A general catalytic reaction sequence to access alkaloid-inspired indole polycycles

Article abstract of DOI:10.1039/c5cc01555c

A catalytic two-step reaction sequence was developed to access a range of complex heterocyclic frameworks based on biorelevant indole/oxindole scaffolds. The reaction sequence includes catalytic Pictet-Spengler cyclization followed by Au(i) catalyzed intramolecular hydroamination of acetylenes. A related cascade polycyclization of a designed β-carboline embodying a 1,5-enyne group yields the analogues of the alkaloid harmicine. This journal is

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A General Catalytic Reaction Sequence to Alkaloid-
Inspired Indole Polycycles
Cite this: DOI: 10.1039/x0xx00000x
Adithi Dandaa,b, Kamal Kumara,b* and Herbert Waldmanna,b*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Figure 1. a) Natural and synthetic small molecules embodying the
indoloquinolizines and related scaffolds; b)
indoloquinolizines and related frameworks.
A catalytic two-step reaction sequence was developed to
access a range of complex heterocyclic frameworks based on
biorelevant indole/oxindole scaffolds. The reaction sequence
includes a catalytic Pictet-Spengler cyclization followed by a
Au(I) catalyzed intramolecular hydroamination of acetylenes.
A general retrosynthesis of
In an attempt to generate a compound collection based on the
indoloquinolizine and related scaffolds which occur widely in the
alkaloid world (for representative examples see Figure 1a), we
devised the reaction sequence shown in Figure 1b. Acetylenic
aldehydes and tryptamines were expected to cyclize in a Pictet-
A related cascade polycyclization of a designed
β-carboline
embodying a 1,5-enyne group yields analogues of the alkaloid
harmicine.
Spengler reaction4 to yield tetrahydro-
β-carbolines, which under
The synthesis of natural product-inspired compound collections
draws inspiration from the structural frameworks of natural product
classes in order to imbibe the inherent biological relevance
associated with these evolutionary selected scaffolds.1 Among the
various natural product classes indole alkaloids and related
heterocycles are of major interest since they represent a large class
of compounds endowed with manifold bioactivities.2 Synthetic
access to a broad range of complex molecular frameworks is usually
hampered by the lack of general synthesis protocols. In fact,
synthesis optimization of the core-scaffolds is the most time
consuming and challenging task in building a compound collection.
Consequently, concise and general synthesis routes that could
rapidly and efficiently build up a range of complex molecular
frameworks, in particular, based on natural product structures are
very much desired.3
suitable reaction conditions could undergo a hydroamination
reaction5 with the alkyne to yield the desired indoloquinolizine
framework.6 It was planned to explore different acetylenic scaffolds
in the optimized general route and provide structurally diverse indole
alkaloid based compounds.7
In the initial experiments aimed at identifying a catalyst
suitable to accelerate the sequence of imine formation and Pictet-
Spengler cyclization (step a), we employed tryptamine (1) and o-2-
8
phenylethynyl benzaldehyde (2) as model substrates. Treatment of
the starting materials with one equivalent of trifluoroacetic acid
(TFA) led to formation of Pictet-Spengler adduct 3a in less than
20% yield. Heating the reaction mixture to 50° C for 24 h almost
doubled the yield of Pictet-Spengler adduct 3a (entry 1, Table 1).
However, the substantial amount of substrate/product decomposition
was observed that rendered the purification of 3a very difficult. The
literature precedence that ytterbium complexes can catalyse Pictet-
spengler cyclizations9 led us to explore Yb(OTf)3 as a catalyst.
Treating a mixture of tryptamine and aldehyde 2 with 10mol% of
Yb(OTf3) and subjecting it to microwave irradiation provided only a
very low yield of 3a (entry 2). Addition of the ionic liquid
[bmim]Cl-AlCl3 (0.32 mL/mmol of tryptamine) to the reaction
mixture at room temperature enhanced the yield of 3a to 65% (entry
3). Under microwave heating conditions, the yield for 3a further
improved to 74% and the reaction was complete within one hour.
The use of ytterbium complexes for hydroamination reactions has
also been described.10 However, under the optimized conditions for
the Pictet-Spengler cyclization (entry 4, Table 1), formation of the
hydroamination product 4a was not observed. Owing to their
alkynophilicity, gold and other coinage metal complexes have
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DOI: 10.1039/C5CC01555C
emerged as highly useful catalysts for addition and cyclization differently substituted tryptamines (1) and different acetylenic
reactions involving diverse nucleophiles and alkynes.11 While silver aromatic aldehydes (2) leading to a set of indoloquinolizines 4 via
triflate failed to provide the intramolecular hydroamination reaction the two-step reaction sequence (Scheme 1). Under the optimized
of adduct 3a, i.e. a 6-endo-dig cyclization (step b) to yield 4a (entry conditions, the reaction sequence tolerates various tryptamines with
5, Table 1), we examined this reaction with selected gold electron-rich and poor aromatic ring and affording the corresponding
complexes.12 Treatment of 3a with AuCl(SMe2) in dichloroethane indoloquinolizines in moderate to good yields (Scheme 1).
(DCE) at room temperature provided only 25% yield for the Acetylenic aldehydes carrying electron-rich and -poor aryl moieties
indoloquinolizine 4a and even after heating the reaction mixture to on the acetylene were equally effective in the reaction sequence.
50° C the reaction did not go to completion. Resorting to gold(I) Pleasingly, benzaldehyde with acetylene substituted with
a
phosphine complex Au(OTf)PPh3 in DCE enhanced the yield for 4a cyclopropyl group also afforded the corresponding indoloquinolizine
substantially (entry 7, Table 1). Under these reaction conditions, (4f) in moderate yield (Scheme 1). Notably, tryptamines with
Au(PPh3)SbF6 as well as Au(III)Cl3 were similarly effective (entries electron-poor functional groups, for instance, 5-chloro-tryptamine
8-9, Table 1). Interestingly, the gold complexes (CH3CN)[(2- are very poor substrates for the Pictet-Spengler cyclization and
biphenyl)di-adamantylphosphine]-gold(I) (X) and its tert-butyl thereby cannot yield the desired indoloquinolizines (4c) in
analogue (Y) were found to be very effective hydromination acceptable yields. However, under the conditions of the developed
catalysts. In DCE the gold complex (Y) provided a good yield of protocol, 4c was obtained in moderate yield over two steps which
indoloquinolizine 4a (entry 10). However, its catalytic efficiency in demonstrate the synthetic value of the catalytic reaction sequence.13
acetonitrile was only low and owing to the very low solubility of Y
in toluene, no hydroamination product was observed even after 24 h
of the reaction (entries 12-13). Since the catalyst X provided the
indoloquinolizine 4a only in moderate yield (entry 11, Table 1), we
chose the gold complex Y for the hydroamination reaction of the
Pictet-Spengler adducts.
Table 1. Optimization of two step sequence leading to Indoloquinolizine 4a
Yield [%]a
Entry Catalyst
(mol%) for a
TFA (100)
Catalyst
Solvent Temp.
(°C)
Reaction
(10 mol%) for b
Time (h)
3a
< 40
12
4a
NA
NA
NA
1
2
3
--
--
DCM
DCM
DCM
r t to 50
MW, 120
r t
24
1
Yb(OTf)3 (10)
Yb(OTf)3 (10)
--
24
65
+ [bmim]Cl-AlCl3b
Yb(OTf)3 (10)
+ [bmim]Cl-AlCl3
4
--
DCM
MW, 120
1
74
NA
b
Scheme 1. Synthesis of substituted indoloquinolizines by a sequence of Pictet-
Spengler cyclization and gold mediated hydroamination reactions. The yields are
depicted over two reaction steps.
5
6
--
--
AgOTf
AuCl(SMe2)
DCE
DCE
r t
r t
1
1
NA
NA
Trace
25
7
8
--
--
Au(OTf)PPh3
DCE
DCE
r t
r t
1
1
NA
NA
40
35
Au(PPh3)SbF6
9
--
--
--
--
--
AuCl3
Cat. Y
Cat. X
Cat. Y
Cat. Y
DCE
DCE
DCE
MeCN
r t
r t
r t
r t
1
NA
NA
NA
NA
NA
37
62
42
48
NR
Having successfully established
a
synthesis of
10
11
12
13
1
1
1
24
indoloquinolizines (4), we next explored the utility of the two-step
protocol for the synthesis of complex, hexacyclic indoloquinolizines
(7) which embody a spirooxindole ring-system fused to a tetrahydro-
Toluene r t
b
aisolated yield; 0.32 mL/mmol of 2; rt = room temperature; NA = not applied; NR = no
β
-carboline ring. To this end, instead of acetylenic aldehydes (2),
acetylenic isatines (5) were employed with tryptamines (Scheme 2).
Isatines have been successfully employed in similar cyclization
reactions.14 However, acetylenic isatines have not been explored for
the synthesis of complex natural product-inspired scaffolds.
Pleasingly, the reaction between tryptamine and 5a proceeded
smoothly in the presence of TFA in toluene at 50° C to provide the
reaction; MW
=
microwave irradiation, DCE- 1,2-dichloroethane, DCM-
dichlorometahne. All reactions for the hydroamination step b were performed at 0.1
mmol scale in 2 mL of solvent.
desired tetrahydro-β-carboline (6a, Scheme 2, see details in the
Supporting Table 1) and did not require catalysis by ytterbium salts.
However, we realized that the hydroamination step in the sequence
did not proceed as desired under the previously optimized reaction
conditions. A limited reaction screening led us to employ 10 mol%
of AuCl(SMe2) to catalyse the hydroamination reaction and to afford
the desired hexacyclic indoloquinlizine (6a) in 76% yield (see
Supporting Table 1).
Thus, a two-step reaction sequence was established to synthesise
indoloquinolizines 4 in which a mixture of 1 and 2 with Yb(OTf)3 in
the presence of [bmim]Cl-AlCl3 (0.32 mL/mmol of tryptamine) in
DCM was subjected to microwave irradiation at 120° C for 1.0 h to
yield the Pictet-Spengler cyclization products 3 followed by
treatment of the pure adducts 3 with the gold catalyst Y (10 mol%)
at room temperature to afford the desired indoloquinolizines 4
(Scheme 1). The product 4a was easily purified by flash column
chromatography. These reaction conditions were then applied to
Under these conditions for the two-step protocol variation of
the tryptamines (1) as well as acetylenic isatines (5) delivered a set
of hexacyclic indoloquinolizines (7) with good overall yields over
two synthetic steps (Scheme 2). Only in the case of 5-
2 | J. Name., 2012, 00, 1-3
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chlorotryptamine, the Pictet-Spengler cyclization failed in the the catalytic polycyclization cascade was then attempted with the
presence of TFA, and we had to resort to ytterbium catalysis Pictet-Spengler product 10a employing various gold complexes (see
(Scheme 1). Both aryl and alkyl functionalized acetylenic isatines details in Supporting Table 2). Au(PPh3)OTf did not provide 12 in a
gave the desired products (7a-h) in good yields. Notably, the reaction with 10a. However, under these conditions a cyclization
products were formed as single isomers.13 Apparently the gold cascade lead to harmicine18 analogue 13a (Scheme 3) embodying a
mediated 6-endo-dig cyclization was preferred over a 5-exo-dig cyclopentyl ring (30% yield, see Supporting Table 2). Attempts with
cyclization that would lead to highly ring-strained spiro-products (8, different Au(I) catalysts, Au(PPh3)NTf2, AuCl(SMe2), and also a
Scheme 2). Furthermore, in the proton NMR spectra for 7g-h, the Au(III) catalyst (AuCl3), under different reaction conditions led only
to the formation of 13a in moderate and varying yields. Formation of
cyclization product 12 was not observed (see the Supporting
Information Table 3). Interestingly, catalyst Y was again found to be
suitable for the synthesis of natural product analogues 13 when the
reaction was performed in DCE and under microwave heating at
80°C. Under the optimized reaction conditions (Scheme 3),
differently substituted adducts 10 underwent the cascade
polycyclization and yielded the tetracyclic indoles 13 in good yields
as mixtures of diastereoisomers (Scheme 3). The syn-configuration
in the minor diastereomer of 13 was established by observation of a
nOe signal between Ha and Hb. A significant difference in the
chemical shift of Ha in the proton NMR spectrum of the major
diastereomer thus indicates an anti-configuration (see the Supporting
Information for details).
enamine proton Ha appears as singlet at ~ δ 5.27 ppm which clearly
suggests formation of a six-membered ring. In the 5-exo-dig-
cyclization products 8g-h, the allylic coupling would have resulted
in splitting of the signal for Ha (Scheme 2 and see details in the
Supporting Information). Infact,
a
similar observation for
indoloquinolizines (4) also ruled out a 5-exo-dig cyclization (Scheme
1).
Our results indicate that the polycyclization cascade was a
stepwise process that occurs via the cyclopropyl gold carbene
intermediate 11. Mechanistically, we assume that a gold mediated 6-
endo-dig cyclization leads to the formation of cyclopropane gold
complex 11. The selective formation of harmicine analogues 13
suggests that the ring-closure by addition of the secondary amine in
a 5-exo-tet mode was favoured17 over a 6-endo-tet pathway which is
in accordance with Baldwin´s rules (Scheme 3).19
Yb(OTf)3 (10mol%), [bmim]Cl-
AlCl3 (0.32mL\ mmol of 10),
DCE, MW, 1h, 120°C
O
Me
NH
R
+
1
H
N
H
9
10 (65-84%)
Catalyst Y (10mol%),
DCE, MW, 1h, 80o
C
Scheme
2
.
A
two-step protocol to highly complex and hexacyclic
6). The yields are
H
Me
Ha
R
b
Me
R
a
AuL
indoloquinolizines embodying spoirooxindole ring-system (
depicted over two reaction steps.
b
NH
Au
NH
N
Me
H
N
Me
c
H
c
H
Me
a
Hb
Me
11
Selective activation of acetylenes in enyne substrates
opens up interesting opportunities for rapid construction of complex
polycycles.15 Carboxylic acids and electron-rich phenols have
successfully been employed as nucleophiles in gold-mediated
polycyclization of 1,5-enynes.16 The conspicuous absence of
electron-rich indoles as nucleophiles in this reaction intrigued us to
investigate the cascade polycyclization of 1,5-enyne appended
R
N
6-endo-tet
5-
exo-tet
c
a
N
H
b
(disfavored)
12
R
N
N
Hb
Ha
N
H
N
13a; R = H, 70% (dr 1:1.6)
13b; R = OMe, 67% (dr 1.1.7)
13c; R = Me, 62% (dr 1:1.7)
13d; R = Cl, 49% (dr 1.1.5)
H
H
(+)-Harmicine
13 (favored)
tetrahydro-β-carboline 10 (Scheme 3). A successful polycyclization
reaction of 10 would ensure a rapid access to indole-derived
polycycles of higher structural complexity. We assumed that the
activation of the alkyne in the Pictet-Spengler adduct 10 by gold
complexes might trigger an addition of the olefin and concomitant
addition of the secondary amine in 10 to a more-stabilized
carbocation i.e. the methyl-substituted carbon of the olefin (pathway
a) to provide yohimbane alkaloid scaffold 12.16a Alternatively, a
stepwise process involving the nucleophilic opening of the
cyclopropyl gold carbene 11 formed by addition of the olefin to the
gold-activated alkyne, may yield either scaffold 12 (pathway b) or
the harmicine analogue 13 (pathway c).17 Under the optimized
reaction conditions (Scheme 1), tryptamine and enyne aldehyde 9
yielded the Pictet-Spengler adduct 10a in 84% yield (Scheme 3 and
see the Supporting Information for details). A reaction screening for
Scheme 3. A cascade polycyclization route to hexahydro-1H-indolizino[8,7-b]indoles
and a proposed reaction mechanism.
Conclusions
In conclusion, we have developed a general two-step catalytic
synthetic access to a range of indole alkaloid-inspired complex
molecular frameworks. Conditions were optimized for a
sequence of Pictet-Spengler cyclization followed by the
hydroamination of acetylenes to afford diverse and complex
indoloquinolizines. We also discovered a Au(I) catalyzed
cascade polycyclization providing access to structurally
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Acknowledgements
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This work was supported by the Ministry of Innovation,
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and Europäischer Fonds für Regionale Entwicklung and by the
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Notes and references
a Max Planck Institute of Molecular Physiology, Department of Chemical
Biology, Otto-Hahn Str. 11, 44227-Dortmund, Germany
bFakultät Chemie, Chemische Biologie, Technische Universität
Dortmund, Otto-Hahn Str. 6, 44227-Dortmund, Germany.
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Fax: +49-231-133-2499
email: kamal.kumar@mpi-dortmund.mpg.de;
Herbert.waldmann@mpi-dortmund.mpg.de.
Electronic Supplementary Information (ESI) available: [details of any
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