Liquid-phase parallel synthesis of tetrahydro-β-carbolines

Article abstract of DOI:10.1016/S0040-4039(03)01100-6

Parallel synthesis of β-carbolines on soluble polyethylene glycol (PEG-OH) support is demonstrated. One-pot condensation of polymer-bound tryptophan residues with various aldehydes and ketones has been carried out in the presence of p-TSA as a catalyst to deliver immobilized 1,2,3,4-tetrahydro-β-carbolines. Subsequent disengagement of the appendant from the polymer support afforded the desired products in good yield and acceptable purity.

Full text of DOI:10.1016/S0040-4039(03)01100-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4923–4926
Liquid-phase parallel synthesis of tetrahydro-b-carbolines
Wen-Ben Yeh, Mei-Jung Lin and Chung-Ming Sun*
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan
Received 2 January 2003; revised 8 April 2003; accepted 22 April 2003
Abstract—Parallel synthesis of b-carbolines on soluble polyethylene glycol (PEG-OH) support is demonstrated. One-pot
condensation of polymer-bound tryptophan residues with various aldehydes and ketones has been carried out in the presence of
p-TSA as a catalyst to deliver immobilized 1,2,3,4-tetrahydro-b-carbolines. Subsequent disengagement of the appendant from the
polymer support afforded the desired products in good yield and acceptable purity. © 2003 Elsevier Science Ltd. All rights
reserved.
Combinatorial chemistry employs a novel concept and
technique to rapidly synthesize and screen large num-
bers of compound libraries. The synthetic procedures
for generating such libraries are now well documented.
Solid-phase organic synthesis has become a selective
tool to generate structurally diverse compounds based
potencies towards benzodiazepine receptor comparable
with that of clinically active benzodiazepines (Fig. 1).
5
Knowledge of lead structures from screening libraries
guides the design of more focused libraries and acceler-
ates the lead optimization process. Tetrahydro-b-carbo-
lines possess multiple sites for functionalization,
permitting the generation of a large number of struc-
turally diverse compounds. Our research efforts partic-
ularly draw on the development of liquid-phase
combinatorial synthesis to construct heterocyclic
1
on known pharmacophores. Being a unique rigid hete-
rocyclic system, b-carboline derivatives are well known
2
for their wide range of pharmacological properties.
They have been shown to inhibit monoamine oxidase A
and bind with nanomolar affinity to serotonin recep-
3
6,7
tors. Tetrahydro-b-carboline is
a
common basic
molecules. In our present investigation we wish to
nucleus found in a large number of tryptophan-derived
natural product alkaloids such as yohimbine, alsto-
phylline and reserpine. The indole alkaloids recently
isolated from fungi are found to contain tetrahydro-b-
carboline core and they have demonstrated as effective
blockers of eukaryotic cell cycle progression. In particu-
lar, demethoxyfumitremorgin 1a has been identified as
the most effective among similar natural products iso-
report the synthesis of 1,2,3,4-tetrahydro-b-carbolines
by liquid-phase methodology using commercially avail-
able building blocks. Our synthetic strategy is mainly
based on the chemistry of Pictet–Spengler reaction as
illustrated in Scheme 1.
Polyethylene glycol (PEG-OH, MW ꢀ5000) has been
used as a soluble support to maintain homogeneous
conditions at different steps of the reaction but purifica-
tion of the product is as similar as solid-phase method,
i.e. simple filtration and washings. To demonstrate the
feasibility of the Pictet–Spengler reaction in liquid-
phase methodology, we used a wide variety of alde-
hydes and ketones to fuse with the tryptophan nucleus
and build up diverse 1,2,3,4-tetrahydro-b-carboline
moieties.
4
lated. Certain tetrahydro-b-carboline-3-methylcarb-
oxylates such as 2a and 2b were shown to exhibit
The polymer support PEG-OH was esterified with
Fmoc-
catalytic amount of DMAP in dichloromethane at
room temperature. Polymer-bound Fmoc- -tryptophan
was then deprotected using 5% piperidine to knock
off Fmoc in dichloromethane to furnish tryptophan 4
connected to the support.
L-tryptophan in the presence of DCC, and a
Figure 1. Pharmacologically active tetrahydro-b-carbolines.
L
3
*
Corresponding author. Tel.: +(886)-3-8662500 ext. 21215; fax:
(886)-3-8663910; e-mail: cmsun@mail.ndhu.edu.tw
+
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01100-6

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W.-B. Yeh et al. / Tetrahedron Letters 44 (2003) 4923–4926
Most of the literature reports on the synthesis of
,2,3,4-tetrahydro-b-carbolines used strong acidic con-
1
8
ditions, usually excess trifluoroacetic acid (TFA). To
avoid such harsh reaction conditions, we used a cata-
lytic amount of p-toluenesulphonic acid (p-TSA) to
enhance cyclization. To the best of our knowledge,
there has not been any report on the liquid-phase
synthesis of tetrahydro-b-carboline using p-TSA as a
catalyst. Immobilized tryptophan 4 was treated with
various aldehydes and catalytic amount of p-TSA in
dichloromethane at room temperature to afford PEG-
bound tetrahydro-b-carbolines 5 (Table 1).
In our reaction condition, the use of p-TSA catalyst
during the cyclization was found to be advantageous in
the improvement of yields and help to obtain cleaner
products. Besides aldehydes, various ketones also
underwent cyclocondensation smoothly with compound
4 in refluxing chloroform to afford PEG-supported
tetrahydro-b-carbolines in excellent crude yield and
acceptable purity (Table 2).
Scheme 1. Synthesis of 1,2,3,4-tetrahydro-b-carbolines.
Reagents and conditions: (i) DCC (3.0 equiv.), DMAP (0.1
equiv.), CH Cl , rt, 48 h; (ii) 5% piperidine in CH Cl , rt, 8 h;
2
2
2
2
(
iii) aldehyde (3.0 equiv.), p-TSA (0.1 equiv.), CH Cl , rt, 8 h
2 2
or ketone (3.0 equiv.), p-TSA (0.1 equiv.), CHCl , reflux, 8 h;
3
(
iv) 1% KCN/CH OH (10 mL), rt, 24 h.
3
Table 2. p-TSA-catalysed synthesis of tetrahydro-b-carbo-
lines
Table 1. p-TSA-catalysed synthesis of tetrahydro-b-carbo-
lines

W.-B. Yeh et al. / Tetrahedron Letters 44 (2003) 4923–4926
4925
At the last stage the target molecules 6 were isolated by
the detachment of the polymer support using KCN/
3. Ho, B. T. J. Pharm. Sci. 1972, 61, 821.
4. (a) Wang, H.; Ganesan, A. Org. Lett. 1999, 1, 1647; (b)
Cui, C. B.; Kakeya, H.; Osada, A. Tetrahedron 1997, 53,
59; (c) Usui, T.; Kondoh, M.; Cui, C. B.; Mayumi, T.;
Osada, H. Biochem. J. 1998, 333, 543–548; (d) Kondoh,
M.; Usui, T.; Mayumi, T.; Osada, H. J. Antibiot. 1998,
51, 801; (e) Liu, X.; Deschamp, J. R.; Cook, J. M. Org.
Lett. 2002, 4, 3339.
5. Cain, M.; Weber, R. W.; Guzman, F.; Cook, J. M.;
Barker, S. A.; Rice, K. C.; Crawley, J. N.; Paul, S. M.;
Skolnick, P. J. Med. Chem. 1982, 25, 1081.
6. (a) For a review, see: Sun, C. M. Comb. Chem. High
Throughput Screening 1999, 2, 299; (b) For a book chap-
ter, see: Sun, C. M. In Combinatorial Chemistry Methods
and Protocols, Methods in Molecular Biology Series;
Bellavance, L., Ed.; Soluble Polymer-Supported Synthesis
of Heterocyclic Libraries. Humana Press: New Jersey,
2002; Chapter 10, pp. 345–371; (c) Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F. Chem. Eur. J. 2000,
6, 133; (d) Reggelin, M.; Brenig, V.; Zur, C. Org. Lett.
2000, 2, 531.
CH OH and the reaction was monitored by the conven-
3
1
7f
tional H NMR. Cyclocondensation of aldehydes and
ketones with PEG-bound tryptophan 4 results in the
formation of cis and trans diastereomeric tetrahydro-b-
13
carbolines 5 which were differentiated by their
C
9
NMR data. The ratio of cis and trans diastereomers
was determined by HPLC and subsequently were sepa-
rated by flash chromatograph on silica gel. The NMR
spectra of the individual diastereomers clearly explained
which proton signals differed significantly between two
isomers. The carbon signals (entry 14, Table 1) for C-1
and C-3 assigned to cis isomer [C-1 (53.67 ppm), C-3
(
56.78 ppm)] resonated at further down field from that
of its trans counterpart in which C-1 and C-3 resonated
1
0
at 52.29 and 52.51, respectively. Comparsion of the
NMR spectra before and after cleavage assured that the
diastereochemical ratio has not been changed. Epimer-
ization of the stereocenter at C-1 has not detected
during the cleavage.
7
. (a) Pan, P. C.; Sun, C. M. Tetrahedron Lett. 1998, 39,
9505; (b) Shey, J. Y.; Sun, C. M. Synlett 1998, 12, 1423;
(c) Shey, J. Y.; Sun, C. M. J. Comb. Chem. 1999, 1, 361;
(d) Yeh, C. M.; Tung, C. L.; Sun, C. M. J. Comb. Chem.
2000, 2, 341; (e) Bendale, P. M.; Sun, C. M. J. Comb.
Chem. 2002, 4, 359; (f) Shey, J. Y.; Sun, C. M. Tetra-
hedron Lett. 2002, 43, 1725; (g) Wu, C. Y.; Sun, C. M.
Synlett 2002, 10, 1709; (h) Sun, C. M.; Swamy, K. M. K.;
Lin, M. J.; Yeh, W. B.; Chen, F. Y.; Tseng, W. H. Comb.
Chem. High Throughput Screening 2003, 6, 123.
Liquid-phase combinatorial synthesis described herein
has proved to be a powerful tool in generating b-carbo-
line libraries. Furthermore, the 1,2,3,4-tetrahydro-b-
carboline motif is more amenable to molecular
5
modifications. Skolnick et al. demonstrated that sub-
stitution at the 3-position resulted in increased potency
of carboline moiety. Particularly compounds having
methyl ester functionality at the 3-position such as 2a
3
and 2b turned out to be more potent [ H] diazepam
binding agents than those analogs without the methyl
ester functional group. In summary, we have demon-
strated in this report a rapid parallel synthesis of bio-
logically important b-carboline libraries 6 bearing a
variety of functional groups. This methodology exem-
plifies the importance of liquid-phase combinatorial
synthesis for lead optimization and offers easy access to
8. For solid-phase Pictet–Spengler reaction, see: (a) Mayer,
J. P.; Bankaitis-Davis, D.; Zhang, J.; Beaton, G.; Bjer-
garde, K.; Andersen, C. M.; Goodman, B. A.; Herrera,
C. J. Tetrahedron Lett. 1996, 37, 5633; (b) Yang, L.; Guo,
L. Tetrahedron Lett. 1996, 37, 5041; (c) Fantauzzi, P. P.;
Yanger, K. M. Tetrahedron Lett. 1998, 39, 1291; (d) van
Loevezijn, A.; van Maarseveen, J. H.; Stegman, K.; Vis-
ser, G. M.; Koomen, G.-J. Tetrahedron Lett. 1998, 39,
4737; (e) Li, X.; Zhang, L.; Zhang, W.; Hall, S. E.; Tam,
J. P. Org. Lett. 2000, 2, 3075.
compound
collections
containing
this
crucial
heterocycle.
9
. Ungemach, F.; Sorens, D.; Weber, R.; Dipierro, M.;
Campos, O.; Mokry, P.; Cook, J. M.; Silverton, J. V. J.
Am. Chem. Soc. 1980, 102, 6976.
Acknowledgements
10. Typical procedure for the synthesis of tetrahydro-i-carbo-
We thank the National Science Council (NSC) of Tai-
wan for its general financial support and Ms. Shu-Yun
Sun, Instrumentation Center, National Taiwan Univer-
sity for assistance in mass spectral measurements.
line: The loading of PEG-OH 1 with Fmoc- -tryptophan
2 to give 3 was carried out by the conventional DCC/
L
DMAP coupling method. Piperidine (5%) in CH Cl was
2
2
used for the deprotection of Fmoc group from 3 to
obtain PEG- -tryptophan 4. The PEG-bound -tryp-
L
L
tophan 4 (500 mg) was stirred magnetically with 4-bro-
References
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2
(
10 mL) at room temperature for 8 h. After completion
1
2
. (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
55; (b) Dolle, R. E. J. Comb. Chem. 2000, 2, 383.
. (a) Hermkens, P. H. H.; Plate, R.; Kruse, C. G.;
of the reaction, a sufficient amount of diethyl ether (90
mL) was added to the reaction mixtures under vigorous
stirring to precipitate out the immobilized 1,2,3,4-tetra-
hydro-b-carboline 5. The precipitate was filtered and
washed thoroughly with ether (3×20 mL). The cleavage
5
Scheeren, H. W.; Ottenheijm, H. C. J. J. Org. Chem.
1
992, 57, 3881; (b) Chi, D. Y.; O’Neil, J. P.; Anderson, C.
J.; Welch, M. J.; Katzenellenbogen, J. A. J. Med. Chem.
994, 37, 928; (c) Leteurtre, F.; Sackett, D. L.; Madalen-
of polymer-bound product was done in KCN/CH OH at
3
1
room temperature with stirring overnight. The polymer
support was separated by precipitation by the addition of
diethyl ether. The filtrate on evaporation yielded the
desired crude compound. The cis/trans isomers were then
goitia, J.; Kohlhagan, G.; Macdonald, T. L.; Hamel, E.;
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28.

4
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W.-B. Yeh et al. / Tetrahedron Letters 44 (2003) 4923–4926
separated by column chromatograph (gradient elu-
tion:50% ethyl acetate/hexane).
C H BrN O S: m/z 390.0037. Found 390.0022.
17 15 2 2
trans-3-Methoxycarbonyl-1-(4-bromothiophen-2-yl)-1,2,3,
1
cis-3-Methoxycarbonyl-1-(4-bromothiophen-2-yl)-1,2,3,4-
4-tetrahydro-b-carboline (Table 1, entry 14): H NMR
1
tetrahydro-b-carboline (Table 1, entry 14): H NMR (300
(300 MHz, CDCl ) l 7.81 (s, NH), 7.54 (d, J=7.5 Hz,
3
MHz, CDCl ) l 7.61 (s, NH), 7.53 (d, J=7.8 Hz, 1H),
1H), 7.29 (d, J=7.5 Hz, 1H), 7.26 (s, 1H), 7.22–7.11(m,
2H), 6.88 (s, 1H), 5.61 (s, 1H), 4.02 (dd, J=7.5, 5.1 Hz,
1H), 3.75 (s, 3H), 3.23 (dd, J=15.6, 5.1 Hz, 1H), 3.05
3
7
7
3
.28 (d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.22–7.13 (m, 2H),
.11 (s, 1H), 5.57 (s, 1H), 3.95 (dd, 1H, J=11.1, 4.2 Hz),
.83 (s, 3H), 3.22 (dd, 1H, J=15.3, 4.2 Hz), 3.01 (dd, 1H,
13
(dd, J=15.6, 7.5 Hz, 1H); C NMR (75 MHz, CDCl ) l
3
13
J=15.3, 11.1 Hz); C NMR (75 MHz, CDCl ) l 172.6,
173.8, 147.7, 136.1, 131.9, 128.3, 126.8, 123.2, 122.4,
119.7, 118.5, 111.1, 109.2, 108.3, 52.5, 52.2, 50.3, 24.6;
mass specrum (EI) m/z 390 (M+). HRMS calcd for
3
1
1
45.8, 136.2, 132.9, 128.6, 127.0, 123.6, 122.4, 119.9,
18.5, 111.1, 109.2, 108.7, 56.7, 53.6, 52.4, 25.2; mass
specrum (EI) m/z 390 (M+). HRMS calcd for
C H15BrN O S: m/z 390.0037. Found 390.0022.
17 2 2