Dehydrative Mannich-Type Reaction for the Synthesis of Azepinobisindole Alkaloid Iheyamine A

Article abstract of DOI:10.1021/acs.orglett.8b00330

A concise synthesis of the azepinobisindole alkaloid iheyamine A from an indole-2,3-epoxide equivalent has been achieved. This method features a formal C3 electrophilic reaction of an indole-2,3-epoxide equivalent with tryptamine to form a 3-aminoindoline and a novel In-catalyzed dehydrative Mannich-type reaction of the hemiaminal to give the azepinobisindole core.

Full text of DOI:10.1021/acs.orglett.8b00330

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dehydrative Mannich-Type Reaction for the Synthesis of
Azepinobisindole Alkaloid Iheyamine A
Takumi Abe* and Koji Yamada*
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 0610293, Japan
S
* Supporting Information
ABSTRACT: A concise synthesis of the azepinobisindole
alkaloid iheyamine A from an indole-2,3-epoxide equivalent
has been achieved. This method features a formal C3
electrophilic reaction of an indole-2,3-epoxide equivalent with
tryptamine to form a 3-aminoindoline and a novel In-catalyzed
dehydrative Mannich-type reaction of the hemiaminal to give
the azepinobisindole core.
heyamines A (1) and B were isolated from a colonial ascidian
Polycitorella sp. by Higa and co-workers in 1999 (Figure 1),1
Scheme 1. Mannich Reaction of Indoles with Nucleophiles
I
Figure 1. Azepinobisindole alkaloids iheyamines A (1) and B.
and their structure consists of a central azepane ring between two
indole rings. These alkaloids have attracted considerable interest
because of their intriguing structural features and cytotoxity
against tumor cells.2 The first elegant total synthesis of
iheyamines A (1) was accomplished by Sperry and co-workers
in 2016 via intermolecular cross-Mannich reaction between 5-
methoxy-3-acetoxyindole and tryptamine to afford 2,2′-bisin-
dole.3 Recently, Sperry also reported the related synthetic studies
toward iheyamine A, in which intramolecular Mannich
cyclization occurred at the C4 position of 5-methoxyindole not
the C2 position.4
The Mannich reaction of indoles with nucleophiles is a
powerful tool to construct C−C bonds at the C2 position of
indoles (Scheme 1).5 However, only indoles, in which the
enamine form is predominant over the required iminium form,
was deployed in previous studies (Scheme 1a). Thus, the
reaction of alternative, more reactive imine equivalents is highly
desirable to introduce various nucleophiles at the C2 position of
the indoles. We speculated that hemiaminals could be used in
Mannich reactions as imine equivalents via dehydration.
However, to date, Mannnich-type cyclizations of indole rings
at the hemiaminal moiety have not yet been explored because of
their instability.6 As a part of our interest in the total synthesis of
azepinoindole alkaloids by the C4 Pictet−Spengler reaction of
serotonins7a or tryptophans,7b,c we next set out to synthesize 1 by
an intramolecular dehydrative Mannich-type cyclization of
hemiaminals (Scheme 1b). We recognized the potential utility
of bench-stable and weighable-in-air indole-containing hemi-
aminals as C2 electrophiles to react with various nucleophiles via
dehydration and Mannich-type reaction. In connection with our
work on the total synthesis of indole alkaloids,8 we have
Received: January 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00330
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
previously described the use of a novel indole-2,3-epoxide
equivalent, namely, 2-hydroxyindoline-3-triethylammonium bro-
mide (HITAB), as a convenient reagent for formal C3
electrophilic reactions of indoles with nucleophiles.9 In addition,
we found that the hemiaminals derived from HITAB are isolable.
Hence, we envisioned that HITAB could be used as the starting
material for the synthesis of 1. Herein, we report a concise
synthesis of iheyamine A by the intramolecular dehydrative
Mannich-type reaction of the corresponding hemiaminal.
According to our retrosynthetic analysis of 1 (Scheme 2), 3-
amino-2-hydroxyindoline 5b was envisioned to arise from MeO-
1). Initially, 5a, used as a model substrate, was refluxed in MeCN
(entry 1). However, under these conditions, the desired product
a
Table 1. Dehydrative Mannich-Type Reaction of 5a
Scheme 2. Retrosynthesis of Iheyamine A (1)
b
yield (%)
entry
Lewis acids (X equiv)
6a
7a
8a
1
2
0
10
13
15
20
37
59
52
28
60
59
0
0
3
0
10
8
ZnI2 (1)
3
ZnCl2 (1)
4
4
ZnBr2 (1)
0
13
11
0
5
Zn(OTf)2 (1)
Cu(OTf)2 (1)
Yb(OTf)3 (1)
La(OTf)3 (1)
FeCl3 (1)
4
6
13
24
17
24
1
7
0
8
5
9
0
10
11
12
13
14
15
16
17
18
In(OTf)3 (1)
In(OTf)3 (0.5)
In(acac)3 (0.5)
InF·3H2O (0.5)
InBr3 (0.5)
3
6
0
HITAB (2b), which is an equivalent of indole-2,3-epoxide 4, and
tryptamine 3 by C3 electrophilic reaction. Intramolecular
dehydrative Mannich-type reaction of 5b would afford
azepinoindole 6b, which would be easily transformed into
iheyamine A (1) by deprotection and oxidation.
0
0
0
0
0
57
60
61
51
31
26
23
26
12
0
0
InCl3 (0.5)
0
InCl3·4H2O (0.5)
InCl3·4H2O (0.3)
InCl3·4H2O (0.1)
0
Our investigation began with the synthesis of 3-amino-2-
10
5
hydroxyindoline 5 (Scheme 3). HITAB (2a),9 5-MeO-HITAB
a
b
6a (0.2 mmol), Lewis acid (X equiv), solvent (4 mL). Isolated
Scheme 3. Synthesis of 5 from 2
yields.
6a was not obtained. When the reaction was performed in the
presence of ZnI2 as Lewis acid, 6a was obtained in 10% yield
along with byproducts 7a and 8a (entry 2). The Ciamician−
Plancher rearrangement is known to give 2,3-disubstituted
indoles from 3,3-disubstituted indolenines via 1,2-migration.10 In
our cases, the Ciamician−Plancher rearrangement formed spiro
compound 8a along with small amounts of the desired 6a.
Although 6a was obtained in low yield, this result showed the
feasibility of our strategy. A variety of zinc complexes were
screened, but no improvement was observed (entries 3−5). To
our delight, the use of Yb(OTf)3 or In(OTf)3 dramatically
increased the yield of 6a (entries 6−10).11 Interestingly, the
dehydrative Mannich-type reaction was found to proceed also
with a catalytic amount of the indium complex (entries 11).
Because of the high cost of Yb(OTf)3 and In(OTf)3, other Lewis
acids were investigated (entries 12−16), and the best results
(61% yield) were achieved using InCl3·4H2O (0.5 equiv) (Table
1, entry 16). It is noteworthy that the dehydrative Mannich-type
reaction could be performed in the presence of water and under
air atmosphere. Decreasing the catalyst loading below 50 mol %
resulted in significantly lower yields (entries 16−18). To the best
of our knowledge, this is the first example of an indium-catalyzed
(2b), and 5-Cl-HITAB (2c) were prepared from commercially
available indoles in one-pot, gram quantity and without column
chromatography purification. A C3 electrophilic reaction of 2a−
c with tryptamines 3a−c afforded 5a−i via indole-2,3-epoxide
4a−c in 87−96% yields with trans selectivity.
With 5 in hand, we tested the feasibility of the key dehydrative
Mannich-type reaction to form the azepinobisindole core (Table
B
DOI: 10.1021/acs.orglett.8b00330
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Letter
intramolecular Mannich-type reaction of a hemiaminal with
release of water.6
With the optimized conditions in hand, we then explored the
substrate scope of the reaction. As shown in Scheme 4,
However, no desired product 6a was obtained under all
conditions. Given the difficulties reported in the pioneering
study by Sperry and co-workers,4 it was not surprising that the
intramolecular Mannich reaction of indoles to form 2,2′-
bisindoles was challenging. Thus, it is noteworthy that the
hemiaminal 5a was highly suitable as a pivotal intermediate in the
construction of 2,2′-bisindoles containing an azepane ring.
Our synthesis of 1 commenced with 6a (Scheme 6). Upon
treatment with H2/Pd−C in AcOH/AcOEt, deprotection of the
a,b
Scheme 4. Substrate Scope
Scheme 6. Completion of the Synthesis of Iheyamine A (1)
benzyl group of 6a was achieved, affording 9 in 98% yield. The
reaction of 9 with sodium amalgam gave the detosylated
compound 10 in 69% yield. Finally, DDQ oxidation of 10
afforded iheyamine A (1) in 89% yield. The identity of synthetic
1 was confirmed by comparison of the spectral data with those of
the natural product.1,3
In conclusion, a concise synthesis of azepinobisindole alkaloid
iheyamine A was achieved by a formal C3 electrophilic reaction
of HITAB with tryptamine and an indium-mediated dehydrative
Mannich-type reaction of a hemiaminal. A key feature of our
strategy is the use of stable hemiaminals for the construction of
2,2′-bisindoles containing an azepane ring. As previous studies of
the Mannich reaction are limited to indoles,4,5 the reaction
developed herein represents a significant advance in synthetic
chemistry. The hemiaminals in this route could potentially be
used to synthesize other related azepinobisindole alkaloids, such
as iheyamine B1 and trigonolimine C.12 The total synthesis of
these alkaloids by dehydrative Mannich-type reaction of
hemiaminals is currently being investigated in our laboratory.
a
b
5 (0.2 mmol), InCl3·4H2O (0.1 mmol), MeCN (4 mL). Isolated
c
yields. 5 (1 mmol), InCl3·4H2O (0.5 mmol), MeCN (20 mL).
tryptamine derivatives 5a−f reacted smoothly to produce
azepinoindoles 6a−f in 32−61% yields. Notably, the dehydrative
Mannich-type reaction was also amenable to scale up (5b, 1
mmol). Further investigations showed that serotonin derivatives
5g−i could also be employed, affording 6g−i in 43−71% yields.
Because straightforward methods to access these azepinoindoles
are limited to intermolecular 2,2′-bisindole synthesis,2−4 the
present protocol is of great synthetic significance.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00330.
For comparison, intramolecular Mannich reactions of indole
7a were carried out in the presence of various acids (Scheme 5).
Synthesis procedures and spectral and characterization
data, including 1H and 13C NMR spectra (PDF)
Scheme 5. Attempted Synthesis of 6a from 7a
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: abe-t@hoku-iryo-u.ac.jp.
*E-mail: kyamada@hoku-iryo-u.ac.jp.
ORCID
Takumi Abe: 0000-0003-1729-1097
C
DOI: 10.1021/acs.orglett.8b00330
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Rescek, D.; Oyola-Cintron, Y. Tetrahedron Lett. 2010, 51, 4303. (f) Loh,
C. C. J.; Raabe, G.; Enders, D. Chem. - Eur. J. 2012, 18, 13250.
(11) (a) Frost, C. G.; Hartley, J. P. Mini-Rev. Org. Chem. 2004, 1, 1.
(b) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int. Ed.
2004, 43, 1414. (c) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int.
Ed. 2006, 45, 793. (d) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.;
Takemoto, Y. J. Org. Chem. 2007, 72, 4462. (e) Yanada, R.; Hashimoto,
K.; Tokizane, R.; Miwa, Y.; Minami, H.; Yanada, K.; Ishikura, M.;
Takemoto, Y. J. Org. Chem. 2008, 73, 5135. (f) Yanai, H.; Oguchi, T.;
Taguchi, T. J. Org. Chem. 2009, 74, 3927. (g) Kuninobu, Y.; Tatsuzaki,
T.; Matsuki, T.; Takai, K. J. Org. Chem. 2011, 76, 7005.
(12) (a) Tan, C.-J.; Di, Y.-T.; Wang, Y.-H.; Zhang, Y.; Si, Y.-K.; Zhang,
Q.; Gao, S.; Hu, X.-J.; Fang, X.; Li, S.-F.; Hao, X.-J. Org. Lett. 2010, 12,
2370. (b) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133,
10050 . For a report of total synthesis of (−)-trigonolimine C and
stereochemical revision, see:. (c) Han, S.; Movassaghi, M. J. Am. Chem.
Soc. 2011, 133, 10768. (d) Reddy, N. B.; Ramana, C. V. Chem. Commun.
2013, 49, 9767.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by JSPS KAKENHI Grant
No. 16K18849 (T.A.) for Grant-in-Aid for Young Scientists (B).
■
REFERENCES
■
(1) Sasaki, T.; Ohtani, I. I.; Tanaka, J.; Higa, T. Tetrahedron Lett. 1999,
40, 303.
(2) Bremner, J. B.; Sengpracha, W.; Skelton, B. W. Synth. Commun.
2008, 38, 1931.
(3) Lindsay, A. C.; Leung, I. K. H.; Sperry, J. Org. Lett. 2016, 18, 5404.
(4) Lindsay, A. C.; Sperry, J. Tetrahedron 2017, 73, 4355.
(5) For selected examples of the Mannich-type reaction of indoles, see:
(a) Smith, G. F.; Walters, A. E. J. Chem. Soc. 1961, 940. (b) Bergman, J.;
Koch, E.; Pelcman, B. Tetrahedron Lett. 1995, 36, 3945. (c) Gilbert, E. J.;
Van Vranken, D. L. J. Am. Chem. Soc. 1996, 118, 5500. (d) Chisholm, J.
D.; Van Vranken, D. J. Org. Chem. 2000, 65, 7541. (e) Bergman, J.; Koch,
E.; Pelcman, B. J. Chem. Soc., Perkin Trans. 2000, 1, 2609. (f) Hao, X.;
Liu, S. Tetrahedron Lett. 2011, 52, 5640. (g) Xu, M.; An, R.; Huang, T.;
Hao, X.; Liu, S. Tetrahedron Lett. 2016, 57, 1247. For selected examples
of the C2 functionalization of indoles, see: (h) Morimoto, N.; Morioku,
K.; Suzuki, H.; Takeuchi, Y.; Nishina, Y. Org. Lett. 2016, 18, 2020.
(i) Nandi, R. K.; Ratsch, F.; Beaud, R.; Guillot, R.; Kouklovsky, C.;
Vincent, G. Chem. Commun. 2016, 52, 5328. (j) Nowrouzi, F.; Batey, R.
A. Angew. Chem., Int. Ed. 2013, 52, 892. (k) Alam, R.; Diner, C.; Jonker,
́
S.; Eriksson, L.; Szabo, K. J. Angew. Chem., Int. Ed. 2016, 55, 14417.
(6) For selected examples of the dehydrated Mannich-type reaction of
hemiaminals, see: (a) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org.
Chem. 1995, 60, 717. (b) Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M.
Org. Lett. 2004, 6, 1469. (c) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (d) Lesma, G.;
Colombo, A.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 590.
(e) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132,
5030. (f) Shi, S.; Wei, X.; Shimizu, Y.; Kanai, M. J. Am. Chem. Soc. 2012,
134, 17019. (g) Koley, D.; Srinivas, K.; Krishna, Y.; Gupta, A. RSC Adv.
2014, 4, 3934. (h) Koley, D.; Krishna, Y.; Srinivas, K.; Khan, A. A.; Kant,
R. Angew. Chem., Int. Ed. 2014, 53, 13196. (i) Zhang, S.; Li, L.; Hu, Y.; Li,
Y.; Yang, Y.; Zha, Z.; Wang, Z. Org. Lett. 2015, 17, 5036. (j) Srinivas, K.;
Singh, N.; Das, D.; Koley, D. Org. Lett. 2017, 19, 274. For reviews of
reactions with hemiaminals, see: (k) Huang, Y.-Y.; Cai, C.; Yang, X.; Lv,
Z.-C.; Schneider, U. ACS Catal. 2016, 6, 5747. (l) Wu, P.; Nielsen, T. E.
Chem. Rev. 2017, 117, 7811.
(7) (a) Yamada, K.; Namerikawa, Y.; Haruyama, T.; Miwa, Y.; Yanada,
R.; Ishikura, M. Eur. J. Org. Chem. 2009, 2009, 5752. (b) Yamada, K.;
Yamaguchi, S.; Hatae, N.; Abe, T.; Iwamura, T.; Ishikura, M. Heterocycles
2011, 83, 815. (c) Abe, T.; Yamada, K. J. Nat. Prod. 2017, 80, 241.
(d) Abe, T.; Haruyama, T.; Yamada, K. Synthesis 2017, 49, 4141.
(8) (a) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13,
3356. (b) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem.
2012, 2012, 5018. (c) Abe, T.; Nakamura, S.; Yanada, R.; Choshi, T.;
Hibino, S.; Ishikura, M. Org. Lett. 2013, 15, 3622. (d) Abe, T.; Itoh, T.;
Choshi, T.; Hibino, S.; Ishikura, M. Tetrahedron Lett. 2014, 55, 5268.
(e) Itoh, T.; Abe, T.; Choshi, T.; Nishiyama, T.; Yanada, R.; Ishikura, M.
Eur. J. Org. Chem. 2016, 2016, 2290. (f) Abe, T.; Yamada, K. Org. Lett.
2016, 18, 6504. (g) Itoh, T.; Abe, T.; Choshi, T.; Ishikura, M.
Heterocycles 2016, 92, 1132. (h) Itoh, T.; Abe, T.; Choshi, T.; Nishiyama,
T.; Ishikura, M. Heterocycles 2017, 95, 507. (i) Abe, T.; Takahashi, U.;
Matsubara, Y.; Yamada, K. Org. Chem. Front. 2017, 4, 2124. (j) Abe, T.;
Kida, K.; Yamada, K. Chem. Commun. 2017, 53, 4362.
(9) Abe, T.; Suzuki, T.; Anada, M.; Matsunaga, S.; Yamada, K. Org. Lett.
2017, 19, 4275.
(10) For pioneering reports of the Ciamician−Plancher rearrange-
ment, see: (a) Ciamician, G.; Plancher, G. Ber. Dtsch. Chem. Ges. 1896,
29, 2475. (b) Plancher, G. Gazz. Chim. Ital. 1898, 28, 374. (c) Plancher,
G. Atti. Accad. Lincei. 1900, 9, 115. (d) Boyd-Barrett, H. S. J. Chem. Soc.
1932, 321 . For recent examples, see:. (e) Eisenbeis, S. A.; Phillips, J. R.;
D
DOI: 10.1021/acs.orglett.8b00330
Org. Lett. XXXX, XXX, XXX−XXX