Organocatalytic Formal (3 + 2) Cycloaddition toward Chiral Pyrrolo[1,2- a]indoles via Dynamic Kinetic Resolution of Allene Intermediates

Article abstract of DOI:10.1021/acs.orglett.0c01812

We report the chiral phosphoric acid catalyzed formal (3 + 2) cycloaddition of 3-substituted 1H-indoles and propargylic alcohols containing a functional directing group (p-NHAc or p-OH). This work represents a straightforward method to synthesize chiral pyrrolo[1,2-a]indole bearing a tetrasubstituted carbon stereocenter. The reaction proceeds smoothly with a wide array of substrate tolerance to deliver various chiral pyrrolo[1,2-a]indoles in up to 93percent yield and 98percent ee. The utility of this method is highlighted by the diverse transformations of the products into various indole derivatives.

Full text of DOI:10.1021/acs.orglett.0c01812

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Letter
Organocatalytic Formal (3 + 2) Cycloaddition toward Chiral
Pyrrolo[1,2‑a]indoles via Dynamic Kinetic Resolution of Allene
Intermediates
Jian-Fei Bai, Lulu Zhao, Fang Wang, Fachao Yan, Taichi Kano, Keiji Maruoka, and Yuehui Li*
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sı Supporting Information
ABSTRACT: We report the chiral phosphoric acid catalyzed
formal (3 + 2) cycloaddition of 3-substituted 1H-indoles and
propargylic alcohols containing a functional directing group (p-
NHAc or p-OH). This work represents a straightforward method
to synthesize chiral pyrrolo[1,2-a]indole bearing a tetrasubstituted
carbon stereocenter. The reaction proceeds smoothly with a wide
array of substrate tolerance to deliver various chiral pyrrolo[1,2-
a]indoles in up to 93% yield and 98% ee. The utility of this method is highlighted by the diverse transformations of the products into
various indole derivatives.
hiral pyrrolo[1,2-a]indole scaffolds are key skeletons
It is generally considered that indoles are nucleophilic at the
C3, C2, and N1 positions, and this unique property provides
the possibility to regioselectively functionalize indole-contain-
ing substrates by cascade reaction sequences, thus resulting in
C
found in a range of natural products and pharmaceut-
1
icals. As representative examples shown in Figure 1, such
5
chiral polycyclic indole derivatives. Clearly, the key to
synthesize pyrrolo[1,2-a]indoles directly from indoles is to
rationally employ proper electrophiles, which could regiose-
lectively react with the C2- and/or N1-position of indoles. In
2
013, Xiao et al. reported a Cu-catalyzed asymmetric Friedel−
Crafts alkylation/N-hemiacetalization cascade reaction be-
tween 3-substituted indoles and β,γ-unsaturated α-ketoesters
4b
(
Scheme 1a). The process enables the efficient construction
of diversely functionalized pyrrolo[1,2-a]indoles with a N-
hemiacetal group. Shortly thereafter, Wang et al. described a
Pd-catalyzed cascade reaction of 3-alkylindoles with oxindolyl
β,γ-unsaturated α-ketoesters to synthesize various spiro-
polycyclic indole derivatives (Scheme 1b). In light of the
importance of pyrrolo[1,2-a]indoles with a tetrasubstituted
carbon stereocenter, it is still highly desirable and challenging
to develop methods for rapid construction of pyrrolo[1,2-
a]indole skeletons with novel and complex structures under
mild conditions.
Figure 1. Representative examples of natural and biologically active
products containing the pyrrolo[1,2-a]indole core.
4h
compounds exhibit antitumor, analgetic, or anticancer proper-
2
ties and have attracted much attention in medicinal chemistry.
Thus, developing efficient catalysis methodologies for enantio-
enriched pyrrolo[1,2-a]indoles is highly desirable. In recent
decades, a number of seminal studies were conducted for the
construction of chiral pyrrolo[1,2-a]indoles, including cycliza-
tion of N-substituted indoles, (3 + 2) cycloaddition of
nitrovinylindoles or 1H-indole-2-carbaldehyde, and a C-2
On the other hand, propargylic alcohols are easily available
building blocks and have been extensively applied in the
6
construction of heterocyclic compounds. However, it remains
difficult to control the enantioface selection of propargylic
3
,4
Received: May 29, 2020
functionalization and annulation sequence of indoles.
Despite the significance of these approaches, most of these
strategies utilize prefunctionalized substrates or require
multiple steps, and the direct asymmetric catalytic function-
alizations of indoles to pyrrolo[1,2-a]indoles bearing the
tetrasubstituted carbon stereocenter remains rare.
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01812
A
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a
Scheme 1. Asymmetric Synthesis of Pyrrolo[1,2-a]indoles
Table 1. Optimization of the Reaction Conditions
Bearing the Tetrasubstituted Carbon Stereocenter
b
c
Entry
Catalyst
Solvent
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
CH Cl2
51
70
16
65
75
70
79
42
75
78
72
73
61
69
73
78
51
81
83
85
86
−41
−66
−51
−77
−17
81
22
24
77
87
84
90
81
86
90
87
3
90
2
CH Cl2
2
CH Cl2
2
CH Cl2
2
CH Cl2
2
CH Cl2
2
4g
5a
5b
5c
5d
5c
5c
5c
5c
5c
5c
5c
5c
5c
4f
CH Cl2
2
CH Cl2
2
CH Cl2
2
10
11
12
13
14
15
16
17
18
19
20
21
CH Cl2
2
CH Cl2
2
d
d
d
d
d
d
d
d
d
d
CH Cl2
2
CHCl3
toluene
C H Cl
6
5
C H CF
3
6
5
cation species which are generated in situ by elimination of the
hydroxy group, leaving catalytic asymmetric cycloaddition of
propargylic alcohols to indoles uncertain. On the basis of our
continuing interest in asymmetric synthesis, herein we report
an organocatalytic enantioselective synthesis of chiral pyrrolo-
CH CN
3
,
,
,
,
e
f
CH Cl2
2
CH Cl2
90
91
90
2
f
f
,
g
C H Cl/CH Cl
2
6
5
2
CHCl3
[1,2-a]indoles using 3-substituted 1H-indoles and propargylic
a
Use of 1a (0.06 mmol), 2a (0.066 mmol), a catalyst (0.003 mmol),
alcohols containing functional directing groups (NHAc or OH;
b
and a solvent (0.6 mL), room temperature (RT), 48 h. Determined
7
,8
Scheme 1).
Therefore, the stereochemistry of the
1
by H NMR with 1,2-dichloroethane as internal standard.
c
d
propargylic carbocation intermediate could be controlled via
hydrogen bonding of the p-acetamido/hydroxy group with a
chiral Brønsted acid catalyst.
Determined by chiral HPLC. 4 Å Molecular sieves (50 mg) was
e
f
used. Phenylboronic acid (20 mol %) was used. 4-Fluorophenylbor-
g
onic acid (20 mol %) was used. C H Cl/CH Cl = 0.4/0.2 mL.
6 5 2 2
We initiated our investigation by using 3-methyl-1H-indole
1
%
a and propargylic alcohol 2a as model substrates, with 5 mol
with weaker acidity appear to be suitable and act as a hydrogen
bond donor providing enhanced reactivity without detrimental
effect on enantioselectivity. To our delight, the addition of 4-
fluorophenylboronic acid increased the yield of 3a to 83% with
90% ee (Table 1, entry 19). Subsequently, it was found the
optimized reaction conditions required catalyst 5c (5 mol %),
4-fluorophenylboronic acid (20 mol %), and 4 Å molecular
sieves in C H Cl/CH Cl mixed solvents (Table 1, entry 20).
9
of chiral phosphoric acids or phosphoramides as catalyst.
Gratifyingly, the reaction proceeded smoothly in dichloro-
methane at room temperature in the presence of catalyst 4a,
and the desired pyrrolo[1,2-a]indole 3a was obtained in 51%
yield with 41% ee (Table 1, entry 1). Screening of other
catalysts with different backbones and steric environments
Table 1, entries 2−11) showed that catalyst 5c with chiral
spirocyclic skeleton was suitable, affording 3a in 78% yield with
7% ee (Table 1, entry 10). Therefore, we chose 5c as the
catalyst for further optimizations. The addition of 4 Å
molecular sieves improved the enantioselectivity, albeit with
a slightly lower yield (Table 1, entry 12). Furthermore, solvent
screening was carried out in the hope of improving the reaction
yield. Disappointingly, no better results were obtained (Table
(
6
5
2
2
In addition, with H8-BINOL-derived catalyst 4f in CHCl , the
3
8
product 3a could also be obtained in similar yield and
enantioselectivity (Table 1, entry 21 vs 20; see the SI for
details).
With the optimized conditions in hand, the reaction scope
was initially assessed using a range of 3-substituted 1H-indoles
1 with propargylic alcohol 2a (Scheme 2, 3a−3o). All 3-
methyl-1H-indoles showed excellent reactivity with either
electron-withdrawing groups (Cl or Br) or electron-donating
groups (Me or OMe) on the phenyl ring, generating the
products in 64−81% yields with 87−98% ee (3b−3m).
1
, entries 13−17). Different Brønsted acids with varying acidity
were also evaluated as additives (Table 1, entries 18−19; for
10
more examples, see the Supporting Information (SI)). While
stronger acids led to lower enantioselectivities, boronic acids
B
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a
Scheme 2. Scope of 3-Substituted 1H-Indoles and Propargylic Alcohols
a
Conditions A: Use of indole 1 (0.13 mmol), propargylic alcohol 2 or 6 (0.12 mmol), 5c (0.006 mmol), 4-F-C H B(OH) (0.024 mol), and 4 Å
6
4
2
molecular sieves (100 mg) in C H Cl/CH Cl (0.8/0.4 mL) at RT for 48 h. Yields of isolated products are reported. The enantiomeric excess was
6
5
2
2
b
determined by chiral HPLC methods. Conditions B: Use of 1 (0.13 mmol), propargylic alcohol 2 or 6 (0.12 mmol), 4f (0.006 mmol), 4-F-
C H B(OH) (0.024 mmol), and 4 Å molecular sieves (100 mg) in CHCl (1.2 mL) at RT for 48 h.
6
4
2
3
However, 7-bromo and 7-methyl substituted 1H-indoles
electron-withdrawing (Br or Cl) and electron-donating (Me or
reacted with relatively lower yields due to steric hindrance
OMe) groups were compatible, and the reactions produced the
desired products in moderate to good yields (63−80%) and
high enantioselectivities (90−95% ee, 3p−3x). Propargylic
alcohols with a 2-naphthyl or 3-thienyl group also gave good
yields (71−73%) and excellent enantioselectivities (91−92%
(
3d and 3m). The 3-substituted group of 1H-indole appears to
have less effect on the reaction, and both 3-ethyl and 3-phenyl
H-indoles afforded the cyclic adduct 3 in good yields and
1
enantioselectivities (3n−3o). Next, we explored the scope of
propargylic alcohols. A number of propargylic alcohols 2
having aryl, heteroaryl, and alkyl groups were well tolerated
under optimized conditions (Scheme 2, 3p−3ab). In addition,
the electronic properties of the substituents on terminal aryl
groups of alkynes have little effect on the reaction. Both
4
ee, 3y−3z). In addition, alkyl (R = benzyl and cyclohexyl)
substituted propargylic alcohols 2 proceeded smoothly to
afford the desired products in moderate yields and relatively
low enantioselectivities (3aa−3ab). Encouraged by these
3
results, propargylic alcohols 6 (R = Ph) with pronounced
C
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Letter
steric hindrance were also investigated. The reaction gave
desired adducts in higher yields compared with propargylic
alcohol 2 (3ac−3ag). Various substituted 1H-indoles reacted
with propargylic alcohols 6 and afforded cyclic products in
good to excellent yields (71−93%) and enantioselectivities
intermediates, the racemic allene 11 was synthesized and
fully characterized. It was further discovered that, in the
presence of catalyst 5c under optimized reaction conditions, 11
was smoothly converted into the corresponding product 3a in
95% yield and 80% ee, and the ee of 11 continued to increase
to >99% as the reaction proceeded further (Scheme 3b).
Based on these results and previous reports, we proposed the
following plausible reaction mechanism for the formation of
3ac (Figure 2). Firstly, the in situ dehydration of the
(
88−92% ee). The absolute configuration of 3ag was
determined to be (R) by X-ray crystallographic analysis, and
the configuration of other pyrrolo[1,2-a]indoles 3 were
assigned by analogy.
To probe the reaction mechanism, several control experi-
ments were carried out (Scheme 3). N-Methylated propargylic
Scheme 3. Several Control Experiments
Figure 2. Plausible reaction mechanism.
propargylic alcohol generates the aza-p-QMs intermediate in
the presence of chiral phosphoric acid (CPA). CPA serves as a
bifunctional catalyst to activate both the aza-p-QMs
intermediate and 1a by hydrogen bonding (TS1). Due to
the steric hindrance of aza-p-QMs at the 6-position, the
reaction prefers kinetically the 1,8-conjugate addition of the
C2-position of indole 1a to generate the chiral tetrasubstituted
allene (TS2). Finally, the hydrogen-bonded chiral allene is
protonated to generate the benzylic cation (TS3), which
undergoes intramolecular cyclization to provide the cyclic
product 3ac. The presence of the N−H moiety in propargylic
alcohols is pivotal, which not only accelerates the dehydration
of propargylic alcohol to form aza-p-QMs but also interacts
with the catalyst to control chiral induction during dynamic
kinetic resolution of the allene intermediate.
alcohols (7a and 7b) and 2,4-diphenylbut-3-yn-2-ol (7c)
reacted with indole 1a giving no adducts 8 under the
optimized conditions (Scheme 3a). The application of the
present method to a propargylic alcohol with a p-
hydroxyphenyl substituent (7d) also provided the desired
product in 62% yield and 87% ee. The reaction of propargylic
alcohol 7e with the acetamido group at the ortho-position gave
cyclic product 8e in 14% yield and 6% ee. These results
indicate that a hydrogen-bond donor at the para-position of
propargylic alcohols is essential for activation and chiral
induction.
12
To demonstrate the synthetic value of these pyrrolo[1,2-
a]indole derivatives, further transformations of 3a were carried
13,14
With respect to the mechanism of formation of pyrrolo[1,2-
a]indole skeletons, we considered that it may proceed through
two pathways: the first pathway could involve the attack of aza-
quinone methides (aza-p-QMs) by the C2 of indoles through
out (Scheme 4).
Dihydropyrroloindole 9a was formed by
hydroboration of 3a followed by oxidation in good yield (71%)
with excellent diastereoselectivity (d.r. > 20/1). This sequence
provided an expeditious access to indole derivatives possessing
13a
1
,8-addition to generate allene followed by intramolecular N−
three contiguous stereocenters. The brominated product 9b
could be obtained in 84% yield by the reaction of 3a with
bromine, which can be used as a versatile intermediate for
further modifications. The acetamido group of 3a was
hydrolyzed to an amino group after being treated with 4 N
C bond formation, while the second pathway is the attack of N
in indoles to aza-p-QMs through 1,6-addtion to generate N-
propargyl indole followed by intramolecular C−C bond
formation. To better understand the reaction pathway, density
functional theory (DFT) calculations were carried out, which
revealed that the 1,8-addition to generate tetrasubstituted
allene has a lower energy barrier than 1,6-addition (5.5 vs 19.8
8
g
HCl, and the amine was further converted into the
13b
corresponding halide derivative 9c in 82% yield. In addition,
indole 1p reacted smoothly with propargylic alcohol 10 under
the optimized conditions to give pyrrolo[1,2-a]indole 9d in
11
kcal/mol; for details see SI). In order to validate the
mechanism on the generation of tetrasubstituted allene
14
47% yield with 94% ee.
D
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Scheme 4. Synthetic Applications
AUTHOR INFORMATION
Corresponding Author
■
Yuehui Li − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, P. R. China;
orcid.org/0000-0002-4520-1418; Email: yhli@licp.cas.cn
Authors
Jian-Fei Bai − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, P. R. China
Lulu Zhao − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Fang Wang − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, P. R. China
Fachao Yan − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Taichi Kano − Department of Chemistry, Graduate School of
Science, Kyoto University, Kyoto 606-8502, Japan;
In conclusion, we have developed the first organocatalytic
asymmetric formal (3 + 2) cycloaddition of 3-substituted 1H-
indoles with readily available propargylic alcohols containing a
functional directing group (p-NHAc or p-OH). Under mild
reaction conditions, a variety of valuable chiral pyrrolo[1,2-
a]indoles bearing the tetrasubstituted carbon stereocenter were
conveniently constructed with excellent reactivity, regioselec-
tivity, and enantioselectivity. In this system, an acetamido
group that acts as both the activating and directing group is
crucial for the cycloaddition and favorable for hydrogen
bonding and chiral induction with chiral phosphoric acid
catalysts. Besides, chiral pyrrolo[1,2-a]indoles were amenable
to further transformations and enabled convenient synthesis of
indole derivatives. This protocol provided a potentially
effective method for the construction of various chiral cyclic
compounds from propargylic alcohols. Further studies of this
process with respect to other nucleophiles are currently
underway.
orcid.org/0000-0001-5730-3801
Keiji Maruoka − Department of Chemistry, Graduate School of
Science, Kyoto University, Kyoto 606-8502, Japan;
orcid.org/0000-0002-0044-6411
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01812
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the NSFC
21633013, 21602228, 91745104) and NSF of Jiangsu
■
(
Province (BK20180248). We are grateful to Prof. Shoufei
Zhu at Nankai University for the kind gift of the chiral
phosphoric acids 5a−c.
ASSOCIATED CONTENT
sı Supporting Information
■
*
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