Enantioselective BINOL-Phosphoric Acid Catalyzed Pictet-Spengler Reactions of N-Benzyltryptamine
Nishant V. Sewgobind, Martin J. Wanner, Steen Ingemann,
FIGURE 1. Tetrahydro- -carbolines obtained via organocatalytic
Rene´ de Gelder,† Jan H. van Maarseveen, and
asymmetric Pictet-Spengler reactions. SCHEME 1. Pictet-Spengler Reaction Van’t Hoff Institute for Molecular Sciences, UniVersity ofAmsterdam, Nieuwe Achtergracht 129, 1018 WS, Amsterdam,
Various stereoselective Pictet-Spengler reactions have been
described of which especially Cook’s approach using tryptophan esters as chiral precursors is noteworthy.4b However, the ester functionality had to be removed in a multistep sequence. Recently, an organocatalytic approach toward enantioenriched tetrahydro- -carbolines (e.g., 2 in Figure 1) was developed mediated by a chiral thiourea catalyst (5-10 mol % catalyst,
Optically active tetrahydro- -carbolines were synthesized via
65-81% yield, and 85-93% ee).5 This reaction appeared to
an (R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-
be limited to aliphatic aldehydes and, in addition, N-acetyl group
Spengler reaction of N-benzyltryptamine with a series of
aromatic and aliphatic aldehydes. The tetrahydro- -carbolines
List and co-workers developed an asymmetric Pictet-Spengler
were obtained in yields ranging from 77% to 97% and with
cyclization of an iminium diester that provided tetrahydro- -
ee values up to 87%. The triphenylsilyl-substituted BINOL-
carbolines 3 in 40-96% yield and 62-96% ee with triisopro-
phosphoric acid proved to be the catalyst of choice for the
pylphenyl-substituted (S)-BINOL phosphoric acid (20 mol %)
reaction with aromatic aldehydes. For the aliphatic aldehydes,
as the catalyst.6 Although both aromatic and aliphatic aldehydes
were accepted in this reaction, the method required the presence
acid was identified as the best catalyst.
of two ester functionalities and is therefore of limited utility.
Within our research program on the development of asym-
metric reactions of iminium ions catalyzed by chiral Brønsted
Compounds containing the tetrahydro- -carboline core (1)
acids,7 we recently reported a catalytic asymmetric Pictet-
are of great interest because of their inherent biological
Spengler reaction via an N-sulfenyliminium ion catalyzed by a
activity.1–3 Tetrahydro- -carbolines are generally obtained via
bis-trifluoromethylphenyl-substituted (R)-BINOL phosphoric
the Pictet-Spengler reaction of tryptamine with a variety of
acid (5-10 mol %). Both alkyl- and aryl-substituted tetrahydro-
aromatic and aliphatic aldehydes in the presence of a Brønsted
-carbolines 4 were obtained in 77-90% yield in two steps
(cyclization and removal of the tritylsulfenyl group in a one-pot procedure) with ee values up to 87%.8
† X-Ray crystal structure determination: Institute for Molecules and Materials,
Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands.
(4) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030–2036.
(1) For their use as anti-viral agents, see: (a) Gudmundsson, K. WO
(b) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797–1842.
2007002051, 2007. (b) Gudmundsson, K.; Miller, J. F.; Sherrill, R. G.; Turner,
(5) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558–
E. M. WO 2006015035, 2006. For the application in the development of
anticancer agents, see:(c) Shen, Y.-C.; Chen, C.-Y.; Hsieh, P.-W.; Duh, C.-Y.;
(6) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086–
Lin, Y.-M.; Ko, C.-L. Chem. Pharm. Bull. 2005, 53, 32–36. For their application
in the treatment of male erectile dysfunction, see: (d) Sui, Z.; Guan, J.; Macielag,
(7) For recent reviews on catalysis by chiral Brønsted acids, see: (a) Connon,
M. J.; Jiang, W.; Qiu, Y.; Kraft, P.; Bhattacharjee, S.; John, T. M.; Craig, E.;
S. J. Angew. Chem., Int. Ed. 2006, 45, 3909–3912. (b) Akiyama, T.; Itoh, J.;
Haynes-Johnson, D.; Clancy, J. Bioorg. Med. Chem. Lett. 2003, 13, 761–765.
Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999–1010. (c) Taylor, M. S.; Jacobsen,
(2) (a) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761–793. (b) Yu,
E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543. (d) Akiyama, T. Chem.
J.; Wang, T.; Liu, X.; Deschamps, J.; Anderson, J. F.; Liao, X.; Cook, J. M. J. Org.ReV. 2007, 107, 5744–5758. (e) Connon, S. J. Org. Biomol. Chem. 2007, 5, Chem. 2003, 68, 7565–7581. (c) Liao, X.; Zhou, H.; Yu, J.; Cook, J. M. J. Org.
3407–3417. For a convenient protocol for the synthesis of these chiral phosphoric
Chem. 2006, 71, 8884–8890. (d) Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett.
acids, see: (f) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; Ko¨ckritz,
2007, 9, 3491–3494.
A.; Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008, 64, 1316–1322.
(3) (a) Herraiz, T. J. Chromatogr. A 2000, 881, 483–499. (b) Herraiz, T.;
(8) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K.; van Maarseveen,
Galisteo, J.; Chamorro, C. J. Agric. Food Chem. 2003, 51, 2168–2173.
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–7487.
10.1021/jo8010478 CCC: $40.75 2008 American Chemical Society
J. Org. Chem. 2008, 73, 6405–6408 SCHEME 2. Winterfeldt Oxidation and Known Pyrroloquinolone Derivatives N-Substituted tetrahydro- -carbolines are the starting materi-
FIGURE 2. Chiral phosphoric acids.
als of choice for the pharmaceutically relevant pyrroloquinolones
Catalyst Screeninga 5 via the Winterfeldt oxidation.9
Pyrroloquinolones (e.g., 6 in Scheme 2) are selective phos-
phodiesterase 5 (PDE5) inhibitors,10 and the related quinolac- tacins such as 7 are known to play a key role in apoptosis.11,12 Pyrroloquinolone 610h was proven to be superior in selectivity and potency in the treatment of male erectile dysfunction compared to the nowadays commercially available Viagra (sildenafil),13 Levitra (vardenafil),14 and Cialis (tadalafil).15
Pyrroloquinolones such as 6 have been synthesized via an
asymmetric Pictet-Spengler reaction from tryptamine func-
tionalized with 1-naphthalen-1-yl-ethylamine as the chiral
auxiliary.10a Starting from tryptophan a diastereoselective
Pictet-Spengler reaction was achieved and the ester group was
removed in 4 steps.10h Another route starts with (one pot)
consecutive imine formation from tryptamine in boiling toluene,
followed by an acid-catalyzed Pictet-Spengler cyclization and
resolution with a chiral acid to afford the tetrahydro- -carboline
intermediate with high optical purity. After installing the
N-benzyl the stage was set for the Winterfeldt oxidation.10e,g
Reaction was conducted with 8 (0.05 mmol), 12 (3 equiv), and
powdered 4 Å MS (75 mg) in toluene (0.5 mL) with 2 mol % catalyst
Because N-benzyl-protected tetrahydro- -carbolines are the
at 70 °C for 24 h. b Determined by 1H NMR spectroscopy. c Determined
most commonly used substrates for the Winterfeldt oxidation
by HPLC on a chiral column (Chiralcel OD).
we herein report an asymmetric organocatalytic Pictet-Spenglerreaction directly starting from N-benzyltryptamine.
As 2,3-dihydrobenzofuran-5-carboxaldehyde 12 is employed
in the synthesis of PDE5 inhibitors,10 we have chosen this
(9) (a) Winterfeldt, E. Liebigs Ann. Chem. 1971, 745, 23–30. (b) Warneke,
J.; Winterfeldt, E. Chem. Ber. 1972, 105, 2120–2125. (c) Boch, M.; Korth, T.;
particular aldehyde to study the enantioselective Pictet-Spengler
Nelke, J. M.; Pike, D.; Radunz, H.; Winterfeldt, E. Chem. Ber. 1972, 105, 2126–
reaction starting from N-benzyltryptamine 8 providing tetrahy-
dro- -carboline 13. A series of enantiopure phosphoric acid
(10) (a) Jiang, W.; Sui, Z.; Chen, X. Tetrahedron Lett. 2002, 43, 8941–8945.
(b) Jiang, W.; Sui, Z.; Chen, X. Org. Lett. 2003, 5, 43–46. (c) Jiang, W.; Sui,
catalysts were screened (see Figure 2) and the results are listed
Z.; Macielag, M. J.; Walsh, S. P.; Fiordeliso, J. J.; Lanter, J. C.; Guan, J.; Qiu,
Y.; Kraft, P.; Bhattacharjee, S.; Craig, E.; Haynes-Johnson, D.; John, T. M.; Clancy, J. J. Med. Chem. 2003, 46, 441–444. (d) Lanter, J. C.; Sui, Z.; Macielag,
Low ee values were obtained with the binol phosphoric acids
M. J.; Fiordeliso, J. J.; Jiang, W.; Qiu, Y.; Bhattacharjee, S.; Kraft, P.; John,
9a-f, except when triphenylsilyl catalyst 9c was used (Table
T. M.; Haynes-Johnson, D.; Craig, E.; Clancy, J. J. Med. Chem. 2004, 47, 656–
1, entry 3). The H8-BINOL phosphoric acids 10a and 10b gave
662. (e) Li, X.; Branum, S.; Russell, R. K.; Jiang, W.; Sui, Z. Org. Process Res. DeV. 2005, 9, 640–645. (f) Jiang, W.; Guan, J.; Macielag, M. J.; Zhang, S.; Qiu,
almost full conversions and similar ee values as the related
Y.; Kraft, P.; Bhattacharjee, S.; John, T.M. ; Haynes-Johnson, D.; Lundeen, S.;
BINOL phosphoric acids. VAPOL hydrogen phosphate 11
Sui, Z. J. Med. Chem. 2005, 48, 2126–2133. (g) Willemsens, B.; Vervest, I.;
proved to be unsuitable for this reaction as only low conversion
Ormerod, D.; Aelterman, W.; Fannes, C.; Mertens, N.; Marko´, I. E.; Lemaire, S. Org. Process Res. DeV. 2006, 10, 1275–1281. (h) Lemaire, S.; Willemsens,
and enantioselectivity were obtained.
B.; Marko´, I. E. Synlett 2007, 5, 709–712.
With catalyst 9c giving the best result, we then investigated
(11) Clark, B.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H. Org. Biomol.Chem 2006, 4, 1512–1519, and references cited therein.
the influence of catalyst loading and reaction temperature for
(12) Zhang, X.; Jiang, W.; Sui, Z. J. Org. Chem. 2003, 68, 4523–4526.
this catalyst. In the absence of catalyst, it appeared that 13 was
(13) Brook, G. Drugs Today 2000, 26, 125–134.
formed as a racemic mixture in a yield of 23-35% after 24 h
(14) Sorbera, L. A.; Martin, L.; Rabasseda, X.; Castaner, J. Drugs Future2001, 26, 141–144.
(as observed in three different experiments).16 Increasing the
(15) (a) Sorbera, L. A.; Martin, L.; Leeson, P. A.; Castaner, J. Drugs Future
amount of catalyst to 5 mol % gave full conversion after 13 h
2001, 26, 15–19. For the discovery of tadalafil, see: (b) Daugan, A.; Grondin, P.; Ruault, C.; Gouville, A.-C. L. M.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudinie`re, R. J. Med. Chem. 2003, 46, 4525–4532. (c) Daugan, A.; Grondin,
(16) See for an uncatalyzed Pictet-Spengler reaction with N-benzyltryptamine
P.; Ruault, C.; Gouville, A.-C. L. M.; Coste, H.; Kirilovsky, J.; Linget, J.-M.;
see: Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka,
Hyafil, F.; Labaudinie`re, R. J. Med. Chem. 2003, 46, 4533–4542.
E.; Hutchins, L.; DiPierro, M.; Cook, J. M. J. Org. Chem. 1979, 44, 535–545. J. Org. Chem. Vol. 73, No. 16, 2008Solvent and Additive Screeninga Scope of the Reactiona a Reaction was conducted with 8 (0.05 mmol), 12 (3 equiv), and 14l
drying agent (75 mg) in 0.5 mL of solvent with 2 mol % 9c at 70 °C
for 24 h. b Reaction monitored by TLC. c Determined by HPLC on a
chiral column (Chiralcel OD). d Stirred for 48 h. a Reaction was conducted with 8 (0.2 mmol), aldehyde (3 equiv), and
and 13 was obtained with an ee of 85%. With 10 mol % catalyst
powdered 4 Å MS (300 mg) in 2 mL of toluene with 2 mol % of 9c at
the reaction was complete in 4 h and afforded 13 with essentially
70 °C for 24 h unless otherwise stated. b Isolated yield. c Determined by HPLC on a chiral column. d With Chiralcel OD. e 5 mol % of 9c was
the same ee (86%) as obtained with a catalyst loading of 2 or
used. f With Chiralpak AD. g With Chiralcel OD-H. h A different
5 mol % (see also Table 1). The best results in terms of ee
workup procedure was performed to prevent racemization, see the
were obtained at a temperature of 70 °C; at 50 °C the reaction
Supporting Information. i Reaction performed with catalyst 9a (2 mol
of 8 with 12 was complete in 48 h (81% ee) and at 90 °C full
conversion was observed after 12 h (82% ee) with a catalystloading of 2 mol %.
The study of the effects of solvent and additives is sum-
marized in Table 2. The reaction proceeded at best in aromaticsolvents with a clear preference for toluene. In the absence ofmol sieves, the reaction was incomplete after 24 h and theproduct was obtained with a modest ee only (41%). Acomparable result was obtained by using sodium sulfate as thedrying agent. Slightly lower ee values were obtained when 3 Å
FIGURE 3. X-ray crystal structure of 14a.
and 5 Å MS were employed as compared to 4 Å MS. Possibly,water is able to break up the tight complex between the BINOL-
gave the lowest ee and with the easy enolizable phenylacetal-
phosphate and the cyclization precursor.
dehyde no product could be obtained (entry 15).
In our final optimization experiments, the stability of the
The Pictet-Spengler reactions with 2,3-dihydrobenzofuran-
Pictet-Spengler product was examined. We exposed enan-
5-carboxaldehyde 12 and p-bromobenzaldehyde were also
tiopure (S)-13 to the reaction conditions (2 mol % of 9c, 2 equiv
performed on a 1 mmol scale giving 13 and 14a in similar yields
of 13, 4 Å MS, toluene, 70 °C, 24 h) and no racemization was
and ee values. Both products were readily recrystallized to
observed. By application of the same reaction conditions to the
enantiomeric purity. From 14a an X-ray crystallographic
racemic product 13 no enantiomeric enrichment was observed
structure (Figure 3) was obtained revealing the absolute con-
thus suggesting that the BINOL-phosphoric acid catalyzed
figuration which was found to be (S). This is in analogy with
Pictet-Spengler reaction of N-benzyltryptamine with 12 is irreversible under our reaction conditions.
our previous results obtained for the Pictet-Spengler reactionwith N-tritylsulfenyltryptamine.8 The required biologically active
With the optimal reaction conditions identified, we investi-
(R)-enantiomer of benzofuran 13 was prepared with comparable
gated the reaction with a series of aliphatic and aromaticaldehydes. The results are presented in Table 3.
yield and ee by using the corresponding (S)-triphenylsilyl- substituted BINOL catalyst 9c.
All reactions proceeded smoothly to give the corresponding
products 13 and 14 in good to high yields (77-97%). Both
In conclusion, we have developed an organocatalyzed asym-
aromatic (bearing electron donating and electron withdrawing
metric Pictet-Spengler reaction of N-benzyltryptamine (8) with
groups) and aliphatic aldehydes are tolerated. Moderate to good
a variety of aldehydes. Both aromatic and aliphatic aldehydes
ee values were obtained in the range of 61-87%, with the best
can be used in this reaction catalyzed by an enantiopure BINOL-
result with p-nitrobenzaldehyde (Table 3, entry 2). Remarkably,
derived phosphoric acid. The corresponding adducts are obtained
low ee values (0-20%) were obtained with m-chlorobenzalde-
in good to high yields and moderate to good ee values in one
hyde and with 3,5-bis(trifluoromethyl)benz-aldehyde (entries 4
step. In addition, our scaleable method shortens the synthesis
and 5). The reason for the low ee in these two cases is unclear.
toward the pharmaceutically very relevant PDE5 inhibitors of
Of the aliphatic aldehydes tested, 3-phenylpropanal (entry 16)
the pyrroloquinolone class by three steps. J. Org. Chem. Vol. 73, No. 16, 2008Experimental Section
108.8, 71.3, 64.1, 58.1, 48.4, 29.6, 21.2; IR (film) ν 3407, 3027,2896, 2842, 2794, 1613, 1489; HRMS (FAB) m/z calcd for [M +
H]+ C26H25N2O 381.1967, found 381.1972. line (13). A mixture of N-benzyltryptamine (8, 250 mg, 1 mmol), (S)-2-Benzyl-1-(p-bromophenyl)-1,2,3,4-tetrahydro- -carbo-
4 Å (powdered) molecular sieves (1.5 g), and catalyst 9c (17.3 mg, line (14a). Compound 14a was obtained in a yield of 92% (384.7
0.02 mmol) in 10 mL of toluene was stirred for 5 min at room
mg, 87% ee) following the procedure described for 13 with
temperature. Subsequently, 2,3-dihydrobenzofuran-5-carboxalde-
p-bromobenzaldehyde (222.0 mg, 1.2 mmol). Crystals were formed
hyde (12, 178 mg, 1.2 mmol) was added and the mixture was stirred
as described for (S)-13 to give 41.2 mg (10% yield, 10% ee) of
at 70 °C for 24 h under a nitrogen atmosphere. The reaction mixture
solid. The filtrate was concentrated to a small volume and diluted
was then cooled to room temperature and 3 g of silica gel was
with PE (2 mL). After standing in the refrigerator for 18 h, 343.5
added followed by 5 mL of petroleum ether (PE). The resulting
mg (82% yield, 98% ee) of solid was obtained. Recrystallization
slurry was stirred for 5 min and filtered over a Celite path containing
from EtOH gave enantiomerically pure (S)-14a (>99% ee deter-
2 g of silica gel (glass filter) and rinsed with 90 mL of eluent (PE:
mined on a Chiralcel OD column of heptane:isopropanol ) 97:3,
EtOAc ) 5:1). Concentration of the filtrate afforded tetrahydro-
1 mL/min, tr major ) 12.3 min, tr minor ) 16.4 min) which was
-carboline 13 in a yield of 69% (262.3 mg, 84% ee).
used for X-ray crystal structure analysis. Mp 171-172.5 °C; [R]22D
To obtain crystals the solid was dissolved in 0.5 mL of hot EtOAc
+67.4 (c 0.23, CHCl3); 1H NMR (400 MHz; CDCl3) δ 7.56-7.50
and diluted with 1 to 2 mL of PE. The resulting solution was kept
(m, 3H), 7.36-7.31 (m, 6H), 7.30-7.24 (m, 2H), 7.24-7.21 (m,
for 18 h in the refrigerator to give 35.3 mg (9% yield) of racemic
1H), 7.18-7.11 (m, 2H), 4.65 (s, 1H), 3.89 (d, J ) 13.6 Hz, 1H),
crystals. The filtrate was concentrated to a small volume and diluted
3.42 (d, J ) 13.6 Hz, 1H), 3.26-3.21 (m, 1H), 2.96-2.88 (m,
with PE (2 mL). After standing in the refrigerator for 18 h, 227
1H), 2.85-2.80 (m, 1H), 2.73-2.67 (m, 1H); 13C NMR (75.5 MHz;
mg (60% yield, 96% ee) of solid was obtained. Recrystallization
CDCl3) δ 140.7, 139.3, 136.4, 134.1, 131.9, 130.7, 128.7, 128.4,
from EtOH gave enantiomerically pure (S)-13 (99% ee determined
127.2, 127.1, 122.0, 121.8, 119.5, 118.4, 110.9, 109.3, 63.7, 58.3,
by chiral HPLC on a Chiralcel OD column of heptane:isopropanol
48.1, 21.1; IR (NaCl) ν 3406, 2796, 1483; HRMS (FAB) m/z calcd.
) 98:2, 0.8 mL/min, tr major ) 21.0 min, tr minor ) 24.3 min).
for [M + H]+ C24H22N2Br 417.0966, found 417.0954.
70 (c 0.25, CHCl3); 1H NMR (400 MHz;
Supporting Information Available:
3) δ 7.57-7.55 (m, 1H), 7.43-7.34 (m, 5H), 7.31-7.28 (m,
2H), 7.24-7.18 (m, 2H), 7.16-7.11 (m, 2H), 6.80 (d, J ) 8.1 Hz,
data, copies of 1H and 13C NMR spectra, and chromatograms
1H), 4.62-4.58 (m, 3H), 3.98 (d, J ) 13.6 Hz, 1H), 3.40 (d, J )
of the compounds in Table 3, as well as of the catalysts 10a
13.6 Hz, 1H), 3.30-3.24 (m, 1H), 3.23-3.13 (m, 2H), 2.99-2.92
and 10b, and detailed experimental procedures. This material
(m, 1H), 2.85-2.80 (m, 1H), 2.73-2.68 (m, 1H); 13C NMR (75.5
is available free of charge via the Internet at http://pubs.acs.org.
MHz; CDCl3) δ 160.0, 139.5, 136.2, 135.3, 133.2, 128.9, 128.7,128.2, 127.7, 127.2, 126.8, 125.4, 121.4, 119.3, 118.2, 110.7, 108.9,
J. Org. Chem. Vol. 73, No. 16, 2008
Yamanashi Med. J. 17 (3), 69~ 74, 2002 Original Article Effects of Sildenafil (ViagraTM) on the Cyclic AMP Hydrolyzing Phosphodiesterase Activity in the Canine Heart Assessed Using a Modified Enzymatic Fluorometric Assay TechniqueAtsushi SUGIYAMA, Yoshiki SAEGUSA, Akira TAKAHARA Departments of Pharmacology and 1)Neurosurgery, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan Abstra
LIST OF PUBLICATIONS: Jean-Yves DARMON, MD Davido A, Hallali P, Darmon JY, Robinet C, Jullien JL, Corone P. Pleuropericardial cyst two-dimensio-nal echography and C.A.T. scan of a case. Coeur-Paris 1987 ; 18 : 35-8. Andrivet P, Adnot S, Brun-Buisson C, Chabrier E, Darmon JY, Braquet P, Lemaire F. Involvement ofANF in the acute antidiuresis during PEEP ventilation. J Appl Physiol 1988 ; 65 : 19