Synthesis of functionalized pyrroloindolines: Via a visible-light-induced radical cascade reaction: Rapid synthesis of (±)-flustraminol B

Article abstract of DOI:10.1039/c8cc03575j

The development of visible-light-induced synthesis of functionalized pyrroloindolines via a radical cascade reaction is reported. The reaction shows a broad substrate scope and highlights the mild nature of the reaction conditions. A range of substitutions on indole aromatic rings and N-centers is well tolerated, including a free allylic alcohol. Relying on the strategy, a rapid synthesis of (±)-flustraminol B was achieved.

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Synthesis of Functionalized Pyrroloindolines via Visible-Light-
Induced Radical Cascade Reaction: Rapid Synthesis of (±)-
Flustraminol B
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
DOI: 10.1039/x0xx00000x
Kui Wu , Yuliu Du , Zheng Wei and Ting Wang*
www.rsc.org/
The development of visible-light-induced synthesis of induced synthesis of pyrroloindolines via an amidyl radical
functionalized pyrroloindolines via a radical cascade reaction is cyclization/carbon radical functionalization cascade.
reported. The reaction shows a broad substrate scope and
highlights a mild nature of the reaction condition. A range of
substitutions on indole aromatic rings and N-centers are well
tolerated, including a free allylic alcohol. Relying on the strategy, a
rapid synthesis of (±)-flustaminol B was achieved.
The hexahydropyrrolo[2,3-b]indole, commonly referred as the
pyrroloindoline, is a key heterocyclic motif in a wide selection
1
of alkaloids, exhibiting a broad range of biological properties,
2
such as antibacterial activities, cytotoxic activities, and the
3,4
5
inhibition of cholinesterase . Since many pyrroloindoline
natural products bear C3a quaternary centers, the structures
may be categorized by the different atomic attachments on
6
the C3a position, which could be a carbon (as in flustramine B
7
) or asperazine (
8
)), a nitrogen (as in psychotriasine (
10
(
1
2
3
) and
9
pestalazine B (
4
)) or an oxygen (as in brevianamide E
(
5
) and
12
Figure 1. Representative pyrroloindoline natural products.
1
1
flustaminol B
(
6))(Figure 1). Since the early studies of Pikl
13
and Robinson on this class of heterocyclic structures, their
synthetic challenge combined with promising pharmaceutical
values has drawn dramatic attentions in synthetic organic
communities, resulting in a variety of creative ways to prepare
In addition to a clear basis of interest in pyrroloindolines at
both synthetic and biological levels, we considered it as a
compelling target structure to exploit the reactivity of amidyl
radicals. Amidyl radicals represent a valuable class of reactive
species with potentially broad applications in the formation of
1
4,15
such heterocyclic core structures.
Recently, visible-light
1
8-20
photoredox catalysis has been leading efficient access to
C-N and synthesis of N-heterocycles.
Based on Ingold’s
1
6
heterocycles and related natural products. More specifically,
Stephenson reported a visible-light-mediated total synthesis of
pyrroloindoline alkaloid gliocladin C via a single-electron
reductive dehalogenation/intermolecular radical coupling
strategy, where the photocatalytic procedure was used on a
pioneering studies, amidyl radicals exhibited remarkably high
electrophilic character, which offered them an umpolung
reactivity that complemented the nucleophilic character of the
21
N-species in classic polar reaction modes. However, their
usefulness in organic synthesis was limited by the harsh
condition of generation, where hazardous radical initiators,
elevated temperature, or high-energy UV irradiation was
required. Recently, the generation of amidyl radicals via
visible-light photoredox catalysis and their application organic
1
7
C3a-bromopyrroloindoline
substrate.
Interested
in
developing a photocatalytic radical cascade avenue to
pyrroloindoline core structure, we herein report a visible-light-
2
2
synthesis were described by several groups. Particularly,
Leonori reported an elegant transition-metal-free generation
of amidyl radical through a photocatalytic fragmentation of
electron-poor aryloxy amides (7), and its application on
intramolecular hydroamination and intermolecular N-Arylation
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2
2e
reactions (Scheme 1a). In this article, we envision that the was optimal, generating 14 in 78% yield after 10 hours at room
indole acetic acid derived amidyl radical ( ) would first react temperature (Table 1, entries 3-7). Happily, an X-ray structure
with the indole domain via a fast 5-membered ring cyclization. was obtained, which confirmed the cyclic structure of the
The resulting nucleophilic C3a radical (II) could then couple product 14. Other organic bases (Et N, TMEDA, and DMAP)
I
3
with a radical acceptor to provide the pyrroloindoline core were also able to serve as additives in this transformation,
structure (Scheme 1b). The proposed radical process was delivering the pyrroloindoline 14 in 45%, 44% and 37% yield
confirmed by trapping the C3a radical (II) by TEMPO reagent respectively (Table 1, entries 8-10).
(
Scheme 1c). Previously, we have demonstrated that the
a
Table 1. Reaction condition optimization
benzylic carbon radical (II) could react with an electron-
deficient alkene system, introducing a carbon substituent at
O
2
3
NO2
H
C3a position. In this report, we investigated the potential C-H
and C-O functionalization of the C3a carbon radical (II
Scheme 1b).
N
O
Eosin Y (2 mol %)
O
Base, H-Atom Source
Me
N
)
N
H
Me
N
Me
Green LEDs
Me
NO
2
CH
2
Cl
2
(
12
14
15
b
Entry
Base
CO
H-atom source
1,4-cyclohexadiene
1,4-cyclohexadiene
PhSH
Yield (%)
c
1
K
2
3
0
2
3
4
5
6
7
8
9
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
0
0
BnSh
55
25
70
78
45
44
37
L-cysteine
cyclohexanethiol
t-BuSH
Et
3
N
t-BuSH
TMEDA
DMAP
t-BuSH
1
0
t-BuSH
a
Reactions irradiated with two 6 W, 520 nm light-emitting diode (LED) flood
b
c
lamps for 10 h. Isolated yield. Reaction conducted in acetone.
Encouraged by these results, we then focused on attention
on exploring the scope of the photocatalytic hydroamination.
Table 2 summarizes experiments probing various substitution
of indole backbone. We were pleased to find that indole
derivatives bearing both electron-withdrawing group and
election-donating group cyclized smoothly, providing the
corresponding pyrroloindoles in good yields (Table 2, entries 2
and 3). In addition, the procedure well accommodated C2a-
substituted indoles, affording corresponding cyclized products
in good yields (Table 2, entries 4-6).
Next, we tested the reaction by trapping the C3a radical
Scheme 1. Visible-Light-Mediated Construction of Pyrroloindoline
with
a
molecule
of
oxygen.
Pleasingly,
C3a-
hydroxypyrroloindoline 21 was afforded in 75% yield by
employing the standard reaction procedure (Eosin Y, DIPEA,
We started our studies by examining the cascade reaction
2
O , Green LEDs). We then evaluated the scope of this
between indole derivative 12 and different H-atom sources
2e
2
transformation (Scheme 2). A series of indole derivatives were
prepared and subjected to the reaction conditions. In all cases,
the reaction proceeded smoothly to furnish the corresponding
C3a-hydroxypyrroloindolines in good yields (65%-84%). These
(
Table 1). According to Leonori’s report,
organic
photocatalyst eosin Y and green light-emitting diode (LED)
irradiation were employed in the reaction condition
optimization. We started the process according to Leonori’s
hydroamination procedure, using K2CO3 as base, 1,4-
cyclohexadiene (1,4-CHD) as H-atom source, and acetone as
solvent (Table 1, entry 1). Unfortunately, no desired cyclization
product 14 was detected. Switching to the optimal
base/solvent combination in our previous reports, 1,4-CHD still
is not a suitable H-atom source for this type of cyclization. A
survey of various H-atom sources demonstrated that t-BuSH
examples (22-36) demonstrated that the catalytic system was
tolerant of alkyl substitution, halogen substitution, and alkoxy
substitution at C4, C5, C6, and C7 positions. Moreover,
different substitutions on both nitrogen centers (37-43) were
also compatible with the reaction condition. An X-ray structure
of compound 39 was obtained, confirming the
hydroxypyrroloindolines structure. More excitingly, a free
2
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allylic alcohol motif was well tolerated in the reaction Photocatalytic amidyl radical generation, intramolecular
condition, highlighting the mild nature of the reaction system. cyclization, followed by trapping the C3a radical with molecule
In addition, the reaction condition could also be applied to C2a of oxygen furnished the skeleton of the natural product in
substituted indole derivatives, providing corresponding good yield (79%, 53). Reduction of the amide 53 gave the
products (44
-
47) in good yields, 76%, 71%, 77%, and 69% natural product (±)-flustraminol B (
6
) in a total of 4 steps
respectively.
(Scheme 3).
O
a,b
Eosin Y (2 mol %)
DIPEA, O2
HO
Table 2. Hydroamination of indoles
NR
4
OAr
R1
O
R
1
R
2
N
Green LEDs
CH2Cl2
N
R3
N
R3
R
2
R
4
substitution on aromatic ring
HO
O
Ph
HO
N
HO
N
HO
N
O
O
O
c
Entry
1
Indole
Pyrroloindoline
Yield (%)
N
N
N
N
N
H
Me
H
Me
H
Me
H
Me
Et
Me
Me
Me
Me
78
68
21 75%
22
78%
23 68%
24 84%
HO
N
HO
N
HO
N
Me
O
Br
O
MeO
O
N
N
N
H
Me
H
Me
H
Me
2
3
Me
Me
Me
29. 4-Br: 72%
30. 5-Br: 73%
31. 6-Br: 80%
32. 7-Br: 83%
33. 4-OMe: 75%
2
2
2
2
5. 4-Me: 77%
6. 5-Me: 75%
7. 6-Me: 65%
8. 7-Me: 66%
34. 5-OMe: 68%
3
3
5. 6-OMe: 80%
6. 7-OMe: 83%
79
82
78
75
substitution on N-centers
HO
O
HO
N
O
HO
N
N
O
N
H
Me
N
H
Me
N
H
Me
4
5
Et
3
HO
N
8
75%
39 76%
OH 37 65%
HO
HO
N
HO
O
O
O
N
N
N
N
N
H
Me
N
H
MOM
Me
H
Ac
H
Me
TIPS
Me
Bn
4
0
70%
41 67%
4
2
81%
43 53%
C2 substituted examples
6
HO
O
HO
F
HO
N
HO
O
O
O
MeO
N
N
N
N
Me Me
N
N
Me Me
N
Me Me
Me Me
Cl
a
Me
Me
Reactions irradiated with two 6 W, 520 nm light-emitting diode (LED) flood
Me
Me
b
c
44 76%
45 71%
lamps for 10 h. Ar=2,4-(NO
2
)
2
6
-C H
3
. Isolated yield.
46 77%
47 69%
Scheme 2. Hydroxyamination of Indoles
Having established the feasibility of the visible-light
mediated radical cascade strategy, we turn to the synthesis of
1
1
marine alkoid flustraminol B. The flustramines, flustramides,
and flustraminols are a small family of marine alkaloids
6
,11,24
isolated from the Bryozoa Flusta foliacea.
Structurally,
they are a unique subgroup of the pyrroloindoline natural
products because of the incorporation of a (C6)-bromine
substituent on the indoline ring system. Early biological studies
have shown both flustramines A and B could block voltage-
activated potassium channels and exhibit skeletal and smooth
2
5
muscle relaxant properties. However, the whole alkaloid
family has not been well studied on broad biological
investigations. Given that the pyrroloindoline skeleton might
represent a valuable template for pharmaceutical studies, we
were prompted to pursue a rapid access to this class of natural
Scheme 3. Rapid synthesis of (±)-flustraminol B
A plausible mechanism for the reaction is outlined in
Scheme 4a. Although it is known that DIPEA could reductively
quench excited eosin Y (EY*), the Stern-Volmer emission
quenching experiments suggested that aryloxy-amide 12
quench EY* at a significantly higher rate (Scheme 4b).
Consequently, we propose that the EY* reduced the aryl unit
2
6
products. The synthesis of (±)-flustraminol B commenced
with N-prenylation of commercial available 6-bromoindole
acetic acid, delivering 50 in 98% yield. Amide coupling of 50
and 51 provided the desired aryloxy amide 52 in 75% yield.
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to generate 12a, which then afforded the amidyl radical 12-I
7
8
9
M. Varoglu, T. H. Corbett, F. A. Valeriote, P. Crews, J. Org.
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went through an intramolecular cyclization, affording C3a
radical (12-II). The C3a radical was then trapped by O
delivering the C3a-hydroxypyrroloindoline product (21). The
)
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.5
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i-Pr
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EY
2
1
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.5
2
530 nm LEDs
.5
1
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i-Pr
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NEt
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EY*
0
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10
15
20
25
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[
Quencher] (mM)
O
O
NO
2
NO
2
N
O
N
O
Me
Me
N
N
NO
2
Me
12
NO
2
Me
1
2a
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O
Me
O
O2
HO
N
O
N
H
N
N
N
Me
N
Me
H
Me
Me
Me
Amidyl Radical
Carbon Radical
21
1
2-I
12-II
Scheme 4. Proposed Mechanism
1
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of (±)-flustraminol B was achieved.
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Conflicts of interest
There are no conflicts to declare.
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