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, 3), 123
(100), 111 (16), 109 (16), 107 (31), 95 (26), 81 (55), 69 (22), 67 (26),
55 (26); EI-HRMS m/z calcd for C
10
H
16
O [M]
152.1201, found
152.1199.
4.1.2. (5E)-4,4,7-Trimethylocta-1,5,7-triene (3).
14
To a solution of
aldehyde 2 (5.20 g, 34.2 mmol) in dry benzene (200 mL), under
nitrogen, was added dried 4
A molecular sieves (1.00 g) and a cat-
alytic amount of dried p-TsOH(60 mg, 0.32 mmol). The mixture was
heated at 70
C for 3 h. Once the reaction cooled, water (100 mL)
was added and the aqueous layer was extracted with Et
2
O
(2100 mL). The combined organic layers were dried over MgSO
4
and ltered before the solvents were removed under reduced
pressure to give the crude intermediate compound (4.99 g, 96%) as
a light brown oil; R
f
0.65 (ethyl acetate/hexane 1:4); IR (neat) n
max
1721, 1608, 1479, 1366, 970, 676 cm
1
; d
H
(500 MHz, CDCl
3
) 9.69
(1H, t, J 3.1, CHO), 6.12 (1H, d, J 16.1, trans-CH), 5.71 (1H, d, J 16.1,
trans-CH), 4.94 (2H, s, ]CH
2
), 2.37 (2H, d, J 3.1, CH
2
), 1.76 (3H, s,
CH
3
), 1.17 (6H, s, 2CH
3
); d
c
(125 MHz, CDCl
3
) 203.2, 141.5, 137.7,
129.9, 115.9, 55.2, 35.2, 27.8 (2C), 18.6; EIMS (rel intensity) m/z 152
(M
, 6), 135 (15), 123 (73), 109 (81), 96 (77), 95 (81), 81 (80), 67 (92),
55 (56); EI-HRMS m/z calcd for C
10
H
16
O [M]
152.1201, found
152.1197.
To a suspension of methyltriphenylphosphonium bromide
(23.4 g, 65.5 mmol) in THF (100 mL) was added dropwise n-
butyllithium (2.5 M, 27.6 mL, 69.0 mmol) at 10
C. The mixture
was warmed to roomtemperature and after 30 min it was cooled to
10
C. A solution of the rearranged aldehyde (4.99 g, 32.8 mmol)
in THF (50 mL) was then added dropwise via canula and the mix-
ture stirred for 3 h at roomtemperature. Water (100 mL) was added
and the aqueous layer was extracted with Et
2
O (2100 mL). The
combined organic layers were dried over MgSO
4
, ltered and the
solvent removed under reduced pressure. The crude residue was
puried by column chromatography, eluting with petroleum ether,
to give 3 (2.20 g, 45%) as a colourless oil; R
f
0.71 (petroleum ether);
IR (neat) n
max
1682, 1640, 1609, 1467, 1437, 1383, 1363, 969, 912,
882 cm
1
; d
H
(500 MHz, CDCl
3
) 6.11 (1H, d, J 16.1, trans-CH), 5.80
(1H, ddt, J 10.2, 17.2, 7.5, H-2), 5.69 (1H, d, J 16.1, trans-CH),
5.07e5.02 (1H, m, H-1a), 5.05e5.01 (1H, m, H-1b), 4.95 (1H, br s, H-
8a), 4.94 (1H, br s, H-8b), 2.12 (2H, d, J 7.5, H-3), 1.88 (3H, s, 7-Me),
H
H
H
H
O
H
H
O
H
H
O
7b
H
H
ix) L-Selectride
(1SR,3SR,7RS)-8b
(1SR,3RS,7RS)-8b
Tebbe reagent
Ti=CH
2
MgCl
2
.THF,
(1SR,3SR,7RS)-1
(1SR,3RS,7RS)-1
Ratio 1 (1SR,3SR,7RS)-8b: 1.4 (1SR,3RS,7RS)-8b
81%
51%
84%
Scheme 3. Completion of the synthesis of the sex pheromone of Lutzomyia longipalpis (1SR,3SR,7RS)-1 and its diastereoisomer.
S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5105
1.08 (6H, s, 2(4-Me)); d
c
(125 MHz, CDCl
3
) 142.2, 140.1, 135.5, 128.8,
116.8, 114.6, 47.5, 35.9, 27.0 (2C), 18.7; EIMS (rel intensity) m/z 150
(M
, 7), 137 (11), 123 (28), 111 (100), 97 (29), 95 (34), 85 (44), 83
(52), 71 (58), 55 (72); EI-HRMS m/z calcd for C
11
H
18
[M]
150.1409,
found 150.1401.
4.1.3. (1SR,2RS)-1-Carboxaldehyde-2-(1
0
,1
0
-dimethylbut-3
0
-enyl)-4-
methylcyclohex-3-ene (4). To a solution of ZnCl
2
(0.2 equiv, 1.00 g,
7.34 mmol) in CH
2
Cl
2
(250 mL) was added acrolein (4.0 equiv,
10.3 mL, 147 mmol), then triene 3 (5.49 g, 36.6 mmol). The reaction
was stirred overnight, then preabsorbed onto silica. Purication by
quick ltration through silica gel, eluting with petroleEtOAc (95:5)
gave 4 (7.17 g, 95%) as a clear, colourless oil. Analysis of the minor
product aldehyde signal d 9.57 (1H, d, J 2.0, CHO) and integration by
NMR showed the ratio of isomers to be 94:6, a diastereomeric ex-
cess of 88%; R
f
0.34 (diethyl ether/petroleum ether 1:19); IR (neat)
n
max
1712, 1638, 1446, 1390, 1368, 912 cm
1
; d
H
(500 MHz, CDCl
3
)
9.90 (1H, d, J 5.8, CHO), 5.78 (1H, ddt, J 10.4, 16.8, 7.5, H-3
0
), 5.50 (1H,
d, J 1.2, H-3), 5.04e5.02 (1H, m, H-4
0
a), 5.03e5,00 (1H, m, H-4
0
b),
2.67 (1H, br qu, J 3.9, H-1), 2.34e2.29 (1H, br m, H-2), 2.11e1.86 (6H,
m, H
2
-5, H
2
-6, H
2
-2
0
), 1.73 (3H, s, 4-Me), 0.87 (3H, s, Me-1
0
a), 0.84
(3H, s, Me-1
0
b); d
c
(125 MHz, CDCl
3
) 208.3, 135.2, 134.9, 121.2, 117.6,
47.5, 46.9, 45.4, 36.0, 27.4, 27.0, 25.6, 25.0, 23.8; EIMS (rel intensity)
m/z 206 (M
, 4), 191 (2), 177 (2), 165 (13), 147 (8), 137 (24), 124 (65),
109 (21), 95 (46), 93 (90), 83 (76), 67 (20), 55 (100); EI-HRMS m/z
calcd for C
14
H
22
O [M]
, 1), 216 (3), 201 (3), 177 (10), 175 (10), 133 (18),
119 (10), 109 (32), 95 (100), 81 (23); EI-HRMS m/z calcd for C
16
H
26
O
[M]
, 100), 191 (21), 161 (21), 159 (24), 147 (42), 134 (37), 123 (50),
121 (42), 105 (41), 94 (71), 79 (60); EI-HRMS m/z calcd for C
14
H
22
O
[M]
C was added
isopropenylmagnesium bromide (1 M in THF, 25.5 mL 25.5 mmol)
dropwise. The reaction mixture was warmed to room temperature
and stirred for 4 h. The reaction was quenched with aqueous am-
moniumchloride (70 mL) and the aqueous layer was extracted with
Et
2
O (350 mL). The combined organic layers were dried over
MgSO
4
ltered and the solvent removed under reduced pressure.
The crude residue was puried by column chromatography, eluting
with petroleumether/EtOAc (9:1), to give 5b (3.70 g, 88%) as a clear,
colourless oil; R
f
0.74 (diethyl ether/petroleum ether 1:4); IR (neat)
n
max
3560, 1638, 1448, 1371, 994, 900 cm
1
; d
H
(500 MHz, CDCl
3
)
5.88 (1H, ddt, J 10.3, 17.0, 7.4, H-3
00
), 5.62 (1H, s, H-3), 5.22 (1H, s, H-
3
0
a), 5.09e5.06 (1H, m, H-4
00
a), 5.07e5.04 (1H, m, H-4
00
b), 4.96 (1H,
s, H-3
0
b), 4.60 (1H, s, H-1), 2.97 (1H, s, OH), 2.39 (1H, br s, H-2),
2.33e2.21 (1H, m, H-5a), 2.21 (2H, d, J 7.4, H-2
00
), 2.15 (1H, br s, H-1),
1.95 (1H, ddd, J 2.9, 7.0, 13.7, H-5b), 1.89 (1H, dd, J 7.0, 18.3, H-6a),
1.73 (6H, s, 2
0
-Me, 4-Me), 1.55 (1H, m, H-6b), 1.08 (3H, s, 1
00
-Me), 1.07
(3H, s, 1
00
-Me); d
c
(125 MHz, CDCl
3
) 145.0, 138.5, 135.4, 122.6, 117.4,
109.7, 76.4, 45.9, 45.6, 35.6, 33.6, 28.7, 25.6, 24.4, 24.3, 24.0, 20.1;
EIMS (rel intensity) m/z 248 (M
220.1827, found
220.1821.
4.1.11. (1SR,2SR,7RS)-2-Acetoxy-3,6,6,9-tetramethylbicyclo[5.4.0]un-
deca-3,8-diene (10). Alcohol 6b (20 mg, 0.091 mmol) was added to
a solution of pyridine (0.5 mL) and acetyl chloride (0.25 ml) in Et
2
O
(10 mL) and reuxed overnight. The reaction was diluted with Et
2
O
(30 mL), extracted with water (50 mL), washed with aqueous HCl
(1 M, 20 mL), and brine (20 mL) and the ethereal solution dried
(MgSO4), ltered and the solvent removed in vacuo to yield 10
(20 mg, 84%) as a clear, colourless oil; R
f
0.32 (diethyl ether/pe-
troleum ether 1:9); IR (neat) n
max
1736, 1669, 1436, 1370, 1237,
1029 cm
1
; d
H
(500 MHz, C
6
D
6
) 5.61 (1H, br d, J 7.4, H-2), 5.57 (1H, s,
H-8), 5.52, (1H, t, J 7.2, H-4), 2.27 (1H, br s, H-7), 2.22 (1H, br s, H-1),
2.10 (1H, dd, J 7.2, 14.2, H-5a), 2.00e1.94 (1H, m, H-5b), 1.90 (3H,
obscured m, H
2
-10, H-11a), 1.89 (3H, s, MeCO
2
), 1.76 (3H, s, 3-Me),
1.73 (3H, s, 9-Me), 1.52e1.48 (1H, m, H-11b), 0.99 (3H, s, 6-Me), 0.96
(3H, s, 6-Me); d
c
(125 MHz, CDCl
3
) 170.6, 137.5, 135.3, 124.1, 122.2,
75.4, 47.4, 37.9, 36.5, 35.0, 29.8, 28.5, 27.7, 24.8, 23.7, 20.8, 20.5;
EIMS (rel intensity) m/z 262 (M
, 100), 203 (30), 175 (22), 162 (15), 147 (22), 135 (17), 121 (60),
109 (41), 93 (24), 79 (24); EI-HRMS m/z calcd for C
15
H
22
O [M]
,
79), 205 (12), 163 (6), 151 (19), 123 (100), 107 (13), 94 (53), 79 (32),
69 (12), 56 (26); EI-HRMS m/z calcd for C
15
H
24
O [M]
220.1827,
found 220.1827.
(1SR,3SR,7RS)-8b. Chiral GC; 42.01, 42.25 min; R
f
0.42 (diethyl
ether/petroleum ether 1:19); IR (neat) n
max
1702, 1451, 1389, 1375,
1365, 1187, 865 cm
1
; d
H
(500 MHz, CDCl
3
) 5.59 (1H, br s, H-8),
2.80e2.78 (1H, m, H-1), 2.70 (1H, d sextet, J 2.5, 6.6, H-3), 2.19 (1H,
br s, H-7), 2.09 (1H, ddd, J 1.7, 5.4, 10.0, H-11a), 1.90e1.86 (1H, m, H-
10a), 1.83 (1H, t, J 10.0, H-11b), 1.81e1.77 (1H, m, H-5a), 1.74 (3H, s,
9-Me), 1.75e1.70 (1H, m, H-10b), 1.45 (1H, dq, J 14.5, 3.8, H-4a),
1.36e1.30 (1H, m, H-4b), 1.27 (1H, dt, J 14.5, 3.5, H-5b), 1.10 (3H, s, 6-
Me), 0.98 (3H, d, J 6.6, 3-Me), 0.87 (3H, s, 6-Me); d
C
(125 MHz,
CDCl
3
) 219.4, 134.4, 122.4, 48.1, 46.4, 45.3, 37.3, 36.1, 31.6, 30.9, 29.7,
27.0, 24.8, 24.0, 17.1; EIMS (rel intensity) m/z 220 (M
220.1827, found
220.1823.
4.1.14. (1SR,3RS,7RS)-1. 3-Methyl-a-himachalene.
8
To a solution of
ketone (1SR,3RS,7RS)-8b (80 mg, 0.36 mmol) in THF (2 mL) at
78
C was added dropwise a solution of Tebbe reagent (0.5 M in
toluene, 1.45 mL, 0.73 mmol). The solution was stirred overnight,
warming to room temperature, and quenched by adding 15%
aqueous NaOH (2 mL) very slowly. The crude residue was puried
by a ltration through a pad of Celite and then silica, eluting with
5% diethyl ether in petrol, to give (1SR,3RS,7RS)-1 (66 mg, 84%) as
a colourless oil.
Chiral GC; 39.74 min; R
f
0.80 (petroleum ether); IR (neat) n
max
1634, 1386, 1363, 885 cm
1
; d
H
(500 MHz, CDCl
3
) 5.52 (1H, br s, H-
8), 4.89 (1H, s, methyleneeH), 4.85 (1H, s, methyleneeH),
2.48e2.38 (1H, m, H-3), 2.39e2.35 (2H, m, H-1, H-7), 2.09e1.99 (3H,
m, H-10, H-11a), 1.84e1.78 (1H, m, H-4a), 1.73 (3H, s, 9-Me),
1.73e1.65 (1H, m, H-11b), 1.54 (1H, ddd, J 3.4, 8.2, 13.9, H-5a), 1.36
(1H, ddd, J 3.3, 9.7, 13.9, H-5b), 1.28 (1H, dt, J 3.3, 9.7, H-4b), 1.13 (3H,
d, J 6.9, 3-Me), 0.97 (3H, s, 6-Me), 0.83 (3H, s, 6-Me); d
c
(125 MHz,
CDCl
3
) 158.9, 133.9, 123.6, 105.4, 44.1 (2C), 42.5, 38.0, 37.4, 34.1,
32.0, 30.3, 25.1, 24.0, 23.8, 21.8. EIMS (rel intensity) m/z 218 (M
,
19), 203 (30), 175 (19), 162 (18), 148 (26), 133, (17), 121 (48), 107
(34), 94 (100), 79 (49); EI-HRMS m/z calcd for C
16
H
26
[M]