mL of 1 phosphate buffer (pH 7), and
30 mmol of sodium periodate in 80 mL water was added. This mix-
ture was stirred for 3 h. The precipitate was filtered off and washed
with dichloromethane. The filtrate was extracted with dichlorome-
thane, and the combined organic layers were washed with brine,
dried and concentrated. The residue was chromatographed on silica
(2S)-2-Methyl-3-penten-1-ol (7): To a suspension of [(R)-3-hydroxy-
2-methylpropyl]triphenylphosphonium
bromide
(6;
10.0 g,
24,1 mmol) in 100 mL dry tetrahydrofuran, was added butyllithium
(1.6 solution in hexane; 30.0 mL, 48 mmol) at Ϫ25 °C. After
stirring for 10 min., freshly distilled acetaldehyde (2.00 mL,
35.5 mmol) was added at the same temperature. The reaction mix-
ture was then allowed to warm to room temperature. Subsequently,
100 mL of saturated aqueous ammonium chloride was added, and
the mixture was extracted three times with 50 mL portions of a 1:1
(v/v) pentane/diethyl ether mixture. The combined organic extracts
were dried with magnesium sulfate and concentrated under reduced
pressure. The precipitated triphenylphosphane oxide was filtered
off and washed carefully with pentane. The filtrate was again con-
1
(hexane/ethyl acetate, 50:1) to yield 540 mg (44 %) of rac-4b. Ϫ H
NMR (400.1 MHz, CDCl3): δ ϭ 2.69Ϫ2.60 (m, 1 H, H-4),
2.54Ϫ2.36 (m, 2 H, H-2), 1.74Ϫ1.65 (m, 1 H, H-6), 1.37Ϫ1.24 (m,
4 H, H-5,7), 1.04 (pseudo-t, 6 H, H-4Ј,6Ј), 0.90Ϫ0.83 (m, 6 H, H-
1,8). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 216.0 (o), 43.9 (ϩ),
40.4 (Ϫ), 34.2 (Ϫ), 32.3 (ϩ), 22.7 (Ϫ), 19.3 (ϩ), 17.4 (ϩ), 14.1 (ϩ),
7.8 (ϩ). Ϫ MS (70 eV): m/z ϭ 39 (11), 41 (27), 43 (7), 55 (14), 57
(100), 71 (2), 86 (23), 99 (2), 127 (1), 156 (0.1) [Mϩ].
1-Bromo-2-methylpentane (rac-9c): This synthesis was essentially
the same as for rac-9b. Bromine (0.53 mL, 10 mmol), triphenylpho-
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Eur. J. Org. Chem. 2001, 3175Ϫ3179