Organocatalytic enantioselective tandem sulfa-Michael/aldol reaction to access dihydrothiopyran-fused benzosulfolane skeletons bearing three contiguous stereocenters

Article abstract of DOI:10.1039/d0cc04840b

The first organocatalytic diastereo- and enantioselective tandem sulfa-Michael/aldol reaction of 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzaldehydes with benzo[b]thiophene sulfones was developed. With multiple hydrogen-bonding thiourea as a catalyst, a wide range of polycyclic dihydrothiopyran-fused benzosulfolanes were smoothly obtained with excellent results (up to 99% yield, 420 : 1 dr and 99% ee) under mild reaction conditions.

Full text of DOI:10.1039/d0cc04840b

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Yang, J. Zhao,
Y. You, Z. Wang and W. Yuan, Chem. Commun., 2020, DOI: 10.1039/D0CC04840B.
Volume 54
Number
January 2018
Pages 1-112
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
1
4
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC04840B
Journal Name
COMMUNICATION
Received 00th January 20xx,
Accepted 00th January 20xx
Organocatalytic enantioselective tandem sulfa-
Michael/aldol reaction to access dihydrothiopyran-
fused benzosulfolane skeletons bearing three
contiguous stereocenters
DOI: 10.1039/x0xx00000x
www.rsc.org/
a,c
b
b
b
b
Lei Yang, Jian-Qiang Zhao, Yong You, Zhen-Hua Wang, and Wei-Cheng Yuan *
The first organocatalytic diastereo- and enantioselective tandem strategies to access sulfur-containing polycyclic compounds,
sulfa-Michael/aldol reaction of 2-mercaptoindole-3-carbaldehydes such as dihydrothiopyran-fused benzosulfolanes (Figure 1,
and 2-mercaptobenzaldehydes with benzo[b]thiophene sulfones bottom), is pharmaceutically intriguing and significant.
was developed. With multiple hydrogen-bonding thiourea as the
O
HO
catalyst, a wide range of polycyclic dihydrothiopyran-fused
benzosulfolanes were smoothly obtained with excellent results
core skeleton
OH
CO2CH3
HO
H
O
Me
O
Me
OH
O
OH
dihydropyran-fused
dihydrobenzofuran
well studied)
(
up to 99% yield, >20:1 dr and 99% ee) under mild reaction
O
O
H
O
CO2CH3
(
H
O
Me
conditions.
(
+)-paeoveitol
rubioncolin B
HO2C
O
S
H
O
sulfur analogues
Me
Fused polycyclic heterocycles are ubiquitous in a wide range
OH
N
H
1
O
O
O
N
N
N
of natural and unnatural biologically active molecules. Among
HN
H N
S
H
NH
NHAc
O
Bn
Cl
S
them, dihydropyran-fused dihydrobenzofurans as a type of
oxygen-containing tricyclic skeletons have been well studied
by organic chemists and pharmacologists (Figure 1, top),
because many chiral compounds containing this skeletons
have shown a wide spectrum of significant bioactivities, such
2
tazobactam
HIV I protease inhibitor
work design
HO
O
HO
O
S
H
H
H
O
O
S
S
dihydrothiopyran-fused
dihydrobenzothiophene
(
unknown)
N
S
S
H
H
dihydrothiopyran-fused benzosulfolanes
2
Figure 1. Project design.
as anti-inflammation, anti-bacteria, and anti-tumor activity.
The replacement of the oxygen atom in the dihydropyran-
fused dihydrobenzofuran skeletons with sulfur atom generally
Benzo[b]thiophene sulfones, behaving as powerful
dipolarophiles, have been used in 1,3-dipolar cycloaddition
reactions with various dipoles for the construction of polycyclic
results
in
the
corresponding
sulfur
analogues
dihydrothiopyran-fused dihydrobenzothiophenes (Figure 1,
bottom). It is a very promising strategy that replacing the
oxygen atom in biologically active molecules with sulfur atom
for the research and development of pharmaceuticals, and
some reports also prove the benefits of this strategy in
5-8
benzosulfolane compounds. However, a survey of literature
reveals that only two examples about the catalytic
enantioselective cycloaddition of benzo[b]thiophene sulfones
have been documented so far: in the first
[
4
Cu(MeCN) ]PF
6
/DTBM-Segphos
catalyzed
reaction
of
3
enhancing the pharmacological activity. In particular, many
azomethine ylides with benzo[b]thiophene sulfones resulted in
sulfur-containing fused polycyclic compounds have shown
6
exo-pyrrolidine-fused benzosulfolanes (Scheme 1), while in
4
potential biological activities in medicinal chemistry. In this
the other, the same reaction also could provide exo-
pyrrolidine-fused benzosulfolanes with Cu(MeCN) PF /DTBM-
4 6
context, as we can visualize, the molecules containing
dihydrothiopyran-fused
dihydrobenzothiophene
motifs
Segphos complex but endo-cycloadducts as major products
probably also have some biological activities in drug discovery.
Accordingly, the development of new and facile synthetic
7
with AgOAc/ThioClickFerrophos complex (Scheme 1). To our
surprise, the involvement of benzo[b]thiophene sulfones to
access polycyclic benzosulfolane compounds with asymmetric
organocatalysis has yet to be developed, even though the
asymmetric organocatalysis has become an efficient and
versatile tool for the construction of elaborated polycyclic
a. National Engineering Research Center of Chiral Drugs, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China.
b.
Institute for Advanced Study, Chengdu University, Chengdu 610106, China.
E-mail: yuanwc@cioc.ac.cn
University of Chinese Academy of Sciences, Beijing, 100049, China
9
c.
heterocycles. In this context, on the basis of our long-standing
†
Electronic Supplementary Information (ESI) available: Experimental procedures,
studies
on
organocatalytic
asymmetric
tandem
spectral data of new compounds, and crystallographic data. CCDC 2007793 and
1
0
2
007795. For ESI and crystallographic data in CIF or other electronic format. See transformations, we envisioned that 2-mercaptoindole-3-
DOI: 10.1039/x0xx00000x
carbaldehydes and 2-mercaptobenzaldehydes should react
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
OH
O
O
CHO
O
with benzo[b]thiophene sulfones via an asymmetric tandem
sulfa-Michael/aldol reaction process, thus leading to the
construction of dihydrothiopyran-fused benzosulfolane
skeletons bearing three contiguous stereocenters (Scheme 1).
To the best of our knowledge, the synthesis of chiral
dihydrothiopyran-fused indole compounds via a catalytic
asymmetric approach is rarely reported. Herein, we wish to
report our success in this tandem reaction catalyzed by a
multiple hydrogen-bonding thiourea organocatalyst. Notably,
this work represents the first organocatalytic asymmetric
transformation of benzo[b]thiophene sulfones.
O
H
View Article Online
S
S
2
0 mol% Cat.
DOI: 10.1039/D0CC04840B
SH
+
N
solvent, rt, time
N
S
H
Boc
a
Boc
1
2a
3a
iPr
CF3
CF3
S
CF3
S
N
O
N
N
H
N
N
N
H
H
NH
H
H
H
1
1
MeO
CF3
MeO
N
A
B
N
CF3
S
CF3
S
O
O
N
H
N
H
N
H
N
N
N
H
H
H
tBu
N
Ph
N
CF3
CF3
C
D
Scheme
1
Catalytic asymmetric transformations of
entry Cat. solvent time (h) yield (%)b
drc
ee (%)c
benzo[b]thiophene sulfones.
1
2
3
4
5
6
7
A
B
C
CHCl
CHCl3
CHCl
CHCl3
CH Cl
3
16
48
36
36
36
36
36
72
72
72
48
51
95
98
98
97
98
98
98
98
98
98
86:14
59:41
78:22
92:8
90:10
93:7
95:5
97:3
97:3
97:3
27
57
94
95
96
96
97
98
98
98
98
previous work: transition metal catalysis
O
S
O
O O
S
R1
H
R2O C
H
O
S
2
O
[Cu] or [Ag]
chiral ligand
3
R1
N
CO2R2
+
+
HN
HN
ref. 6 and ref. 7
H
D
D
D
D
D
D
D
D
H
CO2R
2
R1
2
2
exo
endo
MTBE
this work: asymmetric organocatalysis
CHO
HO
O
O
toluene
toluene
toluene
toluene
toluene
CHO
H
H
HO
O
O
SH
S
d
H
O
S
8
9
N
S
O
SH
organocatalyst
Boc
organocatalyst
e
N
S
S
f
Boc
10
H
the first organocatalytic asymmetric reaction of benzo[b]thiophene sulfones
dihydrothiopyran-fused benzosulfolane skeletons containing three contiguous stereocenters
the combination of indoles and dihydrothiopyran-fused benzosulfolanes
f,g
1
1
97:3
a
Unless otherwise noted, the reactions were carried out with 1a (0.12 mmol), 2a
promising in medicinal application as potential biologically active candidates
(
0.1 mmol), and 20 mol% of catalyst in 1.0 mL of solvent at room temperature.
b
c
d
o
e
Isolated yields. Determined by chiral HPLC analysis. Run at 0 C. 10 mol% D
C. The ratio of 1a:2a = 1.1:1, and 10 mol% D was used at 0 C. 0.5
mL of toluene was used.
We initiated our investigation with the reaction of 2- was used at 0
mercaptoindole-3-carbaldehyde 1a and benzo[b]thiophene
sulfone 2a in CHCl at room temperature (Table 1). With 20
mol% quinine-derived thiourea A as the catalyst, the reaction
gave the polycyclic product 3a in 51% yield with 86:14 dr and
o
f
o
g
3
Having identified the optimal reaction conditions, the
scope and limitation were explored for different 2-
mercaptoindole-3-carbaldehydes and benzo[b]thiophene
sulfones (Table 2). The asymmetric tandem reaction tolerated
a wide range of 2-mercaptoindole-3-carbaldehydes bearing an
electron-withdrawing substituent on the aryl group, regardless
of their positions, affording products 3b-f in excellent yields
and stereoselectivities (entries 2-6). Similarly, the substrates
bearing an electron-donating group on the aryl ring of 2-
mercaptoindole-3-carbaldehydes were also compatible with
the conditions. Almost quantitative yields and >20:1 dr with
2
7% ee (entry 1). Application of catalyst B, which derived from
quinine and L-valine bearing multiple hydrogen-bonding
donors, afforded product 3a in 95% yield with 59:41 dr and
5
7% ee (entry 2). Likewise, multiple hydrogen-bonding
thiourea catalyst C, which derived from (S,S)-cyclohexane-1,2-
diamine and L-phenylglycine, could also efficiently promote
the cycloaddition reaction and furnished 3a in quantitative
yield with improved diastereo- and enantioselectivity (entry 3).
To our delight, replacing the phenyl group of catalyst C with
more sterically hindered tertiary butyl group resulted in the
catalyst D, and the reaction with D proceeded smoothly to give
9
3-99% ee were obtained for products 3g-i (entries 7-9).
Benzo[b]thiophene sulfones having an electron-withdrawing
substituent on the aryl ring were able to participate
successfully in the asymmetric tandem reaction to give
products 3j-q in excellent results (entries 10-17). Meanwhile, it
was also found that the developed protocol allowed the
installation of various electron-donating substituents at
different positions on the aromatic ring, and these substrates
smoothly gave rise to their corresponding products 3r-t in
acceptable results (entries 18-20). Product 3s was obtained in
3
a in 98% yield with 92:8 dr and 95% ee (entry 4). Afterwards,
experiments were carried out with different solvents including
CH Cl , MTBE and toluene, and it revealed that toluene was
2
2
the best candidate in the light of stereoselectivitiy (entry 7 vs
o
5
-6). Lowering the reaction temperature to 0 C, 3a was
obtained with slightly improved dr and ee values (97:3 dr and
8% ee) (entry 8). Decreasing the catalyst loading from 20
9
mol% to 10 mol%, the reaction afforded 3a with unchanged
results (entry 9). Adjusting the ratio of substrates 1a to 2a
from 1.2:1 to 1.1:1, the excellent results were still maintained
8
1% yield with >20:1 dr but only 61% ee. It was probably due
to the more steric hindrance from the methyl group in the C7-
position of the benzo[b]thiophene sulfone (entry 19).
Additionally, phenyl group at the C5- or C6-position was also
well tolerated, furnishing products 3u and 3v in almost
quantitative yields with 98% and 99% ee, respectively (entries
(
entry 10). Ultimately, enhancing the concentration of 2a to
.2 mmol/mL was able to markedly accelerate the rate of the
reaction without loss in the yield and stereoselectivity (entry
1).
0
1
2
1 and 22). However, it was found that both N-Me and N-Bn
Table 1. Optimization of reaction conditionsa
substituted 2-mercaptoindole-3-carbaldehydes did not react
with 2a under the standard conditions (no shown in Table 2).
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
ChemComm
Journal Name
COMMUNICATION
O
S
HO
O
O
S
Disappointingly, 2-methyl benzo[b]thiophene sulfone and 3-
methyl benzo[b]thiophene sulfone were also tested, but no
reaction occurred (no shown in Table 2). This negative
outcome may be ascribed to the too much steric hindrance
reducing the reactivity.
O
H
View Article Online
R1
1
CHO
SH
R
1
0 mol% D
DOI: 10.1039/D0CC04840B
+
toluene, -20 oC
R2
S
R2
5 h
H
O
4
2
5a-f
HO
O
O
HO
O
O
HO
S
O
H
H
H
S
S
S
Table 2. Substrates scope of 2-mercaptoindole-3-
S
S
Cl
a
H
H
H
carbaldehydes 1 and benzo[b]thiophene sulfones 2
F
5
a: 92% yield
5b: 98% yield
>20:1 dr, 95% ee
5c: 98 %yield
>20:1 dr, 93% ee
R1
HO
O
O
S
R1
CHO
O
S
H
>20:1 dr, 93% ee
O
1
0 mol% D
HO
O
O
HO
O
O
H
H
HO
S
O
O
S
SH
+
toluene, 0 o
S
Br
S
OMe
Me
C
H
N
N
S
R2
48 h
H
R2
Boc
a, R1 = H;
d, R1 = 6-Cl; 1e, R1 = 5-Br;
Boc
S
S
1
2
3a-v
H
H
Ph
1b, R1 = 5-F;
1c, R1 = 5-Cl
1f, R1 = 6-Br
g, R1 = 5-Me; 1h, R1 = 5-MeO; 1i, R1 = 6-MeO
H
1
5
d: 90% yield
5
e: 99% yield
20:1 dr, 96% ee
5f: 89% yield
>20:1 dr, 98% ee
1
1
>20:1 dr, 96% ee
>
a
Unless otherwise noted, the reactions were carried out with 4 (0.11 mmol), 2
(0.1 mmol), and catalyst D (10 mol%) in 0.5 mL of toluene at -20
refer to isolated pure compounds. The dr value was determined by H NMR. The
ee was determined by chiral HPLC analysis.
R2 (2)
3/yield (%)b
drc
ee (%)d
o
C for 5 h. Yields
entry
1
1
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1a
1a
1a
1a
1a
1a
1a
1a
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
4-F (2b)
5-F (2c)
4-Cl (2d)
5-Cl (2e)
7-Cl (2f)
4-Br (2g)
5-Br (2h)
6-Br (2i)
5-Me (2j)
3a/98
3b/99
3c/98
3d/96
3e/95
3f/95
3g/98
3h/97
3i/98
>20:1
10:1
7:1
98
97
95
97
93
97
93
97
99
99
98
97
98
78
97
98
99
98
61
99
98
99
e
In order to illustrate the potential applicability of the
methodology, the model reaction between 1a and 2a was
carried out on a gram scale (Scheme 3). Under the standard
reaction conditions, the gram-scale reaction proceeded
smoothly and afforded 3a in almost quantitative yield with
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
13:1
>20:1
13:1
>20:1
>20:1
12:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1
2
>
20:1 dr and 99% ee. Meanwhile, a preparative scale reaction
of 4a and 2a was also performed, and provided 5a in excellent
results. These preparative scale reactions indicate that the
developed protocol has the potential to be used as a practical
strategy for the synthesis of chiral dihydrothiopyran-fused
benzosulfolane compounds.
1
1
1
1
1
0
1
2
3
4
3j/99
3k/97
3l/98
3m/98
3n/99
3o/99
3p/99
3q/99
3r/98
3s/81
3t/99
3u/98
3v/98
e
1
1
1
5
6
7
Scheme 3 Preparative scale reactions of 3a and 5a.
HO
O
O
S
OH
O
O
O
O
H
H
S
S
1a (2.75 mmol)
10 mol% D
toluene, 0 o
4a (1.10 mmol)
10 mol% D
e
1
1
8
9
N
S
S
2a
toluene, -20 o
C
H
5a
H
C
f
Boc
1a 7-Me (2k)
1a 6-MeO (2l)
1a 5-Ph (2m)
48 h
5 h
3a
0.292 g, 96% yield
1.09 g, 98% yield
2
2
2
0
1
2
>20:1 dr, 93% ee
>
20:1 dr, 99% ee
1a
6-Ph (2n)
Moreover, we tried to evaluate their potential bioactivity
randomly selected pentaheterocyclic
indolodihydrothiopyran-fused benzosulfolanes 3 by testing
their cytotoxicity in vitro using the K562 leukemia cell line. The
preliminary results revealed that the tested compounds
exhibited cytotoxicity with median inhibitory concentration
a
All the reactions were carried out with 1 (0.11 mmol), 2 (0.1 mmol), and catalyst
o
b
c
of
D (10 mol%) in 0.5 mL of toluene at 0 C for 48 h. Isolated yield. Determined by
1
d
e
f
H NMR. Determined by chiral HPLC analysis. Run for 60 h. Run for 72 h.
Encouraged by the success of the above tandem reaction,
we further investigated the asymmetric tandem reaction of 2-
mercaptobenzaldehydes 4 and 2 for the synthesis of (IC ) values in the micromolar range (see Supporting
5
0
tetraheterocyclic benzodihydrothiopyran-fused benzosulfolane Information). Compared with commercially available broad-
compounds (Scheme 2). Using D as the catalyst, the reaction of spectrum anticancer drug cisplatin as a positive control,
compounds 3d, 3g and 3i showed impressive cytotoxicity
against K562 leukemia cells with IC50 values in the lower
micromolar range (Figure 2). The results suggest that these
structurally novel polycyclic benzodihydrothiopyran-fused
benzosulfolane derivatives might be promising in drug
discovery for further investigation.
2
-mercaptobenzaldehyde 4a and 2a proceeded to completion
o
in toluene at -20 C for 5 h, affording the desired product 5a in
9
2% yield with >20:1 dr and 93% ee. Substrates bearing either
electron-withdrawing or electron-donating group at the
aromatic ring of benzo[b]thiophene sulfones, regardless of
their positions, all could react with 2-mercaptobenzaldehyde
smoothly to give products 5b-e in 90-99% yields with >20:1 dr
and 93-96% ee values. Moreover, substrate bearing electron-
donating group such as methyl group on the C5-position of 2-
mercaptobenzaldehyde was also well tolerated, furnishing 5f
in 89% yield with excellent diastereo- and enantioselectivity.
HO
O
O
S
HO
O
O
S
HO
O
O
H
H
H
Me
S
N
S
N
S
N
S
MeO
Cl
H
H
H
Boc
Boc
Boc
3d
3g
IC50 = 17.08 uM
3i
IC50 = 12.04 uM
IC50 = 10.31 uM
Figure 2. Biological activities evaluation of target products in
K562 leukemia cell line.
Scheme 2 Substrates scope of 2-mercaptobenzaldehydes and
benzo[b]thiophene sulfones.a
Based on our experimental results and previously relevant
reports regarding to the multiple hydrogen-bonding
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
bifunctional thiourea in asymmetric catalysis,13 we proposed a
Hossain, D. V. D. Helm and T. R. Breitman, J.VMieweAdr.ticClehOenmlin.e,
987, 30, 1474; (b) L. A. V. Vliet, N. Rodenhuis, D. Dijkstra, H.
Wikstrom, T. A. Pugsley, K. A. Serpa, L. T. Meltzer, T. G.
Heffner, L. D. Wise, M. E. Lajiness, R. M. Huff, K. Svensson, S.
Sundell and M. Lundmark, J. Med. Chem., 2000, 43, 2871.
1
DOI: 10.1039/D0CC04840B
plausible transition state model to account for the
stereochemistry of the tandem reaction (see Supporting
Information).12 The benzo[b]thiophene sulfone was activated
and oriented by the thiourea NH and amide NH of the catalyst 4. For reviews, see: (a) K. Takimiya, S. Shinamura, I. Osaka and
E. Miyazaki, Adv. Mater., 2011, 23, 4347; (b) C. Wang, H.
Dong, W. Hu, Y. Liu and D. Zhu, Chem. Rev., 2012, 112, 2208.
. (a) F. Sauter and G. Büyük, Monatsh. Chem., 1974, 105, 254;
D, while 2-mercaptoindole-3-carbaldehyde was deprotonated
and activated by the tertiary amine moiety of the catalyst to
enhance the nucleophilicity. Under this dual-activation mode
and stereoselective induction of chiral catalyst D, the sulfur
anion of 2-mercaptoindole-3-carbaldehyde attacks the Re-face
of C3-position of benzo[b]thiophene sulfone via a sulfa-
Michael addition process. Subsequently, the C2-position of
benzo[b]thiophene sulfone attacks the aldehyde group of 2-
mercaptoindole-3-carbaldehyde from Re-face through an
intramolecular aldol reaction process. As a result, this tandem
reaction generates the polycyclic dihydrothiopyran-fused
benzosulfolane products with stereospecific configurations.
The absolute configuration of adduct 3a was assigned as (C7R,
C8R, C9S) and 5a was also assigned as (C7R, C8R, C9S) with the
single crystal X-ray analysis. The stereochemistry of the other
5
(b) U. Fischer and F. Schneider, Helv. Chim. Acta., 1980, 63,
1
719; (c) A. F. Marinone, P. Ceva, A. Mascherpa, E. Albini and
P. Caramella, Tetrahedron, 1982, 38, 3629. (d) A. Bened, R.
Durand, D. Pioch and P. Geneste, J. Chem. Soc., Perkin Trans.
2
, 1984, 1, 1; (e) N. Malatesti, A. N. Boa, C. Clark and R.
Westwood, Tetrahedron Letters, 2006, 47, 5139; (f) N. V.
Lakshmi, P. Thirumurugan, C. Jayakumar and P. T. Perumal,
Synlett, 2010, 6, 955; (g) S. S. Y. Wong, M. G. Brant, C. Barr,
A. G. Oliver and J. E. Wulff, Beilstein J. Org. Chem., 2013, 9,
1
419. (h) K.-K. Wang, Y.-L. Li, G.-Y. Ma, M.-H. Yi and B.-K.
Zhu, J. Heterocyclic Chem., 2019, 56, 2274.
. H. Deng, F. He, C. Li, W. Yang and W. Deng, Org. Chem.
Front., 2017, 4, 2343.
6
7
8
. M. Harada, S. Kato, R. Haraguchi and S.-I. Fukuzawa, Chem. -
Eur. J., 2018, 24, 2580.
. S. Kathiravan, I. A. Nicholls. Org. Lett., 2019, 21, 9806.
9. For selected reviews, see: (a) A. G. Doyle and E. N. Jacobsen,
Chem. Rev., 2007, 107, 5713; (b) D. Enders, C. Grondal and
M. R. M. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570; (c) H.
Pellissier, Adv. Synth. Catal., 2012, 354, 237; (d) T. Chanda
and C.-G. Zhao, Adv. Synth. Catal., 2018, 360, 2; (e) L. Klier, F.
Tur, P. H. Poulsen and K. A. Jørgensen, Chem. Soc. Rev., 2017,
products was assigned by analogy assuming a common
reaction pathway.14
In conclusion, we have developed a highly diastereo- and
enantioselective tandem sulfa-Michael/aldol reaction of 2-
mercaptoindole-3-carbaldehydes and benzo[b]thiophene
sulfones by using multiple hydrogen-bonding thiourea as the
catalyst. A series of structurally diverse pentaheterocyclic
indolodihydrothiopyran-fused benzosulfolanes, bearing three
contiguous stereocenters, were smoothly obtained with
excellent results (up to 99% yield, >20:1 dr and 99% ee) under
mild reaction conditions. These products are featured by the
fusion of two privileged substructures including indole and
dihydrothiopyran-fused benzosulfolane in one molecular
structure, which maybe serve as the potentially promising
candidates for drug discovery. We also demonstrated that this
4
6, 1080; (f) J. Song, D.-F. Chen and L.-Z. Gong, Natl. Sci.Rev.,
017, 4, 381; (g) F. Vetica, P. Chauhan, S. Dochain and D.
2
Enders, Chem. Soc. Rev., 2017, 46, 1661.
1
0. (a) J.-Q. Zhao, L. Yang, X.-J. Zhou, Y. You Z.-H. Wang, M.-Q.
Zhou, X.-M. Zhang, X-Y Xu, and W.-C. Yuan, Org. Lett., 2019,
2
1, 660; (b) Y.-P. Zhang, Y. You, J.-Q. Zhao, X.-M. Zhang, X.-
Y. Xu and W.-C. Yuan, J. Org. Chem., 2019, 84, 7984; (c) X.-
M. Chen, C.-W. Lei, D.-F. Yue, J.-Q. Zhao, Z.-H. Wang, X.-M.
Zhang, X.-Y. Xu and W.-C. Yuan, Org. Lett., 2019, 21, 5452;
(
d) Y. You, T.-T. Li, S.-P. Yuan, K.-X. Xie, Z.-H. Wang, J.-Q.
Zhao, M.-Q. Zhou and W.-C. Yuan, Chem. Commun., 2020,
6, 439.
1. (a) S. Singh, A. Srivastava and S. Samanta, Tetrahedron Lett.,
012, 53, 6087; (b) L. Wu, Y. Wang and Z. Zhou, Tetrahedron:
Asymmetry, 2014, 25, 1389.
2. For details see the ESI†.
5
catalytic
mercaptobenzaldehydes
system
could
to
be
access
extended
to
2-
1
1
tetraheterocyclic
2
benzodihydrothiopyran-fused benzosulfolanes. This work
represents the first organocatalytic asymmetric tandem
reaction of benzo[b]thiophene sulfones.
13. For selected reviews of multiple hydrogen-bonding
bifunctional thiourea in asymmetric catalysis, see: (a) A. G.
Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713; (b) X.
Yu and W. Wang, Chem. Asian J., 2008, 3, 516; (c) Z. Zhang
and P. R. chreiner, Chem. Soc. Rev., 2009, 38, 1187; (d) X.
Fang and C.-J. Wang, Chem. Commun., 2015, 51, 1185.
We are grateful for financial support from the National
Key R&D Program of China (2018YFC0807301-3), the National
NSFC (21572223, 21871252, and 21901024).
1
4. CCDC-2007793 (3a) and CCDC-2007795 (5a) contain the
Notes and references
supplementary crystallographic data for this paper.
1
. For selected reviews, see: (a) G. Mehta and A. Srikrishna,
Chem. Rev., 1997, 97, 671; (b) K.-I. Takao, R. Munakata and
K.-I. Tadano, Chem. Rev., 2005, 105, 4779; (c) M. Chauhan
and R. Kumar, Med. Chem. Res., 2015, 24, 2259; (d) R. A.
Craig and B. M. Stoltz, Chem. Rev., 2017, 117, 7878.
2
. (a) A.-P. Zhang, M.-Z. Chen and S.-Y. Xu, Chin. Pharmacol.
Bull., 1993, 9, 454; (b) F.-L. Hsu, C.-W. Lai and J.-T. Cheng,
Planta Med., 1997, 63, 323; (c) Y.-F. Qiao, K. Takeya and H.
Itokawa, Chem. Pharm. Bull., 1990, 38, 2896; (d) H. Itokawa,
Z. Z. Ibraheim, Y.-F. Qiao and K. Takeya, Chem. Pharm. Bull.,
1
993, 41, 1869.
3
. (a) L. W. Spruce, S. N. Rajadhyaksha, K. D. Berlin, J. B. Gale, E.
T. Miranda, W. T. Ford, E. C. Blossey, A. K. Verma, M. B.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC04840B
Table of Contents
R2
CHO
SH
R3
R2
HO
S
O
O
S
CHO
H
R3
HO
O
O
S
H
O
S
N
O
SH
Boc
organocatalyst
N
R1
organocatalyst
H
S
R1
H
(10 mol%)
toluene, -20 o
R1
(10 mol%)
Boc
up to 99% yield
>20:1 dr and 99% ee
up to 99% yield
20:1 dr and 98% ee
toluene, 0 o
C
C
>
the first organocatalytic asymmetric tandem reaction of benzo[b]thiophene sulfones
dihydrothiopyran-fused benzosulfolane skeletons containing three contiguous stereocenters
the combination of indoles and dihydrothiopyran-fused benzosulfolanes
promising in medicinal application as potential biologically active candidates
The first organocatalytic enantioselective tandem sulfa-Michael/aldol reaction of
benzo[b]thiophene sulfones was developed for the construction of dihydrothiopyran-fused
benzosulfolane skeletons.