Syntheses of (-)-Funebrine and (-)-Funebral
mixture was stirred for 15 min. Water was added, and the
mixture was extracted with CHCl3. The organic phase was
washed with brine, dried (MgSO4), and concentrated under
reduced pressure to give the crude mesylate, which was
dissolved in DME (80 mL). To the solution was added NaI (2.09
g, 14.3 mmol), and the mixture was heated under reflux. After
consumption of the mesylate (1.5 h), Bu3SnH (2.9 mL, 10.8
mmol) was added, and the mixture was further heated under
reflux for 3 h. After cooling to room temperature, the mixture
was diluted with Et2O. An 8% aqueous solution of KF was
added, and the mixture was stirred vigorously for 16 h. The
mixture was filtered, and the filtrate was washed with water
and brine, dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on silica gel eluting with n-hexane-AcOEt (4:1) to
afford 10 (851 mg, 82%), mp 120-121 °C (n-hexane-AcOEt).
g, 96%), mp 212-215 °C. [R]22 -1.89 (c 1.00, MeOH) {lit.1
D
mp 212-215 °C [R]25 -14.8 (c 0.695, MeOH)}; 1H NMR [270
D
MHz, D2O, 1,4-dioxane (δ 3.81 ppm) was used as an internal
standard] δ 1.34 (3H, d, J ) 6.3 Hz), 1.54 (3H, d, J ) 5.9 Hz),
2.45 (1H, qdd, J ) 6.3, 9.6, 11.6 Hz), 4.25 (1H, d, J ) 11.6
Hz), 4.52 (1H, qd, J ) 5.9, 9.6 Hz); 13C NMR [67.8 MHz, D2O,
1,4-dioxane (δ 66.5 ppm) was used as an internal standard] δ
12.3, 17.3, 42.6, 55.6, 82.3, 173.2. Anal. Calcd for C6H12NO2-
Cl: C, 43.51; H, 7.30; N, 8.46. Found: C, 43.25; H, 7.39; N,
8.55. The spectral data shown above were identical with those
reported.1,3
1-[(3S ,4S ,5R )-3-Am in o-4,5-d im e t h ylt e t r a h yd r ofu r a -
n on e]-2,5-bis(isobu ten yl)p yr r ole (14) (Ta ble 1, en tr y 3).
Compound (-)-3‚HCl (169.0 mg, 1.0 mmol) was partitioned
between saturated aqueous NaHCO3 (0.5 mL) and CHCl3-
Et2O (10:1). The organic phase was dried and concentrated
under reduced pressure to give (-)-3 (128.3 mg). 1H NMR (270
MHz, CDCl3) δ 1.20 (3H, d, J ) 6.6 Hz), 1.40 (3H, d, J ) 6.3
Hz), 1.63 (2H, br), 1.78 (1H, qdd, J ) 6.6, 9.6, 11.5 Hz), 3.24
(1H, d, J ) 11.5 Hz), 4.05 (1H, qd, J ) 6.3, 11.5 Hz). This
compound was used for the next step without further purifica-
tion.
[R]26D +17.5 (c 1.00, CHCl3); IR (CHCl3) 3438, 1781, 1717 cm-1
;
1H NMR (270 MHz, CDCl3) δ 1.21 (3H, d, J ) 6.6 Hz), 1.43
(3H, d, J ) 6.3 Hz), 1.46 (9H, s), 2.00 (1H, m), 4.05-4.25 (2H,
m), 4.99 (1H, br d, J ) 6.5 Hz); 13C NMR (67.8 MHz, CDCl3)
δ 14.4, 18.8, 28.6, 46.5, 58.1, 80.3, 80.9, 156.0, 175.0. Anal.
Calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C,
57.60; H, 8.57; N, 5.81.
To a stirred mixture of 13 (201.5 mg, 1.04 mmol) and MS
4A (6 g) in toluene (30 mL) was added Ti(OEt)4 (0.2 mL, 1.0
mmol) at room temperature, and the mixture was further
stirred at the same temperature for 1 h. A solution of (-)-3
(128.3 mg, 0.99 mmol) in toluene (20 mL) was added to the
mixture, and the mixture was heated under reflux for 6 h.
After cooling, the mixture was filtered through a pad of Celite.
To this filtrate was added a 10% aqueous solution of potasium
sodium tartrate (0.5 mL), and the mixture was stirred for 1 h.
To the mixture was added MgSO4 and Celite, and the mixture
was further stirred for 30 min. The mixture was filtered
through a pad of Celite, and the filtrate was concentrated
under reduced pressure. The residue was chromatographed
on silica gel with n-hexane-AcOEt (10:1) to give 14 (139.2 mg,
48%) along with recovered 13 (95.1 mg, 47%). 14: mp 78-80
To confirm the optical purity and absolute configuration, a
derivative was prepared. To a stirred suspension of MeNH2‚
HCl (25.2 mg, 0.38 mmol) in toluene (1 mL) was added a 1.0
M solution of Me3Al in n-hexane (0.38 mL, 0.38 mmol) at room
temperature. After 1 h, a solution of 10 (20.0 mg, 87 µmol) in
toluene-CH2Cl2 (1:2, 1.5 mL) was added to the mixture, and
the mixture was heated under reflux for 1 h. After the mixture
was cooled to room temperature, MeOH (three drops) and a
saturated solution of NaHCO3 (two drop) were added to the
mixture, and the mixture was stirred for 30 min. The mixture
was filtered though a pad of Celite, and the filtrate was dried
(MgSO4) and concentrated under reduced pressure. The resi-
due was dissolved in CH2Cl2 (1.5 mL), and to the solution were
added (R)-R-methoxy-R-trifluoromethylphenylacetic acid (33.2
mg, 0.14 mmol), dicyclohexylcarbodiimide (31.5 mg, 0.15
mmol), and DMAP (6.2 mg, 50 µmol). After being stirred for
15 h, the mixture was concentrated under reduced pressure.
The residue was chromatographed on silica gel (n-hexane-
AcOEt, 3:1) to give (2R,1′R,2′S,3′S)-3′-[(tert-butyloxycarbonyl)-
amino]-1′,2′-dimethyl-3′-methylcarbamoyl-2-methoxy-2-phenyl-
2-trifluoromethyl acetate (12a ) (23.4 mg, 56%), and 10 (5.6 mg,
28%) was recovered. 12a : mp 93-96 °C. IR (CHCl3) 3443,
1748, 1717, 1676 cm-1; 1H NMR (270 MHz, CDCl3) δ 0.93 (3H,
d, J ) 7.3 Hz), 1.26 (3H, d, J ) 7.3 Hz), 1.45 (9H, s), 2.30 (1H,
dquin, J ) 3.3, 7.3 Hz), 2.77 (3H, d, J ) 5.0 Hz), 3.54 (3H, s),
4.26 (1H, dd, J ) 3.3, 8.9 Hz), 5.08 (1H, quin, J ) 7.3 Hz),
5.15 (1H, d, J ) 8.9 Hz), 5.95 (1H, br), 7.42 (3H, m), 7.57 (2H,
m); 13C NMR (67.8 MHz, CDCl3) δ 12.0, 17.5, 26.7, 28.7, 40.7,
55.5, 55.8, 75.8, 80.8, 85.0, 128.2, 128.9, 130.1, 132.4, 156.1,
166.1, 172.0.
°C (n-hexane); [R]25 +242.0 (c 1.0, CHCl3); IR (CHCl3) 1782
D
cm-1; H NMR (270 MHz, CDCl3) δ 1.03 (3H, d, J ) 6.6 Hz),
1
1.45 (3H, d, J ) 6.3 Hz), 1.84 (6H, s), 1.86 (3H, s), 1.88 (3H,
s), 2.46 (1H, qdd, J ) 6.6, 9.6, 11.9 Hz), 4.15 (1H, qd, J ) 6.3,
9.6 Hz), 4.66 (1H, d, J ) 11.9 Hz), 5.80 (1H, s), 5.93 (1H, s),
6.03 (1H, s), 6.09 (1H, s); 13C NMR (67.8 MHz, CDCl3) δ 14.7,
19.6, 20.4, 26.7, 26.8, 45.1, 61.6, 80.4, 109.1, 110.9, 114.8, 116.0,
129.5, 132.1, 137.0, 139.6, 173.5. Anal. Calcd for C18H25NO2:
C, 75.23; H, 8.77; N, 4.87. Found: C, 74.96; H, 8.89; N, 4.92.
The spectral data described above are identical with those
reported3 for racemic 14.
1-[(3S ,4S ,5R )-3-Am in o-4,5-d im e t h ylt e t r a h yd r ofu r a -
n on e]-2,5-d ifor m ylp yr r ole (15). To a solution of 14 (28.5 mg,
0.10 mmol) in 1,4-dioxane-H2O (2:1, 2.4 mL) was added 4%
aqueous OsO4 (45 µL, 7.3 µmol). To the mixture was added
NaIO4 (33 mg, 0.155 mmol) in four portions (total 133 mg, 0.62
mmol) every 15 min. After the mixture was stirred at room
temperature for 20 h, saturated aqueous Na2S2O3 (2 mL) was
added, and the mixture was stirred for 1 h. The mixture was
filtered, and the filtrate was extracted with Et2O. The organic
phase was washed with brine, dried (MgSO4), and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel with (n-hexane-AcOEt,
2:1) to give 15 (11.2 mg, 48%) as a crystalline solid, mp 86-
88 °C. [R]25D +194.2 (c 1.1, CHCl3); IR (CHCl3) 1782, 1694, 1667
With use of a procedure similar to that for the preparation
of 12a , (2R,1′R,2′S,3′S)-isomer 12b (21.5 mg, 51%) was
obtained from 10 (20.0 mg, 87 µmol), and 10 (6.0 mg, 30%)
was recovered. 12b: mp 87-89 °C. IR (CHCl3) 3443, 1750,
1
1717, 1676 cm-1; H NMR (270 MHz, CDCl3) δ 0.86 (3H, d, J
) 7.3 Hz), 1.36 (3H, d, J ) 7.3 Hz), 1.43 (9H, s), 2.30 (1H,
dquin, J ) 3.0, 7.3 Hz), 2.74 (3H, d, J ) 4.6 Hz), 3.60 (3H, s),
4.20 (1H, dd, J ) 3.0, 8.6 Hz), 5.04 (1H, br d, J ) 8.6 Hz), 5.11
(1H, quin, J ) 7.3 Hz), 5.77 (1H, br), 7.35 (3H, m), 7.60 (2H,
m); 13C NMR (67.8 MHz, CDCl3) δ 11.2, 17.4, 26.3, 28.3, 40.2,
54.7, 55.5, 75.5, 80.3, 127.3, 128.4, 129.6, 132.6, 155.6, 165.5,
171.6.
1
cm-1; H NMR (270 MHz, CDCl3) δ 1.14 (3H, d, J ) 6.6 Hz),
1.61 (3H, d, J ) 5.9 Hz), 2.64 (1H, qdd, J ) 6.6, 9.6, 11.5 Hz),
4.30 (1H, qd, J ) 5.9, 9.6 Hz), 6.45 (1H, d, J ) 11.5 Hz), 7.09
(1H, d, J ) 4.3 Hz), 7.16 (1H, d, J ) 4.3 Hz), 9.74 (1H, s), 9.84
(1H, s); 13C NMR (67.8 MHz, CDCl3) δ 14.6, 18.8, 44.6, 62.4,
80.8, 124.3, 124.9, 136.3, 136.7, 171.6, 182.0, 183.4. Anal. Calcd
for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.08;
H, 5.71; N, 5.78. The spectral data described above are
identical with those reported3 for racemic 15.
(3S,4S,5R)-3-Am in o-4,5-d im et h ylt et r a h yd r ofu r a n on e
Hyd r och lor id e [(-)-3‚HCl]. To a stirred solution of 10 (3.53
g, 15.4 mmol) in MeOH (80 mL) was added 35% hydrochloric
acid (80 mL) at 0 °C, and the mixture was allowed to warm to
room temperature. After 2 h, the mixture was concentrated
under reduced pressure to give the crude hydrochloride, which
was recrystallized from MeOH-Et2O to afford (-)-3‚HCl (2.45
1-[(3S,4S,5R)-3-Am in o-4,5-d im et h ylt et r a h yd r ofu r a -
J . Org. Chem, Vol. 69, No. 5, 2004 1479