(endo, endo)-9-Benzyl-9-azabicyclo[3.3.1]nonane-2,6-diol: An intermediate for the preparation of indole alkaloids of the macroline/sarpagine series

Article abstract of DOI:10.1055/s-2000-6350

Two intermediates 9b and 9c already used by Cook and Magnus in their syntheses of indole alkaloids were obtained from the title compound 1 through a Fischer indolization procedure. Related tetracyclic intermediates 6 and 8 were also prepared: 6 having substituents at position 2 or 4 were directly obtained, while 8 with substituents at position 1 or 3 were selectively obtained through a convenient protection-deprotection scheme.

Full text of DOI:10.1055/s-2000-6350

PAPER
447
(endo, endo)-9-Benzyl-9-azabicyclo[3.3.1]nonane-2,6-diol: An Intermediate
for the Preparation of Indole Alkaloids of the Macroline/Sarpagine Series
Dominique Gennet, Patrick Michel,* André Rassat*
Ecole Normale Supérieure and CNRS, 24 rue Lhomond, 75231 Paris Cedex 05, France
Fax +33144323863; E-mail: andre.rassat@ens.fr
Received 31 August 1999; revised 23 October 1999
Abstract: Two intermediates 9b and 9c already used by Cook and
Magnus in their syntheses of indole alkaloids were obtained from
the title compound 1 through a Fischer indolization procedure. Re-
lated tetracyclic intermediates 6 and 8 were also prepared: 6 having
substituents at position 2 or 4 were directly obtained, while 8 with
substituents at position 1 or 3 were selectively obtained through a
convenient protection-deprotection scheme
Key words: bicyclic compounds, indoles, natural products, macro-
line/sarpagine alkaloids, Fischer indolization, heterocycles
Many indole alkaloids possess the basic tetracyclic
skeleton1 (Figure) with eventually substituents such as a
methyl group on nitrogen 5 or 12 and/or hydroxy or meth-
oxy groups on carbon 1, 2, 3 or 4. Alkaloids having this
skeleton have been generally prepared from tryptophane
Reagents and conditions: (a) TBDMSCl/DMAP/Et3N/CH2Cl2; (b)
H2/10% Pd-C MeOH; (c) BzCl/K2CO3/acetone; (d) Swern oxidation;
(e) HF/MeCN
derivatives using a Pictet-Spengler2 reaction. A 9-azabi-
cyclo[3.3.1]nonanone3 has also been used during an at-
tempted synthesis of ajmaline4 through a Fischer indole
synthesis. However, due to the choice of a phenylcarba-
mate as protective group on nitrogen 12, it was not possi-
ble to introduce the desired substituents on carbon 8.
Scheme 1
Fischer indolization8 occurred. We did not investigate the
use of the methods developed to overcome this problem.9
Figure Basic tetracyclic skeleton of indole alkaloids
Because
(endo,endo)-9-benzyl-9-azabicyclo[3.3.1]no-
Scheme 2
nane-2,6-diol (1) was easily available,5 we decided to re-
investigate this strategy and to extend it to alkaloids hav-
ing substituents on the indole nucleus. For this purpose, it
was first necessary to prepare ketone 4 (Scheme 1). Diol
1 was monoprotected by tert-butyldimethylsilyl, and N-
benzyl was replaced by the N-benzoyl group6 to give alco-
hol 3. Ketone 4 was obtained in 37% yield from 1 after
Swern oxidation followed by removal of the silyl protect-
ing group.7
Table Indoles 6 Prepared
Phenyl-
hydrazine
R
X1
X2
Product
Yield (%)a
5a
5b
5c
5d
5e
5f
H
H
H
H
Me
Br
OMe
H
H
H
H
H
H
H
Me
OMe
6a
6b
6c
6d
6e
6f
94
95
92
83
58
Me
Bn
H
H
H
Ketone 4 was then reacted with substituted phenylhydra-
zines in refluxing HCl-saturated methanol (Scheme 2, Ta-
ble). The corresponding derivatives 6 were easily
obtained from 1-alkyl,1-phenylhydrazine (i.e. 5b and 5c)
and from para- (i.e. 5g and 5h) and ortho- (i.e. 5d and 5e)
substituted phenylhydrazines, except from p-methoxy-
phenylhydrazine (5f), where as expected, an abnormal
b
–
5g
5h
H
H
6g
6h
93
71
H
a Isolated yield of purified product.
b A mixture of several products was obtained and was not further in-
vestigated.
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448
D. Gennet et al.
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performed on Merck silica gel plates (60 F254). Flash chromatogra-
phy was performed using Merck silica gel (Geduran SI 60, 0.040-
0.063 mm). Melting points were measured on a Büchi 535 melting
point apparatus. Elemental analyses were performed by the Service
Régional de Microanalyses de l’Université Pierre et Marie Curie
(Paris).
Reaction with meta-subtituted phenylhydrazines obvious-
ly should lead to a mixture of 1- and 3-substituted mole-
cules: for instance, with m-tolylhydrazine we obtained a
1:1 mixture of 8a and 8b. In order to make this reaction
regioselective, we have used a temporary substitution by
bromine at one ortho-position. After Fischer indolization
and hydrogenolysis10 in the presence of Pd/C and K2CO3,
the 1- or 3-substituted 8a and 8b, respectively were ob-
tained (Scheme 3).
(endo, endo)-9-Benzyl-6-[(tert-butyldimethylsilyl)oxy]-9-azabi-
cyclo[3.3.1]nonan-2-ol (2)
A solution of the diol 1 (10.9 g, 44.13 mmol) in CH2Cl2 (100 mL)
was cooled to 0°C under argon, and Et3N (11.5 mL, 81.82 mmol),
DMAP (2 g, 16.3 mmol) and TBDMSCl (7 g, 46.44 mmol) were
added successively. After stirring the resulting mixture for 7 h at
0°C, H2O (100 mL) was added. The aqueous layer was extracted
with CH2Cl2 (100 mL) and the combined organic layers were dried
(Na2SO4) and evaporated. The crude product was purified by flash
chromatography (CH2Cl2/acetone, 95:5 then 80:20) to give 2
(8.04 g, 50%) as a white powder; mp 85°C.
1H NMR (400 MHz, CDCl3): d = 0.00 (s, 3 H), 0.04 (s, 3 H), 0.89
(s, 9 H), 1.67 (br s, 1 H), 1.70-2.11 (m, 8 H), 2.61-2.67 (m, 1 H),
2.70-2.76 (m, 1 H), 3.98 (s, 2 H), 4.08-4.20 (m, 2 H), 7.20-7.40
(m, 5 H).
13C NMR (50 MHz, CDCl3): d = -4.93, -4.69, 17.95, 19.95, 20.11,
25.75, 30.04, 30.74, 54.57, 55.31, 56.30, 68.02, 68.21, 126.75,
128.02, 128.09, 139.88.
IR (KBr): n = 3297, 3088, 3068, 3028, 2932, 2893, 2859, 1495,
1459, 1383, 1367, 1266, 1133, 1087, 1057, 863, 838 cm-1.
MS (CI, NH3): m/z (%) = 362 ([MH]+, 100), 272 (49).
Scheme 3
Anal. Calcd for C21H35NO2Si: C, 69.75; H, 9.76; N, 3.87. Found: C,
69.85; H, 9.78; N, 3.86.
The hydroxy ketone 4 also gives a convenient access to
the two intermediates 9b1a and 9c2b previously used by
Cook1a and Magnus2b in their total syntheses. These mol-
ecules were directly obtained by Swern oxidation of 6b
and 6c, respectively (Scheme 4).
(endo, endo)-9-Benzoyl-6-[(tert-butyldimethylsilyl)oxy]-9-aza-
bicyclo[3.3.1]nonan-2-ol (3)
Argon was bubbled through a solution of the amine 2 (2 g,
5.5 mmol) and wet 10% Pd/C (50%, 250 mg) in MeOH (50 mL).
The resultant suspension was stirred overnight under an atmosphere
of H2 maintained by fixing a balloon filled with H2 to the flask. Af-
ter filtration through Celite, the solvent was removed under reduced
pressure. To the residue, acetone (50 mL), K2CO3 (7.7 g,
55.4 mmol) and benzoyl chloride (3.2 mL, 27.7 mmol) were suc-
cessively added, and the solution refluxed for 8 h. Acetone was then
evaporated under reduced pressure and CH2Cl2 (100 mL) was add-
ed to the residual solution. The organic layer was washed with H2O
(50 mL), dried (Na2SO4) and evaporated. The crude product was
purified by flash chromatography (CH2Cl2/acetone, 80:20) to afford
3 (1.71 g, 82%) as a white solid; mp < 40°C.
Scheme 4
Major Rotamer:
1H NMR (400 MHz, CDCl3,): d = -0.18 (s, 3 H), -0.08 (s, 3 H),
0.79 (s, 9 H), 1.48-1.62 (m, 1 H), 1.66-1.97 (m, 5 H), 2.05-2.12
(m, 1 H), 2.20-2.27 (m, 1 H), 3.52 (br t, 1 H, J = 5.39 Hz), 3.76-
3.86 (m, 2 H), 3.91-4.01 (m, 1 H), 4.69 (br t, 1 H, J = 4.90 Hz),
7.30-7.50 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = -5.27, -5.10, 17.74, 20.85, 22.11,
25.52, 28.77, 30.11, 48.02, 54.46, 66.43, 70.22, 126.14, 128.43,
129.60, 135.71, 170.20.
These results demonstrate that (endo, endo)-9-benzyl-9-
azabicyclo[3.3.1]nonane-2,6-diol (1) which already pro-
vided an easy access to stereoselective synthesis of in-
dolizidine and quinolizidine alkaloids,11 can also in
principle be used for the synthesis of macroline/sarpagine
type alkaloids.
Minor Rotamer:
Unless otherwise specified, materials were purchased from com-
mercial suppliers and used without further purification. CH2Cl2 and
Et3N were distilled from CaH2. THF was distilled from Na-ben-
zophenone ketyl immediately before use. NMR spectra were re-
1H NMR (400 MHz, CDCl3): d = 0.11 (s, 3 H), 0.14 (s, 3 H), 0.93
(s, 9 H), 1.48-1.62 (m, 1 H), 1.66-1.97 (m, 5 H), 1.97-2.05 (m, 1
H), 2.20-2.27 (m, 1 H), 3.18-3.27 (m, 1 H), 3.64 (br t, 1 H,
J = 5.20 Hz), 3.76-3.86 (m, 1 H), 3.91-4.01 (m, 1 H), 4.59 (br t, 1
H, J = 4.92 Hz), 7.30-7.50 (m, 5 H).
corded in CDCl3 or DMSO at 400 MHz for 1H and 50 MHz for 13
C
using CHCl3 (7.30 ppm for 1H, 77.00 ppm for 13C), and using H2O
(3.33 ppm for 1H in DMSO) or DMSO (39.7 ppm for 13C in DMSO)
as internal reference unless otherwise stated. Analytical TLC was
Synthesis 2000, No. 3, 447–451 ISSN 0039-7881 © Thieme Stuttgart · New York

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An Intermediate for the Preparation of Indole Alkaloids of the Macroline/Sarpagine Series
449
13C NMR (50 MHz, CDCl3): d = -4.89, -4.75, 17.87, 21.03, 22.23,
25.67, 29.10, 30.36, 48.08, 53.86, 66.89, 69.50, 126.28, 128.39,
129.44, 135.94, 170.07.
Indoles 6 and 7; General Procedure
A solution of the ketone 4 (2 mmol) and hydrazine (or hydrazine hy-
drochloride) 5 (4 mmol) in MeOH saturated with HCl (30 mL) was
refluxed overnight. The mixture was cooled, diluted with aq 2.5 N
NaOH solution (30 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried (Na2SO4) and evaporat-
ed.12 The residue was dissolved in THF (5 mL) and added to a sus-
pension of LiAlH4 (200 mg, 5.27 mmol) in THF (30 mL) under
argon at 0 °C. After 15 min, the mixture was warmed to r.t., and re-
fluxed overnight. After cooling to r.t., H2O (200 µL), aq 15% NaOH
solution (200 µL) and then H2O (600 µL) were successively added
dropwise. The resulting suspension was filtered through Celite,
rinsed with Et2O, and the solvent removed under reduced pressure.
The crude product was purified by flash chromatography (CH2Cl2/
acetone, 90:10) to afford the corresponding indole as a white moss.
IR (KBr): n = 3422, 3061, 2951, 2885, 2856, 1616, 1578, 1438,
1261, 1101, 1074, 1026, 860, 837, 775, 705 cm-1.
MS (CI, NH3): m/z (%) = 376([MH]+, 100).
Anal. Calcd for C21H33NO3Si: C, 67.16; H, 8.86; N, 3.73. Found: C,
67.23; H, 8.97; N, 3.76.
(endo)-9-Benzoyl-6-[(tert-butyldimethylsilyl)oxy]-9-azabicy-
clo[3.3.1]nonan-2-one
To a solution of oxalyl chloride (1.97 mL, 22.66 mmol) in CH2Cl2
(100 mL) was added dropwise DMSO (3.22 mL, 45.32 mmol) at
-60°C. The mixture was stirred for 2 min, and a solution of alcohol
3 (7.72 g, 20.6 mmol) in CH2Cl2 (10 mL) was then added. After
stirring for 15 min, Et3N (8.69 mL, 61.8 mmol) was added. The
mixture was stirred for 5 min and then allowed to warm to r.t. H2O
(100 mL) was then added and the aqueous layer was extracted with
CH2Cl2 (100 mL). The organic layers were combined, washed in
turn with brine (200 mL), 0.4 N HCl solution (200 mL), H2O
(100 mL), aq satd NaHCO3 solution (200 mL) and H2O (100 mL),
dried (Na2SO4) and evaporated. The crude product was purified by
flash chromatography (hexane/EtOAc, 70:30) to give the corre-
sponding ketone (7.35 g, 95%) as a white solid; mp 76°C.
1H NMR (400 MHz, CDCl3): d = -0.15, -0.05, 0.14 and 0.17 (s, 6
H), 0.79 and 0.93 (s, 9 H), 1.41-1.55 (m, 1 H), 1.63-1.90 (m, 2H),
1.97-2.72 (m, 5 H), 3.72-3.82 and 3.91-3.99 (m, 1H), 4.05-4.18
(m, 1 H), 5.05-5.13 (m, 1 H), 7.35-7.50 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = -5.31, -5.00, -4.89, -4.73, 16.72,
17.78, 25.43, 26.67, 27.90, 35.96, 36.26, 47.74, 53.93, 56.74, 62.35,
68.52, 69.64, 126.44, 126.73, 128.59, 130.09, 134.94, 170.52,
212.06, 212.33.
(endo)-12-Benzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-cy-
clooct[b]indol-9-ol (6a)
Indole 6a (600 mg, 94%) was obtained from 4 (518 mg, 2 mmol);
mp 95-96°C.
1H NMR (400 MHz, CDCl3): d = 1.22-1.33 (m, 1 H), 1.65-1.75
(m, 3 H), 2.08 (dddd, 1 H, J = 13.20, 13.20, 4.20, 4.20 Hz), 2.89-
3.01 (m, 2 H), 3.36 (br t, 1 H, J = 5.06 Hz), 3.73 (s, 2 H), 3.80-3.82
(m, 1 H), 4.11 (ddd, 1 H, J = 11.91, 5.06, 5.06 Hz); 7.16-7.24 (m,
2 H), 7.30-7.38 (m, 6 H), 7.59-7.62 (m, 1 H), 7.68 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.00, 25.48, 30.42, 50.84, 56.76,
57.50, 70.85, 108.06, 110.90, 118.10, 119.19, 121.11, 126.96,
127.01, 128.26, 128.67, 132.65, 135.67, 139.41.
IR (KBr): n = 3404, 3109, 3082, 3057, 2925, 2845, 1703, 1599,
1495, 1452, 1362, 1338, 1311, 1232, 1157, 1118, 1074, 1003, 922,
741, 698 cm-1.
HRMS: m/z calcd for C21H23N2O 319.1810, found 319.1823.
(endo)-12-Benzyl-5-methyl-6,7,8,9,10,11-hexahydro-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (6b)
Indole 6b (631 mg, 95%) was obtained from 4 (518 mg, 2 mmol);
mp 68-70°C.
1H NMR (400 MHz, CDCl3): d = 1.29-1.41 (m, 1 H), 1.70-1.80
(m, 2 H), 2.19 (dddd, 1 H, J = 13.10, 13.10, 4.16, 4.16 Hz), 2.51 (s,
1 H), 3.01-3.10 (m, 2 H), 3.41-3.46 (m, 1 H), 3.64 (s, 3 H), 3.79 (s,
2 H), 3.96-4.01 (m, 1 H), 4.17 (ddd, 1 H, J = 12.01, 4.90, 4.90 Hz),
7.26-7.32 (m, 1 H), 7.34-7.40 (m, 1 H), 7.40-7.48 (m, 6 H), 7.73
(d, 1 H, J = 7.73 Hz).
IR (KBr): n = 3061, 2955, 2930, 2897, 2858, 1732, 1628, 1430,
1327, 1252, 1109, 964, 835, 792 cm-1.
MS (CI, NH3): m/z (%) = 374([MH]+, 100).
Anal. Calcd for C21H31NO3Si: C, 67.52; H, 8.36; N, 3.75. Found: C,
67.60; H, 8.32; N, 3.74.
(endo)-9-Benzoyl-6-hydroxy-9-azabicyclo[3.3.1]nonan-2-one
(4)
To a solution of the above ketone (12.86 g, 34.5 mmol) in MeCN
was added aq 40% HF (7.5 mL). After stirring overnight, aq satd
NaHCO3 solution (100 mL) was added and the resulting solution
extracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were dried (Na2SO4) and evaporated. The crude product was puri-
fied by flash chromatography (CH2Cl2/acetone, 80:20) to afford 4
(7.35 g, 95%) as a white powder, mp 168°C.
1H NMR (400 MHz, DMSO-d6): d = 1.40-1.55 (m, 1 H), 1.83-2.02
(m, 2 H), 2.09-2.41 (m, 3 H), 2.47-2.57 (m, 1 H), 2.81-3.02 (m, 1
H), 3.80-3.90 (m, 2/3 H), 3.90-4.00 (m, 1/3 H), 4.03 (br s, 1/3 H),
4.14-4.22 (m, 2/3 H), 4.99 (br s, 2/3 H), 5.08-5.15 (m, 1/3 H), 5.30
(d, 2/3 H, J = 3.82 Hz), 5.45 (d, 1/3 H, J = 3.44 Hz), 7.62-7.72 (m,
5 H).
13C NMR (50 MHz, CDCl3): d = 15.07, 25.36, 28.92, 29.92, 49.50,
56.84, 57.68, 70.82, 107.51, 108.78, 118.18, 118.81, 120.78,
126.57, 127.00, 128.27, 128.76, 133.82, 137.00, 139.39.
IR (KBr): n = 3383, 3053, 3026, 2920, 2843, 1468, 1369, 1126,
1005, 741, 725, 698 cm-1.
HRMS: m/z calcd for C22H25N2O 333.1967, found 333.1942.
(endo)-5,12-Dibenzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-
cyclooct[b]indol-9-ol (6c)
Indole 6c (748 mg, 92%) was obtained from 4 (518 mg, 2 mmol);
mp 72-74°C.
1H NMR (400 MHz, CDCl3): d = 1.27-1.38 (m, 1 H), 1.52-1.58
(m, 1 H), 1.63-1.80 (m, 2 H), 2.02 (tt, 1 H, J = 13.11, 4.01 Hz),
2.96-3.08 (m, 2 H), 3.37 (br t, 1 H, J = 5.19 Hz), 3.61 (d, 1 H,
J = 13.52 Hz), 3.70 (d, 1 H, J = 13.52 Hz), 3.85 (br s, 1 H), 4.09 (dt,
1 H, J = 11.82, 5.05 Hz), 5.17 (d, 1 H, J = 16.99 Hz), 5.28 (d, 1 H,
J = 16.99 Hz), 6.95-7.00 (m, 2 H), 7.18-7.33 (m, 11 H), 7.65-7.69
(m, 1 H).
13C NMR (50 MHz, DMSO-d6): d = 16.60, 17.57, 25.87, 26.48,
27.45, 35.92, 47.20, 53.55, 56.32, 61.98, 66.97, 67.80, 126.72,
128.60, 129.85, 135.41, 169.48, 212.30.
IR (KBr): n = 3333, 2990, 2972, 2954, 2920, 2867, 2843, 1724,
1603, 1576, 1437, 1342, 1080, 731 cm-1.
MS (CI, NH3): m/z (%) = 260([MH]+, 100).
13C NMR (50 MHz, CDCl3): d = 15.01, 25.14, 29.64, 46.00, 49.60,
56.56, 57.47, 70.58, 108.20, 109.25, 118.11, 119.00, 121.02,
125.75, 126.64, 126.71, 127.12, 128.01, 128.50, 133.53, 136.67,
137.72, 139.09.
Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.34; H, 6.53; N, 5.30.
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D. Gennet et al.
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IR (KBr): n = 3379, 3064, 3027, 2928, 2329, 1495, 1452, 1350,
2.98 (m, 2 H), 3.33-3.38 (m, 1 H), 3.73 (s, 2 H), 3.77-3.81 (m, 1
H), 3.92 (s, 3 H), 4.08-4.15 (m, 1 H), 6.86 (dd, 1 H, J = 8.68,
2.46 Hz), 7.05 (d, 1 H, J = 2.46 Hz), 7.24 (d, 1 H, J = 8.68 Hz),
7.27-7.38 (m, 5 H), 7.60 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.02, 25.52, 30.43, 50.96, 55.94,
56.71, 57.49, 70.81, 100.44, 107.86, 110.79, 111.54, 127.34,
126.93, 128.23, 128.67, 130.81, 133.69, 139.34, 153.74.
1176, 1127, 1009, 737, 697 cm-1.
MS (CI, NH3): m/z (%) = 409([MH]+, 100).
(endo)-12-Benzyl-4-methyl-6,7,8,9,10,11-hexahydro-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (6d)
Indole 6d (248 mg, 83%) was obtained from 4 (230 mg,
0.89 mmol); mp 96-98°C.
1H NMR (400 MHz, CDCl3): d = 1.25-1.40 (m, 1 H), 1.64-1.80
(m, 2 H), 2.05-2.17 (m, 1 H), 2.23 (br s, 1 H), 2.55 (s, 3 H), 2.92-
3.03 (m, 2 H), 3.33-3.38 (m, 1 H), 3.76 (s, 2 H), 3.85-3.88 (m, 1
H), 4.13 (ddd, 1 H, J = 11.87, 5.03, 5.03 Hz), 7.07 (br d, 1 H,
J = 7.21 Hz), 7.17 (dd, 1 H, J = 7.50, 7.50 Hz), 7.32-7.44 (m, 5 H),
7.51 (br d, 1 H, J = 7.78 Hz), 7.81 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.09, 16.73, 25.52, 30.51, 50.90,
56.75, 57.51, 70.92, 108.72, 115.81, 119.47, 119.97, 121.93,
126.56, 126.91, 128.21, 128.61, 132.30, 135.16, 139.36.
IR (KBr): n = 3402, 3082, 3061, 3026, 2997, 2930, 2841, 1626,
1593, 1418, 1454, 1215, 1140, 1115, 964, 735, 700 cm-1.
HRMS: m/z calcd for C22H25N2O2 349.1916, found 349.1918.
(endo)-12-Benzyl-4-bromo-1-methyl-6,7,8,9,10,11-hexahydro-
6,10-imino-5H-cyclooct[b]indol-9-ol (7a)
Indole 7a (563 mg, 68%) was obtained from 4 (518 mg, 2 mmol).
1H NMR (400 MHz, CDCl3): d = 1.26-1.39 (m, 1 H), 1.63 (br s, 1
H), 1.69-1.81 (m, 2 H), 2.04-2.14 (m, 1 H), 2.73 (s, 3 H), 3.11-
3.23 (m, 2 H), 3.31 (br t, 1 H, J = 4.72 Hz), 3.75 (s, 2 H), 3.85 (t, 1
H, J = 3.22 Hz), 4.12 (dt, 1 H, J = 16.89, 5.23 Hz), 6.78 (d, 1 H,
J = 7.85 Hz), 7.20 (d, 1 H, J = 7.85 Hz), 7.26-7.38 (m, 5 H), 7.85
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 17.57, 19.30, 25.50, 30.38, 50.79,
56.79, 57.51, 70.87, 101.69, 109.94, 121.61, 123.31, 126.99,
127.34, 128.59, 128.27, 129.81, 132.67, 134.00, 139.19.
IR (KBr): n = 3420, 3082, 3045, 3024, 2918, 2851, 1452, 744 cm-1.
MS (CI, NH3): m/z (%) = 333([MH]+, 100), 160(51), 106(100).
(endo)-12-Benzyl-4-bromo-6,7,8,9,10,11-hexahydro-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (6e)
Indole 6e (490 mg, 58%) was obtained from
4 (554 mg,
2.13 mmol).
IR (KBr): n = 3416, 3059, 3026, 2926, 2849, 1705, 1616, 1452,
1H NMR (400 MHz, CDCl3): d = 1.20-1.33 (m, 1 H), 1.64-1.81
(m, 3 H), 2.10 (dddd, 1 H, J = 13.15, 13.15, 4.13, 4.13 Hz), 2.89-
2.99 (m, 2 H), 3.34-3.38 (m, 1 H), 3.72 (s, 2 H), 3.86-3.88 (m, 1
H), 4.12 (ddd, 1 H, J = 11.84, 5.16, 5.16 Hz), 7.06 (t, 1 H,
J = 7.76 Hz), 7.27-7.38 (m, 6 H), 7.53 (d, 1 H, J = 7.81 Hz), 7.91
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.09, 25.44, 30.34, 50.81, 56.52,
57.53, 70.75, 104.52, 109.59, 117.29, 120.46, 123.56, 126.98,
128.25, 128.40, 128.58, 133.46, 134.35, 139.13.
1325, 1115, 793, 739, 698 cm-1.
MS (CI, NH3): m/z (%) = 413([MH]+, 93), 411([MH]+, 100).
(endo)-12-Benzyl-4-bromo-3-methyl-6,7,8,9,10,11-hexahydro-
6,10-imino-5H-cyclooct[b]indol-9-ol (7b)
Indole 7b (634 mg, 77%) was obtained from 4 (518 mg, 2 mmol).
1H NMR (400 MHz, CDCl3): d = 1.21-1.33 (m, 1 H), 1.65-1.81
(m, 3 H), 2.09 (tt, 1 H, J = 13.1, 4.1 Hz), 2.57 (s, 3 H), 2.86-2.98
(m, 2 H), 3.34 (td, 1 H, J = 5.02, 1.3 Hz), 3.67 (s, 2 H), 3.85 (t, 1 H,
J = 3.23 Hz), 4.11 (dt, 1 H, J = 11.19, 5.51 Hz), 7.06 (d, 1 H,
J = 7.90 Hz), 7.27-7.37 (m, 5 H), 7.42 (d, 1 H, J = 7.90 Hz), 7.88
(br s, 1 H).
IR (KBr): n = 3423, 3059, 3028, 2926, 2847, 1493, 1420, 1362,
1333, 1306, 1198, 1157, 1132, 1074, 1028, 1009, 773, 733,
698 cm-1.
MS (CI, NH3): m/z (%) = 399([MH]+, 100), 397([MH]+, 93),
381(24), 379(24), 319(22).
13C NMR (50 MHz, CDCl3): d = 15.05, 21.79, 25.51, 30.38, 50.79,
56.53, 57.51, 70.62, 106.58, 109.51, 116.76, 122.03, 126.10,
126.90, 128.19, 128.50, 129.75, 132.56, 134.95, 139.18.
(endo)-12-Benzyl-4-methyl-6,7,8,9,10,11-hexahydro-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (6g)
Indole 6g (310 mg, 93%) was obtained from 4 (259 mg, 1 mmol);
mp 118-120°C.
IR (KBr): n = 3412, 3059, 3021, 2920, 2845, 1705, 1452, 1313,
1157, 1130, 1030, 800, 738, 700 cm-1.
MS (CI, NH3): m/z (%) = 413([MH]+, 93), 411([MH]+, 100).
1H NMR (400 MHz, CDCl3): d = 1.20-1.35 (m, 1 H), 1.63-1.73
(m, 2 H), 2.03-2.14 (m, 1 H), 2.31 (br s, 1 H), 2.61 (s, 3 H), 2.91-
3.01 (m, 2 H), 3.33-3.39 (m, 1 H), 3.73-3.78 (m, 3 H), 4.11 (ddd,
1 H, J = 11.94, 4.89, 4.89 Hz), 7.11 (dd, 1 H, J = 8.18, 1.18 Hz),
7.26 (d, 1 H, J = 8.18 Hz), 7.35-7.45 (m, 5 H), 7.46 (br s, 1 H), 7.62
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.01, 21.48, 25.55, 30.45, 50.86,
56.78, 57.50, 70.90, 107.62, 110.54, 117.88, 122.61, 126.93,
127.24, 128.25, 128.45, 128.65, 132.80, 133.94, 139.43.
Hydrogenolysis of Bromoindoles 7a,b to 8a,b; General Proce-
dure
Argon was bubbled through a solution of bromoindole 7 (1 mmol),
K2CO3 (4 mmol) and 10% Pd/C (100 mg) in MeOH (20 mL). The
resultant suspension was stirred under H2 (balloon) for 4 h, filtered
through Celite, rinsed with MeOH, and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2/acetone 80:20) to afford 8 as a white
moss.
IR (KBr): n = 3402, 3082, 3061, 3026, 2920, 2860, 1452, 1310,
1134, 733 cm-1.
(endo)-12-Benzyl-hexahydro-6,7,8,9,10,11-1-methyl-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (8a)
Indole 8a (108 mg, 82%) was obtained from 7a (164 mg,
0.4 mmol); mp 95-97°C.
MS (CI, NH3): m/z (%) = 333([MH]+, 89), 160(51), 134(100),
106(96).
(endo)-12-Benzyl-2-methoxy-6,7,8,9,10,11-hexahydro-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (6h)
6h (495 mg, 71°%, mp 96-98 °C) was obtained from 4 (518 mg,
2 mmol).
1H NMR (400 MHz, CDCl3): d = 1.22-1.34 (m, 1 H), 1.65-1.75
(m, 3 H), 2.08 (dddd, 1 H, J = 13.18, 13.18, 4.17, 4.17 Hz), 2.86-
1H NMR (400 MHz, CDCl3): d = 1.27-1.42 (m, 1 H), 1.63 (br s, 1
H), 1.68-1.75 (m, 2 H), 2.06 (tt, 1 H, J = 13.13, 3.98 Hz), 2.75 (s,
3 H), 3.17-3.21 (m, 2 H), 3.32 (td, 1 H, J = 4.10, 4.10 Hz), 3.74 (s,
2 H), 3.79 (t, 1 H, J = 3.22 Hz), 4.11 (dt, 1 H, J = 11.85, 4.98 Hz),
6.90 (d, 1 H, J = 7.58 Hz), 7.07 (t, 1 H, J = 7.58 Hz), 7.18 (d, 1 H,
J = 7.58 Hz), 7.26-7.38 (m, 5 H), 7.61 (br s, 1 H).
Synthesis 2000, No. 3, 447–451 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Intermediate for the Preparation of Indole Alkaloids of the Macroline/Sarpagine Series
451
13C NMR (50 MHz, CDCl3): d = 17.70, 19.75, 25.53, 30.43, 50.76,
57.05, 57.47, 70.96, 108.36, 106.63, 120.36, 121.11, 126.14,
126.99, 128.30, 128.68, 130.40, 131.94, 135.57, 139.44.
1H NMR (400 MHz, CDCl3): d = 1.74-1.88 (m, 1 H), 2.12-2.23
(m, 1 H), 2.31-2.40, (m, 1 H), 2.46 (dd, 1 H, J = 16.22, 5.08 Hz),
2.78 (d, 1 H, J = 16.80 Hz), 3.35 (dd, 1 H, J = 16.80, 6.88 Hz), 3.66
(d, 1 H, J = 13.37 Hz), 3.74 (d, 1 H, J = 13.37 Hz), 3.82 (d, 1 H,
J = 6.74 Hz), 4.00-4.05 (m, 1 H), 5.22 (d, 1 H, J = 17.07 Hz), 5.33
(d, 1 H, J = 17.07 Hz), 6.92-6.97 (m, 2 H), 7.18-7.32 (m, 11 H),
7.58-7.64 (m, 1 H).
IR (KBr): n = 3395, 3059, 3028, 2928, 2859, 1452, 1333, 1146,
1074, 743, 700 cm-1.
MS (CI, NH3): m/z (%) = 333([MH]+, 100).
13C NMR (50 MHz, CDCl3): d = 20.23, 29.69, 34.08, 46.23, 48.62,
55.93, 64.73, 106.37, 109.34, 118.08, 119.37, 121.70, 125.57,
126.44, 126.99, 127.26, 128.11, 128.41, 128.57, 132.77, 136.66,
137.29, 137.87, 209.66.
(endo)-12-Benzyl-3-methyl-6,7,8,9,10,11-hexahydro-6,10-imi-
no-5H-cyclooct[b]indol-9-ol (8b)
Indole 8b (194 mg, 75%) was obtained from 7b (318 mg,
0.77 mmol); mp 176-178°C.
1H NMR (400 MHz, CDCl3): d = 1.22-1.34 (m, 1 H), 1.55-1.74
(m, 3 H), 2.06 (tt, 1 H, J = 4.17, 13.12 Hz), 2.51 (s, 3 H), 2.85-2.99
(m, 2 H), 3.34 (t, 1 H, J = 5.31 Hz), 3.71 (s, 2 H), 3.78 (t, 1 H,
J = 3.23 Hz), 4.10 (dt, 1 H, J = 11.9, 5.31 Hz), 7.02 (dd, 1 H,
J = 7.93, 0.76 Hz), 7.17 (s, 1 H), 7.26-7.37 (m, 5 H), 7.48 (d, 1 H,
J = 7.93 Hz), 7.53 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.97, 21.63, 25.43, 30.36, 50.72,
56.72, 57.40, 70.83, 107.84, 110.86, 117.69, 120.79, 124.79,
126.84, 128.16, 128.56, 130.82, 131.77, 136.01, 139.38.
IR (KBr): n = 3065, 3039, 2929, 2831, 1716, 1628, 1491, 1457,
1156, 1051, 732, 699 cm-1.
MS (FAB): m/z (%) = 407([MH]+, 100).
References
(1) (a) Bi, Y.; Hamaker, L. K.; Cook, J. M. The synthesis of
macroline related alkaloids; In Bioactive Natural Products,
Part A; Basha, F., Rahman, A., Eds.; Elservier Science:
Amsterdam, 1993,Vol. 13; p 383.
IR (KBr): n = 3406, 3032, 2930, 2855, 1636, 1497, 1464, 1165,
908, 812, 742, 710 cm-1.
(b) Hamaker, L. K.; Cook, J. M. The Synthesis of Macroline
Related Alkaloids; In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon Press: London,
1995, Vol. 9; p 23.
MS (CI, NH3): m/z (%) = 333([MH]+, 100).
12-Benzyl-5-methyl-5,6,7,8,10,11-hexahydro-6,10-imino-9H-
cyclooct[b]indol-9-one (9b)
(2) (a) Cain, M.; Campos, O.; Guzman, F.; Cook, J. M. J. Am.
Chem. Soc. 1983, 105, 907.
To a solution of oxalyl chloride (240 µL, 2.75 mmol) in CH2Cl2
(25 mL) was added dropwise DMSO (370 µL, 5.21 mmol) at
-60°C. The mixture was stirred for 2 min, and a solution of alcohol
8b (550 mg, 1.65 mmol) in CH2Cl2 (3 mL) was then added. After
stirring for 15 min, Et3N (980 µL, 6.97 mmol) was added. The mix-
ture was stirred again for 5 min and then allowed to warm to r.t. H2O
(25 mL) was then added and the aqueous layer was extracted with
additional CH2Cl2 (25 mL). The organic layers were combined,
dried (Na2SO4) and evaporated. The crude product was purified by
flash chromatography (hexane/EtOAc, 70:30) to give the corre-
sponding ketone 9b (400 mg, 73%) as a white moss; mp 131-
132°C (Lit.13 131.5-133°C).
1H NMR (400 MHz, CDCl3): d = 1.98-2.07 (m, 1 H), 2.12-2.22
(m, 1 H), 2.46-2.56 (m, 2 H), 2.74 (d, 1 H, J = 16.87 Hz), 3.31 (dd,
1 H, J = 16.87, 6.83 Hz), 3.65 (s, 3 H), 3.78 (s, 2 H), 3.81 (d, 1 H,
J = 6.83 Hz), 4.10-4.12 (m, 1 H), 7.16-7.21 (m, 1 H), 7.26-7.39
(m, 7 H), 7.57 (d, 1 H, J = 7.80 Hz).
(b) Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain G. A.
J. Am. Chem. Soc. 1990, 112, 5220.
(c) Bailey, P. D.; McLay, N. R. Tetrahedron Lett. 1991, 32,
3895.
(3) Calvert, B. J.; Hobson, J. D. J. Chem. Soc. 1964, 5378.
(4) Cloudsdale, I. S.; Kluge, A. F.; McClure, N. L. J. Org. Chem.
1982, 47, 919.
(5) Michel, P.; Rassat, A., submitted to J. Org. Chem.
(6) N-benzyl could also be used instead of N-benzoyl 4 in the
indole syntheses, but the yield were not as good, ca 65%
compared to ca 95% with 4.
(7) It is necessary to liberate the alcohol function at this stage,
because when the protected alcohol was used in the
indolization reactions, the expected formation of an indole
derivative was not observed by NMR.
(8) Ishii, H. Acc. Chem. Res. 1981, 14, 275.
(9) (a) Szczepankiewicz, B. G.; Heathcock, C. H. Tetrahedron
1997, 53, 8853.
13C NMR (50 MHz, CDCl3): d = 20.39, 29.30, 29.74, 34.32, 48.84,
56.18, 64.80, 105.69, 108.92, 118.21, 119.25, 121.52, 126.44,
127.33, 128.45, 128.63, 133.15, 137.18, 138.26, 210.00.
(b) Murakami, Y.; Watanabe, T.; Takahashi, H.; Yokoo, H.;
Nakazawa, Y.; Koshimizu, M.; Adachi, N.; Kurita, M.;
Yoshino, T.; Inagaki, T.; Ohishi, M.; Watanabe, M.; Tani, M.;
Yokoyama, Y. Tetrahedron 1998, 54, 45.
IR (KBr): n = 3090, 3064, 3032, 2967, 2935, 2850, 2802,
1715 cm-1.
(10) For a example of hydrogenolysis of a bromoindole, see: Tsuji,
S.; Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S.
S.; Lui, M. S.; Pomponi, S. A.; Diaz, M. C. J. Org. Chem.
1988, 53, 5446.
(11) Michel, P., Thèse de Doctorat 1999, Université Pierre et
Marie Curie, Paris.
(12) Alternatively, the Nb-benzoyl indoles could easily be isolated
at that stage. However, conversion to the Nb- benzyl
derivatives simplified the NMR spectra.
HRMS: m/z calcd for C22H23N2O 331.1810, found 331.1793.
5,12-Dibenzyl-5,6,7,8,10,11-hexahydro-6,10-imino-9H-cy-
clooct[b]indol-9-one (9c)
To a solution of oxalyl chloride (460 µL, 5.28 mmol) in CH2Cl2
(30 mL) was added dropwise DMSO (800 µL, 10.6 mmol) at
-60°C. The mixture was stirred for 2 min, and a solution of the al-
cohol 8c (431 mg, 1.05 mmol) in CH2Cl2 (5 mL) was then added.
After stirring for 15 min, Et3N (2.5 mL, 15.9 mmol) was added. The
mixture was stirred again for 5 min and then allowed to warm to r.t.
H2O (30 mL) was then added and the aqueous layer was extracted
with CH2Cl2 (30 mL). The organic layers were combined, dried
(Na2SO4) and evaporated. The crude product was purified by flash
chromatography (hexane/EtOAc 90:10) to give 9c (301 mg, 70%)
as a white moss; mp 79-80°C.
(13) Mashimo, K.; Sato, Y. Tetrahedron 1970, 26, 803.
Article Identifier:
1437-210X,E;2000,0,03,0447,0451,ftx,en;Z06199SS.pdf
Synthesis 2000, No. 3, 447–451 ISSN 0039-7881 © Thieme Stuttgart · New York