522
T. Yamamoto et al. / Tetrahedron 59 (2003) 517–524
analysis {d 1.19 (d, 3H, J¼6.2 Hz))(a) 1.185 (d, 3H,
J¼6.2 Hz)þ(b) 1.189 (d, 3H, J¼6.2 Hz), d 0.91 (d, 3H,
J¼6.6 Hz))(a) 0.908 (d, 3H, J¼6.6 Hz)þ(b) 0.912 (d, 3H,
98%ee by gas chromatographic analysis using a chiral
stationary phase. MS (m/e); 168 (Mþ, 42%), 153 (14), 135
(21), 125 (47), 110 (64), 95 (53), 83 (60), 69 (100), 43 (66).
1
1
J¼6.6 Hz)}. H NMR (CDCl3); d 5.10 (t, 1H, J¼7.1 Hz),
IR (NaCl); 1708 cm21. H NMR (CDCl3); d 2.16 (s, 3H),
3.89 (dq, 1H, J¼12.8, 6.2 Hz), 2.0 (m, 2H), 1.68 (s, 3H),
1.60 (s, 3H), 1.55 (m, 1H), 1.5 (m, 1H), 1.4 (m, 2H), 1.19 (d,
3H, J¼6.2 Hz), 1.1 (m, 1H), 0.91 (d, 3H, J¼6.6 Hz). MS
(m/e); 170 (Mþ, 10%), 152 (2), 137 (8), 109 (70), 95 (65), 82
(100), 69 (80), 55 (50), 43 (76). IR (NaCl); 3343 cm21 (br).
HRMS calcd for C11H22O; 170.1671, found 170.1702.
2.07 (d, 1H, J¼11.2 Hz), 1.8 (m, 1H), 1.7 (m, 1H), 1.5 (m,
2H), 1.4 (ddd, 1H, J¼1.4, 3.3, 13.1 Hz), 1.2 (m, 1H), 0.96 (s,
3H), 0.93 (s, 3H), 0.9 (m, 1H), 0.8 1 (d, 3H, J¼6.3 Hz).
HRMS calcd for C11H20O; 168.1514, found 168.1518.
(1S,6S)-5; GC/MS (m/e); 168 (Mþ, 34%), 153 (10), 135
(17), 125 (20), 110 (62), 99 (100), 85 (45), 69 (89), 43 (62).
3.2.2. (4S)-4,8-Dimethyl-7-nonen-2-one {(4S)-3}. Jones
reagent, prepared by mixing water (260 g), conc. H2SO4
(83 g, 0.83 mol) and CrO3 (56 g, 0.56 mol), was added
dropwise into an acetone (1 L) solution of the (4S)-alcohol 2
(120 g, 0.71 mol) with stirring at 0–58C for 4 h. After
stirring for further 2 h at the same temperature, NaHSO3
was gradually added until the orange color of the chromium
(VI) disappeared. The mixture was worked up as usual, and
subsequent distillation to give the (4S)-ketone 3 {97 g,
0.58 mol, 81.7%; bp 638C/1.0 Torr, [a]2D4¼210.78 (c 1.00,
EtOH), GC; 99.5%}. MS (m/e); 168 (Mþ, 19%), 150 (8),
135 (25), 110 (58), 95 (100), 85 (42), 69 (47), 43 (64). IR
3.2.5. (1S,6R)-2,2,6-Trimethylcyclohexyl methyl ketone
{(1S,6R)-5}. The (6R)-ketone 5 {(1S,6R)/(1R,6R)¼98.7/1.3;
bp 788C/9 Torr, [a]2D4¼þ23.798 (c 1.07, EtOH)} was
synthesized starting from the (3R)-aldehyde 1 in the same
manner as the synthesis of the (1R,6S)-5. Further purifi-
cation by column chromatography (hexane/EtOAc¼95/5)
gave the geometrically pure trans-ketone (1S,6R)-5 {[a]2D4¼
þ23.928 (c 1.03, EtOH)} for the odor evaluation.
3.3. (E)-(1R,6S)- and (1S,6R)-1-(2,2,6-Trimethylcyclo-
hexyl)-2-buten-1-one {(E)-(1R,6S)- and (E)-(1S,6R)-6}
(NaCl); 1716 cm21 1H NMR (CDCl3); d 5.09 (t, 1H,
.
J¼7.1 Hz), 2.42 (dd, 1H, J¼5.6, 15.7 Hz), 2.22 (dd, 1H,
J¼8.2, 15.7 Hz), 2.0 (m, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.3
(m, 1H), 1.2 (m, 1H), 0.91 (d, 3H, J¼6.6 Hz). HRMS calcd
for C11H20O; 168.1514, found 168.1526.
3.3.1. (6S)-1-(2,2,6-Trimethylcyclohexyl)-2-buten-1-one
{(1R,6S)/(1S,6S)598.9/1.1} {(6S)-6}. Under a nitrogen
atmosphere, N-methylaniline (48.2 g, 0.45 mol) in toluene
(70 ml) was added dropwise to the THF solution (160 ml) of
ethylmagnesium bromide (0.45 mol) with stirring at 0–58C
for 1 h. The (6S)-ketone 5 (trans/cis¼98.6/1.4; 75.6 g,
0.45 mol) in toluene (80 ml) was added dropwise to the
N-methylanilinomagnesium bromide solution with stirring
at 08C for 0.5 h, followed by stirring at 08C for 0.5 h to
complete the reaction. Acetaldehyde (29.7 g, 0.68 mol) in
toluene (50 ml) was then added dropwise to the mixture
with stirring at 08C for 0.5 h and for an additional 1.5 h at
08C. The mixture was decomposed with 3N HCl (150 ml)
and the organic layer was washed three times with 3N HCl
(100 ml). The organic layer was refluxed in the presence of
PTSA (0.5 g) to remove the water produced by dehydration
of the aldol adducts (6S)-4-(2,2,6-trimethylcyclohexyl)-4-
oxo-butan-2-ol (15). The cooled mixture was worked up as
usual, followed by distillation to give the (6S)-enone 6
{(1R,6S)/(1S,6S)¼98.9/1.1; 28 g, 65.4% from the (6S)-
ketone 5; bp 73–758C/0.15 Torr, [a]2D4¼216.108 (c 1.03,
EtOH)}. Compositions of the four diastereomers of the (6S)-
enone 6 by GC were (E)-(1R,6S)-6; 93.1%, (Z)-(1R,6S)-6;
5.8%, (E)-(1S,6S)-6; 1.0%, (Z)-(1S,6S)-6; 0.1%.
3.2.3. (4S)-4, 8-Dimethyl-2,7 (and 1,7)-nonadien-2-yl
acetate {(4S)-4}. A mixture of PTSA (19 g, 0.1 mol) and
toluene (40 ml) was refluxed to remove any water for 1 h,
and then cooled to room temperature. The mixture of the
(4S)-ketone 3 (168 g, 1.0 mol) and isopropenyl acetate
(220.3 g, 2.2 mol) was then added to the solution and
the mixture was heated to 90–1188C for 18 h with slow
removal of the generated acetone by distillation. The
mixture was subjected to the next step without any handling.
Sampling analysis of the reaction mixture by GC showed
presence of three isomers of the enol acetates (4S)-4 with
the composition of (4S)-4a (67.8%), (4S)-4b (26.0%) and
(4S)-4c (6.2%). GC/MS: (4S)-5a; 210 (Mþ, 1%), 168 (17),
150 (68), 135 (38), 109 (77), 95 (57), 85 (100), 69 (47), 43
(100), (4S)-5b; 210 (Mþ, 1%), 168 (10), 150 (57), 135 (30),
109 (68), 95 (43), 85 (98), 69 (36), 43 (100), (4S)-5c; 210
(Mþ, 1%), 167 (8), 150 (64), 135 (38), 109 (100), 95 (75), 85
(30), 69 (62), 43 (94).
3.2.4. (1R,6S)-2,2,6-Trimethylcyclohexyl methyl ketone
{(1R,6S)-5}. To the reaction solution containing a mixture
of enol acetates (4S)-4, 85% H3PO4 (25 g) and toluene
(750 ml) were added dropwise with stirring at 95–1108C
and then the mixture was stirred for an additional 24 h to
complete the cyclization reaction. The mixture was worked
up as usual, followed by distillation, gave the (6S)-ketone 5
{(1R,6S)/(1S,6S)¼98.6/1.4; 104.3 g, 62.1% yield from the
(4S)-3; bp 788C/9 Torr, [a]2D4¼223.788 (c 1.03, EtOH)}.
Further purification by column chromatography (hexane/
EtOAc¼95/5) gave the geometrically pure trans-ketone
(1R,6S)-5 {[a]2D4¼223.928 (c 1.03, EtOH)} for the odor
evaluation.
GC/MS: (E)-(1R,6S)-6; 194 (Mþ, 30%), 179 (43), 151 (57),
125 (28), 111 (55), 95 (19), 83 (33), 69 (100). (Z)-(1R,6S)-6;
194 (Mþ, 15%) 17 9 (15), 151 (23), 125 (15), 109 (23), 95
(11), 83 (21), 69 (100). (E)-(1S,6S)-6; 194 (Mþ, 18%), 179
(45), 151 (38), 125 (73), 111 (43), 95 (23), 83 (17), 69 (100).
(Z)-(1S,6S)-6; 194 (Mþ, 1%), 179 (1), 153 (23), 125 (64),
109 (5), 95 (4), 83 (34), 69 (100).
The enone (6S)-6 was purified by column chromatography
(silica gel impregnated with AgNO3, hexane/AcOEt¼97/3)
to give the geometrically pure (E)-(1R,6S)-6: GC; 99.9%,
1
98%ee, [a]2D5¼218.748 (c 1.02, CDCl3). H NMR: d 0.73
(d, 3H, J¼6.4 Hz), 0.89 (s, 3H), 0.91 (m, 2H), 0.92 (s, 3H),
1.37 (m, 1H), 1.51 (m, 2H), 1.72 (m, 1 h), 1.88 (dd, 3H, J¼
The optical purity of the (1R,6S)-5 was confirmed to be