Construction of Indole Structure on Pyrroloindolines via AgNTf2-Mediated Amination/Cyclization Cascade: Application to Total Synthesis of (+)-Pestalazine B

Article abstract of DOI:10.1021/acs.orglett.9b01399

An N-linked indole structure was constructed on the 3a-position of pyrroloindoline derivatives via a cascade process involving silver-mediated amination of bromopyrroloindolines with 2-ethynylanilines with subsequent 5-endo-dig cyclization. In this reaction, AgNTf₂ was used as a tandem reagent, which activated the bromo group as a σ-Lewis acid and the alkyne moiety as a π-Lewis acid. Switching from the initial step to the second step was conducted by controlling the temperature. This protocol was applied to the synthesis of various pyrroloindolines, α-carboline, and furoindolines and the total synthesis of a dimeric indole alkaloid, (+)-pestalazine B.

Full text of DOI:10.1021/acs.orglett.9b01399

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of Indole Structure on Pyrroloindolines via
AgNTf2‑Mediated Amination/Cyclization Cascade: Application to
Total Synthesis of (+)-Pestalazine B
Hiroyuki Hakamata, Hirofumi Ueda, and Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: An N-linked indole structure was constructed on the 3a-position of pyrroloindoline derivatives via a cascade
process involving silver-mediated amination of bromopyrroloindolines with 2-ethynylanilines with subsequent 5-endo-dig
cyclization. In this reaction, AgNTf2 was used as a tandem reagent, which activated the bromo group as a σ-Lewis acid and the
alkyne moiety as a π-Lewis acid. Switching from the initial step to the second step was conducted by controlling the
temperature. This protocol was applied to the synthesis of various pyrroloindolines, α-carboline, and furoindolines and the total
synthesis of a dimeric indole alkaloid, (+)-pestalazine B.
lkaloids biosynthesized from tryptophan are ubiquitous in
nature. Among these, bis-indole alkaloids comprising a
pyrroloindoline skeleton and an indole segment with a C−N1′
linkage have attracted much attention because of their
structural diversity and fascinating biological activity. Several
of these compounds show potential as lead compounds in drug
discovery (Figure 1).1 For example, (+)-psychotriasine (1),
challenging. Thus, electrophilic substitution of indole prefer-
entially occurs at the C3-position (Scheme 1).5 On the other
A
Scheme 1. Reactive Site of Indole Ring
hand, nucleophilic substitution of indole with alkyl halides is
difficult owing to the low nucleophilicity of the indole
nitrogen, whose lone-pair electrons delocalize over the
aromatic system. In Rainier’s pioneering work, the C−N1′-
linked indolylpyrroloindoline motif was constructed by
reacting the indole N-anion with a cyclopropane intermediate
generated from bromopyrroloindoline (Scheme 1).6 The
substrate scope of this protocol, however, was limited due to
Figure 1. Bis-indole alkaloids containing a C−N1′ linkage.
isolated from plants of the genus Psychotria, was used in
traditional medicines in China and Malaysia,2 while
(+)-chetomin (2), which is produced by several fungi of the
genus Chaetomium, exhibited antitumor activity in multiple
myeloma by blocking the HIF pathway.3
Because of their significant biological activity, enormous
synthetic efforts have been devoted to synthesizing various bis-
indole alkaloids.4 However, constructing a pyrroloindoline-
bearing indole segment with a C−N1′ linkage has remained
Received: April 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01399
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Letter
the strongly basic conditions and requirement for an electron-
withdrawing group at the C2-position to form a cyclopropane
intermediate.7 Several other indirect strategies, for example,
stepwise construction of an indole skeleton via coupling of an
o-halo aniline derivative and subsequent indole formation,8 or
introduction of an indole precursor,9 have been reported.
However, these methods require additional steps after
introducing the indole segment by C−N bond formation. In
this paper, we describe a novel construction of a C−N1′-linked
indolylpyrroloindoline structure by AgNTf2-mediated one-pot
amination10 and an indole formation sequence. Furthermore,
the utility of this protocol was fully demonstrated by total
synthesis of a dimeric indole alkaloid, (+)-pestalazine B (3).
Our working hypothesis is shown in Scheme 2. During
synthetic studies on indole alkaloids, (+)-haplophytine,10a
with AgNTf2 in CH2Cl2 at 0 °C. After 4a was converted to 6aa
at 0 °C, the reaction temperature was raised to ambient
temperature to promote subsequent 5-endo-dig cyclization. As
expected, desired product 7aa was obtained, but the yield was
low (Table 1, entry 1). Considering the stabilization of the
Table 1. Optimization of Reaction Conditions
a
T1
(°C)
time1
(h)
T2
(°C)
time2
(h)
yield
(%)
entry solvent
additive
Scheme 2. Working Hypothesis for C−N1′-Linked
b
1
2
3
4
CH2Cl2
MeCN
MeCN
MeCN
0
0.5
3.5
4.0
5.0
rt
50
50
50
1.0
1.0
4.0
16
<9
<24
Indolylpyrroloindoline
b
0 to rt
0 to rt
0 to rt
DTBP
DTBP
MS4 Å
DTBP
MS4 Å
DTBP
MS4 Å
48
65
5
6
MeCN
MeCN
0 to rt
5.0
4.0
70
70
3.0
15
74
73
c
0 to
45
a
b
Isolated yield. Including a small amount of inseparable byproduct.
c
1.5 equiv of AgNTf2 was used.
carbocation intermediate derived from bromopyrroloindoline
4a, we changed the solvent to acetonitrile. Although the
reactivity of each step decreased, the yield of indole 7aa
improved slightly (Table 1, entry 2). After extensive
optimization, we found that addition of 2,6-di-tert-butylpyr-
idine (DTBP) as a proton scavenger was effective in
suppressing the proto-decomposition of intermediate 6aa,
and the yield of 7aa increased to 48% (Table 1, entry 3).
Eventually, conducting the reaction with a combination of
DTBP and MS4A at 70 °C was most effective, affording 7aa in
74% yield (Table 1, entry 5). Finally, the amount of AgNTf2
could be decreased to 1.5 equiv without reducing the yield
(Table 1, entry 6).
Having optimized the conditions for the AgNTf2-mediated
one-pot sequential process involving intermolecular C−N
bond formation and 5-endo-dig cyclization, we investigated the
substrate scope of bromopyrroloindolines (Figure 2). Regard-
ing protecting groups on two nitrogen atoms, various
combinations of electron-withdrawing protecting groups
provided the corresponding products in good to high yields
(Figure 2, 7aa−ga). This protocol was also applicable to the
reactions of various functionalized substrates. The reactions of
substrates 4ha and 4ia prepared from tryptophan derivatives
proceeded smoothly to give corresponding products 7ha and
7ia, respectively. Notably, this protocol complements Rainier’s
reaction6a since the former 4ha would give a mixture of
diastereomers due to epimerization of the α-position of the
ester, and the latter 4ia should not undergo introduction of an
indole nucleus since formation of the cyclopropane inter-
mediate is impossible. A substrate with a sterically demanding
methyl group on the aminal carbon uneventfully afforded
desired product 7ja. Additionally, this protocol was applied to
a highly elaborate substrate possessing a dioxopiperazine ring
to furnish 7ka in 64% yield. Furthermore, C−N1′-linked
furoindoline 7la, furoindolinone 7ma, and tetrahydro-α-
T988s,10b and amauromines,10c we established AgNTf2-
promoted Friedel−Crafts-type arylation of iodoindolenines or
bromoindolines and allylation of bromoindolines using
electron-rich aromatic compounds and allylsilanes, respec-
tively. In addition to these C−C bond formations, we observed
C−N bond formation of aniline derivatives. With this
observation and two properties of AgNTf2, i.e., high
halogenophilicity and mild π-Lewis acidity, we envisioned
the following sequential reaction. Treating a mixture of
bromopyrroloindoline and 2-ethynylaniline with AgNTf2
would promote C−N′ bond formation between aniline and
the carbocation generated from bromopyrroloindoline, and
subsequent 5-endo-dig cyclization of the 2-ethynylaniline
moiety with alkyne activation by AgNTf2 would afford the
desired C−N1′-linked indolylpyrroloindoline. If 5-endo-dig
cyclization of 2-ethynylaniline occurs faster than intermolec-
ular C−N bond formation, Friedel−Crafts-type reaction of the
indole proceeds to give the undesired byproduct, C3a−C3′-
linked indolylpyrroloindoline. Therefore, control of the relative
reaction rates of the two processes should be crucial to the
success of the sequential formation of the N-linked indole on
pyrroloindoline.
With this idea in mind, we tested the hypothesis using
tricyclic bromopyrroloindoline 4a as a model substrate. On the
basis of our procedure for arylation of bromopyrroloindoli-
nes,10d a mixture of 4a and 2-ethynylaniline 5a was treated
B
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Letter
indolylpyrroloindoline, e.g., 7ka (Figure 2), either by Michael
addition or aldol/deoxygenation.
Our synthesis began with condensation between L-
tryptophan methyl ester 8 and D-leucine derivative 9 (Scheme
3). After the indole nitrogen was protected with Boc2O, a
Scheme 3. Attempt To Construct the Upper
Dioxopiperazine Unit Based on Conjugated Addition
Strategy
Figure 2. Scope of bromopyrroloindoline, its related substrates, and
2-alkynylanilines. (a) The initial step was conducted at −15 °C.
dioxopiperazine ring was formed by removing the Cbz group
under hydrogenation to give 10. Diastereoselective bromocyc-
lization proceeded smoothly under modified Movassaghi
conditions using NBS and BF3·OEt2 to give tetracyclicbromo-
pyrroloindoline 11,15 which underwent a AgNTf2-mediated
amination/cyclization sequence with 2-ethynylaniline 5a under
the optimal conditions to afford the desired C−N1′-linked
indolylpyrroloindoline 12 on a gram scale. After the Boc group
on indoline was switched with a trifluoroacetyl group, we
attempted the proposed Michael addition to enamide 14 with
zinc chloride,16 subsequently removing the protecting groups
using hydrazine. Unexpectedly, however, the detailed spectral
carbolin-2-one derivative 7na, which possesses the main
framework of kapakahine family,11 were constructed using
this protocol.
Next, the scope of the aniline fragment was investigated
using bromopyrroloindoline 4fa (Figure 2). Anilines 5b−e
having various substituents such as methoxy, methyl, bromo,
and trifluoromethyl groups at the para-position gave
corresponding products 7fb−fe in good to excellent yields.
We found that even internal alkynes underwent the second
cyclization to furnish 2-substituted indoles. Thus, the reaction
using 2-alkynylanilines bearing n-butyl or phenyl groups at the
alkynyl terminus gave 7ff or 7fg, respectively. In particular, 2-
alkynylaniline 5h bearing an α-amino-ester unit gave an
isotryptophan derivative 7fh.12
The establishment of a novel protocol for constructing C−
N1′-linked indolylpyrroloindoline prompted us to conduct
synthetic studies on (+)-pestalazine B (3). This was isolated
from Pestalotiopsis theae by Che and co-workers in 2008.13
Because of its fascinating structure, this compound has
attracted considerable attention as a synthetic target, and
three total syntheses have been achieved.14 We envisioned that
(+)-pestalazine B (3) should be easily accessed by introducing
a dioxopiperazinyl methyl unit to the C−N1′-linked
1
data, including H NMR analysis, indicated that the product
structure was not pestalazine B (3) but product 15, which was
possibly generated by addition of the indole unit to an
acyliminium ion generated from enamide 14 and zinc chloride.
The failure of the Michael addition strategy led us to
investigate an aldol/deoxygenation strategy using imidate 1617
(Scheme 4). Since formylation of indole 12 under conven-
tional Vilsmeier−Haack conditions was also ineffective, giving
a side product due to elimination of the Boc group and
performylation on the dioxopiperazine ring, we tested a
modified formylation developed by Doi using dichloromethyl
methyl ether. Consequently, the side reactions were sup-
pressed to give the desired product 17 in 85% yield.18 The
crucial aldol reaction was then examined. An anionic species of
imidate 16 generated by treatment with LHMDS was reacted
C
DOI: 10.1021/acs.orglett.9b01399
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 4. Total Synthesis of (+)-Pestalazine B (3) via an
Aldol Reaction−Deoxygenation Strategy
ACKNOWLEDGMENTS
■
This work was supported by the Drug Discovery and Life
Science Research (BINDS) from AMED under Grant Nos.
JP18am0101100 and JSPS KAKENHI Grant Nos.
JP18H04379 in Middle Molecular Strategy, JP18H04231 in
Precisely Designed Catalysts with Customized Scaffolding, and
JP18H04642 in Hybrid Catalysis and Grants-in-aid for
Scientific Research (B) (18H02549) and (C) (17K08204).
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with aldehyde 17 in the presence of DMPU. The desired aldol
was obtained as a mixture of diastereomers, which was
subjected to the Barton−McCombie protocol to furnish
deoxygenated product. Finally, a Boc and two ethyl groups
were removed under Lewis acidic conditions to achieve the
total synthesis of (+)-pestalazine B (3). All of the spectral data
were identical with those reported in de Lera’s total synthesis,
unambiguous supporting de Lera’s structural revision.14a
In summary, we have developed a novel AgNTf2-mediated
amination/cyclization cascade for constructing an N-linked
indole segment at the 3a-position of pyrroloindolines. This
cascade process is a novel entry of a Ag salt mediated tandem
reaction, in which AgNTf2 plays a dual role: activation of a
bromo group and an alkyne moiety. Owing to the mildness of
the Ag salt mediated activation, the established reaction
conditions displayed high functional group compatibility. The
utility of our process for synthesizing bis-indole alkaloids was
fully demonstrated by the total synthesis of (+)-pestalazine B.
In view of the general applicability of this protocol to
constructing a broad range of scaffolds such as pyrroloindo-
lines, furoindolines, and tetrahydro-α-carboline, this modular
synthetic strategy integrating three building blocks, involving
bromopyrroloindoline, alkynylanilines, and an imidate unit,
should pave the way to accessing various natural and synthetic
dimeric indole compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01399.
Experimental details and procedures, compound char-
acterization data, and copies of 1H and 13C NMR spectra
for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tokuyama@m.tohoku.ac.jp.
ORCID
(10) (a) Satoh, H.; Ojima, K.; Ueda, H.; Tokuyama, H. Angew.
Chem., Int. Ed. 2016, 55, 15157−15161. (b) Sato, S.; Hirayama, A.;
Ueda, H.; Tokuyama, H. Asian J. Org. Chem. 2017, 6, 54−58.
(c) Hakamata, H.; Sato, S.; Ueda, H.; Tokuyama, H. Org. Lett. 2017,
19, 5308−5311. (d) Sato, S.; Hirayama, A.; Adachi, T.; Kawauchi, D.;
Ueda, H.; Tokuyama, H. Heterocycles 2017, 94, 1940−1957.
Hidetoshi Tokuyama: 0000-0002-6519-7727
Notes
The authors declare no competing financial interest.
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