Palladium-catalyzed diastereo- And enantioselective [3 + 2] cycloaddition of vinylcyclopropanes with azadienes: Efficient access to chiral spirocycles

Article abstract of DOI:10.1021/acs.orglett.0c04062

Benzofuran-derived azadienes (BDAs) have been widely used as four-atom synthons in transition-metal-mediated cycloaddition reactions, while the exploitation of their reactivity as a two-atom unit to construct spirocycles is still underdeveloped. Herein, we reported the first palladium(0)-catalyzed diastereo- and enantioselective [3 + 2] annulation of vinylcyclopropanes (VCPs) and BDAs. This transformation is featured with a broad substrate scope (31 examples), allowing for facile access to a variety of enantioenriched spirocycles bearing a quaternary stereogenic center in good yields with excellent regio-, diastereo-, and enantioselectivities (up to 93% yield, >20:1 dr, and mostly >99% ee) under mild reaction conditions. Moreover, the spirocyclic products could be efficiently converted to structurally complex tricyclo[8.3.0.0^1,5]-azatridecane and tricyclo[7.3.0.0^1,5]-azadodecane skeletons.

Full text of DOI:10.1021/acs.orglett.0c04062

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Letter
Palladium-Catalyzed Diastereo- and Enantioselective [3 + 2]
Cycloaddition of Vinylcyclopropanes with Azadienes: Efficient
Access to Chiral Spirocycles
Kai Liu, Jianfeng Yang, and Xiaoxun Li*
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ABSTRACT: Benzofuran-derived azadienes (BDAs) have been widely used as four-atom synthons in transition-metal-mediated
cycloaddition reactions, while the exploitation of their reactivity as a two-atom unit to construct spirocycles is still underdeveloped.
Herein, we reported the first palladium(0)-catalyzed diastereo- and enantioselective [3 + 2] annulation of vinylcyclopropanes
(VCPs) and BDAs. This transformation is featured with a broad substrate scope (31 examples), allowing for facile access to a variety
of enantioenriched spirocycles bearing a quaternary stereogenic center in good yields with excellent regio-, diastereo-, and
enantioselectivities (up to 93% yield, >20:1 dr, and mostly >99% ee) under mild reaction conditions. Moreover, the spirocyclic
products could be efficiently converted to structurally complex tricyclo[8.3.0.01,5]-azatridecane and tricyclo[7.3.0.01,5]-azadodecane
skeletons.
piro[benzofuran-cyclopentane] and related scaffolds are
ubiquitous skeletons existing in a wide array of biologically
diastereo-, and enantioselectivity, especially bearing a spirocy-
clic quaternary stereocenter, is still a highly desirable yet
challenging subject.
S
active molecules, natural products, and pharmaceutical agents
(Figure 1).1 The three-dimensional and rigid structure of
In recent years, benzofuran-derived azadienes (BDAs) have
emerged as versatile building blocks for the efficient
construction of a diverse range of cyclic compounds. In
2016, the Zhao group disclosed the first [4 + 2] cycloaddition
of BDAs and aldehydes catalyzed by N-heterocyclic carbenes
(NHCs) or chiral amines (Scheme 1a).4a Since then, BDAs
have been thoroughly studied in a variety of [4 + n]
cycloadditions (n = 2−6) by serving as four-atom synthons
owing to their intrinsic driving force of aromatization (Scheme
1a).4,5 Among them, Trost,5a Deng,5b Huang,5c Ye,5d and
Chen5e prepared a series of benzofuran-fused medium-sized
heterocycles via [4 + 3] cycloadditions of BDAs with
trimethylenemethane (TMM) or Morita−Baylis−Hillman
(MBH) carbonates or enals, respectively. In 2017, Lu and
co-workers reported the first enantioselective phosphine-
catalyzed [4 + 4] cycloaddition reaction between allene
Figure 1. Representative bioactive molecules containing spiro-
[benzofuran-cyclopentane] and related scaffolds.
spirocycles and their resulting ability to achieve a better
interaction between a ligand and binding site make them more
suitable as core structures in the drug discovery process
compared to planar ring systems.2 Despite great success in
spirocycle synthesis,3 the development of asymmetric catalytic
methods for the efficient construction of highly functionalized
and enantioenriched spirocycles with a good control of regio-,
Received: December 8, 2020
Published: January 27, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04062
© 2021 American Chemical Society
Org. Lett. 2021, 23, 826−831
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a
Scheme 1. Different Reaction Patterns of BDAs
Table 1. Optimization Process
b
c
d
entry
ligand
solvent
yield
ee
dr
1
2
3
4
5
6
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
DCE
DCE
DCE
DCE
toluene
THF
45%
38%
53%
78%
88%
92%
83%
82%
67%
77%
83%
46%
44%
73%
84%
97%
80%
>99%
93%
95%
91%
>99%
1:1
4:1
1:1
2:1
5:1
2:1
7:1
6:1
6:1
5:1
18:1
e
7
toluene
e
8
e
p-xylene
mesitylene
ethylbenzene
9
e
10
11
f
toluene:HFB = 1:2
a
Conditions: all reactions were carried out with 1a (0.1 mmol), 2a
(0.1 mmol), Pd2(dba)3·CHCl3 (2.5 mol %), and ligand (12 mol %) in
the indicated solvent at room temperature under a nitrogen
b
c
atmosphere. Isolated yield of product 3aa. The ee was determined
d
e
by HPLC. The dr was determined by 1H NMR crude. The reaction
was run at 0 °C. The reaction was run at 4 °C. HFB:
Hexafluorobenzene.
f
our delight, the expected [3 + 2] cycloaddition proceeded
smoothly after careful evaluation of different reaction
parameters, and the preliminary result showed that a
combination of Pd2(dba)3·CHCl3 and chiral P-containing
ligands exhibited optimal asymmetric induction in such an
annulation process (more details in the Supporting Informa-
tion).9 The Feringa ligand L1 afforded the desired product 3aa
in 45% yield with 46% ee and 1:1 dr (entry 1). Encouraged by
this promising result, further examination of various chiral
phosphoramidite ligands indicated that they showed a dramatic
impact on both the cycloaddition reaction efficiency and
selectivity. Among them, 3,3′-diphenyl-substituted BINOL
ligand L2 afforded the 3aa in 44% ee with 4:1 dr (entry 2),
whereas the biphenyl skeleton ligand L3 improved the ee (73%
ee, entry 3) albeit with a 1:1 dr. We then turned our attention
to substitutions on the nitrogen moiety of phosphoramidite
ligands. When the chiral methyl-protected diarylprolinol was
employed,10 the ligand L4 was found to be the optimal ligand,
providing the chiral cycloadduct 3aa with a good result (78%
yield, 2:1 dr, and 84% ee, entry 4). Further screening various
solvents and decreasing the reaction temperature (entries 5−
11) revealed that the mixed solvent of toluene and
hexafluorobenzene (HFB) at a ratio of 1:2 was the best one
in terms of cycloaddition reactivity and selectivity, affording
cycloadduct 3aa in 83% yield and >99% ee with 18:1 dr at 4
°C (entry 11). It should be noted that no [4 + 3] cycloaddition
product was observed during the optimization process.
ketones and BDAs.5f Later, the Zhao group developed an
asymmetric formal [4 + 6] annulation of BDAs with vinyl
oxetanes to afford 10-membered heterocycles.5g
These strategies highlighted the power of using BDAs as
four-atom synthons in cycloadditions, but BDAs acting as two-
atom synthons, especially in asymmetric catalysis, is more
challenging and still rare, as the strong driving force of
aromatization to form the benzofuran skeleton after the
addition of nucleophiles makes it energetically and sterically
unfavorable to perform [2 + n] cycloadditions (Scheme 1c). In
2016, the Zhao group reported their seminal study describing a
palladium(0)-catalyzed [2 + 3] annulation of BDAs with
unsubstituted vinylethylene carbonates (VECs) to provide
functionalized spirotetrahydrofurans with good results, albeit in
a racemic version (Scheme 1b).6a In 2020, the Zhao group
disclosed an efficient synthetic method using BDAs and
bromomalonate to prepare spirocyclopropanes.6b To the best
of our knowledge, the asymmetric cycloaddition involving
BDAs as two-carbon synthons has not been disclosed yet. In
conjunction with our interest in transition-metal-catalyzed
cycloaddition reactions involving vinylcyclopropanes
(VCPs),7,8 herein, we report a stereoselective [3 + 2]
cycloaddition reaction of VCPs and BDAs for the concise
preparation of optically active spiro[benzofuran-cyclopentane]
derivatives with multichiral centers including a spirocyclic
quaternary carbon under mild reaction conditions (Scheme
1c).
With optimized reaction conditions in hand, we proceeded
to investigate the substrate scope of azadienes 1 for this
asymmetric [3 + 2] cycloaddition reaction (Table 2). N-
Sulfonyl substituents of azadienes did not affect this trans-
We began our investigation by studying the coupling of
azadiene 1a with VCP 2a as the model reaction (Table 1). To
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a
formation, providing benzofuran-fused spirocycles 3aa−3ac in
good yields with excellent stereoselectivities. A series of N-tosyl
azadienes bearing either electron-withdrawing or electron-
donating groups at the R3 position could participate in this
cycloaddition efficiently, affording the corresponding spiro-
cycles 3ad−3aq in 73−89% yields, 11:1 to >20:1 dr, and
mostly >99% ee. The cycloaddition reaction was applicable to
a wide range of common functional groups, including fluorides
(3ad−3af), chlorides (3ag−3ai), bromides (3aj and 3ak),
nitro (3ao), and ether (3aq), thus providing useful handles for
further derivatization of cycloadducts. In addition, azadienes
with meta substituents (e.g., 3,5-Me) on the aromatic ring, as
well as 1- and 2-naphthyl-substituted substrates, all delivered
the corresponding products with good results (3ar−3at),
indicating that the steric nature of substituents has no influence
on this transformation. Substrates containing heterocyclic
moieties (3au−3aw, all 99% ee) could also undergo the
cycloaddition efficiently.
Table 2. Substrate Scope of [3 + 2] Cycloaddition
Moreover, R2 substitutions on 1 bearing halogens or a
methoxy group at either the C5- or C6-position of the
benzofuran ring were amenable to this cycloaddition, furnish-
ing the enantiopure spirocycles 3ax−3az with 94 to >99% ee.
Notably, the substrates of this transformation were not limited
to the benzofuran skeletons. Benzothiophene-substituted
azadiene 1a′ could also react smoothly to yield 3aa′ with a
good result. In addition, aliphatic-based N-tosyl azadiene 1b′
was examined for the formation of aliphatic-fused bicyclic
spirocycles which are prevalent and invaluable skeletons in
bioactive natural products.11 To our delight, product 3ab′ was
successfully generated in 72% yield with 4:1 dr and >99% ee
with a slightly modified procedure. The absolute configuration
of 3ab′ was unambiguously determined as 1R, 4S, 5S by X-ray
analysis (CCDC 2047650).
Next, we began to explore the substrate scope of VCPs 2.
For example, trifluoroethyl-ester-substituted VCP was suitable
for this stereoselective [3 + 2] cycloaddition, affording the
corresponding spirocycle 3ba in 73% yield with 7:1 dr and 95%
ee. However, VCPs containing bulkier esters (e.g., tert-butyl
ester) were incompatible in this reaction, presumably due to
the steric hindrance of the ester group. We then studied this
cycloaddition of azadienes with 1,1-dicyanocyclopropane 2c.12
Gratifyingly, substrate 1y with a methoxy group on the
benzofuran ring could undergo the cycloaddition with VCP 2c
efficiently, providing an important complement to the
ubiquitous geminal diester VCPs. Further, indene-based
azadiene 1c′ reacted smoothly, delivering cycloadduct 3 cm3′
in high enantioselectivity and moderate diastereoselectivity.
To further demonstrate the synthetic utility of our protocol,
a scale-up cycloaddition reaction of substrates 1a and 2a was
performed with reduced loadings of palladium catalyst (3.0
mol %) and L4 (7.0 mol %), and the desired product 3aa was
isolated in an improved yield (93%) with the levels of
diastereomeric and enantiomeric enrichment unchanged
(Scheme 2a). In addition, various transformations of the
cycloadduct 3aa were performed. Hydrolysis of the N-sulfonyl
derivatives offered the corresponding benzofuranone 4 in 81%
yield, providing a facial method for the synthesis of the core
structure of spiroapplanatumine K.13 The secondary amine 5
could be diastereoselectively obtained via reduction in the
presence of diisopropyl aluminum hydride (DIBAL-H). The
synthetic utilization potential of this new enantioselective
cycloaddition method was further illustrated via the trans-
formation of intermediate 5. Delightfully, electrophilic
a
Conditions: all reactions were performed with 1 (0.1 mmol), 2 (0.1
mmol), Pd2(dba)3·CHCl3 (2.5 mol %), and L4 (12 mol %) in 1 mL of
solvent toluene:HFB = 1:2) at 4 °C under a nitrogen atmosphere.
Isolated yields. The ee values were determined by HPLC. The dr
b
1
values were determined by H NMR crude. Chlorobenzene:toluene
= 1:2 as the solvent at room temperature. HFB: Hexafluorobenzene.
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bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 2. Large-Scale Reaction and Further
Transformation of 3aa
AUTHOR INFORMATION
Corresponding Author
■
Xiaoxun Li − Department of Medicinal Chemistry, Key
Laboratory of Chemical Biology (Ministry of Education),
School of Pharmaceutical Sciences, Cheeloo College of
Medicine, Shandong University, Jinan, Shandong 250012,
China; Suzhou Institute of Shandong University, Suzhou,
Jiangsu 215123, China; orcid.org/0000-0002-4123-
2524; Email: xli@sdu.edu.cn
Authors
Kai Liu − Department of Medicinal Chemistry, Key
Laboratory of Chemical Biology (Ministry of Education),
School of Pharmaceutical Sciences, Cheeloo College of
Medicine, Shandong University, Jinan, Shandong 250012,
China
Jianfeng Yang − Department of Medicinal Chemistry, Key
Laboratory of Chemical Biology (Ministry of Education),
School of Pharmaceutical Sciences, Cheeloo College of
Medicine, Shandong University, Jinan, Shandong 250012,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04062
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
substitution of amine 5 with allyl bromide was followed by a
ring-closing metathesis (RCM) reaction to generate the
structurally more complex tricyclo[8.3.0.01,5]-azepine 6 in
58% yield over two steps. Moreover, highly diastereoselective
bromocyclization of amine 5 to tricyclo[7.3.0.01,5]-piperidine 7
with four contiguous stereogenic centers was achieved in 87%
yield.
We acknowledge financial support for this work from the
National Natural Science Foundation of China (21901142),
the Natural Science Foundation of Shandong Province
(ZR2019QB001), the Natural Science Foundation of Jiangsu
Province (BK20180227), and the Fundamental Research
Funds of Shandong University (21310088963023,
2020QNQT007).
In conclusion, we have developed the first palladium(0)-
catalyzed, stereoselective [3 + 2] cycloaddition reaction of
BDAs as two-atom synthons to provide a reliable strategy for
the synthesis of highly functionalized spiro[benzofuran-cyclo-
pentane] molecules bearing three continuous stereocenters
from readily available VCPs in high efficiency. In addition,
further transformation of the functionalized cycloadducts to a
range of tricyclic skeletons was also demonstrated. We expect
such a protocol to offer alternative and concise strategies for
the synthesis of benzofuran-fused spirocycles and pharmaceut-
ical molecules.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04062.
Optimization tables, experimental procedures, products
characterization, and spectral data (PDF)
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Accession Codes
CCDC 2047650 contains 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_request@ccdc.cam.ac.uk, or by contacting The Cam-
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