Eight-Step Total Synthesis of Phalarine by Bioinspired Oxidative Coupling of Indole and Phenol

Article abstract of DOI:10.1002/anie.201900199

We report for the first time that the benzofuro[3,2-b]indoline framework could be obtained by PIDA-mediated direct oxidative coupling of 2,3-disubstituted-indoles with phenols. Application of this chemistry allows for an eight-step total synthesis of phal

Full text of DOI:10.1002/anie.201900199

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Accepted Article
Title: Eight-Step Total Synthesis of Phalarine via Bioinspired Oxidative
Coupling of Indole and Phenol
Authors: Yanxing Jia, Lei Li, Kuo Yuan, and Qianlan Jia
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10.1002/anie.201900199
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Eight-Step Total Synthesis of Phalarine via Bioinspired Oxidative
Coupling of Indole and Phenol
Lei Li, Kuo Yuan, Qianlan Jia, and Yanxing Jia*
Abstract: We report for the first time that the benzofuro[3,2-b]indoline
framework could be obtained via PIDA-mediated direct oxidative
coupling of 2,3-disubstituted-indoles with phenols. Application of this
chemistry allows for an eight-step total synthesis of phalarine from
commercially available tryptamine.
Compared with these reported strategies, the direct oxidative
coupling of 2 and 3 in a biomimetic manner would be a more
straightforward approach to access phalarine. However, it proved
to be highly challenging because the 3-position of indole is the
most reactive site for electrophilic substitution, direct oxidative
coupling of indoles and phenols produced predominantly the
unwanted benzofuro[2,3-b]indolines.[4a,8-14] In 2006, the group of
Danishefsky initially explored oxidative coupling of 4 and phenol
5 as the relevant models to simulate such biogenesis. However,
only the undesired benzofuro[2,3-b]indoline 6 was obtained
(Scheme 2a). [4a]
During the course of an agronomic investigation of the suitability
of introducing Phalaris coerulescens (blue canary grass) into
Australia, Colegate and co-workers isolated and identified a novel
furanobisindole alkaloid, named phalarine (1) (Scheme 1).[1]
Structurally, 1 possesses an unprecedented benzofuro[3,2-
b]indoline moiety, which has not been found in any other natural
product. However, its regioisomeric benzofuro[2,3-b]indoline
moiety is found in natural products such as diazonamide A[2] and
azonazine.[3] Biogenetically, 1 is postulated to arise from the direct
oxidative coupling of N-Me-tetrahydro-β-carboline (2) with 5-
hydroxy-7-methoxygramine (3) since 2 has been previously
isolated from Phalaris coerulescens.[1]
Scheme 2. a) Danishefsky's initial attempts toward the synthesis of phalarine;
b) Vincent and Lei's synthesis of benzofuro[3,2-b]indoles by directly oxidative
coupling of indoles and phenols; c) Vincent and Lei's oxidative coupling of
phenol with 2,3-disubstitued indole.
Scheme 1. Structure and biogenetic synthesis of phalarine.
The intricate molecular architecture of 1 makes it an attractive
target for synthetic chemists.[4-7] In 2007, the group of Danishefsky
achieved the first total synthesis of racemic phalarine by using a
novel 1,2-rearrangement of azaspiroindolenine to construct the
benzofuro[3,2-b]indoline architecture.[4b,c] In 2010, they further
accomplished the asymmetric synthesis of (-)-phalarine from L-
tryptophan and assigned its absolute configuration.[4d] In 2011,
Chen’s group achieved the formal asymmetric synthesis of
phalarine by employing a hypervalent iodine mediated oxidative
double cyclization to form benzofuro[3,2-b]indoline core.[5]
Notably, the group of Vincent reported the first access to the
benzofuro[3,2-b]indolines in 2014, by the direct oxidative coupling
of 3-substituted N-Ac-indoles and phenols in the presence of DDQ
and FeCl3, in which the Ac protecting group played a crucial role
in reversing the regioselectivity (Scheme 2b).[15] In 2017, Lei and
co-workers achieved the same transformation by using
electricity.[16] Unfortunately, the regioselectivity was reversed with
the use of 2,3-disubstituted N-Ac-indoles (Scheme 2c).[15,16] The
desired benzofuro[3,2-b]indoline was obtained in 25% yield when
2 equiv. of ZnCl2 was added under electrolytic conditions.[16]
As discussed above, the key step to streamline the total
synthesis of phalarine is to prepare the desired benzofuro[3,2-
b]indoline framework via direct oxidative coupling of 2,3-
disubstituted indole and phenol. Inspired by the roles of Directed
Metalation Groups (DMG) in controlling C2 and C7
regioselectivity during indole functionalization, changing the size
of DMGs may lead to the control of C=O bond orientation, due to
the different steric demand.[17] Taking PIDA-mediated oxidative
coupling of N-protected tetrahydrocarbazole with phenol as an
[a]
L. Li, K. Yuan, Q. Jia, and Prof. Y. Jia
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences,
Peking University,
Xue Yuan Rd. 38, Beijing 100191, China
E-mail: yxjia@bjmu.edu.cn
[b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201900199
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example, we envisioned that the high steric demand of indole N-
protecting groups may lead to larger dihedral angle between the
plane of tetrahydrocarbazole and R-C=O in intermediate A, which
would result in steric and/or electrostatic repulsion for other
attacking groups (Scheme 3).[18] Since the size of the carbonyl
group is evidently smaller than the R group, the electrophilic
intermediate B, formed by ligand exchange between phenol and
PIDA, has to approach A in the direction of the carbonyl group.
Two possible transition states (TS), TS-1 and TS-2, could be
considered to lead to two regioisomeric adducts benzofuro[3,2-
b]indoline and benzofuro[2,3-b]indoline, respectively. As the
bulkiness of R group is increased, the dihedral angle would be
enlarged. Thus, the repulsion between carbonyl group and
iodanyl group would be enhanced in TS-2, the less hindered TS-
1 should be favored, allowing the formation of predominantly the
desired benzofuro[3,2-b]indoline. Herein, we have achieved the
reversal of regioselectivity in the oxidative coupling of indoles with
phenols to access the benzofuro[3,2-b]indolines. By utilizing this
method, the concise synthesis of phalarine was realized.
effect on both the regioselectivity and yield. The Cl3CO-protected
substrate 7b did not give any coupling products (Table 1, entry 2).
Gratifyingly, the other substrates with carbonyl groups (7c-7e) all
provided the coupling products in good to excellent yields (Table
1, entries 3-5), in which 7c and 7d slightly favoured the formation
of the desired benzofuro[3,2-b]indolines 9c and 9d, respectively,
and Bz-protected 7c provided the desired 9c with the highest yield.
The Ts-protected substrate 7f, similar to 7a, gave the undesired
10f as the major product (Table 1, entry 6). Surprisingly, the Cbz-
protected substrate 7g gave the undesired 10g as the sole
product (Table 1, entry 7). Encouraged by these promising results,
the tetrahydrocarbazoles protected by benzoyl groups with
different electronic properties (7h-k) were further prepared and
examined (Table 1, entries 8-11). However, all of them (7h-k)
gave similar regioselectivity to that of 7c. The 1-naphthoyl and 2-
naphthoyl-protected 7l and 7m were also evaluated, which gave
similar regioselectivity and yield with that of 7c (Table 1, entries
12-13). Thus, we have accomplished a regioselective oxidative
coupling between 2,3-substituted indoles and phenols favouring
the formation of the benzofuro[3,2-b]indolines.
Table 1: Screening of Protecting Groups.[a]
Entry
Compound
R
Yield[b]
Ratio of 9:10
1
2
7a
7b
7c
7d
7e
7f
Ac
Cl3CCO
Bz
97%
0
1:6.5
-
3
98%
53%
82%
69%
45%
86%
87%
95%
86%
97%
97%
1:0.9
1:0.8
1:1
Scheme 3. Our strategy to reverse the regioselectivity.
4
Piv
5
acryloyl
Ts
To explore the planned synthetic strategy, the key oxidative
coupling between indoles and phenols for the synthesis of
benzofuro[3,2-b]indolines was investigated first. Since Vincent
reported that oxidative coupling of 7a and 8a with FeCl3 and DDQ
provided 9a and 10a in only 4% and 27% yield, respectively
(Scheme 2c),[15] we firstly optimized the oxidation conditions to
increase the yields of 9a and 10a by using 7a and 8a as model
substrates (for the detailed information see SI). We were
delighted to find that the desired 9a and 10a could be obtained in
97% with a ratio of 1 to 6.5 under the optimal reaction conditions
(PIDA in the presence of HBF4 in HFIP at RT) (Table 1, entry 1).
In fact, the formation of undesired benzofuro[2,3-b]indoline 10a
as the major product in 84% yield is very interesting because very
few intermolecular oxidative couplings between indoles and
phenol leading to benzofuro[2,3-b]indolines are known.[9,11,12] The
steric and electronic effects of different nitrogen protecting groups
(the carbonyl, sulfonyl, and alkoxycarbonyl) were subsequently
examined.[19] Therefore, tetrahydrocarbazole with different
nitrogen protecting groups were prepared and subjected to react
with p-methoxyphenol (8a) under the optimized condition (Table
1). As anticipated, the nitrogen protecting groups had significant
6
1:3.1
0:1
7
7g
7h
7i
Cbz
8
p-Br-Bz
p-NO2-Bz
p-MeO-Bz
o-Me-Bz
1-naphthoyl
2-naphthoyl
1:0.9
1:0.9
1:1
9
10
11
12
13
7j
7k
7l
1:1.1
1:0.9
1:0.9
7m
[a] Reaction conditions: 7 (0.1 mmol), 8a (0.15 mmol), PIDA (0.15 mmol),
HBF4 (0.02 mmol), HFIP (1 mL), RT, 1 min. [b] Isolated yield was given.
After obtaining the optimized reaction conditions and suitable
protecting group of indole, the scope of this reaction was
examined with respect to the phenols and indoles (Table 2). A
diverse set of phenols are suitable reaction partners (9n-9w,
Table 2). Unexpectedly, all of them gave better regioselectivity
than that of p-methoxyphenol (8a), in which the p-phenoxyphenol,
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phenol and p-NHTFA-phenol gave the corresponding 9p, 9q and
9w as the sole products, respectively. The indoles fused with five
and seven-membered rings as well as with different substituents
at C2/C3/C5 were then examined. Most of them favoured the
formation of the desired benzofuro[3,2-b]indolines (9x-9ab and
9ae, Table 2). However, 5-substituted tetrahydrocarbazole, 2,3-
dimethylindole, and indole gave the undesired regioisomers as
major products (10ac, 10ad, 10af, and 10ag, Table 2). Most
notably, tetrahydro--carboline could be used as the reaction
partner, providing the desired 9ah and 9ai (confirmed by X-ray
crystallography)[20] as major products. Overall, the substituents on
both phenols and indoles also have the effects on the
regioselectivity. Although we could not fully understand how other
factors affect the regioselecivity, these results indicated the
complexity of the mechanism of this unusual reaction.
on the regioselectivity, the oxidative coupling of the Ac-protected
substrate 7a with p-NHAc-phenol and p-NHTs-phenol were
performed (Scheme 4). They afforded the undesired 10aj and
10ak as the major products, respectively. All our results and the
previous reports[15,16] clearly indicated that the N-protecting group
significantly affected the regioselectivity.
Table 2: Substrate scope of the oxidative coupling.[a,b]
Scheme 5. Retrosynthetic analysis of phalarine.
Having solved the regioselectivity of direct oxidative coupling of
indoles and phenols, we turned our attention to the total synthesis
of 1. We envisaged that 1 could be generated from pentacycle 19
by a sequence of indole formation and Mannich-type nucleophilic
reaction (Scheme 5). The pentacycle 19 could be rapidly
accessed by oxidative coupling of Bz-protected carboline 18 with
the known 3-bromo-5-methoxy-4-nitrophenol 20.[21] Carboline 18
could be prepared by Bz-protection of the known 4,[4] which was
readily prepared from commercially available tryptamine in two
steps.
[a] Reaction conditions: 7a or 11-18 (0.1 mmol), 8 (0.15 mmol), PIDA (0.15
mmol), HBF4 (0.02 mmol), HFIP (1 mL), RT, 1 min. [b] Isolated yield was given.
[c] n.d.: not detected.
Scheme 6. Total synthesis of phalarine.
Scheme 4. Reaction of 7a with p-NHAc-phenol and p-NHTs-phenol.
We then commenced the total synthesis of phalarine (Scheme
6). The known carboline 4 was prepared in 80% overall yield from
commercially available tryptamine (21) following a reported
procedure.[4] Protection of 4 with Bz group provided 18 in 95%
yield. With 18 and 20 in hand, the key oxidative coupling reaction
was performed under the optimized condition. The reaction
As observed above, oxidative coupling of 7c and different
phenols gave the corresponding 9 and 10 with different ratios (9c
and 9n-9w, Table 2). To further verify that either the N-protecting
group or the electronic nature of phenols has a significant effect
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Tomakinian, R. Guillot, C. Kouklovsky, G. Vincent, Chem. Comm. 2016,
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proceeded smoothly to provide the desired benzofuroindoline 19
as the sole product. Attempts to introduce the two carbon-unit for
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and removal of Bz in 23 with LiAlH4 led to the decomposition of
o
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oC. After considerable experimentation, we were pleased to find
that Red-Al was the best choice and the desired product 24 was
obtained in 68% yield.[24] Finally, reaction of 24 with N,N-
dimethylmethylene iminium chloride in the presence of AcOH
provided 1 in 68% yield.[25] The physical data of our synthesized
phalarine (1) are identical to those reported in the literature.[1,4c]
Thus, we achieved the total synthesis of 1 in only eight steps
(longest linear sequence) with 5.5% overall yield from
commercially available tryptamine.
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In summary, we have addressed the challenge of the
regioselectivity of the direct oxidative coupling reaction between
indoles and phenols to construct the benzofuro[3,2-b]indolines.
The resulting method enabled us to accomplish the total synthesis
of phalarine in only eight steps from commercially available
tryptamine. This synthesis represents the shortest pathway for the
total synthesis of phalarine to date.
[12] N. Denizot, A. Pouilhès, M. Cucca, R. Beaud, R. Guillot, C. Kouklovsky,
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (Nos. 21871013 and 21572008).
Keywords: alkaloids • total synthesis • oxidative coupling •
regioselectivity • natural products
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Layout 2:
COMMUNICATION
Lei Li, Kuo Yuan, Qianlan Jia, and
Yanxing Jia*
Page No. – Page No.
Eight-Step Total Synthesis of
Phalarine via Bioinspired Oxidative
Coupling of Indole and Phenol
A new method for the synthesis of benzofuro[3,2-b]indolines was developed by a
PIDA-mediated direct oxidative coupling of 2,3-disubstituted-indoles with phenols.
Application of this chemistry allows for an eight-step total synthesis of phalarine
from commercially available tryptamine.
This article is protected by copyright. All rights reserved.