Chiral Br?nsted Acid from Chiral Phosphoric Acid Boron Complex and Water: Asymmetric Reduction of Indoles

Article abstract of DOI:10.1002/anie.201913656

A new chiral Br?nsted acid, generated in situ from a chiral phosphoric acid boron (CPAB) complex and water, was successfully applied to asymmetric indole reduction. This “designer acid catalyst”, which is more acidic than TsOH as suggested by DFT calculations, allows the unprecedented direct asymmetric reduction of C2-aryl-substituted N-unprotected indoles and features good to excellent enantioselectivities with broad functional group tolerance. DFT calculations and mechanistic experiments indicates that this reaction undergoes C3-protonation and hydride-transfer processes. Besides, bulky C2-alkyl-substituted N-unprotected indoles are also suitable for this system.

Full text of DOI:10.1002/anie.201913656

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Accepted Article
Title: New Chiral Brønsted Acid from Chiral Phosphoric Acid Boron
Complex and Water: Asymmetric Reduction of Indoles
Authors: Kai Yang, Yixian Lou, Chenglan Wang, Liang-Wen Qi,
Tongchang Fang, Feng Zhang, Hetao Xu, Lu Zhou,
Wangyang Li, Guan Zhang, Peiyuan Yu, and Qiuling Song
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913656
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10.1002/anie.201913656
Angewandte Chemie International Edition
RESEARCH ARTICLE
New Chiral Brønsted Acid from Chiral Phosphoric Acid Boron
Complex and Water: Asymmetric Reduction of Indoles
Kai Yang,[a] Yixian Lou, [b] Chenglan Wang, [b] Liang-Wen Qi,[c] Tongchang Fang, [a] Feng Zhang, [a]
Hetao Xu, [a] Lu Zhou, [a] Wangyang Li, [a] Guan Zhang, [d] Peiyuan Yu, [c]* Qiuling Song[a,b,d]
*
Abstract: A new chiral Brønsted acid, generated in situ from
chiral phosphoric acid boron (CPAB) complex and water, was
successfully applied to asymmetric indole reduction. This
“designer acid catalyst”, being more acidic than TsOH as
suggested by DFT calculations, allows for the unprecedented
direct asymmetric reduction of C2-aryl substituted N-unprotected
indoles and features good to excellent enantioselectivities with
broad functional group tolerance. DFT calculations and
mechanistic experiments indicates that this reaction undergoes
C3-protonation and hydride transfer processes. Besides, bulky
C2-alkyl substituted N-unprotected indoles are also suitable for
this system.
(CPAB) complex (Figure 1a) for asymmetric reduction of
ketones.4c Recently, Du’s group developed a chiral ammonia
borane from CPA and ammonia borane.5 The in situ generated
CPAB may provide such an opportunity since the Lewis acid-
base cooperative moiety in CPAB complex has the potential to
activate H2O to produce a new chiral Brønsted acid (Figure 1a).
To the best of our knowledge, this type of chiral Brønsted acid
has never been explored. To support this hypothesis, we
performed some preliminary density functional theory (DFT)
calculations. As shown in Figure 1b, phosphoric acid dimethyl
ester (MeO)2PO2H (a model phosphoric acid) reacts with
catecholborane (CatBH) to form phosphoric acid boron complex
1 with the release of H2 gas. Such a process is highly exergonic,
with a computed free energy of –16 kcal/mol. Water could then
coordinate onto the Brønsted acidic site of 1 to form complex 2
(Figure 1c), which subsequently generates the proposed
Brønsted acid 3. The relative energies obtained from DFT
calculations suggest that this process is thermodynamically
feasible. The generation of such chiral Brønsted acids was
Introduction
As a powerful tool for asymmetric synthesis, a large number of
chiral Brønsted acids and “designer acids” have been developed
and their catalytic activities were studied.1,2 The “designer acids”,
constructed from a combination of individual acids, have some
unique advantages over individual acids, such as higher
reactivity, higher selectivity, and better versatility.2 Despite the
great advances made, the development of new chiral Brønsted
acids is still highly desirable. H2O is a very weak Brønsted acid
that could be converted to a strong Brønsted acid by Lewis
boron complex.3 The combination of chiral Lewis boron complex
and H2O may generate a new chiral Brønsted acid. Chiral
phosphoric acids (CPAs) are not only directly employed in
asymmetric synthesis,1 but also good precursors for the new
chiral catalysts.4 In 2011, Antilla and co-workers reported that
chiral phosphoric acid (CPA) could react with catecholborane
(CatBH) to release H2 and obtain chiral phosphoric acid boron
1
further verified by H and 31P NMR (for details, see Supporting
Information). Furthermore, Brønsted acid 3 is computed to be
more acidic than TsOH, as supported by the DFT-computed free
energy of reaction shown in Figure 1d.
[a]
Dr. K. Yang, T. Fang, F. Zhang, H. Xu, L. Zhou, W. Li, Prof. Dr. Q.
Song
Key Laboratory of Molecule Synthesis and Function Discovery,
Fujian Province University, College of Chemistry at Fuzhou
University, Fuzhou, Fujian, China, 350108
E-mail: qsong@hqu.edu.cn
[b]
[c]
[d]
Y. Lou, C. Wang, Prof. Dr. Q. Song
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou, Zhejiang 310000, P.R. China
Dr. L. Qi, Prof. Dr. P. Yu
Department of Chemistry and Shenzhen Grubbs Institute, Southern
University of Science and Technology, Shenzhen, China 518055
E-mail: yupy@sustech.edu.cn
Figure 1. Chiral Brønsted acid from chiral phosphoric acid boron complex
and water.
G. Zhang, Prof. Dr. Q. Song
As a strong acid, TsOH has been previously shown to
activate C2-alkyl indole to form C-3 protonated iminium tosylate,
which could be subsequently transformed into indoline by a
suitable reducing agent6. Chiral indolines are ubiquitous
structural motifs in natural alkaloids and pharmaceutical
Institute of Next Generation Matter Transformation, College of
Materials Science Engineering at Huaqiao University
668 Jimei Boulevard, Xiamen, Fujian, China, 361021
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.201913656
Angewandte Chemie International Edition
RESEARCH ARTICLE
agents.7 Over past decades, asymmetric synthesis of
enantiopure indolines has attracted tremendous attention.8-10 For
example, asymmetric hydrogenation of N-protected indoles has
achieved great results with excellent enantioselectivities.8
Notably, a variety of excellent methods for direct asymmetric
reduction of N-unprotected indoles, which is a more step-
economical and powerful strategy to access enantioenriched
indolines, has been developed with various catalytic reductive
systems (Figure 2a).6,11 However, all these catalytic systems
have similar limitations on the substrates: (1) C2-aryl substituted
N-unprotected indoles failed in these asymmetric reductions;6b,
11a, 11c-d (2) lack of broad functional group compatibility.
The new Brønsted acid that is more acidic than TsOH may
address these limitations. We envisioned that the new Brønsted
acid could activate 2-phenylindole and give a chiral ion pair
intermediate, which could be stereoselectively reduced to form
chiral indoline (Figure 2b). Preliminary DFT calculations show
that 3 can indeed protonate 2-phenylindole to form such an
iminium intermediate 5, with only a small barrier of reaction
(Figure 2c, 7.7 kcal/mol).
contrast, the reduction could not proceed smoothly under
anhydrous conditions (entry 1-2). This result encouraged us to
further attempt chiral phosphoric acid CP1 as catalyst on this
reaction. Gratifyingly, the desired product was obtained in 30%
ee at -20 oC (entry 3). Through preliminary investigation of
BINOL-derived chiral phosphoric acids, enantioselectivities have
increased significantly from 21% to 78% ee with good yields
(entries 4-8). [H]8-BINOL-derived chiral phosphoric acid catalyst
with 2,4,6-(CH3)3C6H2 on the 3,3’-position afforded slightly higher
enantioselectivity (78% ee, entry 9), however, a lower ee was
obtained by using SPINOL-derived catalyst (entry 10).
Subsequent studies with the reaction temperature (entries
11−12) found that the enantioselectivity was improved to 89% ee
by lowering the temperature to -50 oC (entry 12). A lower
reaction concentration could improve the enantioselectivity,
providing the chiral indoline product 8a in 88 % yield and 91%
ee (entry 13). Both efficiency and enantioselectivity were
significantly diminished when H2O was replaced by MeOH or
iPrOH (entry 14-15).
Table 1. Optimization of the reaction conditions.a
Entry Temp. (oC) CPA
Additive Yield (%)b ee (%)c
1d
2d
3
rt
DPPA
DPPA
CP1
CP2
CP3
CP4
CP5
CP6
CP7
CP8
CP7
CP7
CP7
CP7
CP7
--
trace
87
76
98
76
83
67
81
90
83
89
91
88
76
41
--
rt
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
iPrOH
--
-20
-20
-20
-20
-20
-20
-20
-20
-30
-50
-50
-50
-50
30
75
21
29
18
77
78
-30
81
89
91
61
51
4
5
6
7
Figure 2. Regenerable chiral Brønsted acid for the asymmetric indole
reduction via iminium intermediate.
8
9
Herein, we report the development of a regenerable chiral
Brønsted acid and its application to the asymmetric reduction of
N-unprotected indoles. This protocol shows excellent
enantioselectivities for C2-aryl substituted indoles and tolerates
a broad range of functional groups, which would serve as a
powerful complement to the previously developed indole
reduction methods.
10
11
12
13e
14e
15e
a
Reaction conditions: 6a (0.1 mmol), 7 (0.3 mmol), CPA (10 mol%) and
Results and Discussion
additive (0.3 mmol) in toluene (2 mL) under an Argon atmosphere unless
b
c
d
otherwise specified.
Isolated yield.
Determined by HPLC analysis.
To examine our hypothesis, we initiated our research with
reduction of 2-phenylindole (6a) using catecholborane (7) as
reductant and diphenyl phosphate (DPPA) as catalyst in toluene.
To our delight, 6a was completely converted to the desired 2-
phenylindoline (rac-8a) when H2O was used as an additive. In
Toluene (1 mL). e Toluene (4 mL)
With the optimized reaction conditions in hand, we next
examined the substrate scope of C2-aryl substituted indoles 6
(Table 2). Both electron-rich and electron-deficient substituents
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10.1002/anie.201913656
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 2. Substrate Scope.a,b
Reaction conditions:a 6 (0.1 mmol), 7 (0.3 mmol), H2O (0.3 mmol), CP7 (10 mol%), toluene (4 mL), -50 oC, 24 hours unless otherwise specified;
bEnantioselectivities were determined by chiral HPLC analysis; c -20 oC, 72 hours; d -20 oC, 24 hours. pin = pinacol.
on the indole ring of C2-phenyl substituted indoles 6 worked well
under our catalytic system to furnish chiral indolines 8b-8o in
good to excellent enantioselectivities (83%-96% ee). It should be
noted that substrates with strong electron-withdrawing groups on
the 5-position of indole, such as 5-CF3, 5-CO2Me, 5-CN and 5-
NO2, reacted efficiently to afford the corresponding chiral 2-
phenylindolines 8i-8l in 83-93% ee, which is a valuable feature
that can provide an opportunity for further transformations but
was problematic in previous works of asymmetric indole
reduction. Remarkably, Bpin group was also amenable in our
system to provide 8m in 96% ee, rendering a feasibility for
further structural elaborations. The absolute configuration of 8m
was determinded by X-ray crystallographic analysis (see the
Supplementary Information for details). Substituted 6-F and 4-Cl
substituted indoles also gave satisfactory results (8n and 8o)
with excellent enantioselectivities (92% and 91% ee) and good
yields (78% and 83%). Interestingly, 7-substituted indoline (8p)
excellent results. Notably, substrates with alkenyl or alkynyl
groups, for which hydroboration may compete with indole
reduction, gave the desired chiral indolines 8ac and 8ad in good
yields and enantioselectivities. This catalytic system also
tolerates naphthalene (8ae) and fused heterocycles, the
corresponding desired products (8af and 8ag) were in high
yields with excellent enantioselectivities (87-93% ee).
To evaluate the practicality of our catalytic system, as shown in
Figure 3, we performed the indole asymmetric reduction reaction
on
a gram scale that shows unaffected reactivity and
enantioselectivity (86% yield and 91% ee). Moreover, we
converted the resulting chiral indoline 8a from the gram scale
reaction into several useful molecules. Firstly,
a chiral
intermediate 9 was obtained in 79% yield from 8a and triethyl
methanetricarboxylate that provides a good opportunity for the
development of enantiopure HIF prolyl hydroxylase inhibitor.12
Meanwhile, condensation between (S)-2-phenylindoline (8a) and
10 under EDCl provided a AKT(PKB) phosphorylation inhibitor
11 in 65% yield that could avoid the chiral splitting step in
previous work.13 Then, a chiral ligand 13 was synthesized
through benzoylation and condensation with a small amount of
racemization.14
was
formed
in
opposite
configuration
with
lower
enantioselectivity (64% ee), suggesting that this reaction is
sensitive to the steric environment near the NH group. Then, the
effect of substrates bearing substituents on the C2 aryl ring was
investigated. In this asymmetric N-unprotected indole reduction
reaction, various C2-aryl ring bearing diverse substituents were
also applicable to provide the corresponding chiral indoline
products 8q-8ag in high yields (70-99%) with good to excellent
enantioselectivities (82-93% ee). Indole ring or C2-phenyl ring
bearing halo-substituents were well tolerated, producing the
corresponding products (8e-8g, 8n-8o, 8q-8t, 8z) in good to
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10.1002/anie.201913656
Angewandte Chemie International Edition
RESEARCH ARTICLE
involving hydrogen-bonding interactions in the stereo-
determining transition state.
Figure 4. Mechanistic experiments.
To further probe the mechanism and the origin of
stereoselectivity of this transformation, we conducted DFT
calculations using the full catalyst CP7. Several possible
pathways were evaluated (see Supporting Information for
details). The lowest energy pathway is shown in Figure 5. CP7
reacts with CatBH (7) to form stable complex CPAB 16 and H2,
with a free energy of reaction of 15.2 kcal/mol, in accordance
with our initial calculation using a model phosphoric acid (Figure
1b). Water then coordinates to 16, and reversibly splits into
proton and hydroxyl, generating an active complex 18. Such a
strong Brønsted acid could protonate 2-phenylindole (6a) at its
C-3 position to form chiral iminium intermediate 20. The
activation barrier is only 7.1 kcal/mol via TS-1a, relative to the
stable complex 16. Then, the boron exchange between the
boronic acid of intermediate 20 and CatBH produces
intermediate 22, which allows hydride transfer from the activated
CatBH to the iminium carbon to afford the desired chiral indoline
product 8a and regenerate CPAB 16 for the further activation of
H2O in the next catalytic cycle.
Figure 3. Synthetic applications.
To further explore the reaction mechanism, some
mechanistic experiments were carried out. When water was
replaced by deuterium oxide, two deuterium atoms were
incorporated at the C-3 position of the final product 8-D (Figure
4a), which suggested that the reaction pathway involves a
reversible C3-protonation process to form an iminium
intermediate. Next, 1-methyl-2-phenyl-1H-indole (14) was
employed in the reaction, the racemic product (15) was obtained
(Figure 4b), which indicated that the indole NH moiety played a
crucial role in controlling the enantioselectivity, presumably
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10.1002/anie.201913656
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 5. DFT-computed free energy profile for the asymmetric indole reduction.
The stereo-determining transition structures (TSs) are
shown in Figure 6. TS-2-(S) is lower in energy than TS-2-(R) by
1.4 kcal/mol. This corresponds to a computed ee of 90% at –50
oC, in excellent agreement with the experimentally observed
stereoselectivity (91% ee). No major steric clashes were
observed in these two TSs. The main difference is the eight-
membered ring (including hydrogens) cyclic structures shown in
blue boxes. In the disfavored TS, this eight-membered ring
(Figure 6, lower right corner) is in a more distorted conformation
than it is in the favored TS (Figure 6, lower left corner). The 7-
position on the indole substrate is in closer contact with the
aromatic substituent of the catalyst in TS-2-(S), while it is freely
pointing outside in TS-2-(R). It might explain the opposite
selectivity observed with 7-methylindoline product 8p. This was
confirmed by DFT calculations of the two corresponding TSs
(Figure S6, Supplementary Information).
To our delight, our method was also applicable to bulkyl C2-
alkyl indoles that are also a challenging class of substrates for
asymmetric reduction. The large sterically hindered phosphoric
acid CP9 was more effective for asymmetric reduction of bulkyl
C2-alkyl indoles, providing some bulky C2-alkyl indolines (25a-
25c) with good to excellent enantioselectivities (86%-95% ee) in
good yields (48-78%).
Table 3. Extended Scope of bulky C2-alkly indolesa,b
Reaction conditions: a24 (0.1 mmol), CatBH (0.3 mmol), H2O (0.3 mmol), CP9
(10 mol%), toluene (4 mL), -30 oC, 24 hours unless otherwise specified;
bEnantioselectivities were determined by chiral HPLC analysis.
Conclusion
In conclusion, we have developed a chiral Brønsted acid
which is derived from phosphoric acid boron (CPAB) complex
and water. The chiral Brønsted acid was successfully applied to
Figure 6. DFT-computed stereo-determining transition structures for the
asymmetric indole reduction. C-H hydrogens are omitted for clarity.
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10.1002/anie.201913656
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RESEARCH ARTICLE
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In argon, a 25 mL Schlenk tube was charged with toluene (4 mL), CP7
(0.01 mmol, 0.1 equiv) and catecholborane (0.03 mmol, 3 equiv). The
mixture was stirred at room temperature for 40 minutes, then moved the
tube to corresponding temperature (-50 oC to -20 oC) and stirred for 30
minutes. Indole (0.1 mmol, 1 equiv) and H2O (0.3 mmol, 3 equiv) were
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (21772046, 21931013) is gratefully acknowledged.
Computational work was supported by Center for Computational
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Keywords: Chiral Brønsted Acid • Boron • Water • Indole •
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Asymmetric reduction
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This article is protected by copyright. All rights reserved.

10.1002/anie.201913656
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Kai Yang, Yixian Lou, Chenglan Wang,
Liang-Wen Qi,Tongchang Fang, Feng
Zhang, Hetao Xu, Lu Zhou, Wangyang
Li, Guan Zhang, Peiyuan Yu, Qiuling
Song
Page No. – Page No.
Text for Table of Contents
New Chiral Brønsted Acid from Chiral
Phosphoric Acid Boron Complex and
Water: Asymmetric Reduction of
Indoles
A new chiral Brønsted acid, generated in situ from chiral phosphoric acid boron (CPAB) complex and water, allows for the
unprecedented direct asymmetric reduction of C2-aryl or bulky C2-alkyl substituted N-unprotected indoles and features
good to excellent enantioselectivities with broad functional group tolerance.
This article is protected by copyright. All rights reserved.