Yin et al.
JOCArticle
bath at 80 °C for 5 h. The reaction solution was then quenched
with water and extracted with EtOAc (3 ꢀ 250 mL). The organic
layer was separated and dried (Na2SO4). The EtOAc was then
removed under reduced pressure, and residue was flash chro-
matographed with CH2Cl2/MeOH (4.5:0.5) to provide the
coupling product 10 (0.569 g, 83% yield): 1H NMR (300
MHz, CDCl3) δ 1.63 (3H, d, J= 6.86 Hz), 2.15-2.20 (1H, m),
2.38 (1H, t, J = 9.87 Hz), 2.97 (1H, dd, J = 15.58, 6.20 Hz), 3.27
(1H, d, J = 14.43 Hz), 3.37 (1H, bs), 3.59 (1H, d, J = 5.70 Hz),
3.78 (2H, bs), 4.26 (1H, d, J = 9.11 Hz), 5.49 (1H, q, J = 6.85
Hz), 7.05-7.15 (2H, m), 7.25 (1H, d, J = 7.25 Hz), 7.47 (1H, d,
J = 7.29 Hz), 7.92 (1H, bs); 13CNMR (75.5 MHz, CDCl3) δ
12.68, 22.39, 36.40, 44.55, 50.83, 55.24, 64.17,105.62, 110.89,
118.54, 119.69, 121.26, 122.00, 126.88, 131.88, 135.87, 136.34,
217.00; CIMS (m/e, relative intensity) 291 (Mþ þ 1, 100); EIMS
(m/e, relative intensity) 278 (Mþ, 10), 250 (75), 249 (85), 182 (6),
169 (100), 168 (5); HRMS (m/e, relative intensity) required for
C18H18N2O 278.1419, found 278.1437. The spectral data of this
ketone were identical to the published values.73
Copper-Mediated Cyclization of (6S,10S)-5-Methyl-(-)-9-
oxo-12-[(Z)-20-iodo-20-butenyl]-6,7,8,9,10,11-hexaydro-6,10-
iminocyclooct[b]indole (24) To Provide 3-Ethylidine-12-methyl-
1,3,4,7,12,12b-hexahydro-13-hydroxymethyl-2H,6H-2,6-metha-
noindolo[2,3-R]quinolizin-13-one (25). A mixture of tetracyclic
ketone 24 (1.00 mmol), CuI (99.99%) (50 mol %), 1,2-cis-
cyclohexanediol (50 mol %), and Cs2CO3 (2.0 mmol) was placed
in dry DMF (Aldrich sure seal bottle), after which it was
degassed (3 times) under reduced pressure at rt and refilled with
argon (3 times). The reaction mixture was then placed on a
preheated oil bath (140 °C) under argon and allowed to stir at
140 °C for 12 h. At this point, analysis by TLC (silica gel,
EtOAc/hexane =1:1, double runs) indicated the absence of
starting material 24. The mixture was cooled to rt, diluted with
EtOAc, and filtered through Celite. The reaction mixture was
then washed with H2O (5 ꢀ 100 mL) and brine (100 mL) and
then dried (Na2SO4). The solvent was removed under reduced
pressure, and the oil which resulted was purified by chromato-
graphy on silica gel (EtOAc/hexane 1:1) to provide pure penta-
cyclic ketone 25: 1H NMR (300 MHz, CDCl3) δ 1.28 (1H, t, J =
6.9 Hz), 1.85 (3H, s), 2.40 (1H, m), 2.74 (1H, d, J = 12.2 Hz),
2.95 (1H, m), 3.04 (1H,m), 3.30 (1H, m), 3.61 (3H, s), 3.92(1H, d,
J = 5.4 Hz), 4.01 (1H, m), 4.43 (1H, d, J = 9.4 Hz), 5.40 (1H, q,
J = 6.9 Hz), 7.11 (1H, t, J = 7.5 Hz), 7.22 (1H, t, J = 6.9 Hz)
7.28 (1H, d, J = 8.1 Hz), 7.51 (1H, d, J = 7.5 Hz); 13C NMR
(75.7 MHz, CDCl3) δ 12.7, 22.3, 29.3, 35.5, 44.1, 49.7, 55.4, 64.1,
104.4, 108.8, 118.5, 119.1, 119.5, 121.5, 126.4, 132.1, 136.9,
137.4, 215.8. The spectral data for this material were identical
to the published values.32,59
The spectral properties of this iodide were identical to the
published values.61
(Z)-2-Bromo-2-buten-1-ol 30 (2 g, 10 mmol) was dissolved in
anhydrous ethyl ether (20 mL). Phosphorus tribromide (0.380
mL, 4 mmol) was added dropwise to this solution at 0 °C. This
reaction mixture which resulted was stirred for 12 h at rt. The
reaction was quenched with a cold aq solution of K2CO3 and
extracted with ethyl ether after which it was washed with brine.
The organic layer was dried (Na2SO4) and concentrated in
vacuo to give 21 (2.45 g, 93% yield) which was directly used in
the next step:74 1H NMR δ 6.08 (q, J = 6.4 Hz, 1H), 4.36 (s, 2H),
1.81 (d, J = 6.4 Hz, 3H). The spectral properties of this bromide
were identical to the published values.75
Preparation of Aldehyde 35. To a stirred solution of N-
chlorosuccinimide (400 mg, 3.0 mmol) in dry CH2Cl2 (15 mL)
was added dimethyl sulfide (1.1 mL, 15 mmol) at 0 °C under
argon. A white precipitate appeared immediately after addition
of the sulfide. The mixture was cooled to -78 °C (EtOAc-dry
ice bath), and stirring was continued for 1 h at -78 °C. The
mixture of ether 34 (194 mg, 0.6 mmol) in dry CH2Cl2 (3 mL)
was then added into the resulting white complex at -78 °C, and
the stirring was continued for 2 h at -78 °C. A solution of
triethylamine (1.4 mL, 10 mmol) in CH2Cl2 (0.5 mL) was added
to the mixture. The stirring was continued for an additional 1 h.
The cooling bath was then removed, and after 10 min, ether (20
mL) was added. The organic layer was diluted with a mixture of
CH2Cl2 (45 mL) and MeOH (5 mL), after which it was washed
with a solution of 1% aq hydrochloric acid (5 mL) and twice
with water (2 ꢀ 15 mL). The organic layer was separated and
dried (Na2SO4). The solvent was removed under reduced pres-
sure to provide the crude aldehyde 35 (180 mg, 93%). Analysis
of the 1H NMR spectrum indicated the presence of the desired
aldehydic peak at δ 9.56 or occasionally at 9.60. This material
was employed in a later step without further purification.
16-Epivellosimine (7) was prepared from the alcohol 11 ((E)-
16-epinormacusine B) following the analogous procedure em-
1
ployed for preparation of 35 above. 7: H NMR (300 MHz,
DMSO-d6) δ 1.65 (d, J = 8.4 Hz, 3H), 1.75 (t, 1H), 2.02 (m, 1H),
2.26-2.32 (bs, 1H), 2.55-2.66 (m, 1H), 2.52-2.84 (m, 1H), 2.75
(bs, 1H), 3.51-3.69 (m, 2H), 3.76 (dt, 1H), 4.15 (d, J = 9 Hz,
1H), 5.30 (q, 1H), 7.106-7.14 (m, 2H), 7.24 (d, J = 6 Hz, 1H)
7.43 (d, J = 6 Hz, 1H), 8.18 (s, 1H), 9.16 (s, 1H); 13C NMR (75.7
MHz, CDCl3) δ 12.7, 23.8, 25.1, 26.5, 49.9, 50.1, 53.0, 55.8,
104.7, 110.9, 114.9, 118.0, 119.5, 121.8, 126.2, 136.6, 137.3,
138.2, 200.7. The spectra data were similar to those of the
previous synthetic vellosimine 27, except the aldehydic peak
had shifted to 9.16 from 9.56 (Table 2, Supporting Information).
Oxidation of the Aldehyde 35 into Methyl Ester 36. The crude
aldehyde 35 (87 mg, 0.272 mmol) which resulted from the
Corey-Kim oxidation was triturated with hexane (6ꢀ5 mL)
to remove impurities. The residue was dissolved in anhydrous
MeOH (2 mL), and a solution of 85% KOH (148 mg, 2.21
mmol) and iodine (280 mg, 1.1 mmol) in anhydrous MeOH
(4 mL) were successively added at 0 °C. After 6 h, the reaction
mixture was diluted with CH2Cl2 (80 mL), washed with a 10%
aq solution of Na2S2O3 (20 mL), water (20 mL), and brine
(20 mL), and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue which resulted was purified by
flash chromatography on silica gel (CH2Cl2/MeOH 20/1) to
Preparation of 1-Bromo-2-iodobut-2-ene 21 from But-2-enal
28. Potassium carbonate (24 g, 172 mmol), I2 (72.42 g, 286
mmol), and DMAP (3.48 g, 28.6 mmol) were successively added
to a solution of crotonaldehyde 28 (10 g, 143 mmol) in a mixture
of THF (350 mL) and water (350 mL). After being stirred for
4-5 h, the reaction mixture was diluted with EtOAc and washed
with a solution of saturated aq Na2S2O3. The organic layer was
dried (Na2SO4), and the crude product 29 obtained after eva-
poration in vacuo was used in the next step without purification.
The crude product 29 (143 mmol) was taken up in THF-H2O
(9:1) and cooled to 0 °C. The NaBH4 (2.69 g, 71.5 mmol) was
added slowly, and the reaction was stirred for 1 h. The reaction
mixture was quenched with water and extracted with EtOAc
(3ꢀ500 mL). The organic layer was concentrated and the residue
purified by flash chromatography with silica gel in ethyl acetate/
hexane (1:9) to obtain iodide 30 (27.40 g, 97% yield): 1H NMR δ
5.98 (q, J = 6.3 Hz, 1H), 4.23 (s, 2H), 1.79 (d, J = 6.3 Hz, 3H).
1
provide methyl ester 36 (98 mg, 90%): H NMR (300 MHz,
CDCl3) δ 1.61 (d, J = 6.9 Hz, 3H), 1.98-2.13 (m, 2H), 3.28 (t,
J = 5.6 Hz, 1H), 3.51-3.80 (m, 3H), 3.72 (s, 3H), 3.95-3.98 (m,
2H), 4.52 (d, J = 8.0 Hz, 1H), 5.35 (q, J = 6.8 Hz, 1H), 5.77 (d,
J = 7.9 Hz, 1H), 7.18 (m, 2H), 7.34 (d, J = 6.6 Hz, 1H) 7.68 (d,
J = 5.6 Hz, 1H), 7.89 (s, 1H); 13C NMR (75.7 MHz, CDCl3) δ
(73) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565.
(74) Loh, T.-P.; Cao, G.-Q.; Pei, J. Tetrahedron Lett. 1998, 39, 1453.
(75) Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61, 7873.
3348 J. Org. Chem. Vol. 75, No. 10, 2010