Lewis Acid Catalyzed Formal Intramolecular [3 + 3] Cross-Cycloaddition of Cyclopropane 1,1-Diesters for Construction of Benzobicyclo[2.2.2]octane Skeletons

Article abstract of DOI:10.1021/acs.orglett.5b01927

A novel Lewis acid catalyzed formal intramolecular [3 + 3] cross-cycloaddition (IMCC) of cyclopropane 1,1-diesters has been successfully developed. This supplies an efficient and conceptually new strategy for construction of bridged bicyclo[2.2.2]octane skeletons. This [3 + 3]IMCC could be run up to gram scale and from easily prepared starting materials. This [3 + 3]IMCC, together with our previously reported [3 + 2]IMCC strategy, can afford either the bicyclo[2.2.2]octane or bicyclo[3.2.1]octane skeletons from the similar starting materials by regulating the substituents on vinyl group.

Full text of DOI:10.1021/acs.orglett.5b01927

Letter
pubs.acs.org/OrgLett
Lewis Acid Catalyzed Formal Intramolecular [3 + 3] Cross-
Cycloaddition of Cyclopropane 1,1-Diesters for Construction of
Benzobicyclo[2.2.2]octane Skeletons
Weiwei Ma, Jie Fang, Jun Ren, and Zhongwen Wang*
State Key Laboratory and Institute of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, 94 Weijin Road, Tianjin 300071, P.R. China
S
* Supporting Information
ABSTRACT: A novel Lewis acid catalyzed formal intramolecular [3
+ 3] cross-cycloaddition (IMCC) of cyclopropane 1,1-diesters has
been successfully developed. This supplies an efficient and
conceptually new strategy for construction of bridged bicyclo[2.2.2]-
octane skeletons. This [3 + 3]IMCC could be run up to gram scale
and from easily prepared starting materials. This [3 + 3]IMCC,
together with our previously reported [3 + 2]IMCC strategy, can afford either the bicyclo[2.2.2]octane or bicyclo[3.2.1]octane
skeletons from the similar starting materials by regulating the substituents on vinyl group.
eveloping efficient and general strategies to construct
skeletally complex and diverse polycyclic skeletons is
important for the synthesis of natural products and biologically
active compounds but still remains a big challenge in organic
synthesis. The bicyclo[2.2.2]octane skeleton broadly exists in
biologically important natural and unnatural products (Figure 1).
for construction of various cyclic skeletons.2 We have developed
intramolecular [3 + 2] and [4 + 2] cross-cycloadditions ([3 +
2]IMCC and [4 + 2]IMCC) of donor−acceptor cyclopropanes
with various 2-atom moieties for construction of bridged [n.2.1]
and [n.3.1] skeletons.2f,3 During our recent research on the [3 +
2]IMCC of cyclopropane 1,1-diesters with CC (Scheme 1,
D
Scheme 1. [3 + 2]IMCC versus [3 + 3]IMCC of Cyclopropane
1,1-Diester
Figure 1. Representative natural and unnatural products with
bicyclo[2.2.2]octane skeletons.
Additionally, due to its inherent stereochemistry, this skeleton is
also a powerful building block for the stereoselective synthesis of
natural products with other types of skeletons, for example, cis-
1,4-disubstituted cyclohexanes via cleavage of a carbon−carbon
bond. Stepwise strategies are the most commonly used ones to
access the bridged bicyclo[2.2.2]octane skeleton. However, there
are only a few step-efficient strategies for this skeleton, and the
Diels−Alder [4 + 2] cycloaddition of cyclohexadienes might be
the only commonly used one. Thus, developing efficient and
conceptually new strategies to afford such a bicyclo[2.2.2]octane
skeleton still remains an important and challenging task.1
Donor−acceptor cyclopropanes have been proven to be
versatile building blocks in acid-promoted formal cycloadditions
A),3b to our great surprise, we found that when substituent R was
changed from H to Me, the reaction pathway was switched to [3
+ 3]IMCC, a novel type of cycloaddition. This [3 + 3]IMCC
afforded a bicyclo[2.2.2]octane skeleton (Scheme 1, path B).
The switch of the [3 + 2]IMCC (R = H) to [3 + 3]IMCC (R =
Me) was ascribed to a 1,2-shift of an allylic H, in which steric
hindrance of R might be involved (Scheme 2). Although many
formal [3 + 3] cycloadditions of donor−acceptor cyclopropanes
Received: July 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01927
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Letter
Scheme 2. Synthesis of Substrates 1
Scheme 3. Sc(OTf)3-catalyzed [3 + 3] IMCC of 1a−h
have been reported, most of the three-atom moieties contain
heteroatoms to afford heterocycles.4 There are quite limited
examples with three-carbon moieties to afford cyclohexane
skeletons.4ag−aj Herein, we report our results on a new type of
formal [3 + 3] cycloaddition.
Substrates 1 could be easily prepared from substituted o-
iodobenzaldehydes via Wittig olefination/cyclopropanation/
Suzuki−Miyaura cross-coupling process (Scheme 2).3b,5,6
Substrate 1a was selected for the subsequent cycloaddition
study. We found that while most of the common Lewis acids
could not catalyze the reaction to afford [3 + 3]IMCC
cycloadducts, Sc(OTf)3 and SnCl4 proved to be effective.
Under catalysis of Sc(OTf)3 (0.2 equiv) in 1,2-dichloroethane
(DCE), bridged product 2a was obtained in an excellent yield
(92%) as a pair of diastereoisomers (dr = 3.7:1) (Scheme 3).
Several other substrates 1 with various substituents on the
benzene ring were also proven to be successful (Scheme 3).
Substrates with electron-donating groups (1b−d) afforded the
corresponding cycloadducts 2b−d. It was surprising that unlike
other examples [3 + 3]IMCC of substrate, 1d gave a single
diastereoisomer (2d) exclusively. [3 + 3]IMCC of substrates
with electron-withdrawing groups (1e and 1f) did not work
under the above conditions but successfully proceeded under
catalysis by SnCl4 (0.2 equiv). With unsuccessful second
annulations, the byproducts 2e′ and 2f′ were produced. The
substrate 1h, having a quaternary carbon center in the
cyclopropane ring also worked well to afford the cycloadduct 2h.
Under catalysis by Sc(OTf)3 (0.2 equiv), [3 + 3]IMCC of
several other substrates 1 with various alkyl substituents on the
vinyl group was also successful in affording the corresponding
cycloadducts 2i−m (Scheme 4). It should be noted that when
the reaction of 1i was carried out at a higher temperature (83 °C),
instead of the [3 + 3]IMCC cycloadduct 2i, 2i′ was produced
with an unsuccessful second annulation. This was similar to the
formation of 2e′ and 2f′. When the substituent on the vinyl group
was phenyl (2n), the reaction proceeded as a [3 + 2]IMCC
pathway that was similar to our previously reported diene
examples.3b An explanation for this is that, unlike the alkyl-
substituted alkenes, the phenyl-substituted one gave a more
Scheme 4. Sc(OTf)3-catalyzed [3 + 3] IMCC of 1i−m
stable benzyl cation after the first annulation process. All of these
results indicate that, besides the steric effect of the R group, the
stability of carbocations (before and after the 1,2-H shift) as well
as the different ring strains of the two bridged rings
(bicyclo[2.2.2]octane and bicyclo[3.2.1]octane) might also be
involved in the pathway selection.
It should be noted that the [3 + 3]IMCC reaction could also be
easily carried out on gram scale (Scheme 5). This might exhibit
its potential in natural products synthesis as well as in
B
DOI: 10.1021/acs.orglett.5b01927
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confirmed by NMR spectroscopy, HRMS, and X-ray crystal
structure analysis (Scheme 6).8
Scheme 5. [3 + 3]IMCC reaction in gram scale
The interpretation of the diastereoselectivity can be under-
stood as follows: after the first ring closure, there are two possible
conformations (A and B) of the obtained zwitterion (Scheme 7).
Scheme 7. Interpretation of the Diastereoselectivity
construction of structurally diverse libraries for further chemical
biology study and lead discovery.
The two diastereoisomers of the cycloadducts 2 could be
separated via preparative HPLC. We found that most of the
major diastereoisomers were colorless oils, and the minor ones
were white solids. Three postmodifications were carried out on
the bridged products (Scheme 6). 2a was converted to its
barbituric acid derivative 3. The ester groups of endo-2h were
reduced by LiAlH4. Krapcho decarboxylation7 was carried out on
endo-2m to afford 5. The structures of endo-isomer of 3, endo-2d,
and the minor isomer (exo-2m) of 2m were unambiguously
Scheme 6. Post-modifications of three products and single
crystals of endo-isomer of 3, endo-2d, and exo-2m
Conformation A was considered to be the more preferred one
due to the steric hindrance. In conformation A, the rearranged H
of the benzyl CH2 is the one on the sp3-obital roughly parallel to
the cationic sp2-obital. This results the diastereoselectivity which
prefers the endo isomer.
In summary, we have successfully developed a novel type of
Lewis acid catalyzed [3 + 3]IMCC of cyclopropane 1,1-diesters
in which the 1,2-shift of allylic H is involved. This is a new type of
[3 + 3] cycloaddition of donor−acceptor cyclopropanes with a
three-carbon moiety to afford a cyclohexane skeleton. This
supplies an efficient and conceptually new strategy for
construction of bridged benzobicyclo[2.2.2]octane skeletons.
This [3 + 3]IMCC could be run up to gram scale from easily
prepared starting materials. This [3 + 3]IMCC, together with our
previously reported [3 + 2]IMCC strategy,3b can afford either the
bicyclo[2.2.2]octane or bicyclo[3.2.1]octane skeletons from
similar starting materials by regulating the substituents on the
vinyl group. Further investigation of this [3 + 3]IMCC strategy,
including its potential application to total synthesis of polycyclic
terpenoids and alkaloids as well as construction of structurally
diverse libraries, is being carried out in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01927.
X-ray data for compound 3 (CIF)
X-ray data for compound 2d (CIF)
Detailed experimental procedures, characterization data,
and crystallographic data (PDF)
X-ray data for compound 2m (CIF)
C
DOI: 10.1021/acs.orglett.5b01927
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wzwrj@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NSFC (Nos. 20972069, 21172109, and 21121002),
MOST 973 Project (No. 2010CB126106), National Key
Technologies R&D Program (No. 2011BAE06B05), and the
Ph.D. Candidate Research Innovation Fund of Nankai
University for financial support. We are indebted to Prof. Bin
Zhao for helping us with the X-ray single crystal of compound 3.
We are also indebted to Mr. Chi Zhang, Mr. Bingxia Sun, Mr.
Tianhang Song, Mr. Yizhou Zhan, Mr. Zhixu Zhu, and Mr.
Pengcai Liu for help with some experiments.
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