Enantiopure tetrahydro-β-carbolines via Pictet-Spengler reactions with N-sulfinyl tryptamines

Article abstract of DOI:10.1021/ol006034t

(Equation presented) The influence of N-sulfinyl chiral auxiliaries on the stereochemistry of the Pictet-Spengler reaction has been investigated. From enantiopure (R)-N-p-toluenesulfinyltryptamine a new and efficient route to enantiopure tetrahydro-β-carb

Full text of DOI:10.1021/ol006034t

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1955-1958
Enantiopure Tetrahydro-â-carbolines via
Pictet−Spengler Reactions with
N-Sulfinyl Tryptamines
Christiaan Gremmen, Bianca Willemse, Martin J. Wanner, and
Gerrit-Jan Koomen*
Institute of Molecular Chemistry, UniVersity of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands
gjk@org.chem.uVa.nl
Received May 9, 2000
ABSTRACT
The influence of N-sulfinyl chiral auxiliaries on the stereochemistry of the Pictet−Spengler reaction has been investigated. From enantiopure
(R)-N-p-toluenesulfinyltryptamine a new and efficient route to enantiopure tetrahydro-â-carbolines has been established.
The tetrahydro-â-carboline ring system is an important
structural unit that is commonly encountered in naturally
occurring indole alkaloids and synthetic analogues with
interesting biological activities (Figure 1). Fumitremorgin C
opment of an enantioselective route to tetrahydro-â-
carbolines is therefore of interest for both synthetic organic
and medicinal chemistry.
The Pictet-Spengler condensation is one of the most
powerful methods for the formation of these ring systems.4
In general, this reaction can be characterized by the formation
of an iminium salt after an acid-catalyzed reaction of
tryptamine and an aldehyde. This iminium ion is attacked
intramolecularly by electrons of the pyrrole ring from either
the 2- or 3-position (Scheme 1). The involvement of the
spiro-indolenine intermediate A which is formed after attack
from the indole 3-position was proven by isotopic labeling
Scheme 1
Figure 1. Biologically active tetrahydro-â-carbolines.
(1) is of interest due to its cytostatic activities1 while
compound 2 is an antagonist for the serotonin 2B receptor.2
A large number of therapeutics are marketed as racemic
mixtures. Since it is almost invariably the case that only one
enantiomer has the desired effect, the absence of the other
enantiomer with possible undesirable effects has a number
of clinical advantages including improvement in pharmaco-
logical profile and simplified pharmacokinetics.3 The devel-
10.1021/ol006034t CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/08/2000

experiments.5 However, MNDO calculations have indicated
that the rearragement from intermediate A to B is energeti-
cally unfavorable.6 Direct attack from the indole 2-position
is therefore believed to be the key step in the Pictet-Spengler
condensation.
Over the past decade a number of enantioselective ap-
proaches to the Pictet-Spengler reaction have been reported.
Many of these approaches rely on the use of enantiopure
tryptophan esters.7 The possibility for enantioselective
synthesis of tetrahydro-â-carbolines derived from tryptamine
is limited by the absence of the stereodirecting effect of the
carboxy group.
Introduction of chiral auxiliaries on the nitrogen atom of
the ethylamino side chain of tryptamine induced diastereo-
selectivity in several cases. The use of chiral R-methylbenzyl
groups showed diastereoslectivity only with specific alde-
hydes.8 Acylation of imines from tryptamine with N,N-
phthaloyl amino acid chlorides gave good diastereoselectivity
in Lewis acid-catalyzed Pictet-Spengler reactions.9 Chiral
Lewis acids were used in enantioselective Pictet-Spengler
reactions of N-hydroxytryptamines but gave only satisfactory
results with aromatic aldehydes.10 A general drawback of
these procedures is the fact that removal of the chiral
auxiliaries is often difficult and causes racemization due to
the harsh conditions required for cleavage.
The use of chiral sulfoxides in organic synthesis has found
ample precedent in the literature.11 N-Sulfinylimines have
proven to be excellent starting materials for the enantio-
selective synthesis of R- and â-amino acids,12 R-aminophos-
phonic acids,13 and aziridines.14 We realized that reaction
of the tryptamine-derived sulfinamines 3a-c (Scheme 2)
The main objective of our reserach was to investigate the
effect of several sulfinyl groups on the reactivity and
diastereoselectivity of the Pictet-Spengler condensation.
After optimization of the reaction conditions with racemic
substrates, optically active sulfinamines should then provide
a synthetic route to enantiopure tetrahydro-â-carbolines.
We focused on the p-tolyl, the 2-ethoxynaphthyl, and the
tert-butyl substituents since these moieties gave high dia-
stereomeric ratios in nucleophilic additions to N-sulfinyl
imines as previously described.10-12 The sulfinamines 3a-c
were easily obtained by reaction of the corresponding sulfinyl
chlorides15,16 with tryptamine. Pictet-Spengler reactions of
these sulfinamines were studied under a range of conditions.
The nitrogen-sulfur bond of the sulfinamines turned out
to be vulnerable to hydrolysis under acidic conditions. To
improve the diastereoselectivity of the reaction and to
overcome the problem of hydrolysis, we performed the
reactions at low temperature and studied the effect of a
variety of protic acids such as acetic acid, trifluoroacetic acid,
and p-toluenesulfonic acid on the reaction. In general,
application of these acid catalysts resulted in hydrolysis of
starting material or low diastereoselectivity. The use of Lewis
acids such as TiCl4, Et2AlCl, diisopinocampheylchloro-
borane, Sc(OTf)3, Yb(OTf)3, and BF3‚OEt2 led to the
formation of unstable enamines after the initial formation
of the N-sulfinyliminium ions. The best results for the Pictet-
Spengler reaction were obtained with 10-camphorsulfonic
acid (CSA) as the acid catalyst in a 1:1 mixture of dry
methylene chloride and chloroform at -78 °C.17,18
In Table 1 the results of the Pictet-Spengler reactions of
p-tolylsulfinamine 3a with several aliphatic and otherwise
functionalized aldehydes are summarized. The reactions were
slower with branched aldehydes and required higher con-
centrations of the acid-catalyst. Further increases in con-
centration of the acid-catalyst led to hydrolysis of the
starting material. The steric bulk of the alkyl substituent
caused a decrease in rate of the reaction, but only a slight
effect on the diastereoselectivity was observed.
Scheme 2
Table 1. Pictet-Spengler Reactions of Racemic Sulfinamine
3a
with an aldehyde would in principle lead to the in situ
formation of an N-sulfinyl iminium ion that could undergo
Pictet-Spengler cyclization.
no.
R
time (h) CSA (equiv) yielda(%) ratiob
4
5
6
7
8
9
methyl
ethyl
propyl
butyl
pentyl
isobutyl
4
4
4
4.5
4.5
8
20
20
5
0.2
0.2
0.2
0.2
0.2
0.6
0.6
0.6
0.2
75
82
80
84
69
71
78
73
84
76:24
73:27
78:22
81:19
83:17
81:19
86:14
88:12
82:18
(1) Rabindran, S. K.; He, H.; Singh, M.; Brown, E.; Collins, K. I.;
Annable, T.; Greenberger, L. M. Cancer Res. 1998, 58, 5850.
(2) Audia, J. E.; Evrard, D. A.; Murdoch, G. R.; Droste, J. J.; Nissen, J.
S.; Schenck, K. W.; Fludzinski, P.; Lucaites, V. L.; Nelson, D. L.; Cohen,
M. L. J. Med. Chem. 1996, 39, 2773.
(3) Hutt, A. J.; Tan, S. C. Drugs 1996, 52, 1.
(4) Tatsui, G. J. J. Pharm. Soc. Jpn. 1928, 48, 92.
(5) Bailey, P. D. J. Chem. Res. 1987, 202.
10 isopropyl
11 cyclohexyl
12 4,4-diethoxybutyl
(6) Kowalski, P.; Bojarski, A. J.; Mokrosz, J. L. Tetrahedron 1995, 51,
2737.
(7) Cox, E. D.; Cook, J. M. J. Org. Chem. 1995, 60, 1797.
(8) (a) Soe, T.; Kawate, T.; Fukui, N.; Hino, T.; Nakagawa, M.
Heterocycles 1996, 42, 347. (b) Kawate, T.; Yamanaka, M.; Nakagawa,
M. Heterocycles 1999, 50, 1033.
a After chromatography. b Diastereomeric ratio as determined by 1H
NMR.
1956
Org. Lett., Vol. 2, No. 13, 2000

As shown in Table 2 the reactions of 2-ethoxynaphthyl
sulfinamine 3b gave comparable diastereoselectivity. The
menthyl p-toluenesulfinate (Scheme 3).19 Treatment of
tryptamine with n-butyllithium and chlorotrimethylsilane in
Scheme 3. Synthesis of (R)-3a
Table 2. Pictet-Spengler Reactions of Racemic Sulfinamine
3b
no.
R
time (h)
CSA (equiv)
yielda(%)
ratiob
13
14
15
16
17
methyl
ethyl
propyl
butyl
6
6
6
8
8
0.2
0.2
0.2
0.2
0.2
68
67
62
71
60
76:24
76:24
77:23
82:18
81:19
THF and reaction with the Andersen reagent gave sulfin-
amine (R)-3a in a satisfying yield (73%).20 Likewise, the
enantiomer (S)-3a was obtained starting from (1S,2R,5S)-
(R)-menthyl p-toluenesulfinate (68%).
pentyl
a After chromatography. b Diastereomeric ratio as determined by 1H
NMR.
Pictet-Spengler condensations of (R)-3a were executed
under conditions the same as those mentioned in Table 1.
The results of these reactions were comparable to the results
that were obtained from reactions with racemic 3a. The major
diastereomers were obtained after a single crystallization
(Table 3).
presence of the sterically demanding 2-ethoxynaphthyl
substituent seemed to have an effect only on the rate of the
reaction. The tert-butylsulfinamines 3c gave no product
formation under these reaction conditions. At elevated
temperatures the reaction is characterized by loss of starting
material due to cleavage of the nitrogen-sulfur bond.
Separation of the diastereomers was possible by laborious
column chromatography. However, from the reaction mix-
tures containing the p-tolylsulfinyl substituent (4-12) the
major diastereomers were all obtained in pure form by simple
crystallization. These encouraging results prompted us to
develop a synthesis for (R)-3a.
Table 3. Pictet-Spengler Reactions of (R)-3a
The p-tolylsulfinamine (R)-3a was prepared using the
commercially available Andersen reagent (1R,2S,5R)-(S)-
yield (%)a
[R]D
mp (°C)
b
no.
R
(+)-4
(+)-5
(+)-6
(+)-7
(+)-8
(+)-9
(+)-10
(+)-11
methyl
ethyl
propyl
butyl
pentyl
isobutyl
isopropyl
cyclohexyl
57
61
58
60
57
59
63
57
+212
+196
+190
+167
+158
+190
+215
+196
205-207
229-233
204-206
208-211
179-182
190-193
222-224
240-241
(9) Waldmann, H.; Schmidt, G.; Henke, H.; Burkard, M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2402.
(10) (a) Kawate, T.; Yamada, H.; Soe, T.; Nakagawa, M. Tetrahedron:
Asymmetry 1996, 7, 1249. (b) H. Yamada, T.; Kawate, T.; Matsumizu, M.;
Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348.
(11) The Chemistry of Sulfones and Sulfoxides; Patai, S., Rapoport, Z.,
Stirling, C., Eds.; Wiley and Sons: New York, 1988.
(12) (a) Davis, F. A.; Reddy, E. R.; Portonovo, P. S. Tetrahedron Lett.
1994, 35, 9351. (b) Davis, F. A.; Portonovo, P. S.; Reddy, E. R.; Chiu, Y.
J. Org. Chem. 1996, 61, 440. (c) Davis, F. A.; Reddy, E. R.; Szewczyk, J.
M. J. Org. Chem. 1995, 60, 7037. (d) Davis, F. A.; Szewczyk, J. M.; Reddy,
R. E. J. Org. Chem. 1996, 61, 2222.
a After crystallization. b Acetone, c ) 0.5-1.0.
(13) Mikolaiczyk, M.; Lyzwa, P.; Drabowicz, J.; Wieczorek, M. W.;
Blaszcyk, J. J. Chem. Soc., Chem. Commun. 1996, 1502.
(14) (a) Davis, F. A.; Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997,
38, 5139. (b) Garc´ıa-Ruano, J. L.; Fernande´z, I.; Del Prado Catalina, M.;
Cruz, A. A. Tetrahedron: Asymmetry 1996, 7, 3407. (c) Davis F. A.; Zhou,
P.; Liang, C.-H.; Reddy, E. R. Tetrahedron: Asymmetry 1995, 6, 1511. (d)
Davis F. A.; Zhou, P.; Reddy, G. V. J. Org. Chem. 1994, 59, 3244.
(15) Bell, K. H. Aust. J. Chem. 1985, 38, 1209.
In principle the 10-camphorsulfonate counterion of the
iminium salt could influence the diastereoselectivity of the
Pictet-Spengler reaction. Since no change in the diastereo-
meric ratio was observed using (+)-CSA instead of the
(16) Netscher, T.; Prinzbach, H. Synthesis 1987, 8, 683.
(17) General procedure: A solution of the sulfinamide (0.2 mmol) and
the aldehyde (1.0 mmol) in dry methylene chloride/chloroform (2 mL) was
cooled to -78 °C. The indicated quantity of CSA was added, and the
reaction mixture was stirred at -78 °C for the indicated time. The reaction
was quenched with triethylamine, and the solvents were removed in vacuo.
Purification using column chromatography (silica gel, 1:1 light petroleum/
ethyl acetate) yielded the mixture of diastereomers.
(18) Pure chloroform solidifies at -78 °C, and the solubility of 3a-c in
pure methylene chloride is low.
(19) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 8, 173.
(20) General procedure: To a solution of tryptamine (20 mmol) in THF
(200 mL) at -78 °C was added a solution of n-BuLi (41 mmol) in hexanes.
The reaction mixture was allowed to warm to ambient temperature, and
chlorotrimethylsilane (21 mmol) was added. After stirring for 30 min n-BuLi
(21 mmol) in hexanes was added and the reaction mixture was stirred for
an additional 45 min. The reaction mixture was added to a solution of
(1S,2R,5S)-(S)-menthyl p-toluenesulfinate (10 mmol) in THF. The reaction
was quenched after 1 h by the addition of an aqueous solution of Na2HPO4
(200 mL, 0.1 M). Extractive workup and recrystallization (ethyl actetate)
yielded (R)-3a (73%).
Org. Lett., Vol. 2, No. 13, 2000
1957

racemic catalyst, this possibility was excluded. Removal of
the p-tolylsulfinyl chiral auxiliary was accomplished in high
yield and without racemization using hydrochloric acid in
ethanol at 0 °C which yielded the tetrahydro-â-carboline and
the ethyl ester of p-toluenesulfinic acid.21,22
In summary, the application of N-sulfinyl iminium ion
chemistry to the Pictet-Spengler reaction of tryptamine
provided a synthesis of enantiopure tetrahydro-â-carbolines.
The use of the chiral p-tolylsulfinyl group was characterized
by good yields and diastereoselectivity. Efficient separation
of the diastereomers by crystallization and cleavage of the
chiral auxiliary without racemization furnished the tetrahy-
dro-â-carbolines in excellent enantiopurity. We are currently
conducting further investigations on the scope and limitations
of this procedure by the introduction of substituents on the
phenyl ring of the p-tolylsulfinyl group.
As shown in Table 4 the resulting tetrahydro-â-carbolines
were obtained in enantiopure form and good yield.
Table 4. Removal of the Chiral Auxiliary
Supporting Information Available: Experimental details
and characterization for all new compounds (1H NMR and
mass spectral data). This material is available free of charge
via the Internet at http://pubs.acs.org.
no.
R
yield (%)a
eeb
[R]D
(-)-18
(-)-19
(-)-20
(-)-21
(-)-22
(-)-23
(-)-24
(-)-25
methyl
ethyl
propyl
butyl
pentyl
isobutyl23
isopropyl
cyclohexyl
89
93
91
93
82
90
93
86
>98%
>98%
>98%
>98%
>98%
>98%
>98%
>98%
-44.0c
-62.6
-30.0
-65.8
-40.0
-47.1
-58.3
-68.5
OL006034T
(21) In principle, regeneration of the Andersen reagent is possible when
the chiral auxiliary is removed in the presence of (-)-menthol.
(22) General procedure: To a solution of the N-sulfinyl tetrahydro-â-
carboline (0.5 mmol) in ethanol (2 mL) at 0 °C was added concentrated
hydrochloric acid (100 µL). After stirring for 5 min a saturated solution of
K2CO3 (2 mL) was added. Extractive workup (ethyl acetate) and flash
chromatography yielded the corresponding tetrahydro-â-carboline.
(23) Slywka, G. W. A.; Locock, R. A. Tetrahedron Lett. 1969, 53, 4635.
(24) Yamada, K.; Takeda, M.; Iwakuma, T. Tetrahedron Lett. 1981, 22,
3869.
a After chromatography. b As determined with 1H NMR using (R)-1-(9-
anthryl)-2,2,2-trifluoroethanol. c Lit. (S)-18: [R]D ) -41.24
1958
Org. Lett., Vol. 2, No. 13, 2000