Experimental and theoretical studies on the Nazarov cyclization/Wagner- Meerwein rearrangement sequence

Article abstract of DOI:10.1021/ja211970p

Highly functionalized cyclopentenones can be generated by a chemoselective copper(II)-mediated Nazarov/Wagner-Meerwein rearrangement sequence of divinyl ketones. A detailed investigation of this sequence is described including a study of substrate scope and limitations. After the initial 4π electrocyclization, this reaction proceeds via two different sequential [1,2]-shifts, with selectivity that depends upon either migratory ability or the steric bulkiness of the substituents at C1 and C5. This methodology allows the creation of vicinal stereogenic centers, including adjacent quaternary centers. This sequence can also be achieved by using a catalytic amount of copper(II) in combination with NaBAr₄^f, a weak Lewis acid. During the study of the scope of the reaction, a partial or complete E/Z isomerization of the enone moiety was observed in some cases prior to the cyclization, which resulted in a mixture of diastereomeric products. Use of a Cu(II)-bisoxazoline complex prevented the isomerization, allowing high diastereoselectivity to be obtained in all substrate types. In addition, the reaction sequence was studied by DFT computations at the UB3LYP/6-31G(d,p) level, which are consistent with the proposed sequences observed, including E/Z isomerizations and chemoselective Wagner-Meerwein shifts.

Full text of DOI:10.1021/ja211970p

Article
pubs.acs.org/JACS
Experimental and Theoretical Studies on the Nazarov
Cyclization/Wagner−Meerwein Rearrangement Sequence
David Lebœuf,† Vincent Gandon,*,‡ Jennifer Ciesielski,† and Alison J. Frontier*,†
†Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
‡ICMMO, UMR CNRS 8182, Universite
́
Paris, Sud 11, 91405 Orsay cedex, France
S
* Supporting Information
ABSTRACT: Highly functionalized cyclopentenones can be generated by a
chemoselective copper(II)-mediated Nazarov/Wagner−Meerwein rearrange-
ment sequence of divinyl ketones. A detailed investigation of this sequence is
described including a study of substrate scope and limitations. After the initial
4π electrocyclization, this reaction proceeds via two different sequential
[1,2]-shifts, with selectivity that depends upon either migratory ability or the
steric bulkiness of the substituents at C1 and C5. This methodology allows the
creation of vicinal stereogenic centers, including adjacent quaternary centers.
This sequence can also be achieved by using a catalytic amount of copper(II) in
combination with NaBAr4f, a weak Lewis acid. During the study of the scope of
the reaction, a partial or complete E/Z isomerization of the enone moiety was
observed in some cases prior to the cyclization, which resulted in a mixture of
diastereomeric products. Use of a Cu(II)-bisoxazoline complex prevented the
isomerization, allowing high diastereoselectivity to be obtained in all substrate
types. In addition, the reaction sequence was studied by DFT computations at the UB3LYP/6-31G(d,p) level, which are consistent
with the proposed sequences observed, including E/Z isomerizations and chemoselective Wagner−Meerwein shifts.
conditions suppress proton transfer, extending the lifetime of
the oxyallyl cation and allowing rearrangement pathways to
compete with elimination (Scheme 1). It is possible to achieve the
INTRODUCTION
■
Electrocyclizations are powerful pericyclic reactions that occur
via simple orbital reorganization.1 They are one of the few
methods available to create carbon−carbon bonds stereospecifi-
cally. Cationic electrocyclizations, such as the Nazarov (4π
cationic) cyclization, are initiated by formation of an extended
cationic π-system, which also reacts with conservation of orbital
symmetry.2 In the past few years, numerous examples of catalytic
Nazarov cyclizations have been reported,3−11 and asymmetric
induction in the Nazarov cyclization has been achieved using
chiral auxiliaries,12 chiral Lewis acids,13 or organocatalysts,14 but
the substrate scope is narrow in each case. The Nazarov
cyclization can also serve as a cationic initiation step, generating
an oxyallyl cation intermediate that can be intercepted by a
suitable trapping agent.15 This oxyallyl cation can also be the
starting point for rearrangement sequences.16 In a general sense,
these reactions fit within a larger class of cationic cascades that
involve activation of a carbonyl or alkene functionality to
generate “stabilized” carbocation intermediates, which can
undergo a variety of subsequent transformations. Cation-initiated
C−C bond-forming reactions have great synthetic potential, if
their reactivity and selectivity can be controlled, especially in the
area of terpene and steroid biosynthesis.17
Scheme 1. Spirocycle Synthesis via Nazarov/Wagner−
Meerwein Rearrangement Sequence
stereospecific synthesis of unusual spirocyclic compounds with
adjacent stereogenic centers, including adjacent quaternary
centers. However, this initial study revealed the following
limitations: (i) one full equivalent of Lewis acid promoter was
required for rearrangement, and (ii) the reaction scope was
limited to cyclic substrates.
In our studies on the Nazarov cyclization, we found an
interesting and unusual electrocyclization/rearrangement se-
quence that could efficiently compete with the traditional Nazarov
cyclization when stoichiometric amounts of Ligand-Cu(SbF6)2
were employed.18 Experiments suggest that these reaction
Received: December 22, 2011
Published: April 3, 2012
© 2012 American Chemical Society
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Recently, we have shown that this reaction does not require
the use of a sophisticated ligand and can even be carried out
with a catalytic amount of a copper(II) complex.19 Highly
functionalized cyclopentenones can be prepared stereospecifi-
cally via conrotatory electrocyclization, with high chemo-
selectivity of subsequent Wagner−Meerwein shifts. In many
cases, it is possible to install adjacent quaternary centers with
complete diastereocontrol. The present article is devoted to the
investigations conducted by our laboratory to evaluate the
scope and the limitations of this copper(II)-mediated Nazarov
cyclization/Wagner−Meerwein rearrangement sequence of
acyclic substrates. To gain insight into the mechanism of the
title reaction, the key steps have also been analyzed by means of
DFT calculations.
intermediate 4. After this step, either [1,2]-hydride or carbon
shift can occur. An electron-donating substituent on the aryl
ring enhances its migratory ability. However, the propensity for
migration can also be affected by steric factors. In the case of
intermediate 4, the sp2 carbon shift is presumably interrupted
by the bulkiness of the 2,4,6-trimethoxyphenyl; thus, cyclo-
pentenone 2, resulting from [1,2]-hydride shift, is the only
product observed. The diastereoselectivity is dictated by both
the conrotatory electrocyclization and the suprafacial nature of
the subsequent Wagner−Meerwein migrations. Product 6, the
product expected from the conventional Nazarov cyclization/
elimination sequence, is not observed.
Next, we conducted experiments to test the effect of the
different substituents at C1 and C2, with a 2,4,6-trimethoxy-
phenyl substituent at C5 (Table 1). Consistent with Scheme 2,
in each case, the reaction is completely chemoselective with the
exclusive migration of the R1 group and [1,2]-hydride shift from
C5 to give rise to the corresponding cyclopentenones in good
yields (Table 1, entries 1−4). We noticed that the rearrange-
ment of substrate 11 (Table 1, entry 3) led to the formation of
two products 12 and 13 in a 1:1 ratio and a combined yield of
90%, the latter corresponding to the loss of the silyl group. This
deprotection could result from the presence of the hexafluor-
oantimonate counterion in solution.21
We also examined the cyclization of 1,4-dien-3-ones with a
phenyl group at C1 and various groups at C5, including
4-methoxyphenyl, phenyl, heteroaromatic, cinnamyl, and alkyl
substituents. Almost all the reactions were carried out under
refluxing conditions except for the substrates having an electron-
donating 4-methoxyphenyl substituent at C5 (Table 2, entries 4
and 5). In each case, cyclopentenones were obtained in high
yields (up to 95%). In substrates 1, 16, 18, and 34, we observed
the chemoselective [1,2]-shift of the phenyl from C1 to C2, and
[1,2]-hydride shift from C5 to C1, consistent with the mechanism
shown in Scheme 2 (Table 2, entries 1−3 and 11). However, a
different reaction sequence was observed in substrates without a
bulky TMP or isopropyl group at C5. In these cases, the second
migration was a [1,2]-aryl or -alkenyl shift rather than a [1,2]-
hydride shift (Table 2, entries 4−10). Many of the products were
obtained as mixtures of diastereomers, in ratios ranging from 4:1
to 20:1. The structures of the major products were ascertained by
NOE analysis, which clearly indicated a cis-relationship between
the phenyl and the alkyl moieties.
RESULTS AND DISCUSSION
■
Initial experiments were focused on substrate 1 bearing a 2,4,6-
trimethoxylphenyl (TMP) group at C5 (Scheme 2), because
the bulk and strong electron-donating character of the TMP
group increases reaction rates.4b The reaction was carried out
in dichloromethane at room temperature in the presence of
100 mol % of (MeCN)5Cu(SbF6)2. Complete conversion was
obtained within 5 min to provide cyclopentenone 2 in 92%
yield as a single diastereomer. Relative stereochemistry was
established by NOE analysis.
Scheme 2. Copper-Mediated Cyclization of 1,4-Dien-3-one 1
(TMP = 2,4,6-Trimethoxyphenyl)
In the next set of experiments, the rearrangement of
substrates with opposite C1−C2 double bond geometry
(relative to the C1 Ph) was studied (Table 3). Interestingly,
the major products obtained in most cases were the same as the
ones previously observed with similar ratios (compare Table 2,
entries 4−7 and 9 with Table 3, entries 3−7). These findings
suggest that partial or complete isomerization of the C1−C2
bond occurs prior to cyclization in the presence of the
copper(II) complex. Contrary to expectations, reduced chemo-
selectivity was observed in the rearrangement of substrate 37.
Rather than exclusive migration of the phenyl group as usual
(Tables 2 and 3), a 3:1 ratio of phenyl vs ethyl migration
products was observed (Table 3, entry 2).
Changes in chemoselectivity were also seen in the reactions
of substrates possessing steric bulk at both C1 (R1 = iPr or Ph
and R2 = Ph) and C5 (R3 = aryl) (Table 4). In these substrates,
the substituent with the lower migratory aptitude shifted in
both the first and the second [1,2]-Wagner−Meerwein shift,
compared to the corresponding substrates with less hindered
pentadienyl cation termini (i.e., C1 and C5; see Tables 1−3).
The oxyallyl cation intermediate 3 is generated by a 4π
conrotatory electrocyclization. We previously reported that
the cyclization of mixtures of E and Z isomers of alkylidene
β-ketoesters was stereoconvergent and occurred via an efficient
isomerization process to give the product with the stereo-
chemistry corresponding to the Z isomer cyclization, which
explains the exclusive formation of intermediate 3.4b It is
well-known that the migratory aptitude of aryl groups is
significantly greater than that of alkyl groups,20 so it is not
surprising to observe a chemoselective [1,2]-phenyl shift to give
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a
Table 1.
a
Reaction conditions: substrate in CH2Cl2 (0.03 M) in the presence of 1 equiv of (MeCN)5Cu(SbF6)2 at the indicated temperature. PMP =
4-methoxyphenyl; TMP = 2,4,6-trimethoxyphenyl.
With R1 = Me and R2 = Me, cyclopentenone 45 was obtained
in 66% yield after the expected migration of the electron-
donating 4-methoxyphenyl group from C5 (eq 1).
fidelity of the double bond geometry can be preserved during the
reaction, a highly diastereoselective reaction should occur. With
this goal in mind, we anticipated that placement of a bulky ligand
on copper might slow down the isomerization of the double bond.
To test this hypothesis, we focused on substrate 57, for which the
use of (MeCN)5Cu(SbF6)2 gave rise to a mixture of the three
products 58a, 58b, and 59 resulting from the isomerization of
C1−C2 bond (eq 2). In contrast, use of a bulky bidentate
tBuBOX ligand allowed selective cyclization/rearrangement of 57,
producing cycloadduct 58a was isolated as the sole product (eq 3).
In contrast, with R1 = iPr or Ph and R2 = Ph (Table 4, entries
1 and 3), the rearrangement led to the formation of cyclo-
pentenones 47 and 52 after hydride migration from C5.
Similarly, hydride migration was observed in hindered sub-
strates with a thienyl or a phenyl substituent at C5 (Table 4,
entries 4 and 5). When R1 = iPr, migration of the isopropyl
group rather than the phenyl group was observed from C1
(Table 4, entries 2−5).
It is clear from the results in Tables 1−4 that different sub-
strates follow different reaction pathways during the cyclization/
rearrangement sequence. From the substrates shown in Tables 2
and 3, we know that reaction of both E and Z isomers of a
substrate give the same product mixture, which demonstrates
that E/Z isomerization is facile under the reaction conditions.
Consistent with these findings, E/Z isomerization could be
1
observed by H NMR prior to cyclization in representative
cases. In contrast, E/Z isomerization was not observed in
substrates with R1 = iPr (cf. Table 4, entries 2−5 to Table 3,
entries 1, 3, 5, and 7). The steric hindrance exerted by this
group seems to prevent the σ-bond rotation of C1−C2 required
for the E/Z isomerization. Additional study using DFT calcula-
tions allowed further elucidation of the mechanism (vide infra).
Unfortunately, this isomerization leads to the isolation of a
mixture of two diastereomeric products in a number of cases. If the
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a
Table 2.
a
Reaction conditions: substrate in CH2Cl2 (0.03 M) in the presence of 1 equiv of (MeCN)5Cu(SbF6)2 at the indicated temperature. TMP = 2,4,6-
trimethoxyphenyl. PMP = 4-methoxyphenyl.
Cyclization/rearrangement of substrate 37 (with Z geometry)
was examined next. Without the bulky ligand, E/Z isomerization
was observed, and the chemoselectivity of the first [1,2]-shift
favored the phenyl shift (Table 3, entry 2; 3:1 ratio of 19/38).
Promotion of the same reaction with tBuBox-ligated catalyst not
only suppressed E/Z isomerization, but gave exclusively minor
product 38 in a high yield of 91% (eq 4). Thus, using the bulky
tBuBox ligand prevents the isomerization of both Z and E
substrates, and is also able to reverse the chemoselectivity of the
[1,2]-migration.
As noted above, while the chemoselectivity of [1,2]-shifts
is governed by relative migratory aptitudes in most cases
(Tables 1−3), in substrates with three bulky substituents at C1
and C5 (the reacting termini of the pentadienyl cation),
reaction outcomes are counter to predictions (Table 4). In these
cases, other effects overrule the chemoselectivity dictated by
migratory aptitude predictions. In the case of the observed
migration of isopropyl rather than phenyl (Table 4, entries 2−5),
we propose that the reaction is dominated by thermody-
namics: equilibration of cationic intermediates 60, 61, and 62
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a
Table 3.
a
Reaction conditions: substrate in CH2Cl2 (0.03 M) in the presence of 1 equiv of (MeCN)5Cu(SbF6)2 at the indicated temperature. TMP = 2,4,6-
trimethoxyphenyl. PMP = 4-methoxyphenyl.
occurs to favor formation of 62 (see computational data).
In cases when a hydride migration is observed rather than an
aryl migration in the second [1,2]-shift (Table 4, entries 1−5),
inspection of intermediate 62 is helpful. Migration of the
expected aryl group must proceed through phenonium
intermediate 64, which would experience significant steric
strain from both the presence of the phenonium bridge and the
syn relationship of the phenyl group and the isopropyl group
(Scheme 3). In comparison, the electronically disfavored hydride
shift leads to 63, which lacks the steric congestion of 64.
Originally, a limitation to the method was the requirement for
1 equiv of a Lewis acidic promoter for efficient cyclization/
rearrangement.18,19 With catalytic asymmetric reaction as the
ultimate goal, we sought to develop a transition-metal-catalyzed
version of the reaction. Our observations of both cyclization and
rearrangement sequences suggested that Brønsted basic species in
the reaction mixture facilitate the elimination of a proton, leading
to formation of the normal Nazarov cycloadduct (see Scheme 1),
while coordination of the basic carbonyl lone paired with 1 equiv
of the copper complex slows elimination, allowing rearrangement
pathway to compete.18b On the basis of that model, we wanted to
identify an additive that could bind to the carbonyl lone pairs of
both substrate and product, and could readily exchange with a
reaction promoter, but would not promote the cyclization itself.
Such an additive should work in combination with catalytic
amount of a chiral Lewis acid to coordinate the lone pairs of the
carbonyls, favoring rearrangement over elimination. In our initial
attempts to achieve a catalytic rearrangement, we used a combina-
tion of 10 mol % of (MeCN)5Cu(SbF6)2 and 90 mol % of several
additives such as Zn(OAc)2, Mn(acac)2, Fe(acac)2, LiClO4,
Mg(OTf)2, NaSbF6, NaPF6, or NaBPh4, but these reactions were
sluggish and led to mixtures of products. Furthermore, all these
Lewis acids displayed poor solubility in dichloromethane. BAr4f
is a highly soluble, noncoordinating counterion, and we found
that LiPF6 itself promotes the cyclization, so it was not a suitable
additive. Fortunately, experiments with NaBAr4f were ultimately
successful.5b,19 When dienone 66 was treated with (MeCN)5Cu-
(SbF6)2 (10 mol %) and NaBAr4f (90 mol %) at room
temperature for 10 min, cyclopentenone 67 was formed in 90%
yield (eq 5). It was surprising that a sodium ion, rather than a
chelating additive was sufficient for suppression of the elimination
pathway. The results suggest that only one carbonyl group plays a
role in the proton capture.
Application of these optimal reaction conditions to a rep-
resentative set of substrates demonstrated that the catalytic
protocol was comparable to the stoichiometric reaction (Chart 1).
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a
Table 4.
a
Reaction conditions: substrate in CH2Cl2 (0.03 M) in the presence of 1 equiv of (MeCN)5Cu(SbF6)2 at the indicated temperature. TMP = 2,4,6-
trimethoxyphenyl. PMP = 4-methoxyphenyl. The other diasteromer has also been isolated in 13% yield.22
Scheme 3
cyclization (Scheme 4). They are taken as reference
compounds (free energy of 0.0 kcal/mol). The facile E/Z
isomerization of the C1−C2 double bond, observed during
some of the cyclization studies (Tables 2 and 3), served as the
starting point of the simulation. The calculations suggest the
following sequence for the isomerization: (i) σ-bond rotation
from a1 leads to s-cis/s-trans conformer a2, (ii) diastereomu-
tation of a2 gives a3, (iii) coordination of the phenyl group of
STUDY OF REACTION PATHWAYS BY DENSITY
FUNCTIONAL THEORY
■
To rationalize some of the mechanistic questions raised
during this study, DFT computations were carried out using
dienones a1 as model substrates and Cu2+ as promoter (see
the Supporting Information for details).23−25 Dienones a1 are
s-trans/s-trans conformers with ideal alignment for Nazarov
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Chart 1. Copper-Catalyzed Cyclization of Substituted 1,4-Dien-3-ones
[a] Reaction conditions: substrate in CH2Cl2 (0.03 M) in the presence of NaBAr4f (90 mol %) and (MeCN)5Cu(SbF6)2 (10 mol %) at rt for 0.1−0.5 h.
[b] Reaction carried out at 45 °C. BAr4f = 3,5-bis(trifluoromethyl)phenylborate. TMP = 2,4,6-trimethoxyphenyl. PMP = 4-methoxyphenyl.
Scheme 4. Computed Intermediates for the Cu2+-Mediated Cyclization of Dienones
a3 to the metal center leads to a4, and (iv) a final σ-bond
rotation of a4 leads to the corresponding s-trans/s-trans isomer
a5, aligned for Nazarov cyclization.26
leading to c1−3 and then to d1−6. The latter six complexes
correspond to the six possible enones e1−6 after copper
dissociation.
Then, conrotatory 4π electrocyclization could be computed
from a1 and a5, leading to oxyallyl cations b1 and b2, re-
spectively. From these two complexes, all possible Wagner−
Meerwein rearrangements were modeled (suprafacial 1,2-shifts),
The results are summarized in Tables 5−7, subdivided
into the three main mechanistic categories (isomerization,
electrocyclization, and [1,2]-shifts) for clarity. With respect to
isomerization, the overall transformation of pentadienyl cation
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Table 5. Computed Free Energies for the Isomerization Process at 298 K (UB3LYP/6-31G**//PCM Correction, kcal/mol)
a
Relative to a1 for the a1 → a5 Transformation
entry
a1 → a2
a2 → a3
a3 → a4
ΔG
a4 → a5
ΔG‡
ΔG
ΔG‡
ΔG
ΔG‡
ΔG‡
ΔG
Isomerization
1
2
3
4
5
6
7
Y = Ph, R = Me
8.8
5.6
1.4
1.4
12.1
15.4
17.8
18.6
19.1
24.6
c
b
0.6
b
−8.4
−7.8
−5.5
−7.0
−6.4
−5.4
−7.6
3.5
1.5
2.4
4.7
1.4
6.8
8.9
−2.7
−0.6
0.2
Y = 2-thienyl, R = Me
Y = (E)-cinnamyl, R = Me
Y = 4-MeO-C6H4, R = Me
Y = TMP, R = Me
3.6
0.1
2.3
10.3
9.0
2.6
−0.9
1.0
0.8
−0.6
4.0
4.8
2.4
1.8
−1.4
2.0
−0.6
−6.1
5.1
Y = TMP, R = Et
9.3
3.0
Y = TMP, R = iPr
7.9
b
−0.8
a
c
Free energies of activation are displayed in italics. No convergence of this intermediate, direct collapse to the next one. Could not be located on
the PES.
Figure 1. Geometries and energies of the species involved in the a1 → a5 transformation with Y = 4-MeO-C6H4 and R = Me (UB3LYP/6-31G**//
PCM correction, kcal/mol).
a1 into isomeric a5 is either slightly exergonic (Y = Ph, 2-thienyl,
4-MeO-C6H4) or slightly endergonic (Y = (E)-cinnamyl or
TMP). In contrast, the Ph-coordinated intermediates a4 are
always significantly more stable than a1, but a4 does not
represent a deep potential well. In each Y series, the rate-
determining step is the diastereomutation itself (a2 → a3), as one
would expect, rather than any conformational interconversion.
The relationship between the inversion barrier and the electronic
nature of the Y group is displayed in Table 6. As the energy
Those high-lying transition states show a virtually perpendicular
required to reach TSa2−a3 increases, the C1−C2 bond order
arrangement of the PhC1R and the MeC2C planes (see Figure 1
increases while the C1−C2 bond distance and the natural charge
with Y = 4-MeO-C6H4 and R = Me, MeC1C2Me = 79°).
at C1 both decrease. These values indicate that the most
Electron-withdrawing Y groups are expected to assist the
important resonance form of a2 should be a2′ when Y = TMP.
Notably, the steric hindrance at C1 also plays a dramatic
isomerization process by lowering the C1−C2 bond order, as in
resonance form a2″. On the other hand, electron-donating
influence on the isomerization rate. For example, when R = Me
is changed to R = Et, the free energy of activation of the
a2 → a3 step increases by more than 4 kcal/mol to reach
24.6 kcal/mol (Table 5, entries 5 and 6). When R = iPr (Table 5,
groups should favor a2′ and make the isomerization more
difficult (eq 6).
In the phenyl series, the substrate with Y = TMP has a high
inversion barrier, calculated at 19.1 kcal/mol (Table 5, entry 5).
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entry 7), it was no longer possible to find the isomerization
transition state, presumably because it is too high in energy. The
absence of an isomerization transition state on the potential
energy surface when R = iPr is consistent with the 100%
stereoselective transformation of 49 into 50 (Table 4, entry 3).
The rest of the mechanistic scenario depicted in Scheme 4
was computed for R = Me and Y = Ph, (E)-cinnamyl, 4-
MeOC6H4, and TMP (Table 7). The 4π electrocyclizations
were all found to be endergonic. Nevertheless, those leading to
the less sterically congested isomer b1 are always kinetically and
thermodynamically favored over those leading to b2 (Table 7,
entries 1 and 2). Again, the magnitude of the activation barriers
is critically dependent on the nature of Y. Electron-donating
groups appear to raise the barrier for electrocyclization process
(e.g., 4.1 for Y = Ph vs 15.5 kcal/mol for Y = 4-MeO-C6H4),
probably because these groups stabilize the pentadienyl
cation.28
Recently, the decomplexation of copper from the carbonyl
oxygens of alkylidene β-ketoesters and oxazolidinones, resulting
in an out-of-plane orientation of the C4 carbonyl, has been
proposed to explain the stereochemical outcome of some
copper(II)-catalyzed Nazarov cyclizations.3m To examine this
proposal in the context of our system, TSa1−b1 and TSa5−b2 were
recomputed in the 4-MeO-C6H4 series after decomplexation of
copper from the ester functionality. In the new transition states
TSa1′−b1′ and TSa5′−b2′, the metal establishes an agostic inter-
action with the methyl group at C2 (see Figure 2). However, the
energies of these species relative to a1 are much higher than those
of TSa1−b1 and TSa5−b2 (56.4 and 58.3 kcal/mol, respectively).
An η3-dioxyallyl copper complex was also envisaged, yet we could
not locate any electrocyclization transition state. Instead, a species
corresponding to the rotation of the ester moiety converged.
Again, this transformation requires a prohibitive free energy of
activation of 50.3 kcal/mol. Thus, in both of the cases we
modeled, dechelation is unlikely. Additional calculations using
ligated copper(II) ((CH3CN)2Cu2+)) instead of (Cu (II)2+) did
not allow optimization of these high-lying transition states,
either (vide infra).
With respect to the [1,2]-shifts, the computations are in good
agreement with the expected migratory aptitudes of methyl,
hydride, phenyl, or Y (Figure 3). For instance, the initial methyl
shifts leading from b1/ b2 to c1 (Table 7, entries 3 and 4)
require a considerably higher free energy of activation than the
corresponding phenyl shifts (b1 to c2 or b2 to c3; Table 7,
entries 5 and 6). For the subsequent step (from c2/c3 to
intermediates d), the [1,2] shifts of Y groups are kinetically
favored over [1,2]-hydride shifts (Table 7, entries 10 and 11 vs
entries 9 and 12).
The geometries of the cyclopentenyl cations of type d also
warrant comment. Indeed, the electron-deficient center C5 may
receive electron density from the phenyl or the Y groups. This
interaction is particularly obvious when Y = (E)-cinnamyl, 4-
MeO-C6H4, and TMP, which converge as bicyclo[3.1.0]hexane
derivatives (see d2′, d3′, and d5′).29 For example, as shown in
Scheme 4, when Y = Ph, the carbocationic center is clearly
located on C5 but delocalized throughout the π-system of the
other electron-rich groups, including the (E)-cinnamyl group.
In spite of our efforts, it was not possible to find minima
representing both d and d′ within the same series (Figure 4).
This suggests that the bicyclic structure is always more stable than
the localized secondary carbocation. Although much weaker, this
neighboring stabilization effect is also present in other
intermediates, such as b2 (tertiary carbocation at C2), c2, and
c3 (tertiary carbocation at C1) (see the Supporting Information).
To save computer time, all the calculations presented above
involve unligated copper(II). It is quite clear that some of the
computational results may change with the introduction of
ligands, notably regarding the π-complexes a4 and the agostic
complexes shown in Figure 2. To address this issue, the
Table 6. Relationship between the a2 → a3 Free Energies of
Activation (UB3LYP/6-31G**//PCM Correction, kcal/mol)
and the Polarization of the C1−C2 Bond in a2
C1−C2 natural charge at Wiberg bond
a
a
entry
Y
ΔG‡
(Å)
C1
index
1
2
3
C6H5
12.1
1.429
1.402
1.373
0.200
0.176
0.07
1.35
1.49
1.62
4-MeO-C6H4 18.6
TMP 19.1
a
Natural charges and Wiberg bond indices were calculated from NBO
theory.27
Table 7. Computed Free Energies for the Electrocyclization and the [1,2] Shifts at 298 K (UB3LYP/6-31G**//PCM
a
Correction, kcal/mol), Relative to a1 with R = Me
entry
Y = Ph
Y = (E)-cinnamyl
Y = 4-MeO-C6H4
Y = TMP
ΔG‡
ΔG
3.7
ΔG‡
ΔG
ΔG‡
Nazarov
ΔG
ΔG‡
ΔG
8.7
1
2
a1 → b1
a5 → b2
4.1
21.0
18.4
20.8
15.5
12.6
13.3
19.0
13.0
5.7
23.3
18.7
25.7
19.7
Shifts
3
b1 → c1 (1,2-Me shift)
b2 → c1 (1,2-Me shift)
b1 → c2 (1,2-Ph shift)
b2 → c3 (1,2-Ph shift)
c1 → d3 (1,2-Y shift)
c1 → d4 (1,2-H shift)
c2 → d1 (1,2-H shift)
c2 → d2 (1,2-Y shift)
c3 → d5 (1,2-Y shift)
c3 → d6 (1,2-H shift)
10.6
7.9
5.4
3.5
2.3
6.6
8.9
7.8
7.8
8.6
−8.1
−8.1
2.2
27.7
33.6
18.6
19.3
7.8
5.7
5.7
18.6
22.2
13.7
15.0
3.9
0.4
0.4
27.5
25.9
19.1
23.7
8.9
3.0
3.0
4
5
b
11.3
5.0
8.5
6
3.6
18.4
10.8
−14.0
−14.8
−0.3
5.7
12.3
2.7
7
−3.7
−20.9
−15.6
−4.2
−2.2
−14.4
1.7
8
19.0
2.7
−18.9
−11.3
6.3
17.1
17.6
14.2
15.4
17.4
−14.0
−11.3
9.4
9
15.2
9.7
10
11
12
17.4
21.3
9.5
7.4
7.3
−17.7
15.1
−10.7
−6.0
a
b
Free energies of activation are displayed in italics. No convergence of this intermediate, direct collapse to d2.
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Figure 2. Electrocyclization and ester rotation transition states (UB3LYP/6-31G**//PCM correction, kcal/mol) for Y = 4-MeO-C6H4 and R = Me
(distances in Å).
Figure 3. Geometry of selected [1,2]-shift transition states (UB3LYP/
6-31G**//PCM correction, kcal/mol) for R = Me (distances in Å).
computations related to the 4-MeO-C6H4 series were repeated
with two acetonitrile units on Cu (Scheme 5). As expected,
intermediate a4 is no longer observed in the a1 → a5 sequence.
However, the isomerization transition state connecting a2 and
a3 remains the highest-lying (25.7 kcal/mol), a value that is
actually higher than those of the electrocyclization steps leading
to b1 and b2 (18.3 and 20.3 kcal/mol, respectively). Complex
b1 remains kinetically and thermodynamically favored over b2,
since the electrocyclization steps are still endergonic, and the
methyl shifts leading to c1 remain slower than the phenyl shifts.
In contrast with the unligated series, c2 and c3 do not converge.
They collapse directly to d2 and d5, with the migration of the
Figure 4. Geometry of d2 and d2′ cations (UB3LYP/6-31G**//PCM
correction, distances in Å).
phenyl group immediately followed by migration of the PMP.
This finding is not unique to the calculations with ligated
copper, since c2 is also absent from the potential energy surface
in the (E)-cinnamyl series (see Table 7). With acetonitrile
ligands, the structures of d2, d3, and d5 are quite distinct from
the corresponding ones in the unligated series (phenoniums d2′,
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Article
Scheme 5. Computed Intermediates for the Cu2+-Mediated Cyclization of Dienones with Y = 4-MeO-C6H4 (PMP) and
Acetonitrile on Cu (UB3LYP/6-31G**//PCM Correction, kcal/mol)
d3′, d5′; Scheme 4). This may be because the [(MeCN)2Cu]
moiety is more electron-rich, so the backdonation toward the
organic backbone becomes more efficient. The stabilization of
the charge at C5 (see d2, Scheme 5) by the adjacent PMP (i.e.,
the phenonium) is no longer required since the metal can now
accommodate two formal charges, leading to Lewis structures
that are much more like the final products. Despite these
geometrical differences, the shifts leading to d2 remain the most
kinetically favorable, and d2 represents the framework of the
product experimentally obtained. Thus, both sets of calculations,
using either [(MeCN)2Cu]2+ or the simpler unligated copper-
(II), predict the same experimental outcome. It is nonetheless
interesting to note the favorable effect the ligands have on the
migration at C5.
sometimes we find that other factors overwhelm these
propensities, leading to the selective formation of an isomer
with unexpected connectivity. Isomerization of the Nazarov
cyclization substrate is another complication in some cases,
which also makes prediction of product stereochemistry difficult.
DFT calculations have helped us to gain mechanistic insight into
the substrate isomerization and to understand the factors
dictating selectivity in the cation rearrangements. Furthermore,
we found it was possible to prevent the isomerization with the
use of a bisoxazoline ligand on the copper(II) complex, allowing
controlled, predictable electrocyclization of enone substrates
with the expected stereospecificity. Ongoing research in the
laboratory is focused upon the development of an asymmetric
version of this reaction and application of this strategy toward
the synthesis of natural products.
SUMMARY, CONCLUSIONS, AND PERSPECTIVES
■
ASSOCIATED CONTENT
In summary, we have developed a diastereoselective method for
preparation of highly functionalized cyclopentenones based on
a copper(II)-promoted Nazarov/Wagner−Meerwein sequence.
The scope of the reaction is broad, allowing preparation of
products with adjacent stereogenic centers, and in some cases,
adjacent quaternary centers. The reaction was always efficient
using a stoichiometric amount of a copper-(II) complex, and in
many cases it was possible to lower the amount of copper to
10 mol % by adding a sodium salt to attenuate the basicity of the
carbonyl oxygen. Although chemoselectivity of the sequential
[1,2] shifts is typically high, predicting the structures of the
products is not as simple as one might expect. Sometimes the
chemoselectivity is governed by relative migratory aptitude, and
■
S
* Supporting Information
Complete reference 23, experimental procedures, and charac-
terization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
frontier@chem.rochester.edu; vincent.gandon@u-psud.fr
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
Article
(c) Lemier
̀
e, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.;
ACKNOWLEDGMENTS
■
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2009,
131, 2993. (d) Krafft, M. E.; Vidhani, D. V.; Cran, J. W.; Manoharan,
M. Chem. Commun. 2011, 47, 6707.
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We thank the National Science Foundation (Grant CHE-
0847851, supporting D.L.) and the National Institutes of
Health (NIGMS R01 GM079364, supporting J.C.) for funding
this work. We used the computing facility of the CRIHAN
(Project 2006-013). We thank Prof R. Eisenberg (University of
Rochester) for helpful discussions.
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(22) The following minor product was obtained with a yield of 13%:
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2
̂
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