Lewis Acid-Catalyzed Intramolecular [3 + 2] Cross-Cycloaddition of Donor- Acceptor Epoxides with Alkenes for Construction of Oxa-[n.2.1] Skeletons

Article abstract of DOI:10.1002/cjoc.201900114

The first LA-catalyzed [3 + 2]IMCC of GDA-epoxides with carbon-carbon double bonds has been developed. This provides an efficient and general strategy for construction of bridged oxa-[n.2.1] skeletons. A novel S_N-like mechanism through a carbon-carbon bond cleavage of epoxide ring has been proposed.

Full text of DOI:10.1002/cjoc.201900114

Accepted Article
Title: Lewis Acid-Catalyzed Intramolecular [3+2] Cross-Cycloaddition of Donor-
acceptor Epoxides with Alkenes for Construction of Oxa-[n.2.1] Skeletons
Authors: Lu Chen, Jun Tian, Yizhou Zhan, Jun Ren, and Zhong-Wen Wang*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2019, 37, 10.1002/cjoc.201900114.
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Lewis Acid-Catalyzed Intramolecular [3+2] Cross-Cycloaddition of
Donor-acceptor Epoxides with Alkenes for Construction of Oxa-[n.2.1]
Skeletons †
Lu Chen,a ‡ Jun Tian,a ‡ Yizhou Zhan,a ‡ Jun Ren,a and Zhong-Wen Wang*,a,b
a State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion The first LA-catalyzed [3+2]IMCC of GDA-epoxides with carbon-carbon double bonds has been developed.
This provides an efficient and general strategy for construction of bridged oxa-[n.2.1] skeletons. A novel SN-like mechanism through a carbon-carbon bond
cleavage of epoxide ring has been proposed.
theoretically and practically. While the [3+2]IMPC affords a fused
oxa-[n.3.0] skeleton, the [3+2]IMCC of carbonyl ylides with
Background and Originality Content
Development of highly efficient, general and novel strategies
carbon-carbon double bonds is expected to provide a novel
for construction of structurally complex and diverse polycyclic
strategy for construction of bridged oxa-[n.2.1] skeleton.
skeletons is one of the most important themes in organic
synthesis. Intramolecular (formal) cycloaddition is proved to be
one of the most appropriate options for achieving such tasks. One
key issue in the intramolecular (formal) cycloadditions is the
regioselectivity. From the perspective of organic synthesis, a
Scheme 2 [3+2]IMPC/[3+2]IMCC of carbonyl ylides with carbon-carbon
double bonds.
switch of the regioselectivity will provide
a strategy for
construction of either fused or bridged bicyclic skeletons, which
we named as “Intramolecular Cross-Cycloaddition (IMCC) and
Parallel-Cycloaddition (IMPC)” strategy (Scheme 1).[1]
Scheme
1 Switch of the regioselectivity of intramolecular (formal)
cycloadditions for construction of fused and bridged bicycles.
Donor-acceptor epoxides can be used as precursors of polar
carbonyl ylides via carbon-carbon bonds cleavage. Among such
epoxides,
those
being
activated
by
two
geminal
electron-withdrawing groups, can be named as GDA-epoxides
(geminally double acceptors expoxides) and have received great
attention recently. While thermal[3] or Lewis-acids (LAs)[4,5]
intermolecular [3+2] cycloadditions of GDA-epoxides with various
dipolarophiles have been widely studied, their intramolecular
versions have seldom been investigated.[3d,3e,3h,3j,3k][6,7]
[3+2]IMCC of donor-acceptor epoxides with carbon-carbon
double bonds was seldom investigated,[8] and to the best of our
knowledge, there’re no LA-catalyzed intramolecular [3+2]
cycloadditions of GDA-epoxides with carbon-carbon double bonds
reported yet. Inspired by our previously reported [3+2]IMCC of
cyclopropanes and aziridines (Scheme 3, a/b),[9] we envisage to
introduce a diene moiety to react with GDA-epoxides, by which
the regioselectivity might be switched from the general [3+2]IMPC
to [3+2]IMCC to construct the bridged oxa-[n.2.1] skeleton
Tetrahydrofuran-based polycyclic skeletons exist in many
biologically important natural products and synthetic molecules.
Intramolecular 1,3-dipolar cycloadditions (1,3-DC) of carbonyl
ylides with carbon-carbon double/triple bonds is one of the most
efficient strategy for construction of the tetrahydrofuran-based
polycyclic skeletons.[2] However, most of the reported examples
afforded [3+2]IMPC products (Scheme 2, a). A strategy to switch
the [3+2]IMPC to [3+2]IMCC (Scheme 2, b) is quite important both
*E-mail: wzwrj@nankai.edu.cn
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Homepage: http: //wzw.nankai.edu.cn
† Dedicated to the 100th Anniversary of Nankai University.
‡ These authors contributed equally to this work.
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201900114
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Chen et al.
Report
(Scheme 3, c).[10] Herein, we report the first LA-catalyzed
[3+2]IMCC of GDA-epoxides with carbon-carbon double bonds.
We then prepared GDA-epoxide 3a (2,2-diketone-activated
epoxide) and screened the reaction conditions (Table 2). Under
catalysis of LAs, the [3+2]IMCC product 4a was also successfully
obtained. We found that comparing with that of the
diester-substrate 1a, the reaction rate of 3a was improved greatly.
The yield of 3a was also improved. Both Sc(OTf)3 (0.1 equiv) and
Ni(ClO4)2·6H2O (0.2 equiv) gave excellent yields (entries 2 and 4).
Scheme 3 [3+2]IMCC of cyclopropane 1,1-diesters, aziridine 2,2-diesters
and GDA-epoxides with conjugated dienes.
Table 2 Optimization of reaction conditions of GDA-epoxide 3aa
Entry
LAs
Sc(OTf)3
Solvent
DCE
T
Time (h) Yield (%)b
68
85c
50
83
NR
75
NR
90
1
2
3
4
5
6
7
8
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0.1
0.5
1.5
2
Sc(OTf)3
DCE
Yb(OTf)3
Ni(ClO4)2·6H2O
Sc(OTf)3
DCE
DCE
CH3OH
Toluene
CH3CN
DCM
>48
6
Sc(OTf)3
Sc(OTf)3
>48
1.5
Sc(OTf)3
a Reaction conditions: 3a (0.06 mmol), catalyst (0.2 equiv), activated 4Å
MS (200 mg), solvent (2.0 mL), Ar. Yield determined by 1H NMR
b
Results and Discussion
c
spectroscopy (internal standard: 1-chloro-2,4-dinitrobenzene). 10 mol%
of Sc(OTf)3 was used. DCM = dichloromethane. NR = No Reaction.
We first prepared GDA-epoxide 1a (2,2-diester-activated
epoxide) to test our hypothesis. With DCE (1,2-dichloroethane) as
a solvent, various LAs were screened (Table 1). To our delight,
most of the LAs could promote the reaction and the [3+2]IMCC
product 2a was obtained successfully, among which Sc(OTf)3 and
Ni(ClO4)2·6H2O gave satisfactory yields (entry 1 and entry 9). The
structure of 2a was unambiguously confirmed by X-ray crystal
structure analysis.[12] When SnCl4 was used, the reaction gave a
ring-opening product (see supporting information).
The scope of substrates was investigated under the optimized
conditions (Table 3). [3+2]IMCC of several substituted phenyl
GDA-epoxides successfully afforded products (2b, 2c, 4a-4h)
containing oxa-[2.2.1] skeletons. [3+2]IMCC of one indole
substrate 1d afforded product 2d with a oxa-[3.2.1] skeleton.
Unfortunately, [3+2]IMCC of GDA-epoxides with a linear alkyl
linker failed, probably due to their flexibility comparing with the
rigid benzene-substrates.
Table 1 Optimization of reaction conditions of GDA-epoxide 1aa
Entry
LAs
Sc(OTf)3
Yb(OTf)3
In(OTf)3
Sn(OTf)3
Al(OTf)3
TMSOTf
AlCl3
T (oC)
r.t.
Time (h)
6
Yield (%)b
67
1
2
3
4
5
6
7
8
9
57
r.t.-60
r.t.-60
r.t.-reflux
r.t.-60
0-60
20
18
20
NR
44
20
20
Decompose
Decompose
NR
20
0-40
20
TsOH
r.t.-reflux
r.t.
20
78
Ni(ClO4)2·6H2O
3h
a Reaction conditions: 1a (0.06 mmol), catalyst (0.2 equiv), activated 4Å
MS (200 mg), solvent (2.0 mL), under argon. b Yield determined by 1H NMR
spectroscopy (internal standard: 1-chloro-2,4-dinitrobenzene).
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2
Chin. J. Chem. 2019, 37, XXX－XXX

IMCC of Donor-acceptor Epoxides with Alkenes for Construction of Oxa-[n.2.1] Skeletons
Chin. J. Chem.
Table 3 [3+2] IMCC of GDA-epoxidesa, b
our experiment (from 46% to 17%), the mechanism of
intramolecular cycloaddition is still different from that of the
intermolecular one. We think that besides the generally accepted
1,3-DC of carbonyl ylide through the carbon-carbon bond
cleavage of the epoxide ring, a stepwise SN-like mechanism is also
possible in which partial ee value was obtained (Scheme 6). To
the best of our knowledge, this is probably the first [3+2]
cycloaddition of GDA-epoxide through a carbon-carbon bond
cleavage SN-like mechanism. This result can make the chemistry of
the donor-acceptor epoxides be better understood.
Scheme 5 Asymmetric [3+2]IMCC.
Scheme 6 Proposed mechanism of [3+2]IMCC of GDA-epoxides with
carbon-carbon double bonds.
a
Reaction conditions: Sc(OTf)3 (0.1 equiv), 4 Å MS (0.1 g/mL), DCM (0.03
M), Ar, r.t. b Isolated yield.
Several derivation reactions on [3+2]IMCC products were
carried out (Scheme 4). Vinyl group of 4a was oxidized to
aldehyde 5. Retro Claisen condensation of 4a afforded 6 as a pair
of epimers (d.r. = 13:1), and the major isomer 6a undergo a
Baeyer-Villiger oxidation to afford acetal 7 which was then
converted to indane 8.
Scheme 4 Derivations of [3+2]IMCC products.
Conclusions
In conclusion, we have developed the first LA-catalyzed
[3+2]IMCC of GDA-epoxides with carbon-carbon double bonds.
This provides an efficient and general strategy for construction of
bridged oxa-[n.2.1] skeletons. Additionally,
a novel SN-like
mechanism through a carbon-carbon bond cleavage of epoxide
ring is proposed.
Experimental
Substrate 1 (0.12 mmol, 1.0 equiv) and 4 Å MS (400 mg) in dry
DCM (4 mL, 0.03 M) were degassed with argon atmosphere for 3
times. Sc(OTf)3 (5.9 mg, 0.012 mmol, 0.1 equiv) was then added
to the mixture under argon atmosphere and the reaction mixture
was stirred at room temperature until completion (determined by
TLC). The mixture was passed through a short pad of silica gel and
washed with Et2O (20 mL), the solvents were removed under
reduced pressure and the residue was purified with flash column
chromatography to afford the [3+2]IMCC product 2.
In order to better understand the reaction mechanism, a
chiral substrate 3a’ (46% e.e.) was prepared[11]. [3+2]IMCC of 3a’
afforded chiral products 4a’ (17% e.e.) (Scheme 5). This is quite
different from that of the LA-catalyzed intermolecular versions
reported by Zhang et al in which an intermolecular [3+2]
cycloaddition of a chiral GDA-epoxide with alkyne afforded a
completely racemic product.[4b] Theoretical investigations of the
intermolecular reaction mechanism by Domingo/Mongin and
Zhang/Ma et al also suggested a polar 1,3-DC of zwitterionic
carbonyl ylide through the carbon-carbon bond cleavage of the
GDA-epoxide.[3k,3q,4n] Although there was partial loss of ee value in
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3

Chen et al.
Report
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement (optional)
We thank NSFC (Nos 21372126, 21572103 and 21421062) and
MOST (2017YFD0200504) for financial support.
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[10] Comparing with the linear examples (dipolarophiles being directly linked
to either of the two carbon atoms of the carbonyl ylides) in the context,
branched examples (in the case of cyclic carbonyl ylides, dipolarophiles
being linked to atoms other than the two carbon atoms of the carbonyl
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www.cjc.wiley-vch.de
5

Chen et al.
Report
suitable model to exhibit the switch of regioselectivity between IMPC and
[11] Russo,
A.;
Lattanzi,
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Asymmetric
epoxidation
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carbonyl ylides generated from α-diazo ketones. Tetrahedron 1982, 38,
1477-1484; (b) Padwa, A.; Austin, D.; Hornbuckle, S.; Price, A. Rhodium (II)
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chemoselective effect of catalyst ligand. Tetrahedron Lett. 1992, 33,
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[12] CCDC 1867903 (2a) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chung, Y.; Lee, E.
A Carbonyl Ylide Cycloaddition Approach to
Platensimycin. Angew. Chem. 2008, 120, 4073-4075. Angew. Chem. Int.
Ed. 2008, 47, 4009-4011.
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6
Chin. J. Chem. 2019, 37, XXX－XXX

IMCC of Donor-acceptor Epoxides with Alkenes for Construction of Oxa-[n.2.1] Skeletons
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Lewis Acid-Catalyzed Intramolecular [3+2]
Cross-Cycloaddition
of
Donor-acceptor
Epoxides with Alkenes for Construction of
Oxa-[n.2.1] Skeletons
The first LA-catalyzed [3+2]IMCC of GDA-epoxides with carbon-carbon double bonds has been
developed. This provides an efficient and general strategy for construction of bridged oxa-[n.2.1]
skeletons.
Lu Chen, Jun Tian, Yizhou Zhan, Jun Ren, and
Zhong-Wen Wang*
This article is protected by copyright. All rights reserved.
Chin. J. Chem. 2019, 37, XXX－XXX © 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7