Catalytic Enantioselective Cloke–Wilson Rearrangement

Article abstract of DOI:10.1002/anie.201804614

Racemic cyclopropyl ketones undergo enantioselective rearrangement to deliver the corresponding dihydrofurans in the presence of a chiral phosphoric acid as the catalyst. The reaction involves activation of the donor-acceptor cyclopropane substrate by the

Full text of DOI:10.1002/anie.201804614

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Accepted Article
Title: Catalytic Enantioselective Cloke-Wilson Rearrangement
Authors: Alesandere Ortega, Ruben Manzano, Uxue Uria, Luisa
Carrillo, Efraim Reyes, Tomas Tejero, Pedro Merino, and
Jose L. Vicario
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804614
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10.1002/anie.201804614
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Catalytic Enantioselective Cloke-Wilson Rearrangement
Alesandere Ortega,[a] Rubén Manzano,[a] Uxue Uria, *[a] Luisa Carrillo,[a] Efraim Reyes, [a] Tomas
Tejero,[b] Pedro Merino*[c] and Jose L. Vicario*[a]
Dedication ((optional))
Abstract: Racemic cyclopropyl ketones undergo enantioselective
rearrangement to deliver the corresponding dihydrofurans in the
presence of a chiral phosphoric acid as catalyst. The reaction involves
activation of the donor-acceptor cyclopropane substrate by the chiral
Brønsted acid catalyst that promotes the ring-opening event driven by
the release of ring strain, generating a carbocationic intermediate that
subsequently undergoes cyclization. Computational studies
supported by control experiments support this mechanistic pathway.
process driven by the release of ring-strain. Moreover, the
participation of this intermediate would enable the use of racemic
starting materials and their upgrade into enantiopure adducts by
the use of a chiral catalyst through a DYKAT process.[9] In this
sense, the combination of H-bonding between the phosphate
anion and the enol moiety, together with ion-pairing interactions[10]
between the phosphate and the stabilized carbocationic moiety
were anticipated to provide the required rigid environment for
efficient chirality transfer.[11]
Cyclopropanes are inherently reactive compounds because of
their thermodynamic tendency to undergo ring-opening driven by
the release of ring strain.[1] This feature can be used to unveil
unconventional reactivity patterns in transformations in which
these molecules are involved. A good example this particular
reactivity profile is their ability to undergo rearrangement to form
more stable five- six- or seven-membered cyclic compounds,[2]
being the so-called Cloke-Wilson rearrangement a remarkable
case, in which cyclopropyl ketones form dihydrofurans under
thermal conditions.[3] The need for high temperatures has become
an important limitation for the synthetic applicability of this
reaction,[4] and some very recent attempts have been directed to
find milder conditions that enable expanding this transformation
to more functionalized substrates.[5] Despite all these efforts,
there are no reports regarding catalytic and enantioselective
variants of the Cloke-Wilson rearrangement, with only two cases
regarding enantiospecific processes (Scheme 1).[6]
With these precedents in mind, we turned our attention to the
use of donor-acceptor cyclopropanes[7] such as those shown in
Scheme 1 as suitable substrates for Cloke-Wilson rearrangement
upon activation by a Brønsted acid. In particular, chiral BINOL-
based phosphoric acids[8] were envisioned to be able to protonate
the EWG substituent of the D-A cyclopropane, increasing the
polarity of the C-C bond and facilitating the ring-opening process
that would deliver a carbocation/enol intermediate that, upon ring-
closure, would generate the dihydrofuran scaffold in an overall
Scheme 1. Stereoselective Cloke-Wilson rearrangements.
We first optimized the reaction using cyclopropane 1a as model
substrate (see Table 1). Through some preliminary experiments,
we initially observed that this compound was undergoing fast
rearrangement at r.t. in the presence of diphenylphosphoric acid,
to provide dihydrofuran 2a efficiently. Moreover, we also noticed
that the reaction was taking place at temperatures as low as -30ºC.
We proceeded next to survey the performance of a family of chiral
Brønsted acids (entries 1-8 in Table 1) observing that, while the
archetypical TRIP catalyst 3a was not able to promote the
reaction (entry 1), 2,2’-bis(aryl) substituted BINOL-based
phosphoric acids 3b-e turned to be active catalysts (entries 2-5).
From these acids tested, 3e was found to be the best one in terms
of both yield and enantiocontrol (entry 5). More acidic N-
sulfonylphosphoramide 3f and N,N-bis-sulfonimide 3g promoted
a fast reaction but provided almost racemic material (entries 6 and
7) and spirocyclic catalyst 3h also failed to provide high e.r. Next,
the influence of the solvent was evaluated in combination with
catalyst 3e, observing that changing to m-xylene resulted into a
slight improvement in the e.r. but with an inferior yield (entry 9).
Remarkably, a much faster reaction was observed in halogenated
solvents such as CH2Cl2 or 1,2-dichloroethane (entries 10 and 11),
[a]
A. Ortega, R. Manzano, Prof. U. Uria, Prof. L. Carrillo, Prof. E.
Reyes, Prof. Dr. J. L. Vicario
Department of Organic Chemistry II
University of the Basque Country (UPV/EHU)
P.O. Box 644, 48080 Bilbao (Spain)
E-mail: joseluis.vicario@ehu.es; uxue.uria@ehu.es
Prof. Dr. T. Tejero
Instituto de Síntesis Química y Catálisis Homogénea (ISQH)
Universidad de Zaragoza CSIC
50009 Zaragoza (Spain)
[b]
[c]
Prof. Dr. P. Merino
Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI)
Universidad de Zaragoza
50009 Zaragoza (Spain)
E-mail: pmerino@unizar.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804614
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but with a slightly lower enantioselectivity (entries 10 and 11 vs 9).
For this reason, binary mixtures of xylene with these solvents
were evaluated (entries 12 and 13), obtaining an excellent result
with m-xylene and 1,2-dichloroethane (entry 13). Finally, we also
evaluated the reaction with a lower catalyst loading, observing a
similar performance but requiring a longer time (entry 14).
compound 2f).
A
similar behavior was observed using
cyclopropanes with different alkyl substituents at the ketone
moiety, obtaining in general, excellent results with those
containing linear alkyl substituents (2g-h and 2l) and with a poorer
conversion when the steric bulk was increased (2i): Aroyl-
substituted cyclopropanes were also examined, observing that
compound 1j with a simple phenyl group was found to be inert to
the ring-opening process. In contrast, 4-nitrobenzoyl derivative 1k
in which the polarization of the cyclopropane C-C bond is
increased, provided 2k in high yield and with good e.r.
Cyclopropanes with a variety of substituents as the donor group
were successfully tested, obtaining in general good results
(compounds 2m-q). If electron-withdrawing groups that
decreased the ability of this substituent to stabilize the
carbocationic intermediate were incorporated, the yield was
affected (compound 2p) but still maintaining an excellent
Table 1. Screening for best reaction conditions[a]
enantiocontrol.
Heteroaryl-
and
electron-rich
naphthyl
substituents were also well tolerated (compounds 2r-t).[12]
Interestingly, a cyclopropane such as 1u underwent clean
rearrangement under slightly modified conditions, leading to 2u
with a quaternary stereocentre, although with modest e.r.
Entry Catalyst
Solvent
t [h]
48
48
48
48
48
12
12
72
48
24
24
24
24
48
Yield [%][b]
e.r.[c]
n.d.
1
3a
3b
3c
3d
3e
3f
Toluene
<5
13
45
72
82
91
83
63
63
80
85
76
90
91
2
Toluene
67:33
75:25
90:10
91:9
Table 2. Scope of the reaction.[a]
3
Toluene
4
Toluene
5
Toluene
6
Toluene
50:50
52:48
56:44
96:4
7
3g
3h
3e
3e
3e
3e
3e
Toluene
8
Toluene
9
m-xylene
10
11
12
13
CH2Cl2
93:7
Cl(CH2)2Cl
m-xylene/CH2Cl2
m-xylene/Cl(CH2)2Cl
m-xylene/Cl(CH2)2Cl
91:9
94:6
95:5
14[d] 3e
95:5
[a] Reaction carried out in a 0.1 mmol scale of 1a, using 10 mol% of catalyst in
[b]
the indicated solvent (0.2M) at -30 ºC.
column chromatography.
Yield of pure product after flash
[c]
Determined by HPLC analysis on a chiral
stationary phase (see Supporting Information). [d] 5 mol% of 3e.
With an optimal experimental procedure in hands, we proceeded
to evaluate the scope of the reaction. As it can be seen in Table
2, the reaction was found to proceed excellently with a variety of
substrates with different alkoxide substituents at the ester moiety
(adducts 2b-e), although the e.r. decreased slightly when
increasing the size of this substituent, requiring for slightly lower
temperatures to perform on synthetically useful parameters.
Remarkably, the reaction could also be scaled up without any
negative effect. The yield was significantly affected by the size of
this substituent, observing that the reaction did not take place with
the most sterically demanding tert-butyl ester substrate (see
[a] Reaction carried out in a 0.05 mmol scale of 1a-u with 10 mol% of 3e in m-
xylene/DCE (3:1, 0.2M) at -30 ºC. Enantiomeric ratio (e.r.) was determined by
[b]
HPLC analysis (see Supporting Information).
Reaction carried out at 0.4
mmol scale. [c] Reaction carried out in toluene at -60 ºC
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In addition, cyclopropyl ketones 4a-f that do not incorporate
the electron-withdrawing alkoxycarbonyl substituent together with
the acyl moiety were also found to perform excellently (Table 3).
In this case, the catalyst had to be changed to 3d. Some
representative examples of donor-acceptor cyclopropanes
incorporating an -ketoester or a trifluoroacetyl group as the EWG
substituent reacted efficiently, providing the corresponding 1,2-
dihydrofurans with high yield and e.r.[13]
TS
carbocation
area
Table 3. Enantioselective Cloke-Wilson rearrangement with ketones 4a-f.[a]
C-O bond
formation
cyclopropane
opening
Figure 1. Mechanism of the reaction and evidences for the formation of a
carbocationic hidden intermediate. The different traces correspond to the
evolution of electronic populations of the indicated bonds along the reaction
coordinate. Bolded lines correspond to breaking (red) and forming (blue) bonds.
Dotted lines correspond to aromatic bonds.
[a]
Reaction carried out in a 0.05 mmol scale of 4a-f using 10 mol% of 3d in
DCE/DCM (1:1, 0.2M) at -30 ºC. Enantiomeric ratio (e.r.) was determined by
HPLC analysis (see Supporting Information). [b] Reaction carried out at -60 ºC.
[c] Reaction carried out in DCE.
The development of a planar arrangement capable of surviving
along the reaction has dramatic consequences for the
stereochemical outcome. Any initial chiral information of the
starting substrate is lost during the reaction and four possible
interconnected approaches are possible (See SI). When the real
catalyst 3e was considered the lowest energy transition state
structure corresponded to that leading to the (R)-isomer (Figure
2) in agreement with experimental results. The driving force
ultimately responsible for the high selectivity is the presence of
attractive London interactions between the phenanthryl moiety
and the aromatic ring responsible of stabilizing the carbocation,
that are not present in the transition structure leading to the (S)-
enantiomer. These London interactions are π-stacking
interactions that during the carbocation phase become cation π-
interactions. The presence of such favorable interactions was
corroborated by NCI analysis,[17] which revealed the expected
surface between the two aromatic systems.
We also carried out a computational study using BINOL-
phosphoric acid 3i (R=H) as a simplified catalyst. The reaction
starts through coordination of 3i to 1b (Figure 1, top). At this point,
any attempt to locate an intermediate carbocation failed and only
transition structure TS1 was located. The IRC analysis clearly
showed that TS1 connects 1b with 2b along a concerted but
highly asynchronous pathway. Indeed, the IRC showed a
shoulder, suggesting the presence of a hidden intermediate, a
situation often found when carbocations that are not stable
enough to be characterized as minima are involved.[14]
A
geometrical analysis of C9 environment during the reaction (see
SI) revealed the planarity (as expected for a sp2-hybridization) of
that center. The formation of a carbocationic species CB was
confirmed by a topological analysis of the electron localization
function (ELF),[15] which was used for monitoring the evolution of
the electron population along the reaction coordinate (Figure 1,
bottom). After point 60 of the IRC bonds C1-C2 and C4-C5
increased their population whereas bonds C2-C3, C3-C4, C5-C6
and C6-C1 decreased their population.[16] This situation continues
until several points after TS1, clearly illustrating the formation of a
quinoid form for the aryl moiety compatible with the expected
delocalization of the positive charge. At the start (before point 60)
and the end (after point 160) of the reaction, a degenerated
situation for all the aromatic bonds was observed indicating the
aromatic character of the ring. The ELF analysis also confirms the
early cyclopropane ring opening and the late C-O bond formation
providing enough time for the “virtual existence” of a carbocation.
H-bond
London interactions
3.40
formingbond
TS-(R)
Figure 2. Preferred transition state structure for the reaction (right: NCI analysis).
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an enantioenriched sample of 1b as starting material (Scheme 2).
When this compound was subjected to reaction with catalyst 3e,
adduct (R)-2b was isolated in comparable yield and e.r. as
observed when the racemic material was used (see Table 1).
Remarkably, when using the enantiomer of 3e as catalyst, (S)-2b
was isolated with a similar yield and e.r. Finally, the reaction of
(1S,2S)-1b promoted by an achiral catalyst provided racemic 2b.
In all cases, all reactions took place at a comparable rate,
indicating the absence of any matched/mismatched effect at the
catalyst/substrate interaction stage.
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Scheme 2. Experiments using enantioenriched cyclopropane (1S,2S)-1b.
In conclusion, we have shown that cyclopropyl ketones are
excellent substrates for enantioselective Cloke-Wilson
rearrangement catalyzed by a chiral phosphoric acid. Under the
optimized conditions, the corresponding dihydrofurans are
obtained in high yield and enantioselectivity. Computational and
experimental studies demonstrate that the reaction proceeds
through the formation of a transient carbocationic intermediate
that enables the use of racemic cyclopropanes as starting
materials through a Dynamic Kinetic Asymmetric Transformation
(DYKAT) process.
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Acknowledgements
This research was supported by the Spanish MINECO (FEDER-
CTQ2017-83633-P and FEDER-CTQ2016-76155-R), Basque
Government (IT908-16), UPV/EHU (fellowship to A. O.) and
Government of Aragón (Grupos de Referencia, E34-R17). The
authors acknowledge the resources from the supercomputers
"Memento" and “Cierzo”, technical expertise and assistance
provided by BIFI-ZCAM (Universidad de Zaragoza, Spain)
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Keywords: Asymmetric catalysis · Rearrangement ·
Carbocations · Strained molecules · Organocatalysis
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CCDC 1838380 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.
[13] The absolute configuration of compound 5a was determined by X-ray
analysis of the corresponding p-bromophenyl ester (See SI for details).
CCDC 1838379 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
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[16] The analysis of the electron population is based on the population of the
corresponding basins according to ELF analysis; for details see SI.
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Cohen, W. Yang, J. Am. Chem. Soc. 2010, 132, 6498.
[12] The absolute configuration of compound 2t was determined by X-ray
analysis of the corresponding p-bromophenyl ester (See SI for details).
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Entry for the Table of Contents (Please choose one layout)
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Alesandere Ortega, Rubén Manzano,
Uxue Uria,* Luisa Carrillo, Efraim Reyes,
Tomas Tejero, Pedro Merino* and Jose
L. Vicario*
Page No. – Page No.
Catalytic Enantioselective Cloke-
Wilson Rearrangement
A
paired rearrangement: Racemic cyclopropyl ketones undergo
Text for Table of Contents
enantioselective rearrangement to deliver dihydrofurans in the presence of a
chiral phosphoric acid as catalyst. The reaction involves activation of the D-A
cyclopropane substrate by the Brønsted acid catalyst that promotes the ring-
opening event driven by the release of ring strain, generating a carbocationic
intermediate that subsequently undergoes cyclization.
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