Salen promoted enantioselective nazarov cyclizations of activated and unactivated dienones

Article abstract of DOI:10.1021/ja401908m

A novel class of chiral 5,5′-di(2,4,6-trialkyl)aryl salen-metal complexes have been developed and shown to catalyze highly enantioselective Nazarov cyclization reactions, giving rise to cyclopentenoids in 90:10-98:2 er. Significantly, the catalysts also p

Full text of DOI:10.1021/ja401908m

Communication
pubs.acs.org/JACS
Salen Promoted Enantioselective Nazarov Cyclizations of Activated
and Unactivated Dienones
Gerri E. Hutson, Yunus E. Turkmen, and Viresh H. Rawal*
̈
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
Scheme 1. Enantioselective Nazarov Cyclization Substrates
ABSTRACT: A novel class of chiral 5,5′-di(2,4,6-trialkyl)-
aryl salen-metal complexes have been developed and
shown to catalyze highly enantioselective Nazarov
cyclization reactions, giving rise to cyclopentenoids in
90:10−98:2 er. Significantly, the catalysts also promote, for
the first time, highly enantioselective Nazarov reactions of
“unactivated” dienones, producing hydrindenone products
having in place three contiguous chiral centers.
he Nazarov cyclization reaction, a conrotatory 4π-
Telectrocyclization of divinyl ketones, provides one of the
most effective methods for the synthesis of functionalized
cyclopentenones.1 The reaction has been investigated exten-
sively and is often utilized for the synthesis of cyclopentenoid
natural products.2 Catalysis of the Nazarov reaction has been
the focus of many studies, and both Brønsted acid and Lewis
acid catalyzed processes have been developed.3 The first highly
enantioselective Nazarov reactions were reported in 2003 by
Aggarwal and Belfield, who used chiral copper bisoxazoline
(BOX) and pyBOX complexes as stoichiometric and
substoichiometric catalysts.4 Contributions from several labo-
ratories have led to the identification of other Lewis acidic
metals and chiral scaffolds,5 as well as chiral Brønsted acids,6 for
inducing torquoselectivity in the electrocyclization step.
Enantioselectivity has also been realized upon protonation of
the prochiral intermediate.5a,6b
benzaldehyde,7c a one-point activation to the carbonyl was
expected, wherein unsymmetrical coordination to the catalyst
would impart torquoselectivity.
Initial studies focused on the Nazarov cyclization of alkoxy-
activated dienone 2a in the presence of a number of readily
prepared chiral salens (Table 1). Cobalt(III) salens 1a and 1b,
containing 3,3′-di-tert-butyl and 3,3′-di(triisobutylsilyl)8 groups,
respectively, were ineffective as catalysts, giving no conversion
after 24 h (entries 1 and 2). By contrast, commercially derived
chromium antimonate complex 1c catalyzed the cyclization in 9
h and afforded the product cyclopentenone 3a as a 2.8:1
mixture of cis/trans diastereomers, formed with good to high
enantioselectivities (90:10, 95:5 er; entry 3).11 The introduc-
tion of 4 Å molecular sieves further increased the reaction rate
and enantioselectivity, producing the product in 4.5 h, as a
mixture of 92:8 er (cis) and 96:4 er (trans) diastereomers
(entry 4). While the aluminum salen was catalytically more
active, both it and manganese salens generated the product with
low selectivity (entries 5 and 6). Solvent optimization studies in
the presence of 1c and 4 Å MS revealed that methylene
chloride was indeed the optimal solvent, with other solvents
(DCE, toluene, diethyl ether, MTBE) either leading to lower
er’s or deactivation of the catalyst (ethyl acetate, THF). A
counterion survey revealed that commercially available catalyst
1f promotes the reaction slowly and gives the product with
moderate er’s (entry 7). Exchanging the chloride with
noncoordinating counterions, such as BF4, AsF6, and BArF,
resulted in faster reactions and improved enantioselectivities
(entries 8−10). The greatest improvement was observed with
hexabromocarborane counterion, which converted divinyl
ketone 2a completely to cyclopentenone 3a in <30 min.12
Despite many noteworthy advances, significant challenges
remain for the enantioselective Nazarov reaction. As noted by
Vaidya et al., “Asymmetric catalysis has been limited to specific
substrate types, particularly to the very reactive ones.”3a Tius
and co-workers present a similar assessment of the
enantioselective Nazarov reaction.3b Nearly all successes have
been achieved with “activated” substrates, those possessing an
α-alkoxy or α-electron-withdrawing group or both (Scheme
1).3 We report here a novel family of bulky 5,5′-di(2,4,6-
trialkyl)aryl Cr-salen complexes that catalyze highly enantiose-
lective Nazarov reactions. Significantly, the work provides the
first examples of enantioselective Nazarov reactions of
“unactivated” dienones as well as the first instances of such
reactions to generate three adjacent stereocenters in the
cyclopentyl core.
In connection with our interest in the carbonyl-activating
capability of chiral metal-salen complexes,7,8 we examined the
use of such catalysts for the enantioselective Nazarov
cyclization.9,10 Based on prior studies, including an X-ray
crystal structure of a complex between a cobalt-salen and
Received: February 21, 2013
Published: March 18, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Metal Survey for Salen-Catalyzed Nazarov
Cyclization Reaction
Table 2. Use of 5,5′-Diaryl-Substituted Chromium(III) Salen
Complexes for the Asymmetric Nazarov Cyclization
Reaction
time
(h)
conv
a
b
c
entry
cat., M, X
additive
(%)
er (dr)
1
2
3
1a, Co, SbF6
1b, Co, SbF6
1c, Cr, SbF6
−
−
−
24
24
9
NR
NR
>95
−
−
90:10, 95:5,
(2.8:1)
4
5
6
7
8
9
1c, Cr, SbF6
1d, Mn, SbF6
1e, Al, Cl
4 Å MS
4 Å MS
4.5
48
0.5
48
8
>95
>95
>95
>95
>95
>95
>95
>95
92:8, 96:4
(2.7:1)
60:40, 73:27
(1.9:1)
4 Å MS/AgSbF6
4 Å MS
77:23, 59:41
(1.2:1)
1f, Cr, Cl
83:17, 86:14
(2.2:1)
1g, Cr, BF4
1h, Cr, AsF6
1i, Cr, BArF
1j, Cr, Cl
4 Å MS
86:14, 93:7
(2.6:1)
4 Å MS
8
85:15, 92:8
(1.7:1)
d
10
4 Å MS
3
91:9, 93:7
(1.8:1)
a
b
c
Isolated yields. dr’s determined using 1H NMR. er’s of cis and trans
11
4 Å MS/
e
0.5
90:10, 95:5
(2.8:1)
diastereomers determined using chiral HPLC.
AgB11H6Br6C
a
b
Determined using 1H NMR. er of cis and trans diastereomers
c
determined using chiral HPLC. dr determined using 1H NMR.
salen (4b), in which the biaryl units are expected to be in a
perpendicular arrangement, gave the product with >95:5 er for
each diastereomer (entries 2 and 3). A further increase in the
size of the substitutents on the 5,5′-diaryl groups did not
continue to improve torquoselectivity. Thus, the i-Pr and t-Bu
catalysts (4c and 4d, respectively), while superior to 1c and 4a,
gave higher er only for the minor product diastereomer. The
slower reaction rate for the t-Bu catalyst (entry 5) is consistent
with the original hypothesis that ortho substituents on the 5,5′-
diaryl groups would affect the coordination and orientation of
reactants.
Having identified the mesityl-substituted chromium-salen
complex 4b as optimal, we next examined the scope of these
enantioselective Nazarov cyclizations (Table 3). A broad range
of aromatic and heteroaromatic groups were tolerated at the β-
position of the dienone substrates, with the cyclopentenone
products being formed in good yields and er’s. The higher
diastereoselectivities seen in entries 2 and 4 appear to correlate
with the effective size of the β-substituent. Of interest is the
result shown in entry 8, the cyclization of β-methyl dienone 2h
to give product 3h in good yield and er. Since β-alkyl substrates
undergo Nazarov cyclization more slowly than β-aryl substrates,
this reaction was carried out using 4b but with hexabromo-
carborane counterion. Entry 9 demonstrates the ability of
catalyst 4b to impart asymmetry in the cyclization of acylic
dienones.17
d
e
BArF=tetrakis[3,5-bis(trifluoromethyl) phenyl]borate. AgB11H6Br6C
= silver hexabromocarborane; NR = no Reaction. See SI for details on
tentative assignment of stereochemistry of the product.
To realize further increases in torquoselectivity, we
considered modification of the salen scaffold. Although
replacement of the 3,3′-groups with bulkier groups had proven
successful for activation of the aldehyde carbonyls in Diels−
Alder and carbonyl ene reactions,7,8 such groups were expected
to impede coordination to the dienone carbonyl, which is
flanked with sterically demanding substituents.13 On the other
hand, introduction of the correct substituents at the 5,5′-
positions could further accentuate the subtle asymmetric
topology of the salen framework. Specifically, 2,6-disubstituted
aryl groups at this position would be forced to sit perpendicular
to the salen aryls and thus project above and below the catalyst
plane. Such bulky aryl groups have been successfully
incorporated into a number of chiral Lewis acid catalysts,
such as those by Terada14 and Yamamoto.15 The biaryl
salicylaldehydes required for the modified salens were
synthesized in a single step from the corresponding
bromosalicylaldehyde using a Suzuki-Miyaura cross-coupling
protocol and then converted to the desired chromium complex
using established methods.16
The results of the Nazarov cyclization using the novel 5,5′-
diaryl substituted salens are summarized in Table 2. Compared
to the parent t-butyl-substituted salen, the aryl-substituted
salens generally gave higher enantioselectivities. Whereas the
simple 5,5′-diphenyl-substituted salen complex (4a) was
modestly selective, the corresponding mesityl substituted
A few cascade sequences have been reported wherein the
penultimate enol or metal enolate intermediate in an
enantioselective Nazarov reaction is intercepted with a halogen
or carbon electrophile.3,5 Our longstanding interest in nitrogen-
containing compounds motivated us to briefly examine a
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Journal of the American Chemical Society
Communication
Table 3. Scope of Salen-Promoted Enantioselective Nazarov
Cyclizations
Table 4. Scope of Salen-Promoted Enantioselective Nazarov
Cyclizations of Unactivated Dienones
a
b
c
entry
product
yield (%)
dr
er
d
1
R = Me (9a)
R = Et (9b)
60
65
78
78
76
55
56
62
>20:1
>20:1
>20:1
>20:1
>10:1
>10:1
>10:1
>8:1
95:5
93:7
93:7
97:3
90:10
92:8
92:8
d
2
e
3
R = Ph (9c)
e
4
R = 4-BrC6H4 (9d)
R = 4-MeC6H4 (9e)
R = 2-furyl (9f)
R = 2-benzofuryl (9g)
e
5
d
6
e
7
d
8
R = 2-thienyl (9h)
90:10
a
b
c
Isolated yields. Diastereoselectivity determined by 1H NMR. er
d
values were determined using chiral HPLC. 15 mol % catalyst
loading. 10 mol % catalyst loading.
e
arrangement. The cis product and the expected tetrasubstituted
product were observed in only trace amounts. Divinyl ketones
8b−h were also converted to the corresponding cyclo-
pentanoids, yielding compounds 9b−h with good er and high
diastereoselectivities (entries 2−8). The unactivated substrates
were slower to react and required higher catalyst loadings and
longer reaction times. For example, dienone 8a and 8b required
15 mol % of 4b and 60 h reaction time, while dienones 8c−8h
proceeded in the presence of 10−15 mol % catalyst for 48 h.
The above results represent, to our knowledge, the first highly
torquoselective catalytic Nazarov cyclization reactions of
unactivated dienones. These examples also provide the only
examples of enantioselective Nazarov cyclization reactions to
generate a cyclopentane with three stereogenic centers.
a
b
c
Isolated yields. dr’s determined using 1H NMR. er’s of cis and trans
d
diastereomers determined using chiral HPLC. Catalyst 4e (4b but
with hexabromocarborane counterion) was used. Absolute stereo-
e
The absolute stereochemistry of the salen-promoted Nazarov
cyclization product, enone 9e, was determined through X-ray
crystallography of its dibromo derivative 10, formed in high
diastereoselectivity (dr = 20:1, Scheme 3).18 The crystal
chemistries for 3b−h and 6 were assigned to correlate with 3a.
tandem process that would terminate with the formation of a
C−N bond to the enol intermediate. We have found that
inclusion of diisopropyl azodicarboxylate in the reaction
mixture affords the Nazarov cyclization/azination product. It
is of interest to note that diastereoselectivity for the tandem
process was higher than in the original cyclization (Scheme 2).
Scheme 3. Absolute Stereochemistry of Nazarov Product 9e
Scheme 2. Tandem Enantioselective Nazarov Cyclization/
Azination Reaction
structure also confirmed the relative stereochemistry assigned
to the three chiral centers introduced upon cyclization. A
rationale for the observed torquoselectivity can be put forth by
considering an octahedral complex between the substrate and
the Cr-salen, in analogy with the previously reported structure
of benzaldehyde-Co-salen complex (Scheme 4).7c Steric factors
should favor coordination to the carbonyl lone pair away from
the cyclohexenyl unit, with the substrate residing in the more
open quadrant. In this arrangement, a counter-clockwise
conrotatory cyclization, as viewed from the carbonyl group
oxygen, would move the R group into a less-congested
environment, away from the bulky mesityl group, whereas a
clockwise cyclization would have the opposite effect.
Given the success observed with “activated” substrates, we
next examined the use of the novel bulky chromium-salen
complexes as catalysts for enantioselective Nazarov cyclizations
of unactivated dienones. Thus, treatment of the simple dienone
8a with catalyst 4b promoted a smooth cyclization to afford
cyclopentanoid product 9a in 60% yield and with 95:5 er
(Table 4, entry 1). Interestingly, 1H NMR analysis revealed that
the major product was not the tetrasubstituted alkene, as
before, but was instead the bicyclo[4.3.0]non-1-en-9-one
product (9a) with the two methyl groups in a trans
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(5) (a) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544.
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Shindo, M. Synlett 2009, 2524. (e) Kawatsura, M.; Kajita, K.; Hayase,
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A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440.
(d) Basak, A. K.; Shimada, N.; Bow, W. F.; Vicic, D. A.; Tius, M. A. J.
Am. Chem. Soc. 2010, 132, 8266. (e) Rueping, M.; Ieawsuwan, W.
Chem. Commun. 2011, 11450.
Scheme 4. Proposed Model to Rationalize Enantioselectivity
(7) (a) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000,
122, 7843. (b) Huang, Y.; Iwama, T.; Rawal, V. H. Org. Lett. 2002, 4,
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In summary, a new class of chiral 5,5′-diaryl-substituted
metal salens was developed and shown to catalyze highly
torquoselective Nazarov reactions, very likely through a one-
point activation mode. Significantly, the catalysts also promote,
for the first time, highly enantioselective Nazarov reactions of
unactivated dienones, producing hydrindenone products having
in place three contiguous chiral centers.
(f) Early precedent: Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org.
̊
Chem. 1998, 63, 403.
́
(8) Hutson, G. E.; Dave, A. H.; Rawal, V. H. Org. Lett. 2007, 9, 3869.
(9) Salen complex reviews: (a) Achard, T. R. J.; Clutterbuck, L. A.;
North, M. Synlett 2005, 1828. (b) McGarrigle, E. M.; Gilheany, D. G.
Chem. Rev. 2005, 105, 1563. (c) Cozzi, P. G. Chem. Rev. 2004, 104,
410. (d) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem. 2004, 6,
123. (e) Katsuki, T. Coord. Chem. Rev. 1995, 140, 189. (f) Togni, A.;
Venazani, L. M. Angew. Chem., Int. Ed. 1994, 33, 497.
(10) Chiral vanadium (IV) salen complex was reported to provide no
enantioselectivity in the Nazarov reaction: Walz, I.; Bertogg, A.; Togni,
A. Eur. J. Org. Chem. 2007, 2680.
ASSOCIATED CONTENT
* Supporting Information
Detailed methods and compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(11) Reaction mixture was flashed through silica gel after full
conversion was observed. Presence of starting material leads to overall
reduction in er due to silica gel promotion of racemic Nazarov
cyclization reaction.
AUTHOR INFORMATION
Corresponding Author
vrawal@uchicago.edu
■
(12) Reed, C. A. Chem. Commun. 2005, 1669.
(13) 3,3′-disilyl chromium salen complexes similar to 1b resulted in a
Notes
major reaction rate reduction.
The authors declare no competing financial interest.
(14) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292.
(15) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 10521.
(16) Procedures for complex preparation in SI.
(17) Enantioselective cyclization of acyclic α-alkoxy dienones was
recently reported: Raja, S.; Ieawsuwan, W.; Korotkov, V.; Rueping, M.
Chem. Asian J. 2012, 7, 2361.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM069990). Fellowship
support to G.E.H. from the UNCF/Merck, GlaxoSmithKline,
and Bristol-Myers Squibb is gratefully acknowledged. We thank
Mr. Mohammad Haidar for preparing initial batches of
compounds 4a and 4b, and Dr. Ian Steele (University of
Chicago, Department of Geophysical Sciences) for X-ray
structure determination of compound 10.
(18) Synthesis, characterization, and X-ray analysis of 10, see SI, and
crystallographic data for 10 deposited (CCDC 929060).
NOTE ADDED AFTER ASAP PUBLICATION
■
Reference 3a was incorrect in the version published ASAP
March 25, 2013. The corrected version was re-posted on March
26, 2013.
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