Organocatalytic Regiodivergent C?C Bond Cleavage of Cyclopropenones: A Highly Efficient Cascade Approach to Enantiopure Heterocyclic Frameworks

Article abstract of DOI:10.1002/chem.201803861

Here a highly efficient cascade approach is reported that combines a cycloaddition reaction with a regioselective strain-release process to afford diverse heterocyclic frameworks through bifunctional catalysis. The cooperation of hydrogen-bonding network activation and a regiodivergent strain-assisted effect is the key to promoting this complex chemical transformation, leading to the generation of two different ring systems in high yields with excellent stereoselectivities. The reaction proceeded by a mechanism involving a “spring-loaded” intermediate with switchable C?C bond cleavages achieved by controllable ring-strain release. This reaction was also amenable to gram scale synthesis with only 0.1 mol % catalyst loading.

Full text of DOI:10.1002/chem.201803861

A Journal of
Accepted Article
Title: Organocatalytic Regiodivergent C–C Bond Cleavage of
Cyclopropenones: A Highly Efficient Cascade Approach to
Enantiopure Heterocyclic Frameworks
Authors: Jian Cao, Ran Fang, Jin-Yu Liu, Hong Lu, Yong-Chun Luo,
and Peng-Fei Xu
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To be cited as: Chem. Eur. J. 10.1002/chem.201803861
Link to VoR: http://dx.doi.org/10.1002/chem.201803861
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Organocatalytic Regiodivergent C–C Bond Cleavage of
Cyclopropenones: A Highly Efficient Cascade Approach to
Enantiopure Heterocyclic Frameworks
Jian Cao, Ran Fang, Jin-Yu Liu, Hong Lu, Yong-Chun Luo and Peng-Fei Xu*
Abstract: Here we report a highly efficient cascade approach
combining a cycloaddition reaction with a regioselective strain-
release process to afford diverse heterocyclic frameworks via
bifunctional catalysis. The cooperation of hydrogen-bonding network
activation and regiodivergent strain-assisted effect is the key to
promoting this complex chemical transformation, leading to the
generation of two different ring systems in high yields with excellent
nucleophilic intermediates and facilitated the subsequent formal
[3+2] cycloaddition reations (Scheme 1a).[9h,9i]
Cyclopropenones are ideal candidates for C−C bond cleavage
methodologies because of their considerable ring strain,
polarized nature and aromaticity,[10] and these small unsaturated
rings could be potentially activated by the acidic protons of
squaramide to generate an electrophilic transition state that has
not been reported in the previous literature.[11] Such a transition
state would have a tendency to react with o-hydroxy aromatic
aldimines activated by hydrogen-bonding network due to the
reduced HOMO–LUMO gap and activation energy (Scheme
1b).[12] More interestingly, the different chiral intermediates
generated from the [3+2] cycloaddition can act as “spring-loaded”
reagents with strain energy,[13] which could show strain-assisted
effect[14] and induce nucleophilic attack of phenol group at
different electrophilic sites (either the carbonyl carbon or α-site
of the carbonyl group). To test our hypothesis, two different
computational models were established to calculate the
feasibility of switchable regioselectivity. As expected, different
substituents changed the polarization of the bonds and two
different ring-opening pathways involving either intermediate C
or intermediate D (Scheme 1b) could be predicted. Therefore,
we envisioned that the cleavage precursors (intermediate C and
D) could provide strong driving power and accurate steric site
recognition for the reactions with switchable regioselectivity.
stereoselectivities. The reaction proceeded by
a mechanism
involving a “spring-loaded” intermediate with switchable C–C bond
cleavages achieved by controllable ring-strain release. This reaction
was also amenable to gram scale synthesis with only 0.1 mol %
catalyst loading.
C–C bond cleavage, which has attracted much attention from
and also challenged organic chemists for decades,[1] is of
significant synthetic value for chemical conversions. Among the
basic strategies for facilitating C–C bond cleavage, the most
typical one is to release the potential energy stored in strained
three- or four-membered ring compounds to form more stable
intermediates or products.[2] In 1955, strain release was proved
to be responsible for the enhanced oxidation of steroidal
secondary alcohols.[3] Since then, many outstanding works
about strain release have been reported,[4] which proved that
simple and rapid, click-like access[5a] to new connections could
be achieved by harnessing the strained bonds properly.[5b]
Since the first synthesis of cyclopropenones by Breslow[6a,6b]
and Vol'pin,[6c,6d] numerous research efforts have been paid on
exploring the synthetic value,[7a] the properties[7b-d] and the
applications[7e-j] of this fascinating class of compounds. There
even was
a vivid description for this kind of chemical
compounds: having a simple appearance outside, yet full of
wonder inside, cyclopropenone seems like a miniature carved
ivory altarpiece in a Chinese curio box.[8] As far as we know,
cyclopropenones have been utilized as useful building blocks in
transition metal
catalysis,[9a-g]
organocatalysis[9h,9i]
and
cycloaddition reactions.[9j,9k] These molecules could also be used
as catalysts[9l-o] or for bioorthogonal chemistries.[9p] With regard
to organocatalysis reactions, the ring-opening and C–C bond
activation process of cyclopropenones was resulted from either
1,2-addition or 1,4-addition by Lewis bases, which yielded
Scheme 1. Distinct Modes for the Activation of Cyclopropenones.
[*]
Dr. J. Cao, Prof. R. Fang, Dr. J.-Y. Liu, Dr. H. Lu, Prof. Y.-C. Luo,
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
The study was initiated by testing the model reaction of o-
hydroxy aromatic aldimine (1a) and 2,3-diphenylcycloprop-2-
enone (2a) in the presence of a bifunctional organocatalyst in
CH2Cl2 (1 mL) at 30 oC (Table 1). First, several bifunctional
catalysts were screened to evaluate their catalytic performance.
To our delight, product 3aa was successfully obtained in
moderate to good yield with excellent selectivity when catalysts
E-mail: xupf@lzu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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I–VII were used (entries 1–7). The structure of 3aa was
unambiguously determined by X-ray crystallographic analysis.[15a]
Among these bifunctional organocatalysts, bifunctional
squaramide IV was identified as the optimal one (entries 4).
Subsequently, screening of solvents revealed that mesitylene
was the optimal solvent, and 99% yield, >20:1 d.r. and >99% ee
were obtained from the reaction with mesitylene as the solvent
(entries 9–14). Then the experiments with lower catalytic
loadings were carried out and the results showed that excellent
yields and stereoselectivites could be obtained even in the
presence of 1 mol % catalyst IV (entries 15–17). However, using
0.5 mol % catalyst IV in 1 mL mesitylene led to an obvious
decrease of the yield (entry 18). Finally, the optimal reaction
conditions were determined by further tests as follows: 0.5 mL
mesitylene, 0.5 mol % catalyst and ambient temperature (entries
19-21).
[a]Conditions: Reactions performed with 1a (0.1 mmol), 2a (0.1 mmol),
catalyst (20 mol %) in the indicated solvent (1 mL) at 30 oC. [b] Isolated yield.
[c] Determined by NMR analysis of the combined mixture. [d] Determined by
HPLC analysis using a chiral stationary phase. [e] 10 mol % organocatalyst
was used. [f] 5 mol % organocatalyst was used. [g] 1 mol % organocatalyst
was used. [h] 0.5 mol % organocatalyst was used. [i] 0.5 mL solvent was used.
[j] 0.12 mmol 1a was used. [k] Reaction performed at ambient temperature.
Under the optimized conditions, the substrate scope was then
investigated. As shown in Table 2, in all cases, the products
were obtained as a single diastereomer in high yields with
excellent stereoselectivities. The electronic and steric properties
of substrates 1 had no obvious effects on the yields and
stereoselectivities albeit with slight influences on the reaction
times. With different cyclopropenones 2, excellent results were
generally obtained. The absolute configuration of 3ao was
determined by X-ray crystallographic analysis.[15b] The same
absolute configuration was assigned to all the products.
Table 1. Optimization of the Reaction Conditions[a]
Table 2. Substrate Scope of the Cascade Reactions of the o-Hydroxy
Aromatic Aldimines 1 with Cyclopropenones 2[a,b]
entry
cat.
solvent
time
Yield[b]
d.r.[c]
ee[d]
1
I
CH2Cl2
72 h
5 h
52%
68%
74%
62%
89%
87%
94%
trace
76%
98%
95%
81%
95%
99%
99%
99%
99%
90%
99%
99%
99%
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
n.d.
-94%
-89%
96%
2
II
CH2Cl2
3
III
CH2Cl2
5 h
4
IV
V
CH2Cl2
5.5 h
70 h
72 h
72 h
72 h
5.5 h
24 h
22 h
5 h
98%
5
CH2Cl2
87%
6
VI
VII
VIII
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
CH2Cl2
73%
7
CH2Cl2
-91%
n.d.
8
CH2Cl2
9
DCE
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
98%
10
11
12
13
14
15[e]
16[f]
17[g]
18[h]
19[h,i]
20[h,i,j]
21[h,i,j,k]
CH3CN
94%
THF
98%
toulene
98%
xylene
3 h
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
0.6 h
1.2 h
1.5 h
2 h
[a] Reaction conditions: 1 (0.12 mmol, 1.2 equiv), 2 (0.1 mmol, 1.0 equiv), IV
(0.5 mol %) in mesitylene (0.5 mL) at ambient temperature. [b] Isolated yields.
72 h
12 h
6 h
As illustrated in Scheme 1b, the intermediate obtained from
the cycloaddition has multiple electrophilic sites. Thus, the α-site
of the carbonyl group can be an alternative reactive site with
suitable substituents. Using methylphenylcyclopropenone 2’ as
6 h
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the substrate, a completely different cyclization product 4aa was
delivered in high yield with excellent diastereoselectivity (>10:1
d.r.) and enantioselectivity (98% ee) under the optimized
reaction conditions (Table 3). And different o-hydroxy aromatic
aldimines 1 were well tolerated. The absolute configuration of
the product 4aa was determined by using X-ray crystallographic
analysis.[15c]
in complexe B (the bond length of N···H was reduced compared
with that of complexe A), which implied an enhanced kinetics
control by the catalyst. DFT calculations suggested that the
hydrogen-bonding network could not only stabilize the reaction
intermediate, but also activates the imine within substrate 1
synergistically,[17] compared to that of aldimines without o-
hydroxy.[18]
To further verify the practicality of this organocatalytic cascade
reaction, a gram-scale asymmetric synthesis of 3aa with lower
catalyst loading (0.1 mol %) was carried out (Scheme 2). High
efficiency and excellent selectivity were maintained in the large
scale reaction, further proving the synthetic value of this reaction.
Table 3. Substrate Scope of the Cascade Reactions of the o-Hydroxy
Aromatic Aldimines[a,b]
Scheme 3. DFT Studies of Catalyst-Substrate Coordination
Next, a conformational study of catalyst-substrate complexes
was carried out by DFT calculations to determine the zero
potential energy surface of Gibbs free energy. As showed in
Scheme 4, complex B’ was the preferential conformation over
complex B in steric orientation with a slightly reduced relative
energy.
[a]Reaction conditions: 1 (0.1 mmol, 1 equiv), 2a (0.1 mmol, 1 equiv), IV (20
mol %) in mesitylene (0.5 mL) at ambient temperature. [b] Isolated yields.
Scheme 4. DFT Studies of Catalyst-Substrate Complex Conformation
Regarding the Gibbs free energy of catalyst-substrates
complexe B’ as the zero potential energy surface, we studied
the energetic profile of this cascade reaction by DFT calculations
(Figure 1). Obviously, the stereochemistry of the reaction was
determined by the face selectivity (namely complexes B and B’),
while the regioselectivity was determined by the selective strain-
release (namely different C–C bond cleavages). First, by
comparing two possible approaches to key intermediates (C and
C’), it became clear that the [3+2] cycloaddition starting from
catalyst-substrate complex B was strongly favored, in view of
the considerably higher activation energy required for the
formation of transition state TS-I’ (ΔΔG = 5.4 kcal/mol).
Calculation results illustrated that the excellent enantioselectivity
observed in experiments was the results of overwhelming
superiority of preferential intermediate C over intermediate C’.
For the succedent regioselectivity, there were also two possible
ring closure pathways, the annulation at the carbonyl (C1) group
Scheme 2. Gram-Scale Synthesis of 3aa with 0.1 mol % Catalyst Loading
DFT calculations were carried out to investigate the possible
interactions between the catalyst and substrates/intermediates.
We conducted a reasonable simplification of the squaramide
structure (see Supporting Information) since such simplification
could decrease the computational costs but ensure an almost
identical simulation of the experiments[16] (calculation result of ee
value of product 3aa employing IV’ was >99%, consistent with
experimental results).
DFT calculations revealed the existence of the intramolecular
hydrogen-bonding between the nitrogen atom of imine and the
hydrogen atom of the phenol group (N···H = 1.039 Å, O···H =
1.741 Å for configuration A and N···H = 1.026 Å, O···H = 1.924
Å for configuration B, Scheme 3). And the hydrogen-bonding
interaction between squaramide and the o-hydroxyl group
(configuration B) was more favorable (2 kcal/mol) than the
interaction between squaramide and the enolized carbethoxy
group (configuration A). In addition, DFT calculations indicated
that a proton was transferred from the o-hydroxy group to imine
which would produce the lactonization product
3
and,
alternatively, the annulation at α-site of the carbonyl (C2) group,
leading to the formation of the dihydrobenzofuran product 4. The
predicted regioselectivity has been proved by experiments. As
shown in Scheme 1b, regiodiversity was due to the different C–
C bond cleavages caused by diverse electronic effects.
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In conclusion, we have developed a highly efficient cascade
strategy to access enantiopure heterocyclic frameworks with
switchable regioselectivity. The key to success was the
combination of hydrogen-bonding network activation with
regiodivergent strain-assisted effect, which promoted the whole
catalytic efficiency significantly. Hydrogen-bonding network
activation involved a promoted proton transfer from o-hydroxy
network. The regiodivergent strain-assisted effect provided the
selective strain-release to control the reaction regioselectivity. A
rational mechanistic study based on DFT and experimental
results indicated that selective strain-release was the result of
diverse polarization caused by electronic effects. Intramolecular
hydrogen-bonding, coordination modes, enantioselectivity and
regioselectivity have also been studied by DFT calculations. A
gram-scale synthesis further proved the potential utility of this
methodology.
group to imine to generate
a
more reactive and
thermodynamically stable transition state, which was anchored
on the catalyst through the formation of a hydrogen-bonding
Figure 1. DFT B3LYP/6-31G(d) reaction energy profile of the reaction system.
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We are grateful to the NSFC (21632003 and 21572087), the key
program of Gansu province (17ZD2GC011) and the „„111‟‟
program from the MOE of P. R. China for financial support.
Keywords: strain-release • spring-loaded • switchable regioselectivity • DFT
calculations
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10.1002/chem.201803861
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jian Cao, Ran Fang, Jin-Yu Liu, Hong
Lu, Yong-Chun Luo and Peng-Fei Xu*
Page No. – Page No.
Organocatalytic Regiodivergent C–C
Bond Cleavage of Cyclopropenones:
A Highly Efficient Cascade Approach
to Enantiopure Heterocyclic
Frameworks
Here, we describe a strain-release reaction with switchable regioselectivity. A
rational mechanistic study based on DFT and experimental results indicated that
selective strain-release was the result of changed polarization caused by electronic
effects.
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