Stereodivergent Synthesis of Enantioenriched 2,3-Disubstituted Dihydrobenzofurans via a One-Pot C-H Functionalization/Oxa-Michael Addition Cascade

Article abstract of DOI:10.1021/jacs.1c03498

A one-pot rhodium-catalyzed C-H functionalization/organocatalyzed oxa-Michael addition cascade reaction has been developed. This methodology enables the stereodivergent synthesis of diverse 2,3-disubstituted dihydrobenzofurans with broad functional group compatibility in good yields with high levels of stereoselectivity under exceptionally mild conditions. The full complement of stereoisomers of chiral 2,3-disubstituted dihydrobenzofurans and 3,4-disubstituted isochromans could be accessed at will by appropriate permutations of the two chiral catalysts. The current work provides a rare example of two chiral catalysts independently controlling two contiguous stereogenic centers subsequently via a two-step reaction in a single operation.

Full text of DOI:10.1021/jacs.1c03498

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Stereodivergent Synthesis of Enantioenriched 2,3-Disubstituted
Dihydrobenzofurans via a One-Pot C−H Functionalization/Oxa-
Michael Addition Cascade
Dong-Xing Zhu, Jian-Guo Liu, and Ming-Hua Xu*
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ABSTRACT: A one-pot rhodium-catalyzed C−H functionalization/organocatalyzed oxa-Michael addition cascade reaction has
been developed. This methodology enables the stereodivergent synthesis of diverse 2,3-disubstituted dihydrobenzofurans with broad
functional group compatibility in good yields with high levels of stereoselectivity under exceptionally mild conditions. The full
complement of stereoisomers of chiral 2,3-disubstituted dihydrobenzofurans and 3,4-disubstituted isochromans could be accessed at
will by appropriate permutations of the two chiral catalysts. The current work provides a rare example of two chiral catalysts
independently controlling two contiguous stereogenic centers subsequently via a two-step reaction in a single operation.
Scheme 1. (a) Stereodivergent Synergistic Catalysis, (b)
Stereodivergent Relay Catalysis, and (c) Our Strategy for
Divergent Synthesis of Enantioenriched 2,3-Disubstituted
Dihydrobenzofurans
s we all know, bioactive compounds containing n
n
Astereogenic centers may have 2 stereoisomers, while for
pharmaceutical molecules, their absolute and relative config-
urations are often relevant to their biological activities.1
Consequently, it is meaningful to develop reliable synthetic
methodologies for the construction of all stereoisomers using
readily available starting materials. However, diastereoselectiv-
ity control is a persistent challenge in most current catalytic
systems with multiple stereocenters forming, mainly ascribed
to one of the diastereomers often being inherently preferred,
thus resulting in the prevention of the achievement of all
stereoisomers.2,3 In recent years, merging two or more catalysts
in one reaction to realize a transformation unattainable by an
individual catalyst alone has emerged as a powerful strategy for
creating complex molecular frameworks.4−6 In this regard,
some striking strategies have been developed in the past
decade. Since the pioneering work of Carreira and co-workers
in 2013,7 a synergistic dual-catalysis tactic (Scheme 1a) has
received intense focus in the area of divergent synthesis. This
ingenious design opens up a whole new area and enables an
efficient and rapid way to access all four stereoisomers of a
target compound containing two chiral centers by the
combination of two different chiral catalysts, which simulta-
neously activate two different substrates, independently.
Despite this impressive progress,8,9 stereodivergent systhesis
via relay catalysis (Scheme 1b) is still in its infancy thus far.10,11
Different from the most synergistic catalysis where only one
chemical bond is formed, two or more chemical bonds are
formed in series in cascade or tandem reactions via relay
catalysis. The previously formed stereocenter would more
likely influence the effect of the second catalyst; thus,
controlling the overall regio- and stereoselectivity of the
reaction becomes rather difficult. The ideal solution to this
problem would be that each individual catalysis could proceed
in a highly stereospecific manner with no stereochemical
interaction.
Enantiomerically enriched 2,3-disubstituted dihydrobenzo-
furans have received considerable attention for their frequent
occurrence in numerous biologically active natural products
and pharmacologically relevant therapeutic agents.12 Con-
sequently, a variety of elegant strategies have been developed
for their asymmetric synthesis.13−18 However, a stereo-
Received: April 1, 2021
Published: June 1, 2021
https://doi.org/10.1021/jacs.1c03498
J. Am. Chem. Soc. 2021, 143, 8583−8589
© 2021 American Chemical Society
8583

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Communication
a
divergent synthesis of this valuable framework that allows for
full control over the two vicinal stereogenic centers has not
been disclosed.
Table 1. Evaluation of Reaction Conditions
In our prior work on rhodium(I) carbene19 directed
enantioselective C−H functionalization of aniline deriva-
tives,19g we realized the potential of accessing enantioenriched
2,3-disubstituted dihydrobenzofurans. Encouraged by this
result, we therefore speculated whether stereodivergent
systhesis of all four stereoisomers of 2,3-disubstituted
dihydrobenzofurans could be achieved through a one-pot
cascade C−H functionalization/oxa-Michael addition20 via
relay catalysis in the presence of an appropriate chiral
organobase catalyst in combination with the chiral rhodium/
diene catalyst (Scheme 1c). However, the development of such
a dual-catalytic relay catalysis system is distinctively challeng-
ing. One possible challenge associated with the combination of
a rhodium complex and organobase catalyst in one pot is the
catalysts’ incompatibility and inhibition. Therefore, employing
a suitable organocatalyst that would enable the oxa-Michael
addition with high stereocontrol while maintaining the
efficiency of a rhodium catalyst in the initial C−H
functionalization step is the key to success. Additionally, an
intramolecular asymmetric oxa-Michael addition of α,β-
unsaturated esters remains less explored probably due to the
intrinsic low electrophilicity of α,β-unsaturated esters as the
Michael acceptor and poor reactivity of oxygen as a
nucleophile.21 Furthermore, for most cyclic compounds with
two adjacent stereocenters, one of the diastereomers often can
be accessed easily due to its natural preference, while another
diastereomer is normally inaccessible, as overriding the natural
preference is usually difficult.2 Herein, we report our
development of an efficient method that allows access to the
full complement of stereoisomers of chiral 2,3-disubstituted
dihydrobenzofurans and 3,4-disubstituted isochromans via a
stereodivergent relay catalysis.
To validate the feasibility of our proposed one-pot cascade
reaction, we initiated our study by examining the one-pot
reaction between 1a and 2a in the presence of [Rh((R,R)-
L1)Cl]2 and NEt3 in CH2Cl2 at room temperature. As a result,
the anti product 3a with a 2R,3S configuration was obtained in
almost quantitative yield with high relative and absolute
stereoselectivity (84:16 dr, 94% ee) (Table 1, entry 1). As the
enantioselectivity of the initial C−H functionalization would
play a pivotal role in influencing the following stereoselectivity,
we carried out further investigations on chiral diene ligands.
Pleasingly, (R,R)-L2 was found to show the best performance
(entry 2). With L2 as the optimal ligand, we turned our
attention to find suitable organocatalysts for the following oxa-
Michael addition in a highly stereospecific manner.
yield
dr
b
c
c
entry
ligand
base
solvent
(%)
(anti:syn)
ee (%)
d
1
(R,R)-L1
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
NEt3
NEt3
QN
QD
CN
CD
C1
C2
C3
C4
C5
C6
C7
C8
C1
C1
C3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
toluene
toluene
90
85
94
84
90
88
84
76
78
86
84
87
89
88
84
89
96
84:16
85:15
62:38
95:5
96:4
48:52
98:2
22:78
22:78
98:2
94, 94
97, 97
93, 99
96, −
98, −
91, 99
99, −
78, 99
88, 99
98, -
d
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
96:4
97, -
27:73
25:75
96:4
99:1
99:1
68, 99
64, 99
97, −
99.7, −
99.9, −
−, 98
7:93
a
Reactions were performed with 1a (0.1 mmol) and 2a (0.2 mmol) in
the presence of 2.5 mol % of [Rh(L)Cl]2 and 5.0 mol % of base in
solvent (4.0 mL) for 24 h, unless otherwise noted. Abbreviations: QN,
quinine; QD, quinidine; CN, cinchonine; CD, cinchonidine. Isolated
yield. Determined by chiral HPLC after reduction with LiAlH4.
Et3N was added after C−H functionalization was finished.
b
c
d
based organocatalyst might result in highly diastereoselective
formation of the desired product. Encouraged by these
promising results, we further evaluated a series of cinchona
alkaloid derived bifunctional organocatalysts (C1−C8, Ar =
3,5-(CF3)2C6H3, entries 7−14). To our delight, quinine-
derived thiourea C1 gave the best result in terms of both
diastereoselectivity (anti:syn 98:2) and enantioselectivity (99%
ee) (entry 7). With cinchonine-derived thiourea C3, the
reaction occurred to give the product in favor of the (2S,3S)-
syn diastereomer (anti:syn 22:78) and with high ees for both
isomers (entry 9). Very gratifyingly, a nearly perfect diastereo-
and enantiocontrol could be achieved by replacing the solvent
CH2Cl2 with toluene (entries 16 and 17).
Inspired by the excellent catalytic performance of cinchona
alkaloid based organocatalysts22 in asymmetric oxa-Michael
reaction, we first evaluated four commercially available natural
cinchona alkaloids (entries 3−6). To our delight, the anti
product (2R,3S)-3a was delivered in good yield with 96:4 dr
and 98% ee when cinchonine (CN) was used, while a reverse
of the diastereoselectivity (anti:syn 48:52) was observed with
the use of cinchonidine (CD) (entry 5 vs entry 6). These
results demonstrate that the cinchona alkaloid catalysts are able
to control the configuration of the newly formed carbon
stereocenter likely by the formation of different types of
hydrogen bond interactions with the initial C−H functional-
ization products, which suggested that the combined use of
[Rh((R,R)-L2)Cl]2 and an appropriate cinchona alkaloid
To showcase the stereodivergent synthesis of the complete
set of stereoisomeric products, we conducted the one-pot
cascade experiments under the above optimized reaction
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a c
−
conditions by combining the appropriate enantiomer of the
chiral diene ligand L2 with organothiourea catalyst C1 or C3.
Remarkably, the use of four available catalyst permutations
allowed a stereodivergent access to the full matrix of
stereoisomeric 2,3-disubstituted dihydrobenzofuran products
uniformly in a highly diastereo- and enantioselective manner
(Scheme 2). It is notable that the stereochemistries of all four
stereoisomers were unambiguously confirmed by X-ray
crystallography.
Scheme 3. Scope of Arylvinyldiazoacetates
Scheme 2. Divergent Synthesis of All Four Isomers of 2,3-
Disubstituted Dihydrobenzofurans
With the optimized conditions in hand, we set out to explore
the generality of this one-pot cascade reaction. As shown in
Scheme 3, arylvinyldiazoacetates with different electronic
properties and different substitution patterns on the benzene
ring were all tolerated, delivering the corresponding products
in consistently good yields with excellent diastereo- and
enantioselectivities. Notably, heteroaryl-substituted vinyldia-
zoacetate were also well-behaved, furnishing the chiral
dihydrobenzofurans in good yields with excellent diastereo-
and enantioselectivities (3m−o,t). Additionally, it was found
that halogen could be retained during the process of LAH
reduction, which may provide chances for further derivatiza-
tion (3e,h,r). When [Rh((R,R)-L2)Cl]2 was changed to
[Rh((S,S)-L2)Cl]2, a series of syn products were successfully
obtained in highly enantiomerically enriched form (3q−t).
After exploration of the reaction scope of vinyldiazoacetates,
the effects of aminophenol were subsequently evaluated
(Scheme 4). We were pleased to find that the reaction is
highly compatible with dimethyl, diethyl and dibenzyl
substitution on the amine (3aa−ac). In addition to 3-
(pyrrolidin-1-yl)phenol, 3-(piperidin-1-yl)phenol and 3-(aze-
pan-1-yl)phenol are reactive as well, furnishing the nearly
optically pure products 3ad,ae in good yields. Moreover, 3-
morpholinophenol and 3-(piperazin-1-yl)phenol were also
competent substrates, affording the 2,3-disubstituted dihydro-
benzofurans 3af−ah in excellent diastereo- and enantioselec-
tivities, abeit with slightly low yields. Furthermore, 3-
(pyrrolidin-1-yl)phenol-containing substituents on benzenes
were also suitable substrates for this transformation, providing
a
Reactions were performed with 1 (0.1 mmol) and 2 (0.2 mmol) in
the presence of 2.5 mol % of [Rh((R,R)-L2)Cl]2 and 5 mol % of C1
in toluene (4.0 mL) at room temperature for 24 h, unless otherwise
b
c
noted. Isolated yield. For 3a−p, dr = anti:syn; for 3q−t, dr =
syn:anti; the dr and ee were determined by chiral HPLC after
reduction with LiAlH4. 2.5 mol % of C1 was used. [Rh((S,S)-
L2)Cl]2 was used instead of [Rh((R,R)-L2)Cl]2.
d
e
the products 3ai−al in good yields with high levels of
stereoselectivity. It is quite remarkable that indoline and
tetrahydroquinoline substrates were also well-behaved in this
cascade reaction, providing a series of highly valuable
enantiomerically pure benzo-fused tricyclic heterocycles
3am−ap in good yields. Similarly, syn isomers (e.g., 3aq−at)
could be accessed by a combination of catalysts [Rh((S,S)-
L2)Cl]2 and C1. These results demonstrated that the current
method provides a very reliable and powerful protocol for
stereodivergent access to optically pure 2,3-disubstituted
dihydrobenzofurans.
Encouraged by the above excellent results, we next
wondered whether this one-pot tandem protocol could be
further expanded to the stereodivergent synthesis of chiral 3,4-
disubstituted isochromans,23 other pharmaceutically useful
frameworks.24 To our disappointment, the reaction of 1a
with (3-(pyrrolidin-1-yl)phenyl)methanol under the standard
conditions led to only a trace amount of the expected product.
Fortunately, after careful investigation (see the Supporting
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a−c
Scheme 4. Scope of Aminophenol
Scheme 5. Divergent Synthesis of All Four Isomers of 3,4-
Disubstituted Isochromans
Scheme 6. Gram-Scale Synthesis of 3ac and Its
Derivatization
a
Reactions were performed with 1 (0.1 mmol) and 2 (0.2 mmol) in
the presence of 2.5 mol % of [Rh((R,R)-L2)Cl]2 and 5 mol % of C1
in toluene (4.0 mL) at room temperature for 24 h, unless otherwise
b
c
noted. Isolated yield. For 3aa−ap, dr = anti:syn; for 3aq−at, dr =
syn:anti; the dr and ee were determined by chiral HPLC after
reduction with LiAlH4. [Rh((S,S)-L2)Cl]2 was used instead of
d
appropriate permutation of the chiral rhodium catalyst and
organocatalyst, all four stereoisomers of the products could be
accessed at will in a highly enantiomerically pure form.
Moreover, this dual-catalytic strategy could be extended to the
stereodivergent synthesis of enantioenriched 3,4-disubstituted
isochromans. We believe that this predictable assembly of
chiral dihydrobenzofuran and isochroman structures will
provide new opportunities for their application in drug
discovery. Of particular note, this work provides a rare example
of two chiral catalysts independently controlling two contiguous
stereogenic centers subsequently via a two-step reaction in a single
operation.
[Rh((R,R)-L2)Cl]2.
Information for details), we were able to establish a
stereodivergent process to obtain all four stereoisomers of
3,4-disubstituted isochroman (6) in good yields with high
levels of stereoselectivities through a two-step sequence by
using different catalyst permutations (Scheme 5).
To demonstrate the practicality of this methodology, the
one-pot cascade reaction of 1a and 2c was carried out on a 2
mmol scale under the standard conditions. As shown in
Scheme 6, the product 3ac was obtained in comparable yield
with the same high levels of diastereoselectivity and
enantioselectivity. LAH reduction and N-debenzylation with
Pd(OH)2/C and H2 afforded the pharmceutially interesting
chiral amino alcohol 8 containing a dihydrobenzofuran-
incorporated moiety with no loss of enantiopurity.
In summary, we have developed a stereodivergent relay
catalysis strategy for the rapid synthesis of optically active 2,3-
disubstituted dihydrobenzofurans. This method successfully
combines a rhodium/chiral diene-catalyzed enantioselective
C−H functionalization with a cinchona alkaloid derived
thiourea catalyst controlled diastereoselective intramolecular
oxa-Michael addition in a simple one-pot procedure. By an
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03498.
■
sı
Experimental procedures and spectroscopic data of all
new compounds (PDF)
Accession Codes
CCDC 1978705, 2073588, 2073593, 2073595−2073596, and
2073599 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
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request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Ming-Hua Xu − Shenzhen Grubbs Institute and Department
of Chemistry, Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, People’s Republic of China; orcid.org/
0000-0002-1692-2718; Email: xumh@sustech.edu.cn
Authors
Dong-Xing Zhu − State Key Laboratory of Drug Research,
Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Shanghai 201203, People’s Republic of China
Jian-Guo Liu − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03498
(5) For selected reviews on organo-organo catalysis, see: (a) Gu, J.;
Du, W.; Chen, Y.-C. Combined asymmetric aminocatalysis and
carbene catalysis. Synthesis 2015, 47, 3451−3459. (b) Xiao, X.; Shao,
B.-X.; Lu, Y.-J.; Cao, Q.-Q.; Xia, C.-N.; Chen, F.-E. Recent advances
in asymmetric organomulticatalysis. Adv. Synth. Catal. 2021, 363,
352−387.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(6) For selected reviews on metal−metal catalysis, see: (a) Pye, D.
R.; Mankad, N. P. Bimetallic catalysis for C-C and C-X coupling
reactions. Chem. Sci. 2017, 8, 1705−1718. (b) Kim, U. B.; Jung, D. J.;
Jeon, H. J.; Rathwell, K.; Lee, S.-G. Synergistic dual transition metal
catalysis. Chem. Rev. 2020, 120, 13382−13433. Our recent work of
Rh/Pd catalysis: (c) Zhang, Z.-F.; Zhu, D.-X.; Chen, W.-W.; Xu, B.;
Xu, M.-H. Enantioselective synthesis of gem-diaryl benzofuran-
3(2H)-ones via one-pot asymmetric rhodium/palladium relay
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We thank the National Natural Science Foundation of China
(21971103, 21672229), the Guangdong Provincial Key
Laboratory of Catalysis (2020B121201002), and the Shenzhen
Science and Technology Innovation Commission
(JCYJ20200109141408054) for financial support. We are
especially grateful to Dr. Stefan Abele at Idorsia Pharmaceut-
icals Ltd., Switzerland, for his very generous donation of the
key intermediate (1R,4R)-5-phenylbicyclo[2.2.2]oct-5-en-2-
one for diene preparation.
(7) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Enantio- and diastereodivergent dual catalysis: α-allylation of
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