5
To a suspension of LiAlH4 (0.230 g, 6.05 mmol, 1.5 equiv) in
anhydrous Et2O (20 mL), a solution of ester 8 (1.07 g,
4.04 mmol, 1.0 equiv) in anhydrous Et2O (40 mL) was added
slowly at 0 °C. The mixture was stirred for 1 h before it was
(dd, J = 13.1, 3.8 Hz, 1H), 1.01 (td, J = 13.1, 3.8 Hz, 1H), 0.87
ACCEPTED MANUSCRIPT
(s, 3H), 0.85 (s, 3H), 0.75 (s, 3H) ppm; 13C (125 MHz, CDCl3): δ
= 134.7, 122.9, 85.0, 68.4, 53.8, 50.2, 42.4, 39.2, 36.7, 33.3, 33.2,
26.4, 23.9, 22.3, 22.0, 20.5, 18.9, 13.8 ppm.
quenched by the addition of aqueous HCl (1M; 50 mL).
Afterwards, the mixture was extracted with Et2O (4 x 50 mL) and
the combined organic layers were washed with saturated aqueous
NaHCO3 (50 mL), dried over anhydrous MgSO4, and
concentrated under reduced pressure. After purification by
column chromatography (n-pentane/EtOAc = 5:1), alcohol 9
(0.954 g, 4.04 mmol, >99%) was obtained as colorless oil.
9: Rf = 0.39 (n-pentane/EtOAc = 5:1); 1H (400 MHz, CDCl3):
δ = 5.41 (brs, 1H), 3.78 (dt, J = 9.5, 5.2 Hz, 1H), 3.66–3.47 (m,
1H), 2.04–1.91 (m, 1H), 1.92–1.78 (m, 1H), 1.72 (dd, J = 14.2,
7.2 Hz, 2H), 1.66 (s, 3H), 1.66–1.64 (m, 1H), 1.57–1.45 (m, 4H),
1.40 (d, J = 13.9 Hz, 1H), 1.18 (dd, J = 11.9, 5.1 Hz, 1H), 1.13
(dd, J = 13.1, 3.9 Hz, 1H), 0.95 (dt, J = 13.1, 3.9 Hz, 1H), 0.87
(s, 3H), 0.85 (s, 3H), 0.76 (s, 3H) ppm; 13C (100 MHz, CDCl3): δ
= 134.7, 122.8, 64.5, 50.8, 50.2, 42.4, 39.3, 36.6, 32.3, 33.1, 30.6,
23.9, 22.2, 22.0, 18.9, 13.7 ppm.
4.6 Synthesis of (4aS,5S,8aS)-5-((E)-4-iodo-3-methylbut-3-en-1-
yl)-1,1,4a,6-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene
(2)38
To a solution of Cp2ZrCl2 (24.0 mg, 0.0820 mmol, 0.5 equiv)
in anhydrous CH2Cl2 (6.0 mL), Me3Al (2 M in PhMe; 0.24 mL,
0.489 mmol, 3.0 equiv) was added slowly at –30 °C. The pale-
yellow mixture was stirred for 30 min at 23 °C and cooled to
–30 °C again. At this point, H2O (4.40 µL, 0.245 mmol, 1.5
equiv) was added and the mixture stirred for additional 30 min,
and then a solution of alkyne 11 (40.0 mg, 0.163 mmol, 1.0
equiv) in anhydrous CH2Cl2 (0.30 mL) was added. After 1 h, I2
(54.0 mg, 2.12 mmol, 1.3 equiv) dissolved in anhydrous THF
(0.60 mL) was added and the yellow solution was stirred for 4 h
at 0 °C. The reaction was quenched with saturated aqueous
NaHCO3 (10 mL) followed by extraction with n-pentane (3 x
30 mL). The combined organic phases were washed with brine
(20 mL), dried over anhydrous MgSO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (n-pentane) yielding vinyl iodide 2 (44.0 mg,
0.154 mmol, 94%) as colorless solid.
4.4 Synthesis of (4aS,5S,8aS)-5-(2-iodoethyl)-1,1,4a,6-tetrame-
thyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene (10)
To a solution of alcohol 9 (500 mg, 2.12 mmol, 1.0 equiv) in
anhydrous THF (35 mL), PPh3 (666 mg, 2.54 mmol, 1.2 equiv),
imidazole (288 mg, 4.23 mmol, 2.0 equiv), and I2 (644 mg,
2.54 mmol, 1.2 equiv) were subsequently added and the mixture
was stirred for 2 h at 23 °C. The reaction was quenched by the
addition of saturated aqueous Na2S2O3 (50 mL) and extracted
with Et2O (3 x 50 mL). The combined organic phases were dried
over anhydrous MgSO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography (n-
pentane) giving alkyl iodide 10 (693 mg, 2.00 mmol, 95%) as
colorless oil.
2: Rf = 0.94 (n-pentane); 1H (500 MHz, CDCl3): δ = 5.89 (q, J
= 1.1 Hz, 1H), 5.40 (brs, 1H), 2.46 – 2.33 (m, 1H), 2.16 (dddd, J
= 13.7, 10.3, 6.2, 0.8 Hz, 1H), 2.00 – 1.93 (m, 1H), 1.89 – 1.86
(m, 1H), 1.85 (d, J = 1.1 Hz, 3H), 1.83 – 1.78 (m, 1H), 1.68 (brs,
3H), 1.62 – 1.47 (m, 3H), 1.47 – 1.38 (m, 2H), 1.34 – 1.26 (m,
1H), 1.20 – 1.12 (m, 2H), 0.93 (td, J = 13.1, 3.9 Hz, 1H), 0.87 (s,
3H), 0.85 (s, 3H), 0.75 (s, 3H) ppm; 13C (125 MHz, CDCl3): δ =
148.7, 135.0, 122.8, 75.0, 54.4, 50.3, 42.4, 42.2, 39.3, 36.9, 33.3,
33.1, 25.7, 24.2, 24.0, 22.3, 22.0, 18.9, 13.7 ppm.
1
10: Rf = 0.98 (n-pentane); H (400 MHz, CDCl3): δ = 5.42
(brs, 1H), 3.38 (ddd, J = 10.3, 9.4, 4.7 Hz, 1H), 3.14 (td, J = 9.4,
7.5 Hz, 1H), 2.05 (dddd, J = 14.7, 10.3, 7.5, 1.8 Hz, 1H), 2.01 –
1.94 (m, 1H), 1.89 – 1.72 (m, 3H), 1.67 (s, 3H), 1.65 – 1.60 (m,
1H), 1.56 – 1.51 (m, 1H), 1.47 (tq, J = 10.2, 3.4 Hz, 1H), 1.41
(dtd, J = 13.1, 3.2, 1.7 Hz, 1H), 1.19 (dd, J = 12.0, 4.9 Hz, 1H),
1.15 (dd, J = 13.2, 3.9 Hz, 1H), 1.04 (td, J = 13.1, 4.1 Hz, 1H),
0.87 (s, 3H), 0.85 (s, 3H), 0.74 (s, 3H) ppm; 13C (100 MHz,
CDCl3): δ = 133.7, 123.4, 56.6, 50.1, 42.3, 39.3, 36.8, 33.3, 33.1,
32.7, 23.9, 22.2, 22.0, 18.8, 13.9, 8.5 ppm.
4.7 Synthesis of (E)-3-(3´,5´-dimethoxyphenyl)prop-2-en-1-ol
(12)43, 55
Triethyl phosphonoacetate (6.05 mL, 14.1 mmol, 1.8 equiv)
was added to a suspension of NaH (60 w% mineral oil; 0.580 g,
24.0 mmol, 1.8 equiv) in anhydrous THF (71 mL) at 0 °C. The
suspension cleared after stirring for 30 min, and then a solution
of the 3,5-dimethoxybenzaldehyde (7, 2.00 g, 12.0 mmol, 1.0
equiv) in anhydrous THF (4.0 mL) was added. Stirring was
continued for additional 16 h during gradual warming to 23 °C.
The mixture was then quenched with saturated aqueous NH4Cl
(20 mL) and extracted with Et2O (4 x 50 mL). The combined
organic phases were dried over anhydrous MgSO4 and
concentrated under reduced pressure. The obtained crude ester
4.5 Synthesis of (4aS,5S,8aS)-5-(but-3-yn-1-yl)-1,1,4a,6-tetrame-
thyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene (11)
To a suspension of LAEDA (40.0 mg, 0.434 mmol, 1.5 equiv)
in anhydrous DMSO/Et2O (1:1 v/v; 0.6 mL), was added a
solution of iodide 10 (100 mg, 0.289 mmol, 1.0 equiv) in
anhydrous Et2O (0.3 mL) at 0 °C. The reaction was stirred for 1 h
and then another portion of LAEDA (40.0 mg, 0.434 mmol, 1.5
equiv) was added. After 3 h the reaction was quenched by the
addition of H2O (2.0 mL) and extracted with Et2O (3 x 30 mL).
The combined organic phases were washed with H2O (2 x
10 mL), dried over anhydrous MgSO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (n-pentane) giving the alkyne 11 (61.7 mmol,
0.252 mmol, 87%) as colorless oil.
was dissolved in anhydrous CH2Cl2 (50 mL) and DIBAL-H (1
M
in CH2Cl2; 36.0 mL, 36.1 mmol, 3.0 equiv) was slowly added at 0
°C. The reaction mixture was stirred for 1 h and then quenched
by careful addition of aqueous HCl (1M; 30 mL). The mixture
was stirred for 30 min and then extracted with Et2O (4 x 50 mL),
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography (Et2O/n- pentane = 2:1) giving allylic alcohol 12
(2.01 g, 10.4 mmol, 86%) as colorless oil.
12: Rf = 0.66 (n-pentane/Et2O = 1:3); 1H (500 MHz, CDCl3): δ
= 6.56 – 6.55 (m, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.53 – 6.51 (m,
1H), 6.38 – 6.36 (m, 1H), 6.34 (dd, J = 15.9, 5.7 Hz, 1H), 4.63
(brs, 1H), 4.31 (d, J = 5.6 Hz, 2H), 3.79 (s, 6H) ppm; 13C
(125 MHz, CDCl3): δ = 161.0 (2C), 138.9, 131.1, 129.2, 104.7
(2C), 100.0, 63.7, 55.4 (2C) ppm.
1
11: Rf = 0.76 (n-pentane); H (500 MHz, CDCl3): δ = 5.41
(brs, 1H), 2.37 (dddd, J = 16.7, 9.1, 5.0, 2.6 Hz, 1H), 2.18 (dtd, J
= 16.7, 8.3, 2.6 Hz, 1H), 2.02 – 1.97 (m, 1H), 1.96 (t, J = 2.6 Hz,
1H), 1.89 – 1.83 (m, 2H), 1.76 – 1.70 (m, 2H), 1.68 (s, 3H), 1.59
– 1.48 (m, 1H), 1.48 – 1.37 (m, 3H), 1.22 – 1.17 (m, 1H), 1.15