Synthesis of Michellamines A-C
J . Org. Chem., Vol. 64, No. 19, 1999 7199
rt
1
yellow oil: [R]D -19 (c ) 1.8, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 7.57 (d, J ) 8.1 Hz, 2H), 7.18 (d, J ) 8.1 Hz, 2H),
6.26 (t, J ) 2.1 Hz, 1H), 6.12 (d, J ) 2.1 Hz, 2H), 4.65 (d, J )
6.9 Hz, 1H), 3.70 (s, 6H), 3.44 (dddq, J ) 6.9, 6.9, 6.9, 6.6 Hz,
1H), 2.57 (d, J ) 6.9 Hz, 2H), 2.38 (s, 3H), and 1.12 (d, J ) 6.6
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 143.1, 139.5,
137.5, 129.5, 127.0, 107.2, 98.7, 55.2, 50.9, 43.7, 21.7, and 21.5;
LRMS m/z (intensity) 349 (M+, 10), 198 (100), 155 (84), and
91 (54); IR (neat) 3283, 2967, 2935, 1598, 1430, 1159, and 834
cm-1. Anal. Calcd for C18H23NO4S: C, 61.87; H, 6.64. Found:
C, 61.85; H, 6.66.
9.40 (s, 1H), 7.39-6.95 (m, 16H), 6.91 (d, J ) 8.0 Hz, 1H),
6.76 (s, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 5.01 (s, 2H), 4.88 (d, J
) 13.0 Hz, 1H), 4.82 (d, J ) 13.0 Hz, 1H), 4.08 (q, 1H), 4.08
(s, 1H), 3.72 (d, J ) 14.0 Hz, 1H), 3.37 (ddq, J ) 11.5, 4.0, 6.5
Hz, 1H), 3.29 (d, J ) 14.0 Hz, 1H), 2.36 (s, 3H), 2.21 (dd, J )
17.5, 4.0 Hz, 1H), 1.90 (dd, J ) 17.5, 11.5 Hz, 1H), 1.40 (d, J
) 6.5 Hz, 3H), and 1.01 (d, J ) 6.5 Hz, 3H). R-55: 1H NMR
(500 MHz, CDCl3) δ 9.42 (s, 1H), 7.39-6.95 (m, 16H), 6.90 (d,
J ) 8.0 Hz, 1H), 6.85 (s, 1H), 6.63 (s, 1H), 6.50 (s, 1H), 5.03
(d, J ) 11.5 Hz, 1H), 4.97 (d, J ) 11.5 Hz, 1H), 4.87 (d, J )
13.0 Hz, 1H), 4.82 (d, J ) 13.0 Hz, 1H), 4.08 (q, 1H), 4.08 (s,
3H), 3.77 (d, J ) 14.0 Hz, 1H), 3.37 (ddq, J ) 11.5, 4.0, 6.5
Hz, 1H), 3.34 (d, J ) 14.0 Hz, 1H), 2.36 (s, 3H), 2.24 (dd, J )
17.5, 11.5 Hz, 1H), 1.90 (dd, J ) 17.5, 4.0 Hz, 1H), 1.38 (d, J
) 6.5 Hz, 3H), and 1.05 (d, J ) 6.5 Hz, 3H); HRMS (FAB)
calcd for C44H44NO4 (M + H)+ 650.3270, found 650.3251.
[(1R),1R*,3R*,5R*]- a n d [(1R),1R*,3R*,5S*]-1,2,3,4-Tet-
r a h yd r o-5-(4,5-d im eth oxy-7-m eth yl-1-n a p h th a len yl)-1,3-
d im et h yl-6,8-bis(p h en ylm et h oxy)-2-(p h en ylm et h yl)iso-
qu in olin e (S-56) a n d (R-56). Iodide 28 (294 mg, 0.50 mmol)
and boronic acid 21a (160 mg, 0.65 mmol) were dissolved in
toluene (10 mL). Saturated aqueous NaHCO3 (10 mL) and Pd-
(PPh3)4 (58 mg, 0.05 mmol) were added, and the mixture was
stirred at 110 °C for 12 h. The aqueous layer was separated
and extracted with ether (2 × 15 mL). The combined organic
layers were washed with brine, dried with sodium sulfate, and
concentrated. The residue was dissolved in a minimum amount
of CH2Cl2 and passed through a short SiO2 column with
hexanes/ethyl acetate (9:1, with 3% Et3N). Subsequent puri-
fication by MPLC with the same solvent gave the 5:4 mixture
of product (S-56) and (R-56) as a light yellow solid (272 mg,
82%). S-56: 1H NMR (500 MHz, CDCl3, from the mixture) δ
7.39-6.90 (m, 15H), 7.21 (d, J ) 8.0 Hz, 1H), 6.88 (d, J ) 8.0
Hz, 1H), 6.75 (bs, 1H), 6.69 (d, J ) 1.0 Hz, 1H), 6.54 (s, 1H),
5.02 (s, 2H), 4.87 (d, J ) 12.5 Hz, 1H), 4.82 (d, J ) 12.5 Hz,
1H), 4.10 (q, J ) 6.5 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.72
(d, J ) 14.0 Hz, 1H), 3.36 (ddq, J ) 11.0, 4.5, 6.5 Hz, 1H),
3.30 (d, J ) 14.0 Hz, 1H), 2.35 (s, 3H), 2.21 (dd, J ) 18.0, 4.5
Hz, 1H), 2.00 (dd, J ) 18.0, 11.0 Hz, 1H), 1.41 (d, J ) 6.5 Hz,
3H), and 1.00 (d, J ) 6.5, 3H); 13C NMR (125 MHz, CDCl3,
from the mixture) δ 157.2, 156.3, 156.2, 155.2, 154.3, 137.6,
137.3, 137.7, 136.5, 135.8, 128.6, 128.4, 128.2, 128.0, 127.6,
127.3, 127.0, 126.7, 126.3, 122.4, 120.9, 117.7, 116.0, 108.2,
105.3, 97.3, 70.8, 69.8, 56.5, 56.4, 51.5, 46.2, 45.8, 30.1, 22.1,
20.3, and 19.2. R-56: 1H NMR (500 MHz, CDCl3, from the
mixture) δ 7.39-6.90 (m, 15H), 7.16 (d, J ) 8.0 Hz, 1H), 6.87
(d, J ) 8.0 Hz, 1H), 6.84 (bs, 1H), 6.70 (d, J ) 1.0 Hz, 1H),
6.52 (s, 1H), 5.04 (d, J ) 12.0 Hz, 1H), 4.98 (d, J ) 12.0 Hz,
1H), 4.87 (d, J ) 12.5 Hz, 1H), 4.82 (d, J ) 12.5 Hz, 1H), 4.12
(q, J ) 6.0 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.77 (d, J ) 14.0
Hz, 1H), 3.36 (ddq, J ) 12.0, 4.5, 6.5 Hz, 1H), 3.36 (d, J )
14.0 Hz, 1H), 2.35 (s, 3H), 2.24 (dd, J ) 17.5, 12.0 Hz, 1H),
1.92 (dd, J ) 17.5, 4.5 Hz, 1H), 1.39 (d, J ) 6.0 Hz, 3H), and
1.05 (d, J ) 6.5, 3H); 13C NMR (125 MHz, CDCl3, from the
mixture) δ 157.1, 156.3, 156.1, 155.1, 141.2, 131.6, 137.3, 136.5,
136.4, 135.9, 128.4, 128.3, 128.2, 128.0, 127.6, 127.2, 127.0,
126.9, 126.6, 126.3,122.1, 121.2, 117.9, 116.0, 108.4, 105.3,
97.0, 70.6, 69.8, 56.5, 56.3, 51.4, 46.2, 45.9, 30.9, 22.1, 20.0,
and 19.8; IR of the mixture (thin film) 3029, 2965, 1621, 1584,
1382, 1119, 1095, 1070, 1028, and 966 cm-1. Anal. Calcd for
the mixture C45H45NO4: C, 81.42; H, 6.83; N, 2.21. Found: C,
81.22; H, 6.84; N, 2.21.
(1R)-2-(3,5-Dim eth oxyph en yl)-1-m eth yleth ylam in e (47).
To a stirred solution of 46 (0.51 g, 1.5 mmol) in freshly distilled
THF (5 mL) at -78 °C was added anhydrous ammonia (10
mL). Small pieces of sodium (0.32 g, 14 mmol) were added,
and the resulting blue mixture was stirred for 40 min and
quenched by addition of MeOH (1 mL). After the ammonia had
evaporated, Et2O (50 mL) and 5% HCl (100 mL) were added.
The aqueous layer was basified with 5% NaOH. The aqueous
solution was extracted with Et2O (3 × 50 mL), and the
combined organics were washed with brine (2 × 100 mL), dried
over anhydrous MgSO4, and concentrated to give 47 (0.22 g,
79%) as a pale yellow oil (pure by 1H NMR analysis): 1H NMR
(500 MHz, CDCl3) δ 6.36 (d, J ) 2.0 Hz, 2H), 6.34 (t, J ) 2.0
Hz, 1H), 3.78 (s, 6H), 3.26 (ddq, J ) 8.0, 6.0, 6.5 Hz, 1H), 2.68
(dd, J ) 13.5. 6.0 Hz, 1H), 2.61 (dd, J ) 13.5. 8.0 Hz, 1H), and
1.18 (d, J ) 6.5 Hz, 3H); LRMS m/z (intensity) 195 (M+, 9),
152 (100), 91 (10), 77 (13), and 65 (11). The 47‚HCl was
crystallized from CH2Cl2/cyclohexane: mp 148-150 °C (lit.15b
rt
rt
mp 151 °C); [R]D -14.1 (c )2.29, MeOH) [lit.15b [R]D -14.1
(c ) 0.89, MeOH)].
5-[(1R, 3R)-2-P h en ylm eth yl-6,8-bis-p h en ylm eth oxy-1,3-
d im eth yl-1,2,3,4-tetr a h yd r oisoqu in olin -5-yl]-1-m eth oxy-
8-m eth oxym eth oxy-3-m eth yln aph th alen e (S-54 an d R-54).
THIQ 28 (200 mg, 0.34 mmol), boronic acid 21b (222 mg, 0.82
mmol), and Pd(PPh3)4 (77 mg, 0.067 mmol) were dissolved in
a mixture of toluene (10 mL) and saturated NaHCO3 (5 mL).
The reaction mixture was sealed under N2 and heated at 110
°C for 20 h. The reaction mixture was cooled to room temper-
ature and diluted with EtOAc (20 mL). The organic layer was
washed with brine (2 × 10 mL) and dried over MgSO4.
Purification via column chromatography (SiO2, hexanes/EtOAc
3:1 with 3% Et3N) provided a mixture of atropisomers S-54
and R-54 (190 mg, 81%) in a 5:4 ratio. S-54: 1H NMR (500
MHz, CDCl3) δ 7.39-6.90 (m, 17H), 6.77 (s, 1H), 6.69 (s, 1H),
6.53 (s, 1H), 5.31 (s, 2H), 5.02 (s, 2H), 4.87 (d, J ) 12.5 Hz,
1H), 4.81 (d, J ) 12.5 Hz, 1H), 4.12 (q, J ) 6.5 Hz, 1H), 3.98
(s, 3H), 3.72 (d, J ) 14.5 Hz, 1H), 3.65 (s, 3H), 3.37 (ddq, J )
11.5, 4.0, 6.5 Hz, 1H), 3.30 (d, J ) 14.5 Hz, 1H), 2.36 (s, 3H),
2.22 (dd, J ) 17.5, 4.0 Hz, 1H), 2.00 (dd, J ) 17.5, 11.5 Hz,
1H), 1.41 (d, J ) 6.5 Hz, 3H), and 1.01 (d, J ) 6.5 Hz, 3H).
R-54: 1H NMR (500 MHz, CDCl3) δ 7.39-6.90 (m, 17H), 6.86
(s, 1H), 6.70 (s, 1H), 6.51 (s, 1H), 5.31 (s, 2H), 5.03 (d, J )
12.0 Hz, 1H), 4.97 (d, J ) 12.0 Hz, 1H), 4.86 (d, J ) 12.5 Hz,
1H), 4.81 (d, J ) 12.5 Hz, 1H), 4.11 (q, J ) 6.5 Hz, 1H), 3.98
(s, 3H), 3.77 (d, J ) 14.5 Hz, 1H), 3.65 (s, 3H), 3.37 (ddq, J )
14.0, 4.0, 6.5 Hz, 1H), 3.35 (d, J ) 14.0 Hz, 1H), 2.36 (s, 3H),
2.25 (dd, J ) 17.0, 14.0 Hz, 1H), 1.92 (dd, J ) 17.0, 4.0 Hz,
1H), 1.39 (d, J ) 6.5 Hz, 3H), and 1.05 (d, J ) 6.5 Hz, 3H);
HRMS (FAB) calcd for C46H48NO5 (M + H)+ 694.3532, found
694.3546.
44-[(1R, 3R)-2-P h en ylm eth yl-6,8-bis-p h en ylm eth oxy-
1,3-d im eth yl-1,2,3,4-tetr a h yd r oisoqu in olin -5-yl]-8-m eth -
oxy-5-m eth yln a p h th a len -1-ol (S-55 a n d R-55). The 5:4
mixture of atropisomers 54 (180 mg, 0.26 mmol) was dissolved
in a 10:1 mixture of MeOH-CH2Cl2 (20 mL). Concentrated
HCl (1 mL) was added, and the reaction mixture was stirred
at room temperature for 16 h. The organic solvent was then
removed under reduced pressure. Saturated NaHCO3 (20 mL)
was added, and the mixture was extracted with EtOAc (2 ×
15 mL). The combined organics were washed with brine (2 ×
10 mL) and dried over MgSO4. Purification via column
chromatography (SiO2, hexanes/EtOAc 3:1, with 3% Et3N)
provided a mixture of atropisomers S-55 and R-55 (120 mg,
71%), with a 4:3 ratio. S-55: 1H NMR (500 MHz, CDCl3) δ
5-[(1S, 3R)-5-Meth oxy-4-m eth oxym eth yl-7-m eth yln aph -
th alen -1-yl)-1,2,3-tr im eth yl-6,8-bis-ph en ylm eth oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e (S-58 a n d R-58). Iodide 36 (0.10
g, 0.19 mmol), boronic acid 21b (0.10 g, 0.36 mmol), and Pd-
(PPh3)4 (50 mg, 0.048 mmol) were dissolved in a mixture of
toluene (5 mL) and saturated aqueous NaHCO3 (2 mL). The
reaction mixture was sealed under N2 and heated to 110 °C
for 15 h. The reaction mixture was extracted with EtOAc (2 ×
10 mL), and the combined organics were washed with brine
(2 × 5 mL) and dried over MgSO4. Purification via column
chromatography (SiO2, hexanes/EtOAc 6:1, with 3% Et3N)
provided biaryls S-58 and R-58 (85 mg, 73%) in an ∼5:4 ratio.
This mixture of atropisomers elutes as a single spot on SiO2