Isomeric Farnesylated a-Factor Analogues
J . Org. Chem., Vol. 65, No. 25, 2000 8561
ice/acetonitrile bath. Dimethyl sulfide (8 mmol, 1.77 mL) was
added dropwise by a syringe, and the mixture was warmed to
0 °C, maintained at that temperature for 5 min, and then
recooled to -40 °C. To the resulting milky white suspension
was added dropwise nerol (3,7-dimethylocta-2Z,6-dien-1-ol; 24
mmol, 2.11 mL). The suspension was warmed to 0 °C and
stirred for 2 h. The ice bath was removed, and reaction mixture
was warmed to room temperature and stirred for an additional
30 min. The resulting solution was washed with hexane (2 ×
20 mL). The hexane layers were then washed with brine (2 ×
20 mL) and dried over MgSO4. Concentration afforded 2.305
g (89%) of neryl bromide 21 as an oil which was used directly
in the next step without purification. 1H NMR (300 MHz,
CDCl3): δ 1.54 (s, 3H), 1.62 (s, 3H), 1.69 (s, 3H), 2.03 (m, 4H),
4.02 (d, 2H), 5.03 (t, 1H), 5.38 (t, 1H).
Eth yl 7,11-Dim eth yl-3-oxododeca-6(Z),10-dien oate (22).
The monosodium salt of ethyl acetoacetate (4.26 g, 28.0 mmol)
in 56.0 mL THF (distilled from Na/benzophenone) was cooled
to 0 °C under argon, and treated with butyllithium (2.0 M in
hexane, 14.7 mL, 29.4 mmol). After 20 min, neryl bromide 21
(3.03 g, 1.0 mmol) was added to the resulting dianion solution,
and stirring was continued for additional 30 min at 0 °C. The
reaction was quenched by adding ∼10 mL of 10% aqueous
citric acid, and extracted with ether (3 × 50 mL). The organic
layers were combined, washed with saturated NaCl (2 × 30
mL) and dried over MgSO4. After purification by flash chro-
matography (hexanes/ethyl acetate 9:1), 2.50 g (67%) of the
product 22 was obtained as a pale yellow oil. 1H NMR (500
MHz) δ 1.28 (t, 3H), 1.61 (s, 3H, CH3 at C11), 1.69 (app s, 6H,
CH3 at C7 and C12-CH3), 2.04 (narrow m, 4H), 2.30 (m, 2H),
2.56 (app t, 2H), 3.43 (s, 2H), 4.19 (q, 2H), 5.08 (m, 2H). 13C
NMR (125 MHz) δ 14.8 (O-CH2CH3), 18.4 (CH3 at C11), 22.6
(C5), 24.0 (CH3 at C7), 26.4 (C12), 27.3 (C10), 32.6 (C9), 44.0 (C4),
50.1 (C2), 62.1 (O-CH2CH3), 123.6 (C6), 124.8 (C10), 132.4, 137.5,
167.9, 203.3. The 13C NMR spectrum was partially assigned
as described above (see also Supporting Information).
minum hydride (1.0 M in toluene; 2.38 mmol, 2.38 mL). After
the addition, the mixture was stirred for 1 h at -78 °C. The
reaction was quenched with saturated aqueous potassium
sodium tartrate (40 mL), the organic phase was separated, and
the aqueous phase was extracted with ethyl acetate (3 × 30
mL). The combined organic layers were washed with water
(20 mL) and brine (20 mL) and dried with MgSO4. Filtration
and concentration followed by flash chromatography (hexane/
1
ethyl acetate 9:1) gave 115 mg (62%) of alcohol 13. H NMR
(300 MHz, CDCl3): δ 1.61 (s, 3H), 1.69 (9H), 2.04 (m, 4H), 2.10
(m, 4H), 4.16 (d, 2H), 5.11 (t, 2H), 5.42 (t, 1H). The proton
spectrum obtained for 13 is essentially identical to that
reported previously for this compound.20
Eth yl 3-(((Tr iflu or om eth yl)su lfon yl)oxy)-7,11-d im eth -
yld od eca -2(E),6(Z),10-tr ien oa te (25). To a solution of â-ke-
toester 22 (867 mg, 3.26 mmol) in DMF (8.0 mL; 99.8%
anhydrous) at 0 °C was added potassium bis(trimethylsilyl)-
amide (0.5M in toluene, 3.85 mmol, 7.7 mL). After 2 h, 2-[N,N-
bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (1.39 g,
3.54 mmol) in ∼5 mL of DMF was added to the resulting
enolate solution, and stirring was continued at 0 °C for 3.5 h.
The reaction was then taken up in 30 mL of ether, washed
with ∼5 mL of 10% aqueous citric acid (2 × 20 mL), and water
(20 mL). The organic layer was dried over MgSO4, and
concentrated. Purification by flash chromatography (20:1
hexanes/ethyl acetate) gave 797 mg (60%) of triflate 25 as a
pale yellow oil. None of the isomeric triflate 23 could be
1
observed by proton NMR. H NMR (300 MHz, CDCl3): δ 1.33
(t, 3H), 1.63 (s, 3H), 1.68 (app s, 6H), 2.11 (app s, 4H), 2.32
(m, 2H), 2.98 (t, 2H), 4.29 (q, 2H), 5.12 (m, 3H), 5.95 (s, 1H).
Note the characteristic strong deshielding of the C4-CH2 signal,
by the ester carbonyl, to 2.98 ppm; in contrast, the C4-CH2
signal for the isomeric triflate 23 appears at 2.39 ppm. 13C
NMR (75.4 MHz, CDCl3): δ 13.206, 14.883, 23.062, 24.779,
26.486, 30.084, 31.819, 33.521, 59.094, 61.067, 63.008, 111.628,
113.816, 116.215, 120.452, 122.894, 163.949, 165.196.
Eth yl 3-(((Tr iflu or om eth yl)su lfon yl)oxy)-7,11-d im eth -
yld od eca -2(Z),6(Z),10-tr ien oa te (23). A solution of the â-ke-
toester 22 (9.2 mmol, 2.45 g) in THF (23.0 mL; 99.8%
anhydrous) was added to potassium bis(trimethylsilyl)amide
(0.5 M in toluene, 11.0 mmol, 22.0 mL) at -78 °C. While at
-78 °C, 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-
pyridine (11.0 mmol, 4.3 g) was added and the mixture was
warmed to room-temperature overnight. The mixture was
taken up in 30 mL of ether and washed with a 10% citric acid
solution (2 × 20 mL) and water (20 mL). The ether layer was
dried over MgSO4 and the solvent removed in a vacuum.
Purification by flash chromatography (19:1 hexane/ethyl ac-
etate) gave 3.17 g (86%) of compound 23 as an oil. 1H NMR
(300 MHz, CDCl3): δ 1.31 (t, 3H), 1.61 (s, 3H), 1.69 (s, 6H),
2.04 (s, 4H), 2.28 (t, 2H), 2.40 (t, 2H), 4.26 (q, 2H), 5.06 (t,
2H), 5.74 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.952, 17.538,
23.218, 24.324, 26.335, 31.892, 34.791, 61.167, 111.946, 121.383,
123.790, 131.902, 138.211, 158.296, 162.365.
E t h yl 3,7,11-Tr im et h yld od eca -2(E),6(Z),10-t r ien oa t e
(24). Triflate 23 (0.84 mmol, 337 mg), CuI (0.084 mmol, 16.0
mg), Ph3As (0.084 mmol, 25.8 mg), and bis(benzonitrile)-
palladium(II) chloride (0.042 mmol, 16.0 g) were placed in an
argon-flushed flask and dissolved in NMP (1.01 mL). The
mixture was immersed in an oil bath maintained at a tem-
perature of 100 °C, tetramethyltin (1.68 mmol, 0.23 mL, 397.2
mg; CAUTION: poisonous and volatile; handle only in hood)
was added, and the reaction mixture was stirred for 18 h. It
was then cooled, taken up in ethyl acetate (25 mL), and washed
with saturated aqueous KF (2 × 20 mL) and water (2 × 20
mL). The aqueous layers were back extracted with ethyl
acetate (30 mL), and the combined organic layers were dried
(MgSO4), filtered, and concentrated. Purification by flash
chromatography (hexane/ethyl acetate 19:1) gave 189 mg (85%)
of 24. 1H NMR (300 MHz, CDCl3): δ 1.28 (t, 3H), 1.61 (s, 3H),
1.64 (s, 6H), 2.03 (s, 4H), 2.15 (s, 4H), 4.14 (q, 2H), 5.09 (m,
2H), 5.66 (s, 1H).
E t h yl 3,7,11-Tr im et h yld od eca -2(Z),6(Z),10-t r ien oa t e
(26). In a flame-dried, argon-flushed flask were placed triflate
25 (580 mg, 1.46 mmol), Pd(PhCN)2Cl2 (28 mg, 0.073 mmol),
AsPh3 (45 mg, 0.146 mmol), CuI (28 mg, 0.146 mmol) and 0.80
mL of NMP (99.5%, anhydrous). This mixture was heated to
∼100 °C, tetramethyltin (0.40 mL, 1.91 mmol; CAUTION:
poisonous and volatile; handle only in hood) was added, and
the reaction was stirred for 15 h. The reaction was cooled,
taken up with 100 mL ethyl acetate, and washed with
saturated aqueous KF (3 × 30 mL). The aqueous layer was
back-extracted with ethyl acetate (2 × 15 mL) and the
combined organic layers were dried over MgSO4. Concentration
followed by flash chromatography (hexanes/ethyl acetate 20:
1) gave 26 as a colorless oil (248 mg, 64%). 1H NMR (300 MHz,
CDCl3): δ 1.24 (t, 3H), 1.605 (s, 3H), 1.68 (S, 6H), 1.88 (s, 3H),
2.04 (s, 4H), 2.15 (m, 2H), 2.63 (t, 2H), 4.12 (q, 2H), 5.16 (m,
2H), 5.65 (s, 1H). The identity, and in particular the stereo-
chemistry, of this ester was confirmed by the similarity of the
methyl peaks in its 1H NMR spectrum to that of the Z,Z-
methyl farnesoate originally prepared by Burrell et al.20
3,7,11-Tr im eth yld od eca -2(Z),6(Z),10-tr ien -1-ol (14). A
solution of the ester 26 (0.61 mmol, 160 mg) in toluene (3.0
mL) was treated at -78 °C under argon with diisobutylalu-
minum hydride (1.0 M in toluene; 1.70 mmol, 1.70 mL). After
the addition the mixture was stirred for 1h at -78 °C. The
reaction was quenched with saturated aqueous potassium
sodium tartrate (40 mL), the organic phase was separated, and
the aqueous phase was extracted with ethyl acetate (3 × 30
mL). The combined organic layers were washed with water
(20 mL) and brine (20 mL) and dried by MgSO4. Filtration
and concentration followed by flash chromatography (hexane/
ethyl acetate 9:1) gave 98 mg (74%) of alcohol 14: 1H NMR
(300 MHz, CDCl3): δ 1.61 (s, 3H), 1.69 (s, 6H), 1.75 (s, 3H),
2.10 (two, s, 8H), 4.11 (d, 2H), 5.11 (m, 2H), 5.45 (t, 1H). The
proton spectrum obtained for 14 is essentially identical to that
reported previously for this compound.16,20
3,7,11-Tr im eth yld od eca -2(E),6(Z),10-tr ien -1-ol (13). A
solution of the ester 24 (0.85 mmol, 226 mg) in toluene (4.2
mL) was treated at -78 °C under argon with diisobutylalu-
1-Br om o-3,7,11-tr im eth yldodeca-2(Z),6(E),10-tr ien e (29).
Carbon tetrabromide (0.361 mmol, 121.4 mg), triphenylphos-
phine (0.293 mmol, 78.5 mg), and alcohol 12 (0.278 mmol, 78.5