Reductive pictet-spengler cyclization of nitriles in the presence of tryptamine: Synthesis of indolo[2,3-a]quinolizidine, nazlinine, and elaeocarpidine

Article abstract of DOI:10.1021/np970191s

Preparation of tetrahydro-β-carbolines through catalytic hydrogenation of nitriles in the presence of tryptamine was applied to simple syntheses of indolo[2,3-α]quinolizidine (3), nazlinine (4), and elaeocarpidine (7).

Full text of DOI:10.1021/np970191s

J . Nat. Prod. 1997, 60, 791-793
791
Red u ctive P ictet-Sp en gler Cycliza tion of Nitr iles in th e P r esen ce of
Tr yp ta m in e: Syn th esis of In d olo[2,3-a ]qu in olizid in e, Na zlin in e, a n d
Ela eoca r p id in e
Khalid Diker, Khalid El Biach, Miche`le Do¨e´ de Maindreville, and J ean Le´vy*
Laboratoire de Transformations et Synthe`se de Substances Naturelles, associe´ au CNRS, Universite´ de Reims
Champagne-Ardenne, Faculte´ de Pharmacie, 51 rue Cognacq-J ay, F-51096 Reims Cedex, France
Received March 28, 1997X
Preparation of tetrahydro-â-carbolines through catalytic hydrogenation of nitriles in the
presence of tryptamine was applied to simple syntheses of indolo[2,3-a]quinolizidine (3),
nazlinine (4), and elaeocarpidine (7).
Sch em e 1
One of the easiest syntheses of tetrahydro-â-carbo-
lines is the Pictet-Spengler reaction of tryptamine with
aldehydes, or their equivalent R-keto esters and R-keto
acids.1 However, when targeting polyfunctional com-
pounds, the preparation of the starting polyfunctional
aldehydes may meet with difficulties. We recently
developed an efficient modification of the reaction that
involves trapping, by tryptamine, of an iminium ion
generated in situ by catalytic hydrogenation of a nitrile.2
With regard to the easier access to polyfunctional
nitriles over aldehydes, this modification seemed of
interest for the synthesis of some natural products and
analogues.
Sch em e 2
Resu lts a n d Discu ssion
Hydrogenation of glutaronitrile in acetic acid in the
presence of tryptamine (1) yielded 1-(3-cyanopropyl)-
tetrahydro-â-carboline (2) and indolo[2,3-a]quinolizidine
(3) (Scheme 1).3 After 48 h, the tricyclic nitrile 2 was
isolated in 58% yield while indolo[2,3-a]quinolizidine (3)
began to form (14%). Increasing the reaction time to
72 h raised the yield of 3 to 40% at the expense of 2
(33%). Formation of 3 implies hydrogenation of one
nitrile group of glutaronitrile to a protonated imine that
is trapped by tryptamine yielding a ; elimination of NH3
to iminium ion b; Pictet-Spengler cyclization to c;
hydrogenation of the second nitrile group to a proto-
nated imine that is trapped as aminal d ; elimination of
NH3 to iminium ion e; and finally, hydrogenation to 3.
No nazlinine (4) was detected in the reaction mixture,
indicating that the cyclization to d was entropically
favored over complete hydrogenation of the intermediate
(protonated) imine (Scheme 2).
Sch em e 3
Nazlinine (4) is a racemic alkaloid isolated4 from
Nitraria schoberi; its structure was elucidated through
a biomimetic synthesis5 from tryptamine and tetrahy-
dropyridine. Lithium aluminum hydride reduction of
nitrile 2 expectedly gave (()-nazlinine (4) (79%).
(()-Elaeocarpidine (7) was isolated from Elaeocarpus
species6,7 and synthesized by Harley-Mason and Taylor8
via lactam 6, and by Gribble.9 Only the depicted
relative configuration of elaeocarpidine appears to be
possible, for steric reasons. In our hands, lactam 6 was
easily prepared (76%) through hydrogenation of N-
(cyanoethyl)pyrrolidone 510 in the presence of tryptamine
(Scheme 3). Reduction of 6 with DIBAH in THF
resulted in cyclization to elaeocarpidine (7) (73%). In a
second route, cyanoacetamide was hydrogenated in the
* Phone: (33) 3 26 05 35 70. Fax: (33) 3 26 05 35 52. E-mail:
jean.levy@univ-reims.fr.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
S0163-3864(97)00191-2 CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognosy

792 J ournal of Natural Products, 1997, Vol. 60, No. 8
Diker et al.
presence of tryptamine to give the tricyclic amide 8
(58%) that was reduced with LiAlH4 in THF to yield
the nazlinine analogue 9 (64%). Treatment with methyl
3-formylpropanoate gave lactam 10 (42%) that was at
last reduced with LiAlH4 in THF to give 7 (54%).
The above results then illustrate some syntheses of
tetrahydro-â-carbolines through catalytic hydrogenation
of nitriles in the presence of tryptamine, as an efficient
substitute to the Pictet-Spengler cyclization.
afford 178 mg (79%) of (()-nazlinine (4): UV (MeOH)
λmax 222, 272, 279, 289 nm; IR (film) νmax 3352, 3225,
3063, 2926, 1674, 1454, 1435, 1201, 1141, 800, 723 cm-1
;
EIMS m/ z 243 [M]+ (30), 197 (11), 185 (24), 171 (100),
154 (15), 144 (26); 1H NMR (CDCl3) δ 1.4-1.8 (7H, m),
2.54-2.72 (6H, m), 2.94 (1H, m), 3.27 (1H, m), 3.95 (1H,
m), 7.07 (2H, m), 7.26 (1H, d, J ) 8 Hz), 7.43 (1H, d, J
) 8 Hz), 9.28 (1H, s); 13C NMR (CDCl3) δ 22.4, 22.7,
32.4, 34.3, 41.2, 42.2, 52.3, 108.1, 110.6, 117.6, 118.7,
120.9, 127.2, 135.6, 136.2.
Exp er im en ta l Section
1-[2-(2,3,4,9-Tetr ah ydr o-1H-â-car bolin -1-yl)eth yl]-
p yr r olid in -2-on e (6). 6 was prepared according to the
procedure utilized for compound 2 using 480 mg (3
mmol) of tryptamine 414 mg (3 mmol) of N-(cyanoethyl)-
pyrrolidone and 64 mg (0.06 mmol) of 10% Pd‚C. After
hydrogenation (48 h), compound 6 was isolated as an
oil (650 mg, 76%). 6: UV (MeOH) λmax 226, 282, 290
nm; IR (film) νmax 3406, 3275, 3111, 3055, 2941, 2854,
Gen er a l Exp er im en ta l P r oced u r es. IR spectra
were recorded on a Bomem spectrometer, and UV
spectra on a Philips Unicam 8700 spectrophotometer.
1H (300 MHz) and 13C (75 MHz) NMR spectra were
measured on a Brucker AC300 spectrometer with TMS
as internal standard. Chemical shifts are reported in ∂
ppm. J values are given in. Mass spectra were re-
corded on an Autospec (VG Instruments). Separations
were carried out on TLC plates with Kieselgel 60 PGF254
(Merck no. 7749), using CH2Cl2/MeOH.
1666, 1494, 1452, 1315, 1298, 1267, 1163, 1116 cm-1
;
EIMS m/ z 283 [M]+ (34), 197 (10), 185 (13), 171 (100),
1
144 (13); H NMR (CDCl3) δ 1.83 (4H, m), 2.3 (2H, t, J
) 9 Hz), 2.57 (1H, s), 2.68 (2H, m), 3.0-3.2 (4H, m),
3.35 (1H, m), 3.76 (2H, m), 7.02 (1H, t, J ) 9 Hz), 7.08
(1H, t, J ) 9 Hz), 7.33 (1H, d, J ) 9 Hz), 7.43 (1H, d, J
) 9 Hz), 10.25 (1H, s); 13C NMR (CDCl3) δ 17.7, 22.1,
30.5, 32.4, 39.5, 40.5, 46.9, 48.6, 107.3, 110.7, 117.3,
118.3, 120.7, 126.8, 135.1, 135.4, 175.6.
4-(2,3,4,9-Tetr ah ydr o-1H-â-car bolin -1-yl)bu tyr on i-
tr ile (2). To a solution of tryptamine (800 mg, 5 mmol)
in 10 mL of glacial acetic acid were added glutaronitrile
(700 mg, 7.5 mmol) and 266 mg of 10% Pd‚C in one
portion. The mixture was hydrogenated at room tem-
perature and atmospheric pressure for 48 h. The
catalyst was removed by filtration through Celite and
washed with CH2Cl2. The resulting solution was made
basic with aqueous NH3 and then extracted with
CH2Cl2. The combined CH2Cl2 solutions were dried on
MgSO4, and the solvent was evaporated. The residue
was purified by Si gel chromatography using CH2Cl2-
MeOH (96:4) as eluent to give 696 mg of 2 (58%) and
159 mg of 3 (14%). 2: UV (MeOH) λmax 222, 282, 291
nm; IR (film) νmax 3402, 3227, 2933, 2854, 2806, 2247,
1620, 1456, 1352, 1232, 1153, 1116, 742 cm-1; EIMS
m/ z 239 [M]+ (33), 171 (100), 156 (19), 144 (15); 1H NMR
(CDCl3) δ 1.7-1.98 (4H, m), 2.35 (4H, m), 2.7 (2H, m),
2.97-3.01 (1H, dt, J ) 5.8, 13.5 Hz), 3.24-3.28 (1H, dt,
J ) 5.8, 13.5 Hz), 4.02 (1H, m), 7.08 (1H, t, J ) 7.6 Hz),
7.13 (1H, t, J ) 7.6 Hz), 7.31 (1H, d, J ) 7.6 Hz), 7.47
(1H, d, J ) 7.6 Hz), 8.52 (1H, s); 13C NMR (CDCl3) δ
16.9, 21.4, 22.4, 33.1, 42.0, 51.6, 108.8, 110.8, 117.9,
119.1, 119.8, 121.4, 127.1, 135.0, 135.6. 3: UV (MeOH)
λmax 231, 282, 290 nm; IR (film) νmax 3398, 3200, 3057,
2937, 2849, 2806, 2760, 1466, 1450, 1346, 1321, 1275,
1211, 1184, 1141, 1109, 738 cm-1; EIMS m/ z 225 [M]+
(91), 197 (35), 169 (33), 156 (18), 143 (17), 130 (15), 115
(16), 82 (100); 1H NMR (CDCl3) δ 1.4-1.6 (2H, m), 1.69-
1.84 (3H, m), 2.2 (2H, m), 2.33-2.41 (1H, m), 2.59-2.73
(2H, m), 2.95-3.1 (3H, m), 3.2 (1H, m), 7.08 (2H, m),
7.27 (1H, d, J ) 9 Hz), 7.44 (1H, d, J ) 9 Hz), 7.98 (1H,
s); 13C NMR (CDCl3) δ 21.5, 24.2, 25.6, 29.8, 53.4, 55.6,
60.1, 107.9, 110.6, 117.9, 119.2, 121.1, 127.4, 135.1,
135.9.
2-(2,3,4,9-Tet r a h yd r o-1H -â-ca r b olin -1-yl)a cet a -
m id e (8). Compound 8 was prepared analogously to
compound 2 using 160 mg (1 mmol) of tryptamine 101
mg (1.2 mmol) of cyanoacetamide and 21 mg (0.02
mmol) of 10% Pd‚C. After hydrogenation (48 h), com-
pound 8 was isolated as a solid (133 mg, 58%). 8: mp
196-197 °C; UV (MeOH) λmax 280, 232 nm; IR (KBr)
νmax 3439, 3214, 3048, 2951, 1677, 1451, 1413, 1314,
1257, 743 cm-1; EIMS m/ z 229 [M]+ (29), 184 (9), 171
(100), 156 (25), 144 (15), 130 (18), 115 (12); anal. C
67.64%, H 6.39%, N 18.08%, calcd for C13H15N3O, C
1
68.1%, H 6.59%, N 18.32%; H NMR (DMSO) δ 2 .38-
2.48 (1H, m), 2.55-2.64 (2H, m), 2.68 (1H, dd, J ) 4.5,
14.5 Hz), 2.83-2.96 (1H, m), 3.09-3.19 (1H, m), 3.32
(2H, s), 4.3 (1H, dd, J ) 3.4, 9 Hz), 6.92 (1H, s), 6.94-
7.06 (2H, m), 7.29 (1H, d, J ) 8 Hz), 7.47 (1H, d, J ) 8
Hz), 7.56 (1H, s); 13C NMR (CDCl3) δ 21.0, 39.0, 41.2,
49.3, 107.9, 111.1, 117.8, 119.0, 121.6, 126.5, 132.8,
135.8, 174.7.
2-(2,3,4,9-Tet r a h yd r o-1H -â-ca r b olin -1-yl)et h yl-
a m in e (9). Compound 9 was obtained by the procedure
used for the preparation of 4, using 1.2 g (32 mmol) of
LiAlH4 in 80 mL of THF, and 1.5 g (6.3 mmol) of amide
8, to afford 894 mg (64%) of amine 9: UV (MeOH) λmax
224, 279, 290 nm; IR (film) νmax 3394, 3259, 3057, 2937,
1574, 1469, 1319, 740 cm-1; EIMS m/ z 215 [M]+ (24),
198 (29), 185 (16), 171 (90), 160 (21), 156 (23), 144 (26),
130 (100); 1H NMR (CDCl3) δ 1.88 (2H, s), 2.6-2.72 (2H,
m), 2.8-3.1 (6H, m), 3.16-3.3 (1H, m), 4.05 (1H, t, J )
4.5 Hz), 7-7.12 (2H, m), 7.28 (1H, d, J ) 8 Hz), 7.44
(1H, d, J ) 8 Hz), 10 (1H, s); 13C NMR (CDCl3) δ 22.1,
35.4, 38.6, 42.1, 52.1, 107.9, 110.9, 117.8, 118.8, 120.9,
127.2, 135.4, 135.6.
Na zlin in e (4). To a solution of LiAlH4 (177 mg, 4.66
mmol) in THF (15 mL) was added dropwise with stirring
a solution of 222 mg (0.93 mmol) of nitrile 2 in THF.
The mixture was heated to reflux for 4 h and cooled to
room temperature, and excess hydride was decomposed
by addition of moist THF. MgSO4 was added, the THF
solution was filtered, and the solid was washed with
THF. Evaporation of the THF solution gave an oil,
which was chromatographed on an alumina column, to
Oxoela eoca r p id in e (10). A solution of amine 9 (430
mg, 2 mmol) and methyl 3-formylpropionate (500 mg,
4 mmol) in benzene/MeOH (40:2) was left at room
temperature under N2 for 5 h. Then 3 mL of AcOH was
added and the reaction mixture was refluxed for 3 h.

Synthesis of Natural Tetrahydro-â-carbolines
J ournal of Natural Products, 1997, Vol. 60, No. 8 793
The solvents were then evaporated in vacuo, and the
residue was basified with aqueous NH3 and extracted
with CH2Cl2. The combined organic layers were dried
on MgSO4 and evaporated. The residue was purified
by Si gel chromatography using CH2Cl2-MeOH (93:3)
as eluent to give 246 mg (42%) of 10: mp 294-295 °C;
UV (MeOH) λmax 223, 283, 290 nm; IR (KBr) νmax 3273,
2962, 2922, 2845, 2812, 1678, 1454, 1373, 1307, 1267,
1182, 1093, 908, 734 cm-1; EIMS m/ z 281 [M]+ (100),
252 (13), 224 (8), 197 (19), 171 (83), 156 (25); anal. C
72.51%, H 6.33%, N 14.71%, calcd for C17H19N3O, C
72.57%, H 6.8%, N 14.93%; 1H NMR (CDCl3) δ 1.65 (1H,
ddd, J ) 4.5, 11, 24 Hz), 1.96 (1H, m), 2.2 (1H, m), 2.4
(4H, m), 2.78 (1H, m), 2.9 (2H, m), 3.15 (1H, dd, J )
4.5, 11 Hz), 3.45 (1H, m), 3.95 (1H, t, J ) 7 Hz), 4.2
(1H, dd, J ) 4.5, 11 Hz), 7.05 (2H, m), 7.3 (1H, d, J ) 8
Hz), 7.45 (1H, d, J ) 8 Hz), 9.6 (1H, s); 13C NMR (CDCl3)
δ 21.1, 24.0, 27.5, 29.2, 38.3, 45.8, 58.7, 76.4, 107.2,
110.8, 117.6, 118.8, 121.0, 126.5, 132.7, 136.1, 173.4.
Ela eoca r p id in e (7): (a) The procedure described for
the preparation of 4 was repeated using 26 mg (0.69
mmol) of LiAlH4 and 64 mg (0.23 mmol) of compound
10 in 10 mL of THF to afford 33 mg of (()-elaeocarpidine
(7) (54%). (b) A solution of 6 (51 mg, 0.18 mmol) in THF
(8 mL) was added with 0.6 mL of an 1 M solution of
DIBAH in hexane and left for 1 h at room temperature.
After addition of wet THF and MgSO4, extraction of the
precipitate with THF followed by evaporation afforded
a residue (53 mg), which was purified by TLC to afford
35 mg (73%) of compound 7: mp 195 °C; UV (MeOH)
λmax 221, 231, 280, 289 nm; IR (KBr) νmax 3200, 3109,
3055, 2968, 2818, 1452, 1379, 1302, 1184, 1097, 1010,
734 cm-1; EIMS m/ z 267 [M]+ (100), 252 (10), 239 (43),
225 (29), 210 (25), 197 (22), 169 (62), 154 (34), 143 (18);
1H NMR (CDCl3) δ 1.7-2.1 (6H, m), 2.3 (2H, m), 2.47
(1H, m), 2.7 (2H, m), 2.93 (1H, m), 3.08 (1H, m), 3.18
(2H, m), 3.34 (1H, m), 7.04 (2H, m), 7.27 (1H, d, J ) 8
Hz), 7.43 (1H, d, J ) 8 Hz), 8.93 (1H, s); 13C NMR
(CDCl3) δ 19.2, 21.5, 28.1, 47.1, 50.1, 51.7, 59.5, 83.5,
107.4, 110.7, 117.7, 118.8, 120.9, 126.9, 134.1, 136.0.
Refer en ces a n d Notes
(1) Hahn, G.; Hansel, H. Chem. Ber. 1938, 71, 2163-2175.
(2) Diker, K.; Do¨e´ de Maindreville, M.; Le´vy, J . Tetrahedron Lett.
1995, 36, 2497-2500.
(3) J ohns, S. R.; Lamberton, J . A.; Occolowitz, J . L. Aust. J . Chem.
1966, 19, 1951-1954.
(4) O¨ stu¨nes, L.; O¨ zer, A. J . Nat. Prod. 1991, 54, 959-966.
(5) Wanner, M. J .; Velzel, A. W.; Koomen, G.-J . J . Chem. Soc., Chem.
Commun. 1993, 174-175.
(6) J ohns, S. R.; Lamberton, J . A.; Sioumis, A. A. J . Chem. Soc.,
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(7) J ohns, S. R.; Lamberton, J . A.; Sioumis, A. A.; Suares, H. Aust.
J . Chem. 1971, 24, 1679-1694.
(8) Harley-Mason, J .; Taylor, C. G. J . Chem. Soc., Chem. Commun.
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(9) Gribble, G. W. J . Org. Chem. 1970, 35, 1944-1949.
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NP970191S