Efficient and diverse synthesis of indole derivatives

Article abstract of DOI:10.1021/jo900986z

(Chemical Equation Presented) A convergent 2-step procedure toward an array of indole derivatives involving an Ugi reaction and a Pictet - Spengler reaction is described. The reactions are versatile regarding different starting materials. Hexacyclic 24 can be produced with unprecedented complexity.

Full text of DOI:10.1021/jo900986z

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demand. An efficient synthesis should lead into a target
Efficient and Diverse Synthesis of Indole Derivatives
scaffold in a few synthetic steps, in good yields, and allowing
for extensive variation of the different starting materials to
broadly cover the respective chemical space. A stereoselec-
tive procedure should be possible as well. Multicomponent
reaction (MCR) chemistry is a technique that allows for
efficient and diverse access to multiple bioactive scaffolds.2
This technique recently led to multiple biological active
compounds currently undergoing clinical evaluation or even
being marketed.3 As part of our ongoing program to identify
new and efficient access to scaffolds of biological interest, we
herein report a new and versatile MCR synthesis of tetra-
hydro-β-carboline (Figure 1).4
€
Haixia Liu and Alexander Domling*
Departments of Pharmaceutical Sciences and Chemistry,
University of Pittsburgh, Pittsburgh, Pennsylvania 15261
asd30@pitt.edu
Received May 11, 2009
FIGURE 1. New synthetic access to the tetrahydro-β-carboline
scaffold.
Tetrahydro-β-carboline ring systems are usually formed
from tryptophan or its derivative tryptamine and an alde-
hyde via the classical Pictet-Spengler condensation.5 The
reaction products then serve for further derivatizations in
sequential multistep processes.6 A combination of MCR and
Pictet-Spengler reaction has been described in the past,
however, leading to different types of scaffolds.2a,7 We
figured that our herein described MCR process might be
suitable to rapidly assemble tetrahydro-β-carboline scaffolds
and would thus be complementary to previously reported
methods. Toward this end, we synthesized tryptophan and
tryptamine derived isocyanides and reacted them in the Ugi
4-CR with aldehydes, primary amines, and carboxylic acids.
As a bifunctional amine component we used aminoacetalde-
hyde dimethylacetal, which in a subsequent step would
undergo the Pictet-Spengler reaction to afford highly sub-
stituted tetrahydro-β-carbolines. Such a two-step process
could have advantages over currently sequential processes,
A convergent 2-step procedure toward an array of indole
derivatives involving an Ugi reaction and a Pictet-Spengler
reaction is described. The reactions are versatile regarding
different starting materials. Hexacyclic 24 can be produced
with unprecedented complexity.
Indole alkaloids are the main group of bioactive alkaloids,
including, for example, hypertensive reserpine, antiprolifera-
tive vinblastine, or antiprotocoal apicidin.1 The basic skele-
ton of indole alkaloids, however, is often only accessible via
lengthy sequential synthesis. To optimize the properties of
natural products or to efficiently discover novel unrelated
biological activities, flexible synthetic approaches are in high
(1) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278–311.
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(2) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3220.
(b) Multicomponentreaction; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2005. (c) Sunderhaus, J. D.; Martin, S. F. Chem.;Eur. J.
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(4) (a) Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Domling, A. Org.
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Lett. 2001, 3, 2875–2878. (b) Beck, B.; Picard, A.; Herdtweck, E.; Domling,
A. Org. Lett. 2004, 6, 39–42. (c) Kolb, J.; Beck, B.; Almstetter, M.; Heck, S.;
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2009, 15, 1300–1308. (d) Domling, A. Chem. Rev. 2006, 106, 17–89.
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DOI: 10.1021/jo900986z
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Published on Web 08/07/2009
J. Org. Chem. 2009, 74, 6895–6898 6895
2009 American Chemical Society

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Liu and Domling
JOCNote
SCHEME 1. Stepwise Ugi-4CR and Pictet-Spengler Reaction
SCHEME 2. Versatile Synthesis of Indole Derivatives
since the product diversity should be much larger and the effort
to synthesize the compound should be drastically reduced.8
As a model, we first reacted tryptophan derivative 1,
aldehyde 2, carboxylic acid 3, and bifunctional amine 4 in
methanol at room temperature as shown in Scheme 1. The
Ugi 4-CR proceeded well and the desired product 5a was
isolated in good yield. To our surprise, however, the sub-
sequent Pictet-Spengler reaction of 5a was very sluggish and
the desired product 6 could only be found in traces. Variation
of the reaction conditions including the acid (formic acid,
methane sulfonic acid, PTSA, CSA), solvent, and tempera-
ture did not greatly improve the reaction performance.
This was surprising since the electron-rich indole ring sys-
tems are the archetypical substrates for Pictet-Spengler
reactions.5 We reasoned that the unprotected indole proton
could interfere with the reaction and undergo side reactions,
and we decided to prepare N-protected derivatives. Already
the first protecting group we tried, tert-butyloxycarbonyl (Boc)
in compound 5b, proved to be highly superior and afforded the
product 6 in a clean reaction in good yield (Scheme 1). The two-
step reaction sequence was running very smoothly and the
isolation of the desired compound proved to be very simple and
therefore we went on to try different variations and to find out
the scope and limitations of the reactions.
amino aldehyde 8 (entries 12-15) was used to give corre-
sponding 7-membered-ring products after the Pictet-Spen-
gler reaction, however, in poor yields. The product of
4-fluoro-3-nitrobenzoic acid can be potentially further deri-
vatized by aromatic nucleophilic substitutions (Table 1,
entry 15; Scheme 2).
In the case of tryptophan-derived isocyanide and formal-
dehyde, two products are formed in a ratio of approximately
2:1 (Table 1, entries 1-4); the major compound is the trans
diastereomer (6a, 9a-11a), which can be separated by
column chromatography on silica gel. The stereochemical
assignment of these diastereomers is generally done by 2D
NOESY experiments (Figure 2).
FIGURE 2. Relative configuration of 6a and 6b by NOESY.
Two different N-Boc protected indole-containing isocya-
nides derived from tryptophan9 and tryptamine were pre-
pared.10 Both can be efficiently synthesized on a multigram
scale and react nicely in all reactions investigated herein.
First, we made variations in the carboxylic acid, and as
expected a range of carboxylic acids with different properties
reacted nicely, e.g., aliphatic (Table 1, entries 1-2, 5-6, and
7), aromatic (Table 1, entries 3-4, and 8), and cyclic (Table 1,
entries 1-2, 5-6, and 9). Next, we tried different aldehydes.
Besides formaldehyde we reacted sterically hindered ortho,
ortho-disubstituted difluoro benzaldehyde, which resulted
in product 17 formation in good yield (48%, over two steps)
as two diastereomers (1:1 by 1H NMR) (Table 1, entry 10).
We also tried valeraldehyde (entry 11), which gave two
diastereomers in a ratio of 2:1 which can be separated by
preparative TLC. Finally a different bifunctional primary
The bifunctinal 2-formylbenzoic acid 23 was also investi-
gated, which reacts with tryptophan-derived isocyanide 7 and
bifunctional amine 4 under HCO2H-mediated conditions in a
two-step manner to give polycyclic indole alkaloid 24 in
decent yield with 6 condensed rings in a row (Scheme 3). This
is a remarkable example of an efficient synthesis of a
complex compound containing six annulated rings and con-
comitant formation of three new C-C bonds and four new
N-C bonds in just two steps from simple and commercial
precursors.
SCHEME 3. One-Pot Formation of Polycyclic Indole Deriva-
tive 24
(8) Lee, S.-C.; Choi, S.-Y.; Chung, Y.-K.; Park, S.-B. Tetrahedron Lett.
2006, 47, 6843–6847.
(9) For previous uses of indole-derived isocyanides in MCR see: (a) Beck,
In summary, a new and efficient 2-step sequence to
assemble highly substituted tetrahydro-β-carbolines has
been developed. The sequence comprises an Ugi-4CR fol-
lowed by a Pictet-Spengler ring closure. Using tryptophan-
derived isocyanide yields two diastereomers, slightly favoring
€
B.; Domling, A. Bioorg. Med. Chem. Lett. 2000, 10, 1701–1705. (b) Beck, B.;
€
Domling, D. E. 19943508. (c) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E.
€
S.; Roschenthaler, G.-V.; Nenajdenko, V. G. Tetrahedron 2008, 64, 11706–
11712.
(10) See the Supporting Information for the synthesis of indole-contain-
ing isocyanides.
6896 J. Org. Chem. Vol. 74, No. 17, 2009

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Liu and Domling
JOCNote
TABLE 1. Synthesis of Indole Derivatives
a
b
Ugi-4CR intermediates separated and yields refer to the Pictet-Spengler reactions. Overall yield in two steps (crude
c
Ugi reaction product was directly used for the Pictet-Spengler reaction). Unseparable diastereomers, d.r. determined by
1H NMR. d Separable diastereomers by chromatography, d.r. determined by 1H NMR. e Yield for the Ugi reaction. f Yield for
the Pictet-Spengler reaction.
the trans stereoisomer. The developed short sequence not only
allows for efficient production of many derivatives for screen-
ing purposes, but it also can be potentially used to efficiently
assemble indole alkaloids type natural products.
Experimental Section
General Procedure for the Ugi-4CR Reaction. To a mixture of
aldehyde (1.2 mmol), amine 4 or 10 (1.0 mmol), and carboxylic
acid (1.0 mmol) in MeOH (3.0 mL) was added isocyanide 7a or
J. Org. Chem. Vol. 74, No. 17, 2009 6897

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Liu and Domling
JOCNote
7b (1.0 mmol) at 0 °C and the reaction was stirred at rt for 24 h.
The resulting solution was concentrated under reduced pressure
and the residue was purified by column chromatography on
silica gel or used directly in the next step without further
purification.
25.5, 22.5 ppm; HPLC-MS r_t 10.67, 11.12 min, m/z [M þ H]þ
410; HRMS (EI) m/z calcd for C23H27N3O4 [Mþ] 409.2002,
found 409.2002.
Synthesis of Polycyclic Indole Derivative 24. To a mixture of
formylbenzoic acid 23 (1.2 mmol) and amine 4 (1.0 mmol) in
MeOH (3.0 mL) was added isocyanide 7a (1.0 mmol) at 0 °C. The
reaction mixture was stirred at rt for 24 h. The resulting solution
was concentrated under reduced pressure and the residue was
purified by column chromatography on silica gel to give the
Ugi product (252 mg, 49%). The above Ugi reaction product
(100 mg, 0.20 mmol) was dissolved in cold HCO2H (1.5 mL).
After being stirred at rt for 30 min, the mixture was warmed to
60 °C and stirred for 2 h. The reaction mixture was diluted with
EtOAc and neutralized by carefully adding sat. NaHCO3 solu-
tion. The organic layer was separated, washed once with brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
on silica gel affording compound 24 (67 mg, 54%) as a white
solid. 1H NMR (600 MHz, CDCl3) δ 9.45 (s, 1H), 8.12 (d, J =
7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H),
7.61 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (d, J =
7.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H),
5.50 (dd, J = 4.8, 13.2 Hz, 1H), 5.33 (s, 1H), 5.15 (dd, J = 4.8,
13.2 Hz, 1H), 5.07 (m, 1H), 3.49 (dd, J = 11.4, 13.2 Hz, 1H), 2.97
(m, 1H), 2.86 (m, 2 H); 13C NMR (150 MHz, CDCl3) δ 168.6,
164.4, 140.5, 136.6, 132.8, 131.4, 129.3, 126.4, 125. 1, 123.4,
122.6, 119.8, 118.5, 111.2, 110.2, 106.4, 60.6, 53.9, 42.5, 40.0,
21.0; HPLC-MS r_t 10.13, 10.62 min; m/z [M þ H]þ 344.
General Procedure for the Pictet-Spengler Reaction. The
above Ugi reaction product (150-200 mg) was dissolved in cold
HCO2H (1.5 mL). After being stirred at rt for 30 min, the
mixture was warmed to 60 °C and stirred for 2 h. The reaction
mixture was diluted with EtOAc and neutralized by carefully
adding sat. NaHCO3 solution. The organic layer was separated,
washed once with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel to afford correspond-
ing Pictet-Spengler products in decent yield. Characterization
of 6a: 1H NMR (600 MHz, CDCl3) δ 9.04 (s, 1H), 7.54 (d, J =
7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H),
7.15 (t, J = 7.8 Hz, 1H), 5.98 (d, J = 5.4 Hz, 1H), 5.26 (d, J =
13.2 Hz, 1H), 5.18 (d, J = 10.8 Hz, 1H), 4.61 (d, J = 17.4 Hz,
1H), 4.23 (d, J = 17.4 Hz, 1H), 3.64 (s, 3H), 3.52 (d, J = 16.2 Hz,
1H), 3.15 (dd, J = 5.4, 16.2 Hz, 1H), 2.88 (dd, J = 13.2, 10.8 Hz,
1H), 2.51 (tt, J = 11.4, 3.0 Hz, 1H), 1.82 (m, 3H), 1.53 (m, 2H),
1.27 (m, 5H) ppm; 13C NMR (150 MHz, CDCl3) δ 175.2, 170.7,
165.1, 136.7, 128.2, 126.3, 122.7, 119.9, 118.4, 111.3, 107.3, 52.7,
50.8, 50.1, 49.0, 44.3, 40.9, 30.6, 29.1, 28.9, 25.7, 25.6, 22.8 ppm;
HPLC-MS r_t 10.67, 11.12 min, m/z [M þ H]þ 410; HRMS (EI)
m/z calcd for C23H27N3O4 [Mþ] 409.2002, found 409.2009.
1
Characterization of 6b: H NMR (600 MHz, CDCl3) δ 8.87
(s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.20
(t, J = 7.8 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 5.03 (m, 1H), 4.65
(dd, J = 6.6, 6.0 Hz, 1H), 4.47 (dd, J = 13.2, 3.0 Hz, 1H), 4.28
(dd, JAB = 24.6, 16.2 Hz, 2H), 4.05 (dd, J = 13.2, 8.4 Hz, 1H),
3.71 (s, 3H), 3.49 (dd, J = 15.6, 6.6 Hz, 1H), 3.10 (dd, J = 15.6,
6.0 Hz, 1H), 2.40 (tt, J = 11.4, 3.0 Hz, 1H), 1.69 (m, 3H), 1.54
(m, 2H), 1.26 (m, 5H) ppm; 13C NMR (150 MHz, CDCl3) δ
175.3, 170.0, 166.7, 136.6, 129.5, 126.4, 122.7, 120.0, 118.2,
111.6, 109.1, 56.3, 53.7, 52.6, 49.3, 42.9, 40.7, 29.7, 29.0, 25.6,
Acknowledgment. We are grateful to the University of
Pittsburgh Drug Discovery Institute for financial support.
Supporting Information Available: Detailed experimental
procedures, and spectral data for all new compounds, including
1H, 13C. This material is available free of charge via the Internet
at http://pubs.acs.org.
6898 J. Org. Chem. Vol. 74, No. 17, 2009