Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction

Article abstract of DOI:10.1002/anie.201507041

The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate

Full text of DOI:10.1002/anie.201507041

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507041
German Edition: DOI: 10.1002/ange.201507041
Asymmetric Synthesis
Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained
Tryptamines by a Switchable Cascade Reaction
Corien de Graaff, Lisa Bensch, Sjoerd J. Boersma, R a˘ zvan C. Cioc, Matthijs J. van Lint,
Elwin Janssen, Nicholas J. Turner, Romano V. A. Orru, and Eelco Ruijter*
Abstract: The interrupted Fischer indole synthesis of aryl-
hydrazines and biocatalytically generated chiral bicyclic
imines selectively affords either tetracyclic pyrroloindolines
or tricyclic tryptamine analogues depending on the reaction
conditions. We demonstrate that the reaction is compatible with
a variety of functional groups. The products are obtained in
high optical purity and in reasonable to good yield. We present
a plausible reaction mechanism to explain the observed
reaction outcome depending on the stoichiometry of the acid
mediator. To demonstrate the synthetic utility of our method,
Scheme 1. Biocatalytic generation of chiral bicyclic imine (À)-2 and
pharmaceutically relevant examples of both product classes
were synthesized in highly efficient reaction sequences, includ-
ing a phenserine analogue as a potential cholinesterase
conversion into telaprevir (3) and tetracyclic pyrroloindolines 6.
MCR=multicomponent reaction. HCV=hepatitis C virus.
inhibitor and constrained tryptamine derivatives as selective
Within the rich molecular diversity of natural products,
[
5]
inhibitors of the 5-HT serotonin receptor and the TRPV1 ion
indole derivatives take a privileged position. From a syn-
thetic perspective, the available range of synthetic strategies
to construct and modify indoles led us to investigate the
possibilities to combine readily available reactants in novel
cascade reactions to directly access complex polycyclic,
natural-product-inspired compounds in a stereoselective
fashion.
6
channel.
S
ince the dawn of modern chemistry, nature has served as an
inspiration for the development of new reactions, molecules,
and materials. In a chemical biology context, the biology-
oriented synthesis (BIOS) concept was introduced by Wald-
mann et al. to suggest natural product scaffolds as starting
Regarding 2 as a masked amino aldehyde, we hypothe-
sized its reaction with arylhydrazines would result in an
[1]
points in the quest to find novel bioactive compounds.
[6]
Indeed, this strategy has provided several new molecular
probes for the selective and reversible modulation of cellular
interrupted Fischer indole synthesis via intermediate 5,
which would undergo a double cyclization to afford 6 with
[
2]
[7]
functions. On the other hand, nature also provides essential
tools for the efficient synthesis of complex bioactive com-
pounds in the form of enzymes that offer unrivaled chemo-,
regio-, and stereoselectivity. For example, we recently
a cis junction of both [3.3.0] bicyclic systems (Scheme 1).
Thus, we started our investigations with the benchmark
reaction between cyclic imine 2 and phenylhydrazine (7a). To
our delight, the envisioned stereoselective interrupted Fischer
indolization proceeded smoothly in various solvents with
a range of Brønsted acids (for details, see the Supporting
Information Table S1). Optimal conversion of (Æ)-2 into the
desired tetracyclic pyrroloindoline 6a was achieved with
phenylhydrazine hydrochloride (7b) and TsOH (1.0 equiv) in
toluene with microwave heating to 1308C for 30 min. We next
explored the scope of the reaction with respect to the
[
3]
employed an engineered monoamine oxidase in an efficient
[
4]
synthesis of the hepatitis C drug telaprevir (Scheme 1). Our
success in this area prompted us to investigate the utility of
biocatalytically generated chiral building blocks such as 2 in
other cascade-type reactions by considering them as amino
aldehyde synthons.
[
3]
[8]
arylhydrazine employing (Æ)-2 (Scheme 2). Gratifyingly,
we found that various para-substituted arylhydrazines could
be converted into the corresponding pyrroloindolines 6b–g in
modest to good yield (18–73%). Electron-deficient arylhy-
drazines typically led to lower yields of product, most likely
because of slower formation of the hydrazone intermediate
and/or slower sigmatropic rearrangement. Additionally, meta-
substituted arylhydrazines could be used to obtain the
corresponding pyrroloindolines in modest to reasonable
yield (26–52%). In all cases, the 6-substituted regioisomers
6h–k were the major products, accompanied by varying
amounts of the 4-substituted isomers 6h’–k’. We recognized
that the regioselectivity is mainly governed by the steric
[
*] C. de Graaff, L. Bensch, S. J. Boersma, R. C. Cioc, M. J. van Lint,
E. Janssen, Prof. Dr. R. V. A. Orru, Dr. E. Ruijter
Department of Chemistry and Pharmaceutical Sciences and
Amsterdam Institute of Molecules
Medicines and Systems (AIMMS), VU University Amsterdam
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
E-mail: e.ruijter@vu.nl
Prof. Dr. N. J. Turner
School of Chemistry, University of Manchester and Manchester
Institute of Biotechnology
1
31 Princess Street, Manchester, M1 7DN (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507041.
Angew. Chem. Int. Ed. 2015, 54, 14133 –14136
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14133

.
Angewandte
Communications
Scheme 3. Synthesis of tricyclic tryptamine analogues 11 and
regioisomers 12. [a] Free hydrazine used (instead of the HCl salt) in
combination with TsOH (2.5 equiv). [b] Free hydrazine used; TsOH
(
3.5 equiv), 1508C, 60 min. [c] ee=99% (11a,b), 98% (11d, 12d).
Scheme 2. Synthesis of diverse pyrroloindolines 6. [a] Free hydrazine
used (instead of HCl salt) in combination with TsOH (2.0 equiv).
Determined by comparison with the racemate using HPLC on a chiral
stationary phase. [d] Presumed optically pure by detection of a single
peak by HPLC (on a chiral stationary phase) and in analogy to 11a,
[
b] (À)-2 was used. Bn=benzyl.
1
1b, and 11d. [e] (Partially) racemized as determined by detection of
properties of the meta substituents, most accurately described
[9]
two peaks by HPLC analysis (chiral stationary phase). oNs=2-nitro-
benzenesulfonyl.
as the Winstein–Holness A values. Also N -substituted
a
arylhydrazines could be used to obtain the corresponding
pyrroloindolines 6l,m in reasonable yield (51–54%). Notably,
also the pyrroloazaindoline 6n was accessible as a single
regioisomer via this route in reasonable yield. As expected,
the use of enantiopure (À)-2 (99% ee) led to the formation of
frequent structural motifs in naturally occurring alkaloids
such as the acetylcholine esterase inhibitor physostigmine
(13a; Scheme 4). Its semisynthetic derivative phenserine
(13b) advanced as far as phase III clinical trials for the
treatment of Alzheimerꢀs disease (AD). We soon realized
that our method provided rapid and efficient stereoselective
access to the novel ring-fused physostigmine/phenserine
analogue 17. As initial studies revealed that post-cascade
methylation of the aromatic NH is challenging, we opted to
6
b and 6e in excellent optical purity (99% ee). Finally, the
[12]
pentacyclic derivative 8 could be isolated and crystallized in
optically pure form after o-nosylation and its structure was
[10]
corroborated by X-ray crystallography.
During our optimization of the reaction between 2 and 7
we discovered that the yield of 6 is highly dependent on the
stoichiometry of the acid mediator. We found that, under
otherwise identical conditions, the use of 1.5 equiv of TsOH
employ an N -methylated hydrazine derivative in the cascade
a
process. We discovered that mono-N -Boc-protected N -
b
a
(
instead of 1.0 equiv) led to full conversion into a different
methylhydrazine 15 (Boc = tert-butoxycarbonyl) could be
II
product, that is, tricyclic tryptamine derivative 9, along with
its regioisomer 10 (Scheme 3). Compounds 9 and 10 were
most likely formed through a rearrangement of 6 (see below).
Under these conditions, 6 was not detected in the crude
reaction product. We soon discovered that the poorly
separable regioisomeric mixture of 9 and 10 could be
subjected to in situ o-nosylation to afford compounds 11
and 12 in a ratio of about 4:1, which were found to be readily
separable by flash chromatography (Scheme 3). This rear-
rangement proved quite general, as demonstrated for com-
pounds 11a–d/12a–d (Scheme 3). In addition to relatively
electron-rich systems (11a,b/12a,b), also the electron-defi-
cient products 11c/12c and even the heterocyclic derivatives
conveniently prepared by Cu -catalyzed addition of commer-
[13]
cial boronic acid 14 to di-tert-butyl azodicarboxylate
followed by chemoselective reduction of the N -Boc group.
a
After in situ Boc deprotection (1.0 equiv TsOH, 608C, 1 h),
the cascade reaction proceeded smoothly, in this case with
1
1d/12d were isolated after this two-step procedure in very
good yields, considering the complexity of the transformation.
Interestingly, while products 11a–d and 12d were isolated in
excellent optical purity (98–99% ee), the regioisomers 12a–c
[11]
were found to be partially or completed racemized.
With selective routes to both 6 and 9 in hand, we set out to
investigate applications of our method to the synthesis of
pharmaceutically relevant compounds. Pyrroloindolines are
Scheme 4. Synthesis of phenserine analogue 17.
1
4134 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14133 –14136

Angewandte
Chemie
1
.0 equiv of PPTS (pyridinium p-toluenesulfonate) to provide
a cleaner conversion into 16. Subsequent N-methylation,
hydrogenolysis of the benzyl ether, and carbamate formation
afforded phenserine analogue 17.
Tricyclic constrained tryptamine analogues have been
[14]
reported as potent and selective inhibitors of serotonin and
[
15]
melatonin
receptors as well as the TRPV1 (transient
[16]
receptor potential vanilloid 1) ion channel,
leading to
several conceivable therapeutic applications of this com-
pound class. Compound (Æ)-18 (Scheme 5), a constrained
analogue of the lead compound MS-245 (1-benzenesulfonyl-
3
-(2-dimethylamino)ethyl-5-methoxyindole), is a potent 5-
[14]
HT receptor inhibitor (IC = 1.5 nm).
Recently, Enders
6
50
and co-workers described the asymmetric synthesis of (R)-18
by an organocatalytic cascade reaction of 5-methoxyindole
(
20) and iodonitroalkene 21 to give 22, which could be
[17]
converted in a three-step sequence into (R)-18 (Scheme 5).
We envisioned that we could access (R)-18 in an efficient
three-step sequence using our novel cascade process. Thus,
arylhydrazine 23 was reacted with (À)-2 to give tricyclic
tryptamine derivative 24. In this case, we found the reaction
proceeded most smoothly in a one-pot, two-stage process
involving the interrupted Fischer indolization (1.0 equiv
PPTS, 1308C, 30 min) and the rearrangement (1.0 equiv
TsOH, 1308C, 30 min). The resulting tryptamine derivative
Scheme 5. Stereoselective synthesis of serotonin receptor inhibitor 18
and TRPV1 inhibitor 19.
2
4 was then converted into (R)-18 (99% ee) by N-methylation
and sulfonylation of the indole nucleus. Notably, our route
afforded (R)-18 in higher yield, with a higher ee value, and in
a more time- and step-efficient manner than the route of
Enders et al.
and protonated 6) are in dynamic equilibrium under the
reaction conditions. Only when additional strong acid is
present, intermediate D can undergo a second protonation to
[19]
bivalent cation F.
undergo a Plancher rearrangement
This highly reactive intermediate can
[
20]
Tricyclic tryptamine derivative (Æ)-19 has been reported
as a potent and selective inhibitor of the TRPV1 ion channel,
which has been implicated in the treatment of neuropathic
via either pathway c
or d, with both sterics and electronics favoring pathway c
leading to carbocationic intermediate G. Loss of two protons
finally affords 9. A similar mechanism following pathway d
[16]
pain. We envisioned the application of our cascade method
to the stereoselective synthesis of (R)-19. Indeed, the cascade
reaction of 15 and (À)-2 with in situ Boc deprotection
[
11]
produces isomer 10.
In conclusion, we have developed a cascade reaction of
arylhydrazines and chiral bicyclic imine 2 involving an
interrupted Fischer indolization. The reaction selectively
affords either tetracyclic pyrroloindolines 6 or tricyclic trypt-
amine derivatives 9 depending on the stoichiometry of the
acid mediator. Biocatalytic production of imine 2 allows
efficient control over the overall asymmetry of the reaction.
(
1.0 equiv TsOH, toluene, 608C, 1 h) followed by the
conditions developed for 24 (1.0 equiv PPTS, 1308C, 30 min,
then 1.0 equiv TsOH, 1308C, 30 min) afforded 25. Acylation
followed by hydrogenolysis of the benzyl ether then furnished
(R)-19 in 26% overall yield from 2 with 99% ee.
Based on our experimental observations we propose the
following mechanism for the switchable
cascade reaction described above
Scheme 6). As envisioned, imine 2 under-
(
goes a “transimination” reaction with the
arylhydrazine to afford hydrazone inter-
mediate A which is in tautomeric equilib-
[18]
rium with enehydrazine intermediate B.
A subsequent [3,3]-sigmatropic rearrange-
ment produces C which undergoes intra-
molecular addition of either the aromatic
(
pathway a) or aliphatic (pathway b)
amine to the iminium moiety to give
possible intermediates D and E, respec-
tively, with loss of an ammonium ion. Both
D and E may undergo a second intra-
molecular addition to give (protonated) 6.
Plausibly, the latter three species (D, E, Scheme 6. Proposed mechanism for the formation of 6, 9, and 10.
Angew. Chem. Int. Ed. 2015, 54, 14133 –14136
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14135

.
Angewandte
Communications
Medicinally relevant examples of both product classes were
produced in excellent optical purity by short reaction
sequences. These findings underline the importance of both
rational design and serendipity in the development of novel
reactions for the efficient construction of complex molecular
targets.
Hyman, S. Grimme, M. Schürmann, H. Preut, K. Hübel, S.
Ziegler, K. Kumar, H. Waldmann, Nat. Chem. Biol. 2012, 8, 179.
3] a) V. Kçhler, K. R. Bailey, A. Znabet, J. Raftery, M. Helliwell,
N. J. Turner, Angew. Chem. Int. Ed. 2010, 49, 2182; Angew.
Chem. 2010, 122, 2228. This paper also reports the preparation of
racemic imines such as (Æ)-2 by treatment of the amine with N-
chlorosuccinimide (NCS) followed by KOH.
[
[
4] a) A. Znabet, E. Ruijter, F. J. J. de Kanter, V. Kçhler, M.
Helliwell, N. J. Turner, R. V. A. Orru, Angew. Chem. Int. Ed.
2
010, 49, 5289; Angew. Chem. 2010, 122, 5417; b) A. Znabet,
Experimental Section
M. M. Polak, E. Janssen, F. J. J. de Kanter, N. J. Turner, R. V. A.
Orru, E. Ruijter, Chem. Commun. 2010, 46, 7918.
General procedure for the synthesis of pyrroloindolines 6: Hydrazine
hydrochloride 7 (0.26 mmol, 1.05 equiv) and p-toluenesulfonic acid
monohydrate (0.25 mmol, 1.0 equiv) were added to a solution of 1-
pyrroline 2 (0.25 mmol, 1.0 equiv) in toluene (0.1m). The reaction
mixture was stirred for 30 min at 1308C under microwave irradiation.
The suspension was cooled to RT, washed with saturated aqueous
Na CO /brine (3:1, 20 mL), extracted with CH Cl (2 ” 10 mL), dried
[
[
5] Consequently, indole has been referred to as “The Lord of the
Rings”: M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 2009,
4
8, 9608; Angew. Chem. 2009, 121, 9786.
6] This term was coined by Garg and co-workers; see, for example:
a) B. W. Boal, A. W. Schammel, N. K. Garg, Org. Lett. 2009, 11,
3
1
Chem. 2012, 77, 725; For an organocatalytic asymmetric
reaction, see: d) A. Martínez, M. J. Webber, S. Müller, B. List,
Angew. Chem. Int. Ed. 2013, 52, 9486; Angew. Chem. 2013, 125,
2
3
2
2
458; b) L. Zu, B. W. Boal, N. K. Garg, J. Am. Chem. Soc. 2011,
33, 8877; c) A. W. Schammel, G. Chiou, N. K. Garg, J. Org.
over Na SO , and concentrated under reduced pressure. The crude
2
4
product was purified by flash chromatography.
General procedure for the synthesis of tryptamine analogues 11
and 12: Hydrazine hydrochloride 7 (0.53 mmol, 1.05 equiv) and p-
toluenesulfonic acid monohydrate (0.75 mmol, 1.5 equiv) were added
to a solution of 1-pyrroline 2 (0.50 mmol, 1.0 equiv) in toluene (0.1m).
The reaction mixture was stirred for 30 min at 1308C under micro-
wave irradiation. The suspension was cooled to RT, dissolved in
methanol (3 mL), washed with saturated aqueous Na CO (20 mL),
9
664.
[
[
[
7] Although one chiral center of 2 is lost in the course of the
interrupted Fischer indolization, the all-cis-fused product 6 can
be considered the only energetically feasible stereoisomer.
8] The use of other readily accessible bi- and tricyclic imines did not
afford the target tetracyclic pyrroloindolines under these con-
ditions.
9] S. Winstein, N. J. Holness, J. Am. Chem. Soc. 1955, 77, 5562. For
a recent discussion of the utility of A values as descriptors of
steric size, see: K. C. Harper, E. N. Bess, M. S. Sigman, Nat.
Chem. 2012, 4, 366.
10] CCDC 1415299 (8) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
11] The observed racemization of 10a–c seems to be acid mediated
and occur only after the cascade process (see control experiment
in the Supporting Information). Plausibly, 10d does not undergo
the racemization because of the presence of the additional basic
nitrogen.
2
3
extracted with CH Cl (3 ” 15 mL), dried over Na SO , and concen-
2
2
2
4
trated under reduced pressure. The crude product was dissolved in
CH Cl (0.1m), after which Et N (1.2 equiv) and o-nosyl chloride
2
2
3
(1.2 equiv) were added. The reaction mixture was stirred for 2 h at
RT, washed with brine (20 mL), extracted with CH Cl (3 ” 15 mL),
2
2
dried over Na SO , and concentrated under reduced pressure. The
2
4
crude product was impregnated on SiO2 and purified by flash
chromatography.
[
[
Acknowledgements
We thank Dr. G. Barreca (Chemessentia S.r.L.) for a generous
gift of (À)-2, Dr. A. W. Ehlers (VU University) for assistance
with NMR spectroscopy, and S. Bouwman (VU University)
for HRMS measurements. We kindly acknowledge Dr. M.
Zeller (Youngstown State University) for collecting the X-ray
data and Dr. C. M. L. Vande Velde (University of Antwerp)
for the refinement of the X-ray structure of 8. The X-ray
diffractometer was funded by NSF Grant 1337296. M.
Hazewinkel and E. van Echten (Syncom BV) are acknowl-
edged for chiral SFC analysis of 11d. N.J.T. thanks the Royal
Society for a Wolfson Research Merit Award. This work was
financially supported by the Netherlands Organization for
Scientific Research (NWO).
[
[
12] J. Klein, Expert Opin. Invest. Drugs 2007, 16, 1087.
13] a) K. Kisseljova, O. T sˇ ubrik, R. Sillard, S. Mäeorg, U. Mäeorg,
Org. Lett. 2006, 8, 43; b) T. Uemura, N. Chatani, J. Org. Chem.
2
005, 70, 8631.
[
14] A. Nyandege, R. Kolanos, B. L. Roth, R. A. Glennon, Bioorg.
Med. Chem. Lett. 2007, 17, 1691.
[15] P. J. Garratt, S. Vonhoff, S. J. Rowe, D. Sugden, Bioorg. Med.
Chem. Lett. 1994, 4, 1559.
16] Y. Shishido, M. Jinno, T. Ikeda, F. Ito, M. Sudo, N. Makita, A.
Ohta, A. Iki-Taki, T. Ohmi, Y. Kanai, T. Tamura, M. Shimojo,
Bioorg. Med. Chem. Lett. 2008, 18, 1072.
17] C. C. J. Loh, G. Raabe, D. Enders, Chem. Eur. J. 2012, 18, 13250.
18] We realize that the alkene in intermediate B may be either E or
Z, and both may lead to a cis- or trans-substituted cyclopentane
ring in C.
[
[
[
Keywords: asymmetric synthesis · bioactive compounds ·
[
[
19] This additional protonation seems to be essential for the
formation of 9 and 10, as the use of 1.5 equiv of a weaker acid
such as PPTS led to only trace amounts of 9 and 10.
20] For a recent example of a stereospecific Plancher rearrange-
ment, see: Q.-F. Wu, C. Zheng, S.-L. You, Angew. Chem. Int. Ed.
cascade reactions · synthetic methods · tryptamines
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14133–14136
Angew. Chem. 2015, 127, 14339–14342
2
012, 51, 1680; Angew. Chem. 2012, 124, 1712.
[
[
1] S. Wetzel, R. S. Bon, K. Kumar, H. Waldmann, Angew. Chem.
Int. Ed. 2011, 50, 10800; Angew. Chem. 2011, 123, 10990.
2] For a recent example underscoring the importance of cascade
reactions, see: H. Dückert, V. Pries, V. Khedkar, S. Menninger,
H. Bruss, A. W. Bird, Z. Maliga, A. Brockmeyer, P. Janning, A.
Received: July 29, 2015
Revised: September 1, 2015
Published online: September 25, 2015
1
4136 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14133 –14136