Using nazarov electrocyclization to stage chemoselective [1,2]-migrations: Stereoselective synthesis of functionalized cyclopentenones

Article abstract of DOI:10.1002/anie.201104870

Highly functionalized cyclopentenones have been prepared stereospecifically through a chemoselective copper(II)-mediated Nazarov/Wagner-Meerwein rearrangement sequence. After the initial 4π electrocyclization, this reaction involves two sequential [1,2]-m

Full text of DOI:10.1002/anie.201104870

DOI: 10.1002/anie.201104870
Synthetic Methods
Using Nazarov Electrocyclization to Stage Chemoselective
[1,2]-Migrations: Stereoselective Synthesis of Functionalized
Cyclopentenones**
David Lebœuf, Jie Huang, Vincent Gandon, and Alison J. Frontier*
Since its discovery in 1941, the Nazarov 4p-conrotatory
electrocyclization has become an elegant and efficient way to
prepare substituted cyclopentenones with adjacent stereo-
genic centers.[1,2] Although some inroads have been made
with respect to asymmetric catalysis[3] or development of new
catalytic systems,[4] substrate scope is often quite limited,
especially to construct vicinal quaternary centers. To extend
the reactivity related to the Nazarov cyclization, several
groups have developed new methods involving either the
trapping of the oxyallyl cation intermediate by suitable
reagents[5] or rearrangements[6,7] that lead to highly function-
alized, synthetically useful cyclopentanone products.
pathway leading to spirocyclic products V and VI rather than
the elimination product III (Scheme 1). Only ring contraction
was ever observed: no products resulting from methyl
migration were identified. In many cases, stoichiometric
amounts of copper(II) complexes bearing a large bisoxazoline
ligand were necessary to stabilize oxyallyl cation II for the
rearrangement.
If this rearrangement chemistry could be controlled in a
simpler system like 1, the sequence of stereospecific reactions
would lead to cyclopentenones 2 with adjacent stereogenic
centers (Scheme 2). Furthermore, development of a catalytic
protocol was an essential step toward asymmetric applica-
tions. To achieve chemo- and stereoselectivity in the cycliza-
tion/rearrangement sequence, the challenge was to under-
stand and manage the propensity for E/Z isomerization,
migratory aptitudes, and geometric aspects of migration.
In our early studies of Wagner–Meerwein rearrangements
of oxyallylcation intermediates in the Nazarov cyclization,[7]
we found that it was possible to increase the lifetime of the
oxyallyl cation intermediate II, thus favoring a new reaction
Scheme 2. The challenge: selectivity in cyclopentenone synthesis.
Herein, we describe an efficient, chemoselective method
for cyclization and rearrangement of simple divinyl ketone
substrates 1, using copper(II) complexes (Scheme 2). The
reaction generates adjacent stereogenic centers at the a’ and
b’ positions of the cyclopentenone through a stereospecific
sequence of cyclization/suprafacial shifts. This reaction does
not require the use of a sophisticated ligand, and it can be
carried out with a catalytic amount of a copper(II) complex.
We began our investigation with 1,4-dien-3-ones bearing
different substitution patterns at C1 and C2, and a 2,4,6-
trimethoxylphenyl (TMP) group at C5 (Table 1). Substrates
1a–h were cyclized in dichloromethane in the presence of
1 equivalent of [(MeCN)5Cu(SbF6)2].[8] The substitution pat-
tern and the configuration of 2a–h were consistent with
mechanism A (see Scheme 1). Importantly, the cyclization of
E/Z mixtures of alkylidene b-keto esters was found to be
stereoconvergent: E/Z isomerization is facile under the
reaction conditions, and only the Z isomer cyclizes.[4b] The
relative configuration of the two stereogenic centers created
in the reaction was established by nOe analysis of cyclo-
pentenone 2a (see the Supporting Information for details). It
was possible to achieve chemoselective [1,2]-migration of an
Scheme 1. Spirocycle synthesis through a Nazarov/Wagner–Meerwein
rearrangement sequence. conr.=conrotatory, LA=Lewis acid.
[*] Dr. D. Lebœuf, Dr. J. Huang, Prof. A. J. Frontier
Department of Chemistry
University of Rochester
Rochester, NY 14627 (USA)
E-mail: frontier@chem.rochester.edu
Prof. V. Gandon
Univ Paris-Sud, ICMMO (UMR CNRS 8182)
91405 Orsay (France)
[**] We thank the National Institutes of Health (NIGMS R01 GM079364,
supporting J.H.) and the National Science Foundation (grant
no. CHE-0847851, supporting D.L.) for funding this research. We
thank R. Eisenberg for useful discussions. We used the computing
facility of the CRIHAN (project no. 2006-013).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104870.
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Table 1: Cyclization/rearrangement of C1/C2 variants of 1a–h.[a]
Table 2: Cyclization/rearrangement of C5 variants of 1k–p.[a]
Entry
Substrate
Product (yield [%][b])
Entry
Substrate
Product (yield [%][b], d.r.)
1[c]
2
3
4
5
1i, R=PMP[d]
1j, R=phenyl
1k, R=2-thienyl
1l, R=2-furyl
2i (86, 5:1)
2j (80, 20:1)
2k (95, 7:1)
2l (86, 4:1)
2m (85, 10:1)
1
1a, R=Me
1b, R=Et
1c, R=Ph
2a (92)
2b (95)
2c (95)
2
3[c]
1m, R=cinnamyl
4
5
6
1d, R=Me
1e, R=CH2OTBS
1 f, R=iPr
2e (51)
2e (45)[d]
2 f (79)
6
1n
2n (68)
[a] Reaction conditions: substrate in CH2Cl2 (0.03m) in the presence of
[(MeCN)5Cu(SbF6)2] (1 equiv) at 458C for 0.5–3 h. [b] Yield of isolated
product. [c] Reaction carried out at RT. [d] PMP=para-methoxyphenyl.
7[c]
1g
1h
2g (98)
2h (82)
Our original experiments indicated that both migratory
aptitudes and steric effects influenced which group underwent
a [1,2]-Wagner–Meerwein shift.[7] Thus, the chemoselectivity
of the reactions in Table 1 and Table 2 is remarkable. In
general, the [1,2]-migration of an aromatic group occurred in
preference to a methyl or hydride migration, and is consistent
with expectations based on migratory aptitude.[10] Exceptions
to this are reactions of substrates with the 2,4,6-trimethoxy-
phenyl (TMP) group (Table 1) or a hindered phenyl group
(1g, Table 1). In both cases, steric factors prevent migration of
the aromatic ring. Also consistent with migratory aptitudes,
substituted alkyl groups underwent [1,2]-migration in prefer-
ence to methyl groups (Table 1, entries 5 and 6), and hydride
migration was more favorable than isopropyl migration
(Table 2, entry 6).
An asymmetric version of this reaction was briefly
examined. We chose the bis(oxazoline) ligand (box), which
had already been shown to be an efficient promoter of the
Nazarov/Wagner–Meerwein sequence and able to induce
enantioselectivity for this transformation.[7b] The rearrange-
ment of compound 1h was especially promising, and afforded
cyclopentenone 2h in 80% yield and 95% ee (Scheme 3).
We next turned our attention to developing a catalytic
version of this reaction. Our hypothesis accounting for the
requirement of a stoichiometric amount of copper(II) is this:
the lone pair of electron on the carbonyl group must be bound
to the promoter throughout the reaction, otherwise the basic
8
[a] Reaction conditions: substrate in CH2Cl2 (0.03m) in the presence of
[(MeCN)5Cu(SbF6)2] (1 equiv) at RT for 10 min. [b] Yield of isolated
product. [c] Reaction carried out at 458C. [d] The desilylated product was
also isolated in 45% yield. TBS=tert-butyldimethylsilyl.
aryl group (Table 1, entries 1–3), a methyl group (Table 1,
entries 4 and 8), a siloxymethyl group (Table 1, entry 5), and a
branched alkyl group (Table 1, entries 6 and 7) from C1 to C2.
A hydride shift was the second [1,2]-migration event observed
in all cases, and cyclopentenones 2a–h were obtained in high
yields. In the rearrangement of substrate 1e (Table 1, entry 5),
the formation of two products 2e and 2’e was observed, with
2’e corresponding to the hydroxymethyl compound after loss
of the tert-butyldimethylsilyl group. The compounds were
obtained in a 1:1 ratio and a combined yield of 90%. The
removal of the protecting group can be attributed to the
presence of the hexafluoroantimonate counterion in solu-
tion.[9]
To examine the reactivity of compounds with different
substituents at C5, dienones 1i–n were prepared and sub-
jected to the usual reaction conditions (Table 2). Compounds
with aromatic, heteroaromatic, alkenyl, and alkyl function-
alities were tested. From these experiments, it was possible to
obtain cyclopentenones containing adjacent stereogenic cen-
ters in high yields (Table 2, entries 1–5), or the tetrasubsti-
tuted cyclopentenone 2n as a single diastereomer (Table 2,
entry 6).
In many of the examples in Table 2, a diastereoisomer was
observed in varying amounts. Because each one of the three
steps of the reaction sequence is stereospecific (Scheme 1),
À
the isomer must arise from isomerization of the C1 C2 bond
of the substrate in the presence of the copper(II) complex.
Scheme 3. Copper-mediated enantioselective cyclization of dienone
1h.
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carbonyl unit facilitates loss of a proton from oxyallyl cation
II to give III (see Scheme 1).[7] Our goal was to identify an
additive that could coordinate the carbonyl lone pair elec-
trons without promoting the cyclization. If the additive could
readily exchange with a catalyst for the reaction, the
rearrangement could be achieved selectively using the
combination of additive and catalyst. Our initial attempts to
achieve a catalytic rearrangement of 1o using a combination
of 10 mol% of [(MeCN)5Cu(SbF6)2] and 90 mol% of several
additives, including Zn(OAc)2, [Mn(acac)2], [Fe(acac)2],
LiClO4, Mg(OTf)2, NaSbF6, NaPF6, and NaBPh4 all
failed.[11] The reactions slowed down considerably, thus
leading to mixtures of products in low yields. Furthermore,
all these Lewis acids displayed a poor solubility in dichloro-
methane. Experiments with NaBArF had been promising in
another context,[4d] and proved to be effective as an additive
for catalytic rearrangements with CuII complexes. No reaction
of dienone 1o occurred in the presence of a stoichiometric
amount of NaBArF, but in the presence of [(MeCN)5Cu-
(SbF6)2] (10 mol%) and NaBArF (90 mol%), cyclopentenone
2o was formed in 90% yield as expected (Scheme 4).[12]
These catalytic reaction conditions could be employed for
the cyclization/rearrangement of other substrates as well
itively high free energy of activation, where TSb1-c1 lies at
27.50 kcalmolÀ1. On the other hand, the 1,2-phenyl shift that
leads to c2 is much more accessible (19.07 kcalmolÀ1). From
c2, the hydride-shift transition state lies higher than that of
the TMP shift (17.59 vs. 14.22 kcalmolÀ1). However, the
formation of d2 is endergonic (DG298 = 9.38 kcalmolÀ1) and
readily reversible, while that of the fully conjugated complex
Scheme 5. Results of cyclization/rearrangement using a catalytic
amount of a CuII complex. [a] Reaction conditions: substrate in CH2Cl2
(0.03m) in the presence of NaBArF (90 mol%) and [(MeCN)5Cu-
(SbF6)2] (10 mol%) at RT for 0.1–0.5 h. [b] Reaction carried out at
458C. All yields are of isolated product and the d.r. ratio is in
parentheses. BArF =tetrakis[3,5-bis(trifluoromethyl)phenyl]borate).
Scheme 4. Copper-mediated cyclization of 1,4-dien-3-one 1o.
(Scheme 5). Yields and efficiency were
comparable to experiments conducted with
stoichiometric amounts of copper(II) com-
plexes.[7]
The combination of the BArF counter-
ionꢀs noncoordinating behavior and the
solubility of the NaBArF salt are thought
to account for the singular success of this
additive. The finding that the Na+ ion is
enough to suppress the elimination pathway
is interesting, because it suggests that the
basicity of only one carbonyl group must be
suppressed.
To gain some insight into the mechanis-
tic issues raised during this study, we carried
out DFT studies using dienone 1a as the
model substrate and Cu2+ as the promoter
(see the Supporting Information for all
details).[13–15] From complex a1 (Scheme 6),
the transition state corresponding to the
conrotatory 4p electrocyclization could be
°
located at
298 = 18.98 kcalmolÀ1. It con-
~
G
nects a1 with the five-membered ring inter-
mediate b1 that lies 8.74 kcalmolÀ1 above a1
in free energy. The suprafacial 1,2-methyl
Scheme 6. Calculated free energies (DG, kcalmolÀ1) for the copper(II)-mediated cyclization
shift from b1 to give c1 requires a prohib- of dienone 1a.
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Communications
d1 is appreciably exergonic (DG298 = À11.33 kcalmolÀ1).
sequence. The chemoselectivity of the [1,2]-migrations
depended on both the migratory ability and the steric
demand of the substituents at C1 and C5. Experiments with
a series of alkylidene b-keto ester substrates led to the
creation of adjacent stereogenic centers, including adjacent
quaternary centers. It was found that partial E/Z isomeriza-
tion of the enone moiety occurs in some cases, and it affects
the selectivity of the reaction by compromising the stereo-
chemical fidelity of the substrates. DFT computations support
the possibility of a copper(II)-mediated double bond isomer-
ization to rationalize this finding. It was also found that
selective cyclization/rearrangement could be achieved with a
catalytic amount of the copper promoter in combination with
a weakly Lewis acidic sodium salt. Continuing efforts in our
laboratory are focused on the development of an asymmetric
version of this reaction, and application of this strategy
toward the synthesis of natural products.
Thus, the calculations predict the observed product 2a, with
a cis relationship between the two methyl groups. The
preference for d1 does not seem to have a kinetic origin
since the TMP-migration transition state is more accessible
than that of the hydride migration. However, in spite of the
formation of a phenonium framework in d2, the stabilization
of the carbocation is more efficient in d1.[16]
To support the proposed E/Z isomerization observed
upon CuII mediation of the reaction in some of the tetrasub-
stituted substrates (Table 2), additional calculations were
performed. The E/Z inversion shown in Scheme 6 could be
modeled in four steps from a1: Complex a1, which is
conformationally aligned for a 4p electrocyclization (s-trans/
s-trans), readily rearranges though TSa1-a2 into the slightly
°
more stable conformer a2 ( G298 = 8.98 kcalmolÀ1, DG298
=
~
À0.63 kcalmolÀ1). The diastereomutation then takes place to
give a3, slightly less stable than a1 (DG298 = 0.99 kcalmolÀ1).
The corresponding transition state, TSa2-a3, is the lowest lying
Received: July 12, 2011
Revised: August 17, 2011
Published online: September 26, 2011
°
G
of this sequence at
298 = 19.10 kcalmolÀ1. Then, a3 isomer-
~
izes into the more stable complex a4 in which copper
coordinates to the phenyl group.[14] This coordination is
appreciably exergonic (DG298 = À6.37 kcalmolÀ1), thus indi-
cating that formation of the Z-isomer a4 should be favored
over formation of the E-isomer a2. However, a close look at
the energy values suggests that the formation of products
from the Z isomer is unlikely. First, the isomerization of a4
Keywords: copper · density functional calculations ·
.
homogeneous catalysis · Nazarov cyclization · Wagner–
Meerwein rearrangement
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into the appropriately preorganized conformer a5 passes
°
through the low lying TSa4-a5 ( G298 = 1.39 kcalmolÀ1), but is
~
quite endergonic (DG298 = 2.04 kcalmolÀ1). Second, the elec-
trocyclization of a5 to give b2 requires 25.70 kcalmolÀ1 of free
energy of activation and is strongly endergonic (DG298
=
19.68 kcalmolÀ1). From b2, both shifts display high activation
barriers (25.91 vs. 23.65 kcalmolÀ1). Overall, as a result of the
steric interaction between the phenyl and the TMP groups,
the cyclization of a1 to b1 is more favorable than the
cyclization of a5 to b2—both kinetically and thermodynami-
cally. Thus, starting from either a1 or a5, the same final result
is expected: formation of complex d1 and then product 2a.
This prediction is corroborated by the experimental result
shown in Scheme 7: When the Z-isomer 1r was subjected to
the reaction conditions, product 2a was isolated in 95% yield.
Product 2a was reported in Table 1, except the cyclization
substrate was the E-isomer 1a.
In summary, we have developed an efficient, chemo-
selective method for the preparation of highly functionalized
cyclopentenones based on a stereospecific, copper(II)-medi-
ated Nazarov cyclization/Wagner–Meerwein rearrangement
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Angew. Chem. Int. Ed. 2011, 50, 10981 –10985

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[11] This reaction was also run in the presence of a stoichiometric
amount of LiPF6, but this lithium salt was able to promote the
electrocyclization and thus gave the usual Nazarov product
exclusively.
[12] The reaction of 1o with 10 mol% of [(MeCN)5Cu(SbF6)2] gave
exclusively product III (Scheme 1).
[13] G. W. T. M. J. Frisch, et al. Gaussian03 (v C02), Gaussian, Inc.,
Wallingford CT, 2004. See the Supporting Information of the full
citation.
[14] The geometry optimizations and thermodynamic corrections
were performed with hybrid density functional theory (UB3LYP,
doublet spin state for copper with a + 2 overall charge) with the
6-31G(d,p) basis set. Solvation corrections for dichloromethane
were computed using the polarizable continuum model (PCM)
with UFF radii using the gas phase optimized structures. All
relative energies presented in this manuscript are free energies
(DG) in kcalmolÀ1. Solvation free energies were calculated by
adding the solvation energies to the computed gas phase relative
free energies (DG298).
[15] For rare theoretical reports on copper(II)-mediated Nazarov
reactions, see: a) J. A. Mayoral, S. Rodrꢃguez-Rodrꢃguez, L.
Salvatella, Chem. Eur. J. 2008, 14, 9274; for selected theoretical
reports on proton-mediated Nazarov reactions, see: b) O.
Nieto Faza, C. Silva Lꢄpez, R. ꢅlvarez, A. R. de Lera, Chem.
Eur. J. 2004, 10, 4324; c) A. Cavalli, M. Masetti, M. Recanatini,
C. Prandi, A. Guarna, E. G. Occhiato, Chem. Eur. J. 2006, 12,
2836; d) A. Cavalli, A. Pacetti, M. Recanatini, C. Prandi, D.
Scarpi, E. G. Occhiato, Chem. Eur. J. 2008, 14, 9292; e) R. L.
Davis, D. J. Tantillo, Curr. Org. Chem. 2010, 14, 1561; for a
theoretical report on the retro-Nazarov reaction, see: f) M.
Harmata, P. R. Schreiner, D. R. Lee, P. L. Kirchhoefer, J. Am.
Chem. Soc. 2004, 126, 10954.
[16] See the Supporting Information for geometric details.
Angew. Chem. Int. Ed. 2011, 50, 10981 –10985
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 10985