Catalytic and Enantioselective Control of the C–N Stereogenic Axis via the Pictet–Spengler Reaction

Article abstract of DOI:10.1002/anie.202100363

An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet–Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-β-carbolines with C?N bond axial chirality are obtained via dynamic kinetic reso

Full text of DOI:10.1002/anie.202100363

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 12279–12283
International Edition: doi.org/10.1002/anie.202100363
German Edition: doi.org/10.1002/ange.202100363
Atropisomerism
Catalytic and Enantioselective Control of the C–N Stereogenic Axis via
the Pictet–Spengler Reaction
Ahreum Kim+, Aram Kim+, Sunjung Park, Sangji Kim, Hongil Jo, Kang Min Ok,
Sang Kook Lee, Jayoung Song, and Yongseok Kwon*
Abstract: An unprecedented example of a chiral phosphoric
acid-catalyzed atroposelective Pictet–Spengler reaction of N-
arylindoles is reported. Highly enantioenriched N-aryl-tetra-
À
hydro-b-carbolines with C N bond axial chirality are obtained
via dynamic kinetic resolution. The hydrogen bond donor
introduced on the bottom aromatic ring, forming a secondary
interaction with the phosphoryl oxygen, is essential to achiev-
ing high enantioselectivity. A wide variety of substituents are
tolerable with this transformation to provide up to 98% ee. The
application of electron-withdrawing group-substituted benzal-
dehydes enables the control of both axial and point stereo-
genicity. Biological evaluation of this new and unique scaffold
shows promising antiproliferative activity and emphasizes the
significance of atroposelective synthesis.
A
symmetric catalysis has paved new ground in the prepa-
ration of chiral molecules containing a stereogenic axis by
enabling noncovalent interactions between substrates and
catalysts.[1] In particular, much interest has been focused on
À
the control of axial chirality around a C C bond, which has
led to many valuable methods over the past decade.[2]
À
However, atropisomerism around a C N bond in biaryls has
received relatively less attention,[3,4] even though nitrogen-
containing heterocycles are considered biologically relevant
scaffolds.[5]
b-Carbolines and tetrahydro-b-carbolines are of wide-
spread interest because of their natural abundance and
various biological activities (Figure 1a).[6] Because of their
intriguing biological and physicochemical properties, syn-
thetic efforts have been made to efficiently construct this
scaffold.[7] Because of the ubiquitous indole precursor, the
formation of the C ring (Figure 1b) frequently allows more
straightforward synthetic approaches.[7,8] Given the dense
substitutions at the N-9 position, biaryl frameworks such as N-
Figure 1. a) Biologically active b-carbolines. b) Possible atropisomer-
ism in b-carbolines. c) Enantioselective Pictet–Spengler reactions. d)–
f) Atroposelective dynamic kinetic resolution of substituted indoles.
Pictet–Spengler cyclization is an acid-mediated intramo-
lecular Friedel–Craft type reaction involving iminium ions.[9]
It has been widely used to synthesize complex natural
products, including b-carboline alkaloids.[10] Since the List
group developed an asymmetric Pictet–Spengler reaction of
indoles using a catalytic chiral phosphoric acid,[11] a number of
asymmetric variants of this transformation have been
reported (Figure 1c).[12] Inspired by these elegant method-
ologies, we chose to explore the atroposelective Pictet–
Spengler cyclization of N-arylindoles. To the best of our
knowledge, an atroposelective version of this reaction is
unprecedented.
À
aryl-b-carboline are expected to have C N axial chirality.
[*] A. Kim,[+] A. Kim,[+] S. Park, S. Kim, H. Jo, Prof. Dr. K. M. Ok,
Prof. Dr. Y. Kwon
Department of Chemistry, Sogang University
35 Baekbeom-ro, Mapo-gu, Seoul (Republic of Korea)
E-mail: ykwon@sogang.ac.kr
Prof. Dr. S. K. Lee, Dr. J. Song
College of Pharmacy, Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul (Republic of Korea)
We hypothesized that chiral phosphoric acids[13,14] can
catalyze cyclization atroposelectively via dynamic kinetic
resolution (DKR),[15] based on the difference in rotational
barriers between the substrate and the cyclized product. The
DKR strategy for the atroposelective transformation of 3-
arylindole has recently been investigated.[16] The Gu group
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100363.
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reported palladium-catalyzed atroposelective intramolecular
pattern on the aryl ring (R’ in the Table 1). The reactions of
P2 or P3 containing meta-substituents showed moderate
selectivity (entries 3 and 4). Regardless of the electronic or
steric factor of the para-substituents, poor enantioselectivities
were observed (entries 5–7). The anthracenyl-substituted
catalyst displayed slightly better selectivity (73% ee) than
the phenanthryl substituted catalyst (entries 8 vs. 9). Catalyst
P9 with 2,4,6-tricyclohexyl substituents delivered 2b in the
highest observed enantioselectivity under the initial reaction
conditions (entry 10). The cyclization of 1b with VAPOL-
type chiral phosphoric acid P10 produced 2b with lower
enantioselectivity (entry 11). With the optimal catalyst, P9,
other reaction parameters were evaluated, such as aldehyde
source, solvent, temperature and equivalence.[17] During the
optimizations, slightly higher selectivity was obtained (96%
ee, 2b in Table 2), when the reaction was performed at 28C.
With the optimal reaction conditions in hand, the
substrate scope was examined, as summarized in Table 2.
À
C H cyclization using TADDOL as a chiral ligand (Fig-
ure 1d).[16a] More recently, chiral phosphoric acid-catalyzed
atroposelective C-2 functionalization of the 3,3’-bisindole
skeleton was reported by the Shi group (Figure 1e).[16b] In the
report, they suggested that the acidic activation of electro-
philes by chiral phosphoric acid and the interaction between
the phosphate counterion and NH moiety of indole are crucial
because of the bifunctional activation of a chiral phosphoric
À
acid. From this point of view, since the absence of N H in N-
arylindole could have a detrimental effect on selectivity, an
additional hydrogen bond donor might be required to achieve
high selectivity. Herein, we report a highly atroposelective
Pictet–Spengler cyclization of N-arylindoles catalyzed by
a chiral phosphoric acid (Figure 1 f).
To test our hypothesis, we designed the initial substrate 1a
in which the gem-dimethyl group is introduced to accelerate
the transformation by the Thorpe–Ingold effect (Table 1). To
avoid any other additional effects by potential point stereo-
genicity, paraformaldehyde, an unsubstituted aldehyde
source, was chosen. The reaction of 1a with P1 and
paraformaldehyde afforded tetrahydro-b-carboline 2a in
high yield, albeit with low enantioselectivity (entry 1). How-
ever, completely different results were obtained when the
methyl group was replaced with a benzylamino group. To our
delight, highly improved selectivity was achieved in the
reaction of 1b (87% ee, entry 2). With substrate 1b, chiral
phosphoric acid catalysts have been screened in which the
enantioselectivity is highly affected by the substitution
Table 2: Substrate scope.[a–d]
Table 1: Catalyst screening.[a]
Entry
1
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
P1 ((R)ÀTRIP)
2a, 86
2b, 90
2b, 91
2b, 86
2b, 71
2b, 81
2b, 82
2b, 59
2b, 98
2b, 99
2b, 97
22
87
60
48
6
8
4
66
73
94
12[d]
P1 ((R)ÀTRIP)
P2
P3
P4
P5
P6
P7
P8
P9
P10
9
10
11
[a] Reaction conditions: 1 (0.050 mmol, 1.0 equiv), paraformaldehyde
(0.075 mmol, 1.5 equiv), P9 (0.005 mmol, 10 mol%), PhMe (0.5 mL,
0.1 M). [b] The reported results are the average of two runs. [c] Isolated
yields. [d] Enantiomeric ratios were determined using chiral-phase HPLC
analysis. [e] The reaction with 1.32 g (3.57 mmol) of 1b provided 2b in
95% yield and 96% ee. [f] For crystallization, the 4-bromobenzamide
derivative was prepared. [g] After the cyclization of 1n under the
standard reaction conditions, the crude product was tosylated in situ.
[a] Reaction conditions: 1 (0.050 mmol, 1.0 equiv), paraformaldehyde
(0.075 mmol, 1.5 equiv), P1À10 (0.005 mmol, 10 mol%), PhMe
(0.5 mL, 0.1 M). [b] Isolated yields. [c] Enantiomeric excesses were
determined by chiral-phase HPLC analysis. [d] The opposite enantiomer
was obtained as a major enantiomer.
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Table 3: Substrate scope with benzaldehydes.[a–c]
Initially, different substitution patterns on the bottom arene
of the N-arylindole moiety were tested. The cyclization of
dibenzyl-substituted 1c with the catalyst P9 afforded 2c in
only 26% yield with moderate selectivity (56% ee). The
replacement of the benzylamino group with a methylamino
group and benzamide was tolerable under these reaction
conditions (for 2d, 92% ee; for 2e, 97% ee). In the reaction of
1 f containing the methyl carbamate, cyclized product 2 f was
produced in 67% yield with 76% ee. We observed the
racemization of 2 f on the bench top, which may cause lower
enantioselectivity during the reaction and purification proce-
dures. Then, we examined the substrate bearing additional
substituents on the bottom arene ring. Unfortunately, it was
observed that 1g containing a methyl group next to the
benzylamine was not tolerable under these reaction condi-
tions (30% ee), presumably due to unfavorable steric
repulsions with P9. Substrates 2h and 2i bearing the
electron-donating and electron-withdrawing groups, respec-
tively, afforded the desired product in good yield and with
excellent enantioselectivity. While the cyclization of 1j
produced 2j in 96% yield and 98% ee, the reaction of o,o’-
disubstituted substrate 1k led to a different selectivity
depending on the conversion. Although DKR was not carried
out due to the steric congestion of 1k, kinetic resolution still
resulted in high selectivity (93% ee, see below). The
homologated benzylamine substrate, 1l provided the desired
product 2l, albeit with moderate selectivity (70% ee). The
substitution of the dimethyl group at tryptamine with
cyclohexyl was tolerable to afford 2m in 85% yield and
96% ee. The reaction of the tryptamine derivative 1n
smoothly led to cyclization with high enantioselectivity
(94% ee). The selectivity was measured after in situ tosylation
owing to instability during chromatographic purification of
the naked secondary amine. Our catalytic system was
effective in 5-subsitution of indole with the methoxy and
chloride groups (for 2o, 96% ee; for 2p, 94% ee). The
reaction can be run on a gram scale (1.32 g of 1b) without
diminishing neither the yield nor the enantioselectivity (95%
yield, 96% ee). The absolute configuration of 2b was
determined by X-ray crystallography after amidation with
p-bromobenzoyl chloride.[17]
With excellent overall atroposelectivity, we turned our
attention to the control of the stereogenic center along with
the stereogenic axis. While the control of two different
stereogenic element is highly desirable, a limited number of
examples have been reported.[16b,18] We envisioned that
a stereochemically complex setting in this scaffold would be
realized by employing substituted aldehydes.[11,12] In our first
attempts with benzaldehyde, the cyclization of 1b did not
afford the cyclized product even at higher temperature or
higher catalyst loading. However, when benzaldehydes bear-
ing an electron-withdrawing group were employed, the
reaction afforded the desired products with good to moderate
selectivity (Table 3). For example, the reaction of 1b with p-
nitrobenzaldehyde at 808C smoothly afforded 2q in 9:1 d.r.
and > 99% ee. It was observed that p-substitutions such as
trifluoromethyl-, cyano-, and methyl ester groups are toler-
able (for 2r and 2s, 7:1 d.r.; for 2t, 6:1 d.r.). While the reaction
of 1e with p-nitrobenzaldehyde produced 2u, albeit with
[a] Reaction conditions: 1 (0.050 mmol, 1.0 equiv), aldehyde
(0.075 mmol, 1.5 equiv), P9 (0.010 mmol, 20 mol%), PhMe (0.5 mL,
0.1 M). [b] Isolated yields. [c] Diastereomeric and enantiomeric ratios
were determined using chiral-phase HPLC analysis. [d] The relative
stereochemistry was confirmed by X-ray crystallography of (Æ)-2u.[17]
lower diastereoselectivity, the reaction with m-cyanobenzal-
dehyde produced 2v in 98% yield and 10:1 d.r.
Based on our data thus far, a putative mechanistic model
is proposed, as shown in Figure 2. Condensation of the
substrate and paraformaldehyde afforded imine intermedi-
ates I and ent-I in dynamic equilibrium. Because we observed
the conversion of 1b to 2b without the catalyst,[19] ent-I could
be transformed to ent-2b. However, catalyst P9 could
accelerate the cyclization of I by forming an iminium-
phosphate ion pair and interacting with the phosphate
counterion with the amino group.[14] This interaction could
induce the observed relative stereochemistry in Table 3, in
which the iminium ion could approach the benzylamino group
in the same plane. The DKR mechanistic pathway can be
further supported by the results of 2k. When the reaction was
performed within 12 h, 2k was obtained in 45% yield and
93% ee. However, a longer reaction time (19 h) led to poor
selectivity (83% yield, 36% ee), which clearly showed the
differences between the KR vs. the DKR pathways and the
Figure 2. Putative reaction mechanism.
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importance of catalytic acceleration to achieve high selectiv-
ity compared to the background rate. Further mechanistic
studies are currently ongoing in our laboratory.
Conflict of interest
The authors declare no conflict of interest.
Given the biological significance of b-carboline deriva-
tives,[6,7] especially as potential anticancer agents,[7b] the
antiproliferative activities of 2 were evaluated. To avoid
possible bias from enantiopure compounds, selected racemic
compounds were initially tested and are summarized in
Table 4. In the screening, it was found that the racemic
mixture of 2o showed promising biological activity with an
IC50 of approximately 2 mM. Next, we examined each
enantiomer of 2o. While 2o showed 2 to 3 times lower
activity, retentive antiproliferative activity was observed with
ent-2o. This result supports the importance of atroposelective
methods for biologically relevant compounds.[20]
Keywords: atropisomerism · chiral phosphoric acid · C–
N stereogenic axis · dynamic kinetic resolution · Pictet–
Spengler cyclization
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In conclusion, a new strategy for catalytic and highly
atroposelective Pictet–Spengler reactions of N-arylindoles via
DKR has been established. Chiral phosphoric acids smoothly
led to cyclization to afford the highly enantioenriched N-aryl-
À
tetrahydro-b-carbolines about a stereogenic C N bond axis.
Application to benzaldehydes enables the control of both
point and axial stereogenicity by securing more stereochem-
ically complex molecules. The newly synthesized tetrahydro-
b-carbolines showed promising antiproliferative activity,
which could lead to new and unique scaffolds for drug
discovery.
Table 4: Anti-proliferative activities of 2.[a,b]
Compd.
IC50 (mM)
A549
MDA-MB-231 SK-Hep-1 SNU-638
(Æ)-2b
11Æ2.9
>50
10Æ3.1
>50
11Æ1.9
>50
9.4Æ2.6
>50
25Æ4.1
(Æ)-2d
(Æ)-2e
23Æ6.3
12Æ3.1
3.4Æ1.5
11Æ3.3
2.6Æ0.67
2.6Æ0.93
24Æ12
13Æ3.3
9.5Æ1.9
2.5Æ0.78
10Æ2.8
2.5Æ0.69
3.9Æ1.3
78Æ16
13Æ1.8
(Æ)-2h
10Æ2.4 5.7Æ0.94
2.6Æ0.63 2.4Æ1.1
(Æ)-2i
(Æ)-2m
(Æ)-2o
12Æ3.9
5.8Æ1.7
2.5Æ0.84 2.6Æ0.88
2.6Æ0.72 2.7Æ0.91
(Æ)-2p
Doxorubicin (nM)
98Æ23
36Æ17
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[a] A549: Human lung cancer cell line; MDA-MB-231: Human breast
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SD. The results are representative of three independent experiments.
Measured by the SRB method.[17]
Acknowledgements
This work is supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSTI) (No. 2020R1C1C1006231)
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Manuscript received: January 9, 2021
Revised manuscript received: February 16, 2021
Accepted manuscript online: March 2, 2021
Version of record online: April 23, 2021
Angew. Chem. Int. Ed. 2021, 60, 12279 –12283
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