Reversal of Enantioselectivity in the Copper-Aminophenol Sulfonamide Catalyzed Alkynylation of Isatins by Slightly Tuning the Ligand Structure and Basic Additives

Article abstract of DOI:10.1021/acs.orglett.1c01896

A series of new chiral aminophenol sulfonamide ligands with a monochiral arm has been developed for the first Cu(I) catalyzed enantiodivergent alkynylation of isatins. Dramatic reversal of enantioselectivity was accomplished by slightly tuning the substit

Full text of DOI:10.1021/acs.orglett.1c01896

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Letter
Reversal of Enantioselectivity in the Copper-Aminophenol
Sulfonamide Catalyzed Alkynylation of Isatins by Slightly Tuning
the Ligand Structure and Basic Additives
Huakang He, Zinan Yang, Yu Chai, Ruoran Wu, Peng Chen, Jing Zhou,* and Hui Zhou*
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ABSTRACT: A series of new chiral aminophenol sulfonamide
ligands with a monochiral arm has been developed for the first Cu(I)
catalyzed enantiodivergent alkynylation of isatins. Dramatic reversal
of enantioselectivity was accomplished by slightly tuning the
substituted benzenesulfonamide and achiral basic additives. A wide
range of both terminal alkynes and isatins are tolerated by this new
catalyst system with up to 99% yield and 97% ee.
tuning the substituted benzenesulfonamide and achiral basic
xindoles with a chiral quaternary stereogenic center
Ocontaining a hydroxyl group at the 3-position are additives.
We recently reported a new type of dinucleating amino-
important structure motifs found in biologically active
compounds and natural products.1 Chiral propargyl alcohols
have become an important class of compounds due to their
biological activity, unique reactivity, and applicability in the
synthesis of complex molecules.2 It has been found that some
compounds with the structure motifs of 3-alkynyl-3-hydroxy-2-
oxindoles have important biological activities.3 The enantiose-
lective alkynylation of isatins is one of the easier and most
straightforward approaches to construct optically active 3-
alkynyl-3-hydroxy-2-oxindoles. Since Liu and co-workers
developed the first highly enantioselective alkynylation of
isatins utilizing the bifunctional guanidine/CuI catalyst,4a
several efficient catalytic systems, including Guo’s Cu/
phosphine,4b Chen’s Zn/hydroxy oxazoline,4c Wolf’s Cu/
bisoxazolidine,4d Maruoka’s Ag/PTC,4e Li’s Co/bisoxazoline-
phosphine,4f and Zhang and He’s Ag/amidophosphine-urea,4g
have been developed. Although progress has been achieved,
the development of new catalysts for the enantioselective
alkynylation of isatins remains challenging and interesting.
The development of a simple methodology for preparing
both enantiomers of a chiral compound is important to
medical and bioorganic chemistry.5 Generally, the use of chiral
ligands with different configurations is the most straightfor-
ward method. However, the two enantiomers of the ligands are
not always easily available or economically feasible to
synthesize. Besides, the phenomenon of reversal in stereo-
selectivity with the use of single chiral source derived ligands or
catalysts is also a very interesting topic in asymmetric catalysis
and organic synthesis.6 Herein, we describe an enantioselective
alkynylation of isatins catalyzed by a Cu(I)/aminophenol
sulfonamide complex. Both enantiomers of a series of 3-
alkynyl-3-hydroxy-2-oxindoles are readily accessed by slightly
phenol sulfonamide ligands (Scheme 1) and their complexes of
Cu/Sm,7a Ni/Ni,7b Co/Co,7c and Zn/Sr7d as well as their use
in asymmetric reactions. Albeit the novel activities observed
from the dinucleating ligands, the usage of dual chiral arms
requires double chiral materials, which is not economical. In
this report, we illustrated an improved ligand design, which
reduced the chiral arm to one (L1−L11, Scheme 1). The
redesigned catalytic system enjoys significantly minimized
usage of the chiral element in the ligand.
In the preliminary study, the N-benzyl-protected isatin 1a
and phenylacetylene 2a were chosen as model substrates
(Table 1). In the presence of aminophenol sulfonamide L1/
CuOTf (1:1) and Et3N, only trace 3-alkynyl-3-hydroxyin-
dolinone 3aa was detected (entry 1, Table 1). As the
proportion of CuOTf gradually increased, the reactivity
gradually increased (entry 3 vs entries 1 and 2, Table 1).
Other achiral basic additives instead of triethylamine were also
examined (see the Supporting Information for details). The
highest ee is obtained in the presence of Et3N and iPr2NEt
(entries 3 and 4, Table 1). Moreover, without the basic
additives, although the reaction activity is greatly reduced, the
absolute configuration of the product is reversed (entry 5 vs
entry 3 and 4, Table 1). This shows that the achiral base not
only affects the reactivity but also affects the interaction
Received: June 8, 2021
Published: July 19, 2021
https://doi.org/10.1021/acs.orglett.1c01896
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5739−5743
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Scheme 1. Chiral Aminophenol Sulfonamide Ligands
a
Table 1. Preliminary Screening of Asymmetric Alkynylation
of Isatins
Table 2. Further Optimizations
a
a
Unless otherwise noted, all reactions were carried out with the ligand
(10 mol %), CuOTf·0.5PhH (30 mol %), 1a (0.1 mmol), 2a (0.2
b
mmol), and base in trifluoroethanol (1.0 mL) at rt for 24 h. Yield of
c
d
isolated product. Determined by chiral HPLC. 10 μL of H2O was
a
Unless otherwise noted, all reactions were carried out with L1 (10
e
f
added as an additive. 0.3 mmol of 2a was used. 0.4 mmol of 2a was
mol %), CuOTf·0.5PhH, 1a (0.1 mmol), 2a (0.4 mmol), and base in
used.
b
trifluoroethanol (1.0 mL) at rt for 24 h. Yield of isolated product.
c
Determined by chiral HPLC.
Adding water as an additive and increasing the amount of
phenylacetylene can increase the yield and enantioselectivity of
the product (entry 13, Table 2). Thus, the optimized reaction
conditions for R-3aa (99% yield, 95% ee) entailed the use of
CuOTf/L6 (3:1, 10 mol %) as the catalyst and Et3N (20 mol
%) and H2O (10 μL) as the additives in trifluoroethanol at rt
for 24 h (entry 13, Table 2). To our surprise, when using L6 as
the ligand in the presence of 10 mol % Et3N, the
stereoselectivity of the reaction did not reverse (entry 12,
Table 2, vs entry 6, Table 1). Therefore, we reoptimized the
reaction conditions to obtain the S-enantiomer in high yield
with high enantioselectivity (see the Supporting Information
for details). The S-3aa can be obtained in 99% yield with 86%
between the complex and the substrates. Further screening of
the amount of the base found that, when the amount of Et3N
or iPr2NEt is reduced to 10 mol %, the stereoselectivity of the
reaction can also be reversed (entries 6−8 vs entry 3, entries
9−11 vs entry 4, Table 1).
Further optimization (Table 2; see the Supporting
Information for details) starts with the ligand screening. The
results of the achiral arm screening show that the structure
motif of piperidine is suitable for this asymmetric reaction
(entry 1 vs entries 2−5, Table 2). The screening results of
substituted benzenesulfonamides show that p-nitrobenzene-
sulfonamide has the best effect (entries 6−11, Table 2).
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Scheme 2. Substrate Scope
a
Standard conditions for R-3: L6 (10 mol %), CuOTf·0.5PhH (30 mol %), 1 (0.1 mmol), 2 (0.3 mmol), Et3N (20 mol %), and H2O (10 μL) in
trifluoroethanol (1.0 mL) at rt for 24 h. Standard conditions for S-3: L10 (10 mol %), CuOTf·0.5PhH (30 mol %), 1 (0.1 mmol), 2 (0.4 mmol), i-
Pr2NEt (10 mol %), and H2O (10 μL) in trifluoroethanol (1.0 mL) at rt for 24 h.
ee by switching the substituent on the benzenesulfonamide
from p-NO2- (L6) to 2,4,6-trimethyl- (L10) and changing the
base from Et3N (20 mol %) to iPr2NEt (10 mol %) (entries
14−16, Table 2).
To test the generality of the catalytic systems and the
interesting reversal of the enantioselectivity, a wide range of
isatins and alkynes were exposed to the optimized reaction
conditions (Scheme 2). The reaction could be conducted on a
gram scale, and the corresponding products could be obtained
in 97% yield (0.99 g) with 93% ee for R-3aa and 90% yield
(0.92 g) with 90% ee for S-3aa. To our delight, a complete
switch in stereoselectivity was observed for all of the substrates.
Generally, isatins having different substituents react with 2a in
good to excellent yields with high enantioselectivities (73−
99% yields and 90−95% ee for the R-products; 70−99% yields
and 77−97% ee for the S-products) regardless of the inductive
effect and the position of the substituent (3aa−3na). N-Allyl
and N-H isatins are also tolerant in this catalytic system (3oa
and 3pa). The scope of terminal alkynes was also examined.
Most of the tested aromatic alkynes, such as halogen and
methyl substituted phenylacetylenes on a phenyl ring, can be
employed in this reaction, giving the corresponding products
in good to excellent yields with high enantioselectivities (85−
97% yields and 91−95% ee for the R-products; 86−97% yields
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and 82−97% ee for the S-products) (3ac−3ai and 3ak). Linear
alkynes exhibited lower reactivity, but the enantioselectivity is
maintained (3ab). The reactivity of cyclic alkynes is higher
than that of linear alkynes, but the enantioselectivity is reduced
(3am). The strong electron-withdrawing CN group has a
neglectable influence on the yield. The S-3aj was obtained with
excellent enantioselectivity, while only moderate ee was
obtained for the R-3aj. For p-Et-phenylacetylene, satisfactory
results were obtained for the R-product, but the yield and ee of
the S-product were not good (3al).
To gain some insights into the chiral copper complex, the
relationship between the ee values of product 3aa and the
ligand L6 or L10 at different ratios of the ligand to CuOTf
(1:2 and 1:3)8 was investigated (Figure 1).9 Positive nonlinear
to elucidate the reason for the enantiodivergence, and the
application of these new ligands to develop other asymmetric
transformations is in progress.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01896.
Experimental details, characterization data, and copies of
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Jing Zhou − Chongqing Research Center for Pharmaceutical
Engineering, College of Pharmacy, Chongqing Medical
University, Chongqing 400016, China; Email: 102792@
cqmu.edu.cn
Hui Zhou − Chongqing Research Center for Pharmaceutical
Engineering, College of Pharmacy, Chongqing Medical
University, Chongqing 400016, China; orcid.org/0000-
0001-7018-3277; Email: hzhou@cqmu.edu.cn
Authors
Huakang He − Chongqing Research Center for
Pharmaceutical Engineering, College of Pharmacy,
Chongqing Medical University, Chongqing 400016, China
Zinan Yang − Chongqing Research Center for Pharmaceutical
Engineering, College of Pharmacy, Chongqing Medical
University, Chongqing 400016, China
Yu Chai − Chongqing Research Center for Pharmaceutical
Engineering, College of Pharmacy, Chongqing Medical
University, Chongqing 400016, China
Figure 1. Nonlinear effect studies and the speculated structure of the
complexes determined by HRMS (ESI).
Ruoran Wu − Chongqing Research Center for Pharmaceutical
Engineering, College of Pharmacy, Chongqing Medical
University, Chongqing 400016, China
Peng Chen − Chongqing Research Center for Pharmaceutical
Engineering, College of Pharmacy, Chongqing Medical
University, Chongqing 400016, China
effects in all cases were observed, which suggested catalyst
aggregation. It is amazing that, when the ratio of L10 to
CuOTf is 1:2, the product stereoselectivity is reversed
compared with L10/CuOTf in 1/3. And the absolute
configuration of the product is the same when the ratio of
L6 to CuOTf is 1/2 and 1/3. The ESI-MS studies were also
carried outonly monomeric and dimeric copper complexes
were found, and no dinuclear copper complexes were found
(for details, see the Supporting Information). The speculated
structures of the monomeric and dimeric copper complexes are
shown in Figure 1. As the excess of Cu(I) relative to the ligand
increases, the yield is improved without affecting the ee (entries
1−3, Table 1). In addition, the basic additives can affect the
stereoselectivity of the reaction (entries 3−5, Table 1). We
speculate that the excess copper would not promote the
formation of a dinuclear copper complex but activate the
alkynes through the σ-bond and π-system.10 Combined with
the results of positive nonlinear effects, we speculate that the
dimeric copper complex (Figure 1) should be the catalytically
active species (a proposed catalytic cycle is described in the
Supporting Information).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01896
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work is supported by the National Natural Science
Foundation of China (21672031), Natural Science Foundation
of Chongqing (cstc2019jcyj-msxmX0034), and Scientific and
Technological Research Program of Chongqing Municipal
Education Commission (KJQN201900437).
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In summary, we have developed a series of new chiral
aminophenol sulfonamide ligands with a monochiral arm for
the first Cu(I) catalyzed enantiodivergent alkynylation of
isatins. Dramatic reversal of enantioselectivity was accom-
plished by slightly tuning the substituted benzenesulfonamide
and achiral basic additives. In contrast to previous results, both
enantiomers of a variety of substrates were readily obtained in
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