Lewis Acid-Catalyzed Intramolecular [3+2] Cross-Cycloaddition of Aziridine 2,2-Diesters with Conjugated Dienes for Construction of Aza-[n.2.1] Skeletons

Article abstract of DOI:10.1002/chem.201704695

A novel Lewis acid-catalyzed [3+2] intramolecular cross-cycloaddition (IMCC) between aziridine 2,2-diesters and conjugated dienes has been developed. This is the first regiospecific IMCC of intramolecular 1,3-dipolar cycloadditions of azomethine ylides with carbon=carbon double bonds, and supplies a general and efficient strategy for construction of structurally complex and diverse aza-[n.2.1] skeletons. The [3+2]IMCC could be carried out under mild conditions and in gram scale. More importantly, 3-alkyl-substituted aziridines were also successful. The excellent structural diversity, the facile operation and the versatile post-modifications will support the applications of the [3+2]IMCC in natural products synthesis and drugs discovery.

Full text of DOI:10.1002/chem.201704695

A Journal of
Accepted Article
Title: Lewis Acid-Catalyzed Intramolecular [3+2] Cross Cycloadditions
of Aziridine 2,2-Diesters with Conjugated Dienes for Construction
of Aza-[n.2.1] Skeletons
Authors: Zhongwen Wang, Yizhou Zhan, Tao Liu, and Jun Ren
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Lewis Acid-Catalyzed Intramolecular [3+2] Cross Cycloadditions
of Aziridine 2,2-Diesters with Conjugated Dienes for Construction
of Aza-[n.2.1] Skeletons
Yizhou Zhan, Tao Liu, Jun Ren, Zhongwen Wang*
Abstract: A novel Lewis acid-catalyzed [3+2]IMCC between aziridine
2,2-diesters and conjugated dienes has been developed. The
[3+2]IMCC is the first regiospecific IMCC of intramolecular 1,3-dipolar
cycloadditions of azomethine ylides with carbon-carbon double bonds,
and supplies a general and efficient strategy for construction of
structurally complex and diverse aza-[n.2.1] skeletons. The
[3+2]IMCC could be carried out under mild conditions and in gram
scale. More importantly, 3-alkyl-substituted aziridines were also
successful. The excellent structural diversity, the facile operation and
the versatile post-modifications will support the applications of the
[3+2]IMCC in natural products synthesis and drugs discovery.
General and highly efficient construction of structurally diverse
and complex polycyclic skeletons in biologically important natural
products is quite important for both organic synthesis and drug
discovery. Bridged aza-[n.2.1] skeletons broadly exist in bioactive
Figure 1. Representative natural products and synthetic molecules with aza-
[n.2.1] skeletons.
natural products and synthetic molecules (Figure 1),[1] and are
important building blocks and catalysts in organic synthesis.[2]
However, general and highly efficient synthetic approaches to
these structurally diverse and complex bridged skeletons are
quite limited. Most of the reported methods have been developed
the synthetic applications, regulation of the regioselectivity is
aiming at one specific skeleton. For example, while aza-Diels-
However, whether from the point of view of the theory, or from
generally a real challenge in various types of intramolecular
Alder [4+2] cycloaddition can afford a highly efficient construction
cycloadditions among which type I 1,3-dipolar cycloaddition of
of the 2-aza-[2.2.1]heptane,[2] it’s quite difficult to be applied to
azomethine ylide with carbon-carbon double bond (carbon-
carbon double bond was connected to the carbon atom of
other structurally diverse aza-[n.2.1] skeletons. Thus, developing
a new general and highly efficient strategy to construct those
azomethine ylide) is one of the representatives (Scheme 1). Most
skeletons is highly desirable.
From the structural point of view, a pyrrolidine ring is
embedded in the bridged aza-[n.2.1] skeleton. 1,3-Dipolar
instead of bridged [n.2.1] ones via IMCC (IntraMolecular Cross
of the type I intramolecular 1,3-dipolar cycloadditions give fused
[n.3.0] skeletons via IMPC (IntraMolecular Parallel Cycloaddition)
Cycloaddition).[6,7] Only two examples with carbon-carbon double
bonds were reported to afford [3+2]IMCC cycloadducts, but with
lower regioselectivities.[6a,6b] The IMPC regioselectivities of
azomethine ylides are inherently attributed to the intramolecular
nature of the reactions.[3k] Effort to switch the regioselectivity to
IMCC was failed,[8a] and theoretical calculations also indicate that
the [3+2]IMPC is much more preferred both kinetically and
thermodynamically.[8b,8c]
cycloaddition of azomethine ylide with carbon-carbon double
bond is a general strategy for efficient construction of the
pyrrolidine ring.[3] Besides the formal [3+2] cycloaddition through
C-N bond cleavage,[4] aziridine is often used as a precursor of
azomethine ylide (through C-C bond cleavage under photolysis or
thermal conditions) to participate in the 1,3-dipolar cycloadditions
which have been successfully applied to natural products
synthesis.[3,4b,5]
[*]
Y. Zhan, T. Liu, J. Ren, Prof. Dr. Z. Wang
State Key Laboratory of Elemento-Organic Chemistry,
Institute of Elemento-Organic Chemistry, College of Chemistry ,
Nankai University, 94 weijin road, Tianjin 300071, China
Prof. Dr. Z. Wang
Collaborative Innovation Center of Chemical Science and
Engineering, Nankai University, 94 weijin road, Tianjin 300071, China
E-mail: wzwrj@nankai.edu.cn
Homepage: http://wzw.nankai.edu.cn
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Regioselectivities of Type
I
Intramolecular 1,3-Dipolar
Cycloadditions of Azomethine Ylides with Carbon-carbon Double Bonds.
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As the 1,3-dipolar cycloadditions of aziridines with carbon-
carbon double bonds were generally carried out under harsh
conditions (under photolysis or high temperature conditions),
aiming to develop a more mild method, by using the donor-
acceptor design principle of cyclopropane [donor: electron-
donating group (EWG); acceptor: electron-withdrawing groups
(EWGs)] in combination with Lewis acids (LAs),[9] Johnson et al
developed an intermolecular ZnCl2-promoted [3+2] cycloaddition
of aziridine 2,2-diesters with carbon-carbon double bonds
(Scheme 2, a).[10a,10b] Recently, several other groups reported
related cycloadditions with various dienophiles.[10] In these
intermolecular examples, besides the two geminal EWG groups,
an aryl group in the 3-position of aziridine is necessary as a donor
to further activate the carbon-carbon bond. Several [3+2]IMPC of
EWG-substituted aziridines with carbon-carbon double bonds
have been developed, in most of which the EWG is placed in the
internal position to be connected to the carbon-carbon double
bond moiety (Scheme 2, b).[5] Garner et al reported one example
with an external EWG, in which the carbon-carbon double bond
was mono-substituted and a [3+2]IMPC product was obtained
under thermal condition (Scheme 2, c).[5g] We have recently
developed the IMCC and IMPC strategy of cyclopropanes.[11]
Following our design principle in cyclopropane system (Scheme
2, d),[11g] we envisaged to place two geminal ester groups in the
external position and introduced an additional carbon-carbon
double bond (as a conjugated diene) as an activating group, a
We prepared 1a as a model substrate to optimize the reaction
conditions for the [3+2]IMCC reaction (Scheme 3). Various LAs
and solvents (see in the supporting materials) were screened and
we found that the [3+2]IMCC cycloadduct 2a could be obtained
under most of the reaction conditions at room temperature, and
Sc(OTf)3 or SnCl4 in DCM (dichloromethane) with addition of 4Å
molecular sieves was selected as the optimal condition. It should
be noted that p-TsOH (Bronsted acid) also worked well to give 2a
(81% NMR yield). The structure of 2a was unambiguously
confirmed by NMR spectroscopy and X-ray crystallography
analysis.[12] This reaction could also be carried out in gram scale.
It should also be noted that 2a was also obtained under thermal
o
condition (60 C) in toluene without addition of LAs (31% NMR
yield). The above results are quite different from what Garner et
al (Scheme 2, b) reported[5g] and fully illustrate the necessity of
the introduction of the additional vinyl group for the switch of the
regioselectivity. The above result was also different from the
intermolecular result reported by Zhang et al.[10l]
regioselectivity-switching group and
a
group for further
functionalization in future applications (Scheme 2, e). We herein
report our recent results.
Scheme 3. [3+2]IMCC of 3-Arylaziridine-2,2-diestersa.
Scopes and limitations of the [3+2]IMCC were then
investigated under the optimal reaction conditions. We first
explored the [3+2]IMCC of 3-arylaziridine 2,2-diesters. Most of the
substrates reacted smoothly to afford the desired products in
excellent yields (Scheme 3). [3+2]IMCC of 1a-1k afforded 2-aza-
[2.2.1]heptane cycloadducts. Substrate 1c with electron-donating
group (MeO) was relatively unstable but was with high reactivity.
Substrates 1d and 1e with electron-withdrawing groups (NO2, CN)
were more stable but the reactivity was relatively low. Three
substrates with different ester groups (1f-1h) gave desired
Scheme 2. [3+2] Cycloadditions of EWG-activated Aziridines with Carbon-
carbon Double Bonds.
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products in excellent yields. Three substrates with variously
substituted tosyl (1i-1k) also gave desired products in excellent
yields. It should be noted that substrates without an additional
vinyl group (1l and 1m) also worked well although the reaction
time was prolonged and the yields decreased. This is similar to
our previously reported results on cyclopropanes,[11j] but is quite
different from the intermolecular results reported by Zhang el al in
which no reaction happened with 1-methylstryrene.[13] Examples
with lengthened linkers could also work to afford respectively
[3.2.1]-cycloadduct 2n and [4.2.1]-cycloadduct 2o in moderate
yields.
stereoselectivity, which might be further developed for
conformationally rigid amino acid drugs.[14]
We then explored the [3+2]IMCC of 3-alkylaziridine 2,2-
diesters. To our great delight, quite different from the
intermolecular [3+2] cycloadditions of aziridine 2,2-diesters with
various dienophiles in which 3-aryl groups were necessary as
donors for the activation of carbon-carbon bonds of aziridines,
most of the substrates herein reacted smoothly to afford the
desired products in excellent yields (Scheme 4). Reactions of 1p
gave a mixture of two inseparable isomers (2p and 2p’), which
was different from those of the aryl-linked examples (1a-1k). 2p
and 2p’ were obtained via [3+2]IMCC of the internal and external
carbon-carbon double bonds respectively. [3+2]IMCC of 1q-1s
were successfully carried out to afford 2q-2s respectively. While
2q and 2r contained a [3.2.1] skeleton, 2s and 2t contained a
[4.2.1] one.
Scheme 5. Post-modifications of [3+2]IMCC Cycloadducts.
In conclusion, we have successfully developed LA-catalyzed
[3+2]IMCC of aziridine 2,2-diesters with conjugated dienes. The
[3+2]IMCC supplied
a general and efficient strategy for
construction of structurally complex and diverse aza-[n.2.1]
skeletons. With introduction of a conjugated vinyl group, this
[3+2]IMCC represents the first regiospecific IMCC of
intramolecular 1,3-dipolar cycloaddition of azomethine ylides with
carbon-carbon double bonds. More importantly, 3-alkyl-
substituted aziridines were also successful, which makes the
strategy possess an excellent structural diversity. The excellent
structural diversity, the facile operation and the versatile post-
modifications are also the features of the [3+2]IMCC. We strongly
believe that this strategy will be widely applied to synthesis of
natural products and discovery of new drugs and catalysts.
Acknowledgements
We thank NSFC (Nos 21372126, 21572103 and 21421062) for
financial support.
Keywords: aziridine • cycloaddition • bridged ring • medium-
sized ring • regioselectivity
Scheme 4. [3+2]IMCC of 3-Alkylaziridine-2,2-diesters a.
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[7] The regioselectivity of most of the formal [3+2] cycloadditions of aziridines
(through C-N bond cleavage) were similar to those of the 1,3-dipolar
cycloaddition, except the only example developed by Bergmeier et al.: a)
D. J. Lapinsky, S. C. Bergmeier, Tetrahedron 2002, 58, 7109; b) S. C.
[14] I. V. Komarov, A. O. Grigorenko, A. V. Turov, V. P. Khilya, Russ. Chem.
Rev. 2004, 73, 785.
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10.1002/chem.201704695
Chemistry - A European Journal
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Yizhou Zhan, Tao Liu, Jun Ren,
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Lewis Acid-Catalyzed Intramolecular
[3+2] Cross Cycloadditions of
Aziridine 2,2-Diesters with
Conjugated Dienes for Construction
of Aza-[n.2.1] Skeletons
[3+2]IMCC of aziridine 2,2-diesters with conjugated dienes has been
successfully developed. The [3+2]IMCC is the first regiospecific IMCC of
intramolecular 1,3-dipolar cycloadditions of azomethine ylides with carbon-carbon
double bonds, and supplies a general and efficient strategy for construction of
structurally complex and diverse aza-[n.2.1] skeletons.
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