Vinca and Tacaman Alkaloids
) 7.6 Hz), 4.16 (q, 2H, J ) 7.3 Hz), 4.28-4.34 (m, 2H), 4.73 (s,
1H), 4.75 (s, 1H), 7.30 (t, 1H, J ) 7.9 Hz), 7.46 (t, 1H, J ) 8.6
Hz), 7.60 (d, 1H, J ) 7.9 Hz), and 7.87 (d, 1H, J ) 8.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 12.3, 14.2, 21.2, 28.9, 31.2, 37.8, 42.4,
61.7, 108.1, 114.2, 121.0, 123.6, 125.4, 128.5, 128.8, 129.2, 139.2,
150.1, 159.9, 160.3, 161.8, and 175.8.
3.02 (m, 3H), 4.17 (s, 1H), 4.31 (s, 1H), 4.38-4.47 (m, 2H), 7.27-
7.30 (m, 2H), 7.39-7.41 (m, 1H), and 8.33-8.35 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 7.1, 14.0, 22.0, 22.4, 24.7, 36.9, 38.3,
41.3, 52.5, 56.2, 63.4, 65.7, 80.8, 117.0, 117.7, 119.2, 124.1, 124.7,
129.7, 133.7, 136.6, 169.5, and 172.6; Anal. Calcd. for
C23H28N2O4: C, 69.67; H, 7.12; N, 7.07. Found: C, 69.67; H, 7.22;
N, 6.82.
Rh(II)-Catalyzed Formation of Dipolar Cycloadduct 9. A 0.40
g (0.9 mmol) sample of R-diazo indole 8 was stirred with rhodium-
(II) acetate (2 mg) in 10 mL of benzene and the mixture was heated
at reflux for 1 h. At the end of this time, the mixture was allowed
to cool to rt and the solvent was removed under reduced pressure.
The crude residue was subjected to flash silica gel chromatography
to give 0.35 g (95%) of cycloadduct 9 as a white solid: mp 153-
154 °C; IR (neat) 2970, 1752, 1722, 1690, and 1376 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.87 (t, 3H, J ) 7.3 Hz), 1.00 (dt, 1H, J )
13.7 and 7.3 Hz), 1.22 (dt, 1H, J ) 13.7 and 7.3 Hz), 1.34 (t, 3H,
J ) 7.3 Hz), 1.73-1.81 (m, 1H), 1.99-2.05 (m, 1H), 2.45-2.85
(m, 6H), 3.03 (dt, 1H, J ) 12.4 and 3.5 Hz), 4.28-4.44 (m, 2H),
4.83 (dd, 1H, J ) 13.0 and 4.8 Hz), 7.34-7.42 (m, 2H), 7.52 (d,
1H, J ) 8.3 Hz), and 8.22 (d, 1H, J ) 7.6 Hz); 13C NMR (100
MHz, CDCl3) δ 9.0, 14.0, 20.5, 29.3, 29.8, 31.4, 39.6, 42.4, 46.3,
62.8, 82.9, 92.5, 116.2, 117.6, 119.4, 125.0, 125.9, 128.2, 131.1,
134.4, 165.9, and 173.0; Anal. Calcd. for C23H24N2O5: C, 67.63;
H, 5.92; N, 6.86. Found: C, 67.81; H, 6.15; N, 6.61.
12a-Ethyl-2,3,5,12,12a,12b-hexahydro-1H,4H-3a,9b-diaza-
benzo[a]naphtho [2,1,8-cd]azulene-10,11-dione (11). To a 0.05
g (0.13 mmol) sample of amide 10 in 2 mL of acetonitrile con-
taining 3 drops of tert-butyl alcohol was added 0.07 g (0.26 mmol)
of magnesium iodide. The mixture was heated at reflux for 24 h
and then 0.5 mL of DMF was added. The resulting solution was
refluxed for a further 48 h, allowed to cool to rt, added to CH2Cl2
and extracted with a saturated aqueous solution of NaHCO3. The
organic layer was separated and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chromato-
graphy to give 0.026 g (62%) of 12a-ethyl-11-hydroxy-2,3,4,5,-
11,12,12a,12b-octahydro-1H-3a,9b-diaza-benzo[a]naphtho[2,1,8-
cd] azulen-10-one as a white solid: mp 121-123 °C; IR (neat)
3460, 2937, 2804, 2756, 1686, and 1458 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.69 (t, 3H, J ) 7.6 Hz), 0.84 (dt, 1H, J ) 14.6 and 7.6
Hz), 1.47-1.57 (m, 2H), 1.71-1.96 (m, 4H), 2.06 (dt, 1H, J )
14.6 and 7.6 Hz), 2.45 (dt, 1H, J ) 11.4 and 3.2 Hz), 2.56-2.62
(m, 2H), 2.83-2.92 (m, 1H), 2.98-3.04 (m, 2H), 3.46 (s, 1H),
3.98 (d, 1H, J ) 3.8 Hz), 4.71-4.76 (m, 1H), 7.30-7.37 (m, 2H),
7.43 (d, 1H, J ) 7.6 Hz), and 8.55 (d, 1H, J ) 7.3 Hz); 13C NMR
(100 MHz, CDCl3) δ 6.7, 21.9, 22.2, 25.7, 36.2, 37.0, 43.1, 52.1,
56.4, 67.0, 67.5, 117.2, 117.8, 120.1, 124.3, 125.0, 129.7, 132.8,
136.1, and 174.2.
Formation of Thiolactam 22. To a stirred solution of 0.40 g
(1.0 mmol) of cycloadduct 9 in 30 mL of toluene under N2 was
added 0.50 g (1.2 mmol) of Lawesson’s reagent at rt. The mixture
was heated at reflux for 1 h, cooled to rt, and concentrated under
reduced pressure. The crude residue was subjected to flash silica
gel chromatography to give 0.41 g (95%) of thiolactam 22 as a
white solid: mp 174-175 °C; IR (neat) 2971, 2936, 1751, 1723,
1
1663, 1390, and 1376 cm-1; H NMR (400 MHz, CDCl3) δ 0.87
(t, 3H, J ) 7.0 Hz), 0.91-0.97 (m, 1H), 1.15 (dt, 1H, J ) 13.0
and 7.3 Hz), 1.35 (t, 3H, J ) 7.3 Hz), 1.66 (dt, 1H, J ) 13.7 and
3.5 Hz), 1.90-1.95 (m, 1H), 2.61-2.82 (m, 3H), 2.95-3.00 (m,
1H), 3.18 (dt, 1H, J ) 14.6 and 4.1 Hz), 3.30-3.39 (m, 2H), 4.32-
4.42 (m, 2H), 5.71 (dd, 1H, J ) 13.3 and 4.8 Hz), 7.38-7.46 (m,
2H), 7.57 (d, 1H, J ) 7.6 Hz), and 8.26 (d, 1H, J ) 7.3 Hz); 13C
NMR (100 MHz, CDCl3) δ 9.1, 14.0, 20.0, 31.8, 33.9, 40.1, 42.4,
47.2, 47.8, 62.9, 83.0, 91.3, 116.2, 116.4, 119.5, 125.2, 126.1, 127.7,
130.5,134.4,165.3,165.5,and209.9;HRMSCalcd.for[C23H24N2O4S
+ H+]: 425.1530. Found 425.1527.
12a-Ethyl-11-hydroxy-10-oxo-2,3,5,10,11,12,12a,12b-octahy-
dro-1H,4H-3a,9b-diaza-benzo[a]naphtho[2,1,8-cd]azulene-11-
carboxylic Acid Ethyl Ester (10). An excess amount of Raney
nickel (ca 1.5 g) in a 50 mL round-bottom flask under N2 was
washed three times with water, twice with dry methanol, and finally
three times with dry THF. A 0.15 g (0.35 mmol) sample of
thiolactam 22 in 3 mL of THF was then added dropwise to the
Raney nickel suspension in 5 mL of THF. The mixture was stirred
vigorously for 24 h under 1 atm of hydrogen gas, then filtered
through a pad of Celite, and concentrated under reduced pressure.
The crude residue was not purified but was immediately carried
onto the next reaction.
To a 0.13 g (0.30 mmol) slurry of Dess-Martin periodinane in 5
mL of CH2Cl2 was added 0.5 mL of pyridine and the mixture was
stirred at rt for 5 min. A solution of 0.05 g (0.15 mmol) of the
above alcohol in 3 mL of CH2Cl2 was added dropwise and the
solution was stirred at rt for 1 h. At the end of this time, the mixture
was diluted with CH2Cl2 and poured into a saturated aqueous
NaHCO3 solution containing an excess of Na2S2O3. The mixture
was stirred for 10 min, the organic layer was separated and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.025 g (50%) as a 1.6:1 mixture
of tautomers of keto-amide 11 as an oily foam: IR (neat) 3411,
2932, 2805, 2753, 1727, 1696, and 1458 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.77, 0.79 (t, 3H), 1.21-1.30 (m, 2H), 1.40-1.63 (m,
2H), 1.80-2.05 (m, 2H), 2.29-2.66 (m, 4H), 2.80-3.02 (m, 3H),
3.41, 3.50 (brs, 1H), 5.76 (s, 1H, enol), 6.76 (s, 1H, enol), 7.30-
7.46 (m, 3H), and 8.42, 8.48 (d, 1H); 13C NMR (100 MHz, CDCl3)
δ 7.0, 8.3, 21.8, 21.9, 22.2, 24.5, 25.8, 34.5, 35.1, 39.3, 41.6, 50.8,
51.6, 52.7, 55.7, 56.2, 66.6, 68.2, 117.1, 117.8, 118.0, 118.3, 119.8,
120.8, 122.5, 124.4, 125.0, 125.2, 125.3, 129.9, 130.2, 132.2, 135.6,
137.0, 140.0, 162.6, 163.4, and 197.4.
To a 0.14 g (0.35 mmol) sample of the above adduct in 4 mL of
AcOH and 8 mL of H2O was added 0.4 g of Zn dust. The result-
ing mixture was stirred vigorously at rt for 24 h and filtered through
a pad of Celite. The filtrate was added to CH2Cl2 and extracted
with a saturated aqueous solution of NaHCO3. The organic
layer was separated and the aqueous layer was extracted twice with
CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude re-
sidue was subjected to flash silica gel chromatography to give 0.10
g (75% over 2 steps) of amide 10 as a white solid: mp 54-56 °C;
IR (neat) 3459, 2938, 2805, 2775, 1736, 1687, and 1457 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.75 (t, 3H, J ) 7.6 Hz), 1.07 (dt, 1H,
J ) 14.6 and 7.6 Hz), 1.41 (t, 3H, J ) 7.3 Hz), 1.45-1.75
(m, 4H), 1.85-1.89 (m, 1H), 2.04 (dt, 1H, J ) 14.6 and 7.6 Hz),
2.46 (dt, 1H, J ) 12.1 and 2.5 Hz), 2.60-2.70 (m, 3H), 2.84-
(()-3H-Epivincamine (3). To a 0.02 g (0.06 mmol) sample of
keto-amide 11 in 5 mL of methanol was added 0.06 g (0.60 mmol)
of anhydrous sodium carbonate. After stirring at rt for 1 h, the
solvent was removed under reduced pressure, water was added
and the mixture was extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.02 g (95%) of (()-3H-
epivincamine (3) as white crystals: mp 155-156 °C (lit.20a
mp 163-163.5 °C); IR (neat) 3499, 2933, 2851, 2794, 2744, 1733,
1459, and 1444 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.84 (t, 3H,
J ) 7.3 Hz), 1.06 (dt, 1H, J ) 13.3 and 2.9 Hz), 1.27-1.33
(m, 1H), 1.57-1.61 (m, 1H), 1.82-2.03 (m, 4H), 2.24-2.31
(m, 2H), 2.53 (dt, 1H, J ) 11.4 and 4.4 Hz), 2.68-2.73 (m, 1H),
J. Org. Chem, Vol. 73, No. 7, 2008 2799