Design of C3-Alkenyl-Substituted 2-Indolylmethanols for Catalytic Asymmetric Interrupted Nazarov-Type Cyclization

Article abstract of DOI:10.1002/adsc.201701521

The C3-alkenyl-substituted 2-indolylmethanols have been designed as a new class of substrates for catalytic asymmetric interrupted Nazarov-type cyclizations. In the presence of chiral phosphoric acid as a mild chiral Br?nsted acid, the interrupted Nazarov

Full text of DOI:10.1002/adsc.201701521

Title: Design of C3-Alkenyl-Substituted 2-Indolylmethanols for Catalytic
Asymmetric Interrupted Nazarov-Type Cyclization
Authors: Cong-Shuai Wang, Jia-Le Wu, Can Li, Lin-Zhi Li, Guang-Jian
Mei, and Feng Shi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701521
Link to VoR: http://dx.doi.org/10.1002/adsc.201701521

10.1002/adsc.201701521
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Design of C3-Alkenyl-Substituted 2-Indolylmethanols for
Catalytic Asymmetric Interrupted Nazarov-Type Cyclization
Cong-Shuai Wang,a,‡ Jia-Le Wu,a,‡ Can Li,a Lin-Zhi Li,a Guang-Jian Meia and Feng
Shia,*
a
School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, China
E-mail: fshi@jsnu.edu.cn
‡The two authors contributed equally to the work.
Received: (Will be filled in by the editorial staff)
Supporting information for this article is available on the WWW at http://dx.doi.org/10.1002/adsc.201######. (Please
delete if not appropriate)
Currently, the established catalytic asymmetric
have been designed as a new class of substrates for Nazarov cyclizations mainly utilize divinyl ketones
Abstract. The C3-alkenyl-substituted 2-indolylmethanols
catalytic asymmetric interrupted Nazarov-type cyclizations.
In the presence of chiral phosphoric acid as a mild chiral
Brønsted acid, the interrupted Nazarov-type cyclization of
as substrates to perform the reactions under the
catalysis of chiral strong Brønsted acids (BH*) such
as chiral N-triflylphosphoramide (CPN) or chiral
Lewis acids (LA*) (eq. 1).[3-4] In addition, there are
only limited examples employing aryl vinyl ketones
as substrates to undergo catalytic asymmetric
Nazarov cyclizations in the presence of chiral Lewis
acids (eq. 2).[5] Besides, very limited examples used
diketoesters as substrates to perform the Nazarov
cyclization under the catalysis of chiral bifunctional
organocatalyst or Pd (0)/chiral ligand (eq. 3).[6] So,
great challenges still remain in catalytic asymmetric
Nazarov cyclizations, including: 1) the limited
substrates classes for Nazarov cyclizations; 2) the
requirement of using strong Brønsted acids or Lewis
acids as chiral catalysts in most cases; 3) the limited
interrupted Nazarov-type cyclizations involving
multiple transformations.[7-9]
C3-alkenyl-substituted
nucleophiles occurred
2-indolylmethanols
smoothly to
with
construct
cyclopenta[b]indole frameworks in generally excellent
diastereo- and enantioselectivities (up to >95:5 dr, >99%
ee).
Keywords: asymmetric organocatalysis; cyclization;
enantioselectivity; indolylmethanol; tandem reaction
The Nazarov cyclization belongs to a class of 4π-
electrocyclizations, which is a powerful method for
constructing five-membered rings and has important
applications in synthesizing natural products.[1-2]
However, catalytic asymmetric Nazarov cyclization
is underdeveloped due to the difficulty in controlling
the enantioselectivity of the reaction (Scheme 1).
Survey of the literature reveals there are only
limited examples of catalytic asymmetric interrupted
Nazarov-type cyclizations (Scheme 2).[7] For example,
Rueping and coworker reported a domino Nazarov
cyclization/halogenation reaction sequence (eq. 4),[7a]
and the Tu group devised an interrupted Nazarov
cyclization/semipinacol rearrangement (eq. 5).[7b] In
spite of their elegant work, both of the reactions
require a strong chiral Brønsted acid (CPN) as a
chiral catalyst and the substrate class is confined to
divinyl ketones. Therefore, it has become an urgent
task to develop new class of substrates for catalytic
asymmetric Nazarov cyclizations, which are not only
easily activated by mild chiral Brønsted acids but also
favorable for undergoing interrupted Nazarov-type
cyclizations.
Scheme 1. Profile of catalytic asymmetric Nazarov
cyclizations and the challenges.
1
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10.1002/adsc.201701521
Advanced Synthesis & Catalysis
be noted, compared with CPN, a more significant
advantage of CPA would be the shorter and easier
synthesis of such a catalyst.
Initially, we employed indole 2a as a nucleophile
to
react
with
C3-alkenyl-substituted
2-
indolylmethanol 1a in the presence of CPA 4a in
toluene to testify the possibility of our hypothesis
(Scheme 4). Gratifyingly, the interrupted Nazarov
cyclization indeed occurred to afford the desired
product 3aa in a moderate yield of 49% and an
excellent diastereoselectivity of >95:5 dr although the
enantioselectivity was extremely low. This
preliminary result demonstrated the feasibility of our
hypothesis. However, there are two obvious
challenges embedded in this reaction. The first one is
to control the stereoselectivity, especially the
enantioselectivity of the Nazarov cyclization; the
second one is to control the chemoselectivity of the
interrupted reaction. Actually, the moderate yield of
product 3aa was largely ascribed to the formation of
two byproducts 7 and 8. As shown in Scheme 4, in
the reaction process, indole 2a has a tendency to
directly attack the carbocation A, thus generating
byproduct 7. In addition, the cyclic carbocation C,
which was formed from the Nazarov cyclization, can
generate byproduct 8 via deprotonation instead of
being attacked by indole 2a to give the desired
product 3aa. So, in order to settle these challenges,
we performed condition optimization to improve the
yield and the enantioselectivity of product 3aa (see SI
for details). Screening of BINOL-derived CPAs 4
revealed catalysts 4d-4e bearing two bulky
substituents were superior to others in terms of
controlling the enantioselectivity. Then, the backbone
of CPAs 4d-4e was changed from BINOL to H8-
BINOL and SPINOL, which found H8-BINOL-
derived CPA 5a could catalyze the interrupted
Scheme 2. Limited examples of catalytic asymmetric
interrupted Nazarov cyclizations.
To fulfil this task, we designed C3-alkenyl-
substituted 2-indolylmethanols as a new class of
substrates for catalytic asymmetric interrupted
Nazarov-type cyclizations (Scheme 3). This design
was based on the consideration that C3-unsubstituted
2-indolymethanols
could
form
delocalized
carbocation in the presence of an acid.[10] If an
alkenyl group was introduced to the C3-position of 2-
indolymethanols, the carbocation A could be further
delocalized to generate a 4π carbocation B, which is
similar to the delocalized 4π cation intermediate
produced from aryl vinyl ketone. So, this 4π
carbocation B is able to perform an enantioselective
Nazarov cyclization via the ion pair interaction with
chiral Brønsted acid anion, thus giving rise to a cyclic
carbocation C. Finally, this intermediate C can be
rapidly trapped by nucleophiles (Nu) to accomplish
the catalytic asymmetric interrupted Nazarov-type
cyclization and to construct the cyclopenta[b]indole
framework in a diastereo- and enantioselective
fashion.
It
should
be
mentioned
chiral
cyclopenta[b]indole framework often exists in the
structures of many natural products and
pharmaceutically important compounds.[11]
Nazarov-type
cyclization
in
the
highest
enantioselectivity of 80% ee albeit the yield was still
in a moderate level (48%) due to the generation of
byproducts 7 and 8. In order to improve the yield as
well as the enantioselectivity of product 3aa, the
reaction temperature was altered in the presence of
the optimal catalyst 5a. However, it was found either
lowering or elevating the reaction temperature was
detrimental to the generation of product 3aa. This is
because byproduct 7 would become a main product
when lowering the temperature; while the amount of
byproduct 8 would increase when elevating the
temperature. So, at room temperature, a series of
solvents were carefully evaluated, which disclosed
that chloroform could deliver the desired product 3aa
in a much higher yield of 78% with maintained good
enantioselectivity of 82% ee. Finally, it was found the
addition of 3Å molecular sieves (MS) as additives
could further improve the yield of 3aa to 87% and
enhance the enantioselectivity to 94% ee. So, this
condition was chosen as the optimal one for the
interrupted Nazarov cyclization. It should be
mentioned only one diastereomer of product 3aa was
observed during the condition optimization.
Scheme 3. Design of new class of substrates for catalytic
asymmetric interrupted Nazarov cyclization.
Based on this design and as our continuous
interests in developing new catalytic asymmetric
transformations,[10,12] we utilized chiral phosphoric
acid (CPA)[13-14] as a mild chiral Brønsted acid to
catalyze the interrupted Nazarov-type cyclization,
which constructed cyclopenta[b]indole frameworks in
excellent diastereo- and enantioselectivities. It should
2
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10.1002/adsc.201701521
Advanced Synthesis & Catalysis
(1e)
p-ClC6H4/Ph/H
(1f)
p-FC6H4/Ph/H
(1g)
Ph/m-MeC6H4/H
(1h)
Ph/m-FC6H4/H
(1i)
57
51
59
55
94
6
7
8
9
>95:5
>95:5
>95:5
>95:5
3fa
3ga
3ha
3ia
>99
88
80
55
54
52
82
92
90
10
11
12
Ph/Ph/MeO (1j)
Ph/Ph/Cl (1k)
Ph/Ph/Br (1l)
>95:5
>95:5
>95:5
3ja
3ka
3la
[a]Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in chloroform (2 mL) with 3 Å MS (100
mg) at 25 oC for 12 h, and the molar ratio of 1:2a was 1:1.2.
The absolute configuration of compound 3ba was
determined to be (7R,8S) by single crystal X-ray
diffraction analysis (see SI for details).[15] [b]Isolated yield.
[c]The diastereomeric ratio (dr) was determined by 1H
NMR. [d]The enantiomeric excess (ee) was determined by
HPLC.
Then, we studied the substrate scope of indoles 2
by the reactions with C3-alkenyl-substituted 2-
indolylmethanols 1a. As listed in Table 2, this
interrupted Nazarov cyclization was amenable to a
wide range of substituted indoles 2, affording the
desired products 3 in overall good yields (51%-88%),
excellent diastereoselectivities (all >95:5 dr) and high
enantioselectivities (80% to 98% ee). Specifically,
C4-C7 substituted indoles regardless of their
electronic nature could be applicable to the reaction.
It seemed that the position of the substituents exerted
some effect on the enantioselectivity because C4- and
C5-methyl substituted indoles (2b and 2d) offered the
products 3 in higher enantioselectivity than C6-
methyl substituted indole 2h (entries 2 and 4 vs 8).
Notably, all the products 3 were generated in
uniformly excellent diastereoselectivities.
Scheme 4. Condition optimization and the challenge in
controlling the chemoselectivity of the reaction.
With the optimal reaction conditions known, we
then investigated the substrate scope of C3-alkenyl-
substituted 2-indolylmethanols 1 by the reactions
with indole 2a. As shown in Table 1, this approach
was applicable to a variety of substrates 1 bearing
different R1/R2/R3 substituents, which smoothly
underwent the interrupted Nazarov cyclization in
generally considerable yields (50%-87%), excellent
diastereoselectivities (all >95:5 dr) and high
enantioselectivities (80% to >99% ee). In detail,
ortho-, meta- or para-substituted phenyl groups could
serve as suitable R1 groups (entries 2-7). Moreover,
R2 and R3 groups could be altered with different
electronic nature (entries 8-12).
Table 2. Substrate scope of indoles 1[a]
Table 1. Substrate scope of C3-alkenyl-substituted 2-
indolylmethanols 1[a]
yield
ee
(%)[d]
94
en-
try
R1 (2)
dr[c]
3
(%)[b]
1
2
3
4
5
6
7
H (2a)
4-Me (2b)
4-Br (2c)
5-Me (2d)
5-MeO (2e)
5-Br (2f)
87
79
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
3aa
3ab
3ac
3ad
3ae
3af
yield
(%)[b]
87
ee
(%)[d]
94
en-
try
R1/R2/R3 (1)
Ph/Ph/H (1a)
dr[c]
3
96
90
96
90
98
80
1
2
>95:5
>95:5
3aa
3ba
86
62
59
87
78
o-FC6H4/Ph/H
(1b)
o-MeC6H4/Ph/H
(1c)
m-MeC6H4/Ph/H
(1d)
50
61
68
59
92
96
94
94
3
>95:5
3ca
4
5
>95:5
>95:5
3da
3ea
5-Cl (2g)
3ag
p-MeOC6H4/Ph/H
3
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10.1002/adsc.201701521
Advanced Synthesis & Catalysis
53
88
51
90
94
98
protected indole 2k as a substrate to react with 2-
indolylmethanol 1a (eq. 7), which found no desired
interrupted Nazarov cyclization occurred and only
byproduct 8 was generated. This result demonstrated
that the N-H group in substrates 2 was very important
for carrying out the second step of interrupted
Nazarov cyclizations by forming a hydrogen bond
with the CPA anion. All these results suggested the
CPA catalyst might form dual hydrogen-bonding
interaction with the N-H groups of the two reaction
partners.
8
9
6-Me (2h)
6-Cl (2i)
7-F (2j)
>95:5
>95:5
>95:5
3ah
3ai
3aj
10
[a]Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in chloroform (2 mL) with 3 Å MS (100
mg) at 25 oC for 12 h, and the molar ratio of 1a:2 was 1:1.2.
[b]Isolated yield. [c]The diastereomeric ratio (dr) was
determined by H NMR. [d]The enantiomeric excess (ee)
1
was determined by HPLC.
Next, in order to examine the applicability of
this catalytic asymmetric interrupted Nazarov
cyclization, we employed 2-naphthols 9 as another
class of nucleophiles to react with C3-alkenyl-
substituted 2-indolylmethanols 1 under the similar
reaction conditions (Table 3). To our satisfaction, the
desired domino Nazarov cyclization occurred
smoothly by using 2-naphthols 9 as nucleophiles,
which afforded the corresponding products 10 in
moderate
to
good
yields,
acceptable
diastereoselectivities and high enantioselectivities.
Scheme 5. Control experiments.
Table 3. Application of 2-naphthols 9 as nucleophiles[a]
Based on the control experiment, we suggested a
possible reaction pathway and activation mode of the
catalyst to the substrates. As illustrated in Scheme 6,
in the presence of CPA 5a, C3-unsubstituted 2-
indolymethanols 1 transformed into carbocation A
via dehydration. Then, due to electron delocalization,
a 4π carbocation B was generated to perform an
enantioselective Nazarov cyclization via ion pair and
hydrogen-bonding interaction imposed by the anion
of CPA 5a, thus leading to the formation of cyclic
carbocation C. At this moment, the anion of CPA 5a
simultaneously activated both the nucleophile
(indoles 2) and the cyclic carbocation C via ion pair
R
yield
ee
en-
try
R1/R2/R3 (1)
Ph/Ph/H (1a)
dr[c]
10
(9) (%)[b]
(%)[d]
H
(9a)
H
(9a)
H
(9a)
H
(9a)
1
2
3
4
5
72
90:10
90:10
88:12
85:15
88:12
93
92
93
96
94
10aa
10fa
10ia
10ka
10ab
p-ClC6H4/Ph/H
(1f)
Ph/m-FC6H4/H
(1i)
56
87
and
hydrogen-bonding
interaction,
therefore
facilitating the nucleophilic substitution to give the
final products 3 with observed absolute configuration.
Ph/Ph/Cl (1k)
74
Me
(9b)
Ph/Ph/H (1a)
70
[a]Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in chloroform (2 mL) with 4 Å MS (100
mg) at 25 oC for 12 h, and the molar ratio of 1:9 was 1.1:1.
[b]Isolated yield. [c]The diastereomeric ratio (dr) was
1
determined by H NMR. [d]The enantiomeric excess (ee)
was determined by HPLC.
In order to gain some insights into the activation
mode of the catalyst to the substrates, we performed
some control experiments (Scheme 5). First, N-
methyl protected 2-indolylmethanol 1m was
employed to the reactions with indole 2a under the
standard reaction conditions (eq. 6). In this case, no
reaction occurred, which indicated the N-H group of
substrates 1 played a crucial role in controlling the
reactivity. Namely, the hydrogen-bonding interaction
between the N-H group of substrates 1 and the CPA
anion was necessary for performing the first step of
Nazarov cyclization. Secondly, we utilized N-methyl
Scheme 6. Suggested reaction pathway and activation
mode.
4
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10.1002/adsc.201701521
Advanced Synthesis & Catalysis
12 h which indicated the completion of the reaction by
TLC, the reaction mixture was filtered to remove the
molecular sieves and the solid powder was washed with
ethyl acetate. The resultant solution was concentrated
under the reduced pressure to give the residue, which was
purified through flash column chromatography to afford
pure products 3.
Finally, we performed a one mmol scale reaction
(Scheme 7), which afforded product 3ai in a nearly
maintained good yield and high stereoselectivity.
This result indicated this reaction could be scaled up.
General procedure for the synthesis of products 10
To
the
mixture
of
C3-alkenyl-substituted
2-
indolylmethanols 1 (0.11 mmol), 2-naphthols 9 (0.1 mmol),
catalyst 5a (7.0 mg, 0.01 mmol) and 4 Å MS (100 mg) was
o
added chloroform (2 mL). After being stirred at 25 C for
Scheme 7. One mmol scale synthesis.
12 h which indicated the completion of the reaction by
TLC, the reaction mixture was filtered to remove the
molecular sieves and the solid powder was washed with
ethyl acetate. The resultant solution was concentrated
under the reduced pressure to give the residue, which was
purified through preparative thin layer chromatography to
afford pure products 10.
In summary, we have designed C3-alkenyl-
substituted 2-indolylmethanols as a new class of
substrates for catalytic asymmetric interrupted
Nazarov-type cyclizations. In the presence of chiral
phosphoric acid as a mild chiral Brønsted acid, the
interrupted Nazarov-type cyclization of C3-alkenyl-
substituted 2-indolylmethanols with nucleophiles
occurred smoothly to construct cyclopenta[b]indole
frameworks in generally excellent diastereo- and
enantioselectivities. This approach has not only
provided a new class of substrates for developing
interrupted Nazarov-type cyclizations, but also
enriched the research contents of catalytic
asymmetric Nazarov cyclizations. In addition, this
reaction also serves as a powerful method for
constructing enantioenriched cyclopenta[b]indole
frameworks.
Acknowledgements
We are grateful for financial supports from NSFC
(21772069), Natural Science Foundation of Jiangsu
Province (BK20160003), Six Kinds of Talents Project of
Jiangsu Province (SWYY-025) and Postgraduate Research &
Practice Innovation Program of Jiangsu Province
(KYCX17_1577).
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1H and 13C NMR spectra were measured respectively at
400 and 100 MHz, respectively. The solvent used for NMR
spectroscopy was CDCl3, using tetramethylsilane as the
internal reference. HRMS (ESI) was determined by a
HRMS/MS instrument. Enantiomeric excesses (ee) were
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10.1002/adsc.201701521
Advanced Synthesis & Catalysis
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[15] CCDC 1577461 (3ba) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_
Supporting Information for details.
Data
Centre
request/cif.
via
the
See
6
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10.1002/adsc.201701521
Advanced Synthesis & Catalysis
COMMUNICATION
Design of C3-Alkenyl-Substituted 2-
Indolylmethanols for Catalytic Asymmetric
Interrupted Nazarov-Type Cyclization
Adv. Synth. Catal. Year, Volume, Page – Page
Cong-Shuai Wang, Jia-Le Wu, Can Li, Lin-Zhi Li,
Guang-Jian Mei and Feng Shi*
7
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