Highly Enantioselective Construction of Strained Spiro[2,3]hexanes through a Michael Addition/Ring Expansion/Cyclization Cascade

Article abstract of DOI:10.1002/anie.201912834

We herein report a general organocatalytic enantioselective strategy for the construction of highly strained spiro[2,3]hexane skeletons from methylenecyclopropanes and a broad selection of α,β-unsaturated aldehydes. The reaction proceeds through a Michael addition followed by ring expansion of methylenecyclopropanes and nucleophilic attack of an enamine to realize the construction of spiro[2,3]hexanes. Key to the success of this approach are the utilization of an electron-deficient difluoro-substituted secondary amine catalyst and the intrinsic reactivity of methylenecyclopropanes.

Full text of DOI:10.1002/anie.201912834

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Accepted Article
Title: Highly Enantioselective Construction of Strained
Spiro[2,3]hexanes via Michael-Ring Expansion-Cyclization
Cascade Strategy
Authors: Chuan-Gang Zhao, Zhi-Tao Feng, Guo-Qiang Xu, Ang Gao,
Jing-Wei Chen, Zhu-Yin Wang, and Peng-Fei Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912834
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10.1002/anie.201912834
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COMMUNICATION
Highly Enantioselective Construction of Strained
Spiro[2,3]hexanes via Michael-Ring Expansion-Cyclization
Cascade Strategy
Chuan-Gang Zhao, Zhi-Tao Feng, Guo-Qiang Xu*, Ang Gao, Jing-Wei Chen, Zhu-Yin Wang and
Peng-Fei Xu*
Abstract: We herein report
a
general organocatalytic
quaternary stereocenters itself was considered to be one of the
most difficult tasks among synthetic transformations.[6]
Considerable efforts have been made in the last few years
towards the development of protocols to prepare spirocyclic
compounds, particularly the ones containing at least one middle
ring. Traditionally, the synthesis of spiro[2,3]hexane was limited
to the derivatization of ternary or four-membered ring precursor:
a) cyclopropanation of methylenecyclobutane derivatives or
enantioselective strategy for the construction of highly strained
spiro[2,3]hexane skeletons from methylenecyclopropanes and a
broad selection of α,β-unsaturated aldehydes. The reaction
proceeds through a Michael addition followed by ring expansion of
methylenecyclopropanes and the nucleophilic attack of an enamine
to realize the construction of spiro[2,3]hexanes. The key to the
success of this approach is the utilization of an electron-deficient
difluoro-substituted secondary amine catalyst and the intrinsic
reactivities of methylenecyclopropanes.
decarbonylation of spiro[3.3]heptan-2-one and its derivatives.
[9]
(Scheme 1, eq a)[8],
b) [2
+
2] cycloaddition of
methylenecyclopropane derivatives or ring expansion of
[9]
corresponding spiro precursors (Scheme 1, eq. b).[7],
All of
The synthesis of spirocyclic hydrocarbon frameworks,
especially the ones containing cyclobutane or cyclopropane
units,[1] has risen in prominence over the last few years due to
an increased recognition of their importance as bioactive natural
products (Figure 1).[2] Compared with the common cyclic
molecules, the advantages of the spiro compounds in some
elementary aspects are obvious: a) The compactness of
spirocycles causes reduced lipophilicity;[3] b) The spatial
diversification of the spirocyclic compounds is further promoted
through isomerization;[1a] c) The higher sp3/sp2 ratio of
spirocyclic compounds facilitate the design of new classes of
biologically-active molecules with improved properties.[4]
Unexplored scaffolds may be promising bioactive compounds,
and those inherent characteristics make the spiro compounds
more attractive than common cyclic compounds in drug
discovery.[5]
these strategies had one of the small rings, present in the
starting materials, reserved after the reaction. To the best of our
knowledge,
derivatives have not been reported. Therefore, developing a mild
and efficient method for constructing asymmetric
spiro[2,3]hexanes is still highly desired.
asymmetric
synthesis
of
spiro[2,3]hexane
Figure1 Examples of pharmaceutical compounds containing spirocyclic
rings.
Scheme 1 Feasible Approach to synthesize spiro[2,3]hexanes.
However, the synthesis of spirocyclic hydrocarbon frameworks
containing small rings is considered to be more challenging
because the common carbon atom which connects the two
neighboring rings is a quaternary atom. The construction of
With the rapid development of organocatalysis, chiral
secondary amine catalysis has become one of the most
[11]
powerful tools in the realm of chiral molecule synthesis.[10],
With our ongoing interest in the synthesis of small ring
compounds, we tried to challenge the asymmetric synthesis of
small ring spiro compounds.[12] We envisioned that the iminium
ion generated by difluoro-substituted secondary amine catalysts
may provide further opportunities for developing new reactions.
Electron-rich olefins, one of the most common weak
nucleophiles, have been widely explored as building blocks in
the presence of transition metal catalysts. In contrast, they are
rarely applied in organic catalysis. We questioned whether
olefins can enable conjugate additions to the β-carbon atom of
iminium ion intermediates. This strategy, if successful, would
complement the nucleophile library of traditional iminium ion
catalysis. On the other hand, a method for enantioselective
C-G. Zhao, G-Q. Xu, A. Gao, J-W. Chen, Prof. Z-Y. Wang, Prof. Dr.
P.-F. Xu
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou 730000 (P.R. China)
Fax: (+86) 931-8915557,
[*]
Corresponding Authors:
E-mail: xupf@lzu.edu.cn E-mail: gqxu@lzu.edu.cn
Z-T. Feng
Department of Chemistry, University of California-Davis, One
Shields Avenue,Davis, CA 95616, USA
Supporting information for this article is given via a link at the end of
the document. CCDC 1937150 (3b)
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10.1002/anie.201912834
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COMMUNICATION
synthesis of strained spiro[2,3]hexanes, a compound with
synthetic potential and biological activity, in mild conditions
would be constructed.
entris 7-11). The originally used additive, trifluoroacetic acid,
gave the best results. Further study of the reaction temperature
indicated that increasing the temperature gave slightly better
results (Table 1, entry 13). However, increasing the temperature
to 50 oC led to decomposition of some starting materials and
therefore caused a slight decrease of the yield (Table 1, entry
14).
Table 1 Optimization of the Reaction Conditions[a]
Yield[e]
(%)
ee[g]
(%)
Entry
Catalyst
Additive
dr.[f]
4a
4b
4c
4d
4e
-
TFA
TFA
TFA
TFA
TFA
TFA
TsOH
TfMsA
TCA
BA
nr.
nr.
-
-
-
1
2
-
45
>20:1
>20:1
>20:1
-
79
99
99
-
3
69
4
50
5
nr.
6
4d
4d
4d
4d
4d
4d
4d
4d
60%
32%
trace
nr.
>20:1
>20:1
nd.
92
82
nd.
-
7
8
9
-
10
11
12[b]
13[c]
14 [d]
AcOH
TFA
TFA
TFA
nr.
-
-
38
>20:1
>20:1
>20:1
99
99
99
76
68
[a] Reaction conditions: Reactions performed with 1a (0.1 mmol), 2a (0.15
mmol), catalyst (20 mol%), additives (40 mol%) in solvent (1 mL) at room
temperature for 36 h. For detailed experimental procedures, see the
supporting information. [b] 1a (0.3 mmol), 2a (0.1 mmol). [c] Reaction was
performed at 40 oC. [d] Under 50 oC. [e] Isolated yield. [f] dr. was determined
by 1H NMR analysis of the crude products; nr. = no reaction. [g] ee was
determined by chiral-phase HPLC analysis; nd. = not determined. TMS =
trimethylsilyl, TBS = tert-butyldimethylsilyl, TDS = thexyl-dimethylsilyl TFA =
trifluoroacetic acid, TfOH = triflic acid, TfMsA = trifluoromethanesulfonic acid,
TCA = trichloroacetic acid, BA = benzoic acid, AcOH = acetic acid.
To test the feasibility of our design, the reaction was
investigated using cinnamaldehyde 1a and electron-rich
methylenecyclopropane 2a as the model substrates. First, the
commonly used secondary amines were screened (Table 1,
entries 1−3). Neither the chiral imidazolidinone catalyst 4a nor
diarylprolinol silyl ether catalyst 4b worked in this system. In
order to increase the reactivity of the iminium ion, catalyst 4c,
which contains two electronegative fluorine atoms, was then
tested. We were pleased to find that the desired product 3a was
successfully produced in moderate yield with an encouraging
level of stereoselectivity (Table 1, entry 3). The chiral amine
catalyst 4d, with high steric hindrance and a perfluoro-isopropyl
group on the arene scaffold, gave a dramatic increase in both
yield and stereoselectivity (Table 1, entry 4). Moreover, when
the reaction was carried out in the absence of the secondary
amine catalyst, no product was detected even after 36 h (Table
1, entry 6), which revealed that trifluoroacetic acid was unable to
make the reaction proceed smoothly as the only catalyst. To
achieve higher yield, we attempted to use some additives which
play an important role in the construction of iminium ion (Table 1,
Reaction Conditions: [a] Reactions performed with 1a (0.1 mmol), 2a (0.15
mmol), catalyst (20 mol%) , TFA ( 40 mol%) in acetonitrile (1 mL) at 40 oC for
36 h. [b] with the help of an auxiliary catalyst 5e ( 40 mol%) in DCE (1 mL) for
48 h. All of the dr of products were > 20 : 1,determined by 1H NMR analysis of
the crude products
Scheme 2 Substrate Scope of the Reaction[a]
To investigate the substrate scopes of this asymmetric
transformation, various α,β-unsaturated aldehydes were tested
under the optimized conditions (Scheme 2). A series of
functional groups, such as halides (3b-3c), nitro group (3d),
trifluoromethyl group (3e), and cyano group (3f), at the para
position of the phenyl group were compatible with this
transformation. Aldehydes with electron-donating groups on the
aryls could also produce the corresponding spirocyclic
compounds with excellent diastereo- and enantioselectivities
albeit in decreased yields (Scheme 2, 3g, 3j). This phenomenon
proved that the activities of iminium ions were sensitive to the
electronic effect of substrates. Substrates with the aryl group
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10.1002/anie.201912834
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replaced with a naphthyl group also provided the corresponding
products 3m-3n. As exemplified by 3o-3t (Scheme 2), this
protocol was also effective for various substituted
methylenecyclopropanes. Considering the insolubility of
methylenecyclopropanes bearing a bromine or chlorine atom at
the para position in acetonitrile, the solvent was replaced with
DCE. Nevertheless, the substrates were not converted into
products effectively (conversion rate is less than 10%). To our
delight, with the help of an auxiliary catalyst 5, the reaction could
produce the products with good enantioselectivities and
increased yields (Scheme 2, 3p, 3q).[13] To further explore the
practicability of this strategy, a large-scale asymmetric synthesis
of 3a was performed. Fortunately, the reaction proceeded
smoothly to obtain the spirocyclic compound in good yield with a
slight decrease of ee. The absolute configuration of 3b was
determined by X-ray crystallographic analysis (see the
Supporting Information), and the rest were assigned by
analogy.[14]
Figure 3 Proposed Reaction Mechanism
Based on our experimental results, the following reaction
mechanism was proposed (Figure 3). First, the secondary amine
condenses with the α,β-unsaturated aldehyde to form the
iminium ion (Figure 3 intermediate B). Then Michael attack of
the electric-rich methylenecyclopropane to the β position of the
iminium ion occurred. After that, the cyclopropane expands to
form
a four-membered ring, at the same time a new
cyclopropane was constructed. The rearrangement and the
electrophilic addition happened in a concerted process, rather
than a carbon cation (Figure 3 intermediate D’) process. Finally,
product 3 was obtained by hydrolysis of intermediate E.
Conditions: this is a mixed spectrum. a) a mixture solution of cinnamic
aldehyde : chiral amine : Trifluoroacetate = ( 1:1:1.3 ) in deuterated acetonitrile.
Figure 2 1H NMR of Various iminium ion intermediates.a
Figure 4 DFT calculation of the energy profiles for the reaction process.
Geometries and frequency analysis were performed under B3LYP-D3/6-
31G(d) level of theory.
To determine the influence of secondary amine catalysts on
the reactivities of the intermediates, several 1H NMR
experiments were carried out in CD3CN (Figure 2). It was found
Next, computational studies were carried out to gain
mechanistic insight into the reaction process. After the formation
of 1-S (Figure 4), the reaction process can be carried out in two
ways. However, only one product 3-S was observed. Even
though the predicted free energy barrier via TS2-S is 1.2 kcal
mol-1 lower than that for TS1-S. We speculated that the
predicted free energy barrier via TS2-S is too close to the
intermediate 1-S so that this process is reversible at room
temperature. Whereas, the one through Ts1-S could produce
product irreversibly. The cyclobutyl cationic structure 3-S (Figure
4) is not a minimum on the potential energy surface. Thus, the
rearrangement and the electrophilic addition happens in a
1
that the chemical shifts of iminium ion intermediates in H NMR
were obviously different from one another, and the chemical
shifts of H1 and H2 in intermediates III, IV and V were
significantly higher. This experiment demonstrated that the
difluoro-substituted iminium ion intermediates had higher
reactivities.
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Scheme 3. Transformations of Product 3a
In conclusion, we have developed a highly enantioselective
approach for the synthesis of strained spiro[2,3]hexane
derivatives by Michael-ring expansion-cycloaddition strategy in a
cascade process, and a broad selection of α,β-unsaturated
aldehydes were smoothly transformed to the corresponding
spirocyclic products in moderate to high yields with excellent
diastereo- and enantioselectivities. The reaction could be scaled
up easily, and the synthetic potentials of the obtained products
were illustrated by selective transformations into more complex
skeletons. We believe this approach will find more applications
since it provides ready access to unexplored spiro[2,3]hexane
derivatives.
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We are grateful to the NSFC (21632003, 21572087 and
21572087), the key program of Gansu province (17ZD2GC011)
and the “111” program from the MOE of P. R. China, and
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Keywords:
spirocyclic
hydrocarbon
frameworks
•
organocatalysis • enantioselective
[14] CCDC 1937150 (3b) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
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Entry for the Table of Contents
COMMUNICATION
C.-G. Zhao, Z.-T. Feng, G.-Q. Xu*, A.
Gao, j-W. Chen, Pro. Dr. Z.-Y. Wang
and Pro. Dr. P.-F. Xu*
Page No. – Page No.
Highly Enantioselective Construction
of Strained Spiro[2,3]hexanes via
Michael-Ring Expansion-Cyclization
Cascade Strategy
Highly strained spiro[2,3]hexane skeletons are accessed from readily prepared
starting materials in a Michael-ring expansion-cycloaddition cascade strategy. The
process does not require metals, proceeds by organocatalysis, and can be used to
contribute three continuous carbon stereocenters with good enantioselectivity and
diastereoselectivity.
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