Enantio- and periselective nitroalkene Diels-Alder reaction

Article abstract of DOI:10.1039/c2ob26674a

The periselective Diels-Alder reaction of 5-substituted pentamethylcyclopentadienes and nitroethylene has been realized by helical-chiral hydrogen bond donor catalysts. To our knowledge, this represents the first asymmetric catalytic nitroalkene Diels-Ald

Full text of DOI:10.1039/c2ob26674a

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COMMUNICATION
Enantio- and periselective nitroalkene Diels–Alder reaction†‡
Maurice J. Narcis,a Daniel J. Sprague,b Burjor Captaina and Norito Takenaka*a
Received 24th August 2012, Accepted 10th October 2012
DOI: 10.1039/c2ob26674a
The periselective Diels–Alder reaction of 5-substituted penta-
methylcyclopentadienes and nitroethylene has been realized
by helical–chiral hydrogen bond donor catalysts. To our
knowledge, this represents the first asymmetric catalytic
nitroalkene Diels–Alder reaction via activation of nitro-
alkene, and thus establishes its proof-of-principle.
Asymmetric LUMO-lowering catalysis of the Diels–Alder reac-
Fig. 1 Natural products with a cyclopentane core.
tion is one of the most extensively studied methods, and its
current state is certainly impressive.1 However, dienophiles are
limited to carbonyl compounds, leaving a tremendous gap in an
otherwise robust field of chemistry. The catalytic activation of
nitroalkene (ketene equivalent) for the asymmetric Diels–Alder
reaction has remained nonexistent presumably due to its inherent
nature to undergo the inverse electron-demand hetero Diels–
Alder reaction with Lewis acids to provide nitronate products.2
In 2007, we reported that dual hydrogen bond donors can peri-
selectively catalyze the nitroalkene Diels–Alder reaction, paving
the way to its enantioselective catalysis.3 It should be mentioned
that two different strategies to activate dienes for the nitroalkene
Diels–Alder reaction have successfully been developed. The first
one is in situ generation of dienes from enones via enamine cata-
lysis by chiral amines,4 the concept of which was demonstrated
first by Barbas.4d Another successful strategy, which is the acti-
vation of 3-hydroxy-2-pyrones (dienes) via general base cata-
lysis, has recently been developed by Deng.5
Scheme 1 A proven strategy for the synthesis of cyclopentenes.
It should be mentioned that notable advances in the enantioselec-
tive [3+2] reactions have been reported.9 However, neither of
these [3+2] reactions nor the aforementioned nitroalkene
Diels–Alder reactions can provide cyclopentenes with three con-
tiguous quaternary stereocenters.
Most of the known dual hydrogen bond donor catalysts are
associated with additional complementary functionalities that
activate and constrain an incoming nucleophile to an orientation
necessary for asymmetric induction (such bifunctional catalysts
typically have the additional hydrogen bond donor or acceptor
unit for these purposes).10 Obviously, this bifunctional strategy
is not applicable for cyclopentadienes, and thus the development
of catalysts that do not depend on the additional complementary
functionalities is required. We previously designed and devel-
oped such catalysts using the addition reaction of pyrroles to
nitroalkenes as a platform (catalyst 1 in Table 1 was found
optimum for this reaction).11 To our delight, 1 indeed catalyzed
the nitroalkene Diels–Alder reaction and provided only the
desired product (no hetero Diels–Alder) with definite enantio-
selectivity (Table 1, entry 2). It was somewhat surprising to us
The impetus for this study is to fill a gap in the catalytic asym-
metric Diels–Alder methodologies that can open ready access to
cyclopentenes with multiple contiguous quaternary stereocenters,
a motif found in medicinally relevant complex natural products
(Fig. 1).6 The Diels–Alder reaction of cyclopentadienes and
nitroethylene followed by ring opening is a proven strategy for
the synthesis of highly substituted cyclopentenes (Scheme 1).7,8
aDepartment of Chemistry, University of Miami, 1301 Memorial Drive,
Coral Gables, FL 33146-0431, USA. E-mail: n.takenaka@miami.edu;
Fax: +1 305 284 4571; Tel: +1 305 284 3279
bCurrent address: Department of Chemistry & Vanderbilt Institute of
Chemical Biology, Vanderbilt University, Nashville, TN 37235-1822,
USA
1
that only an endo isomer was detected by H NMR analysis of
the crude reaction mixture.12 In our previous study, it was
demonstrated that catalyst’s enantioselectivity can be tuned by
changing the size of the R group that is designed to extend the
reach of its helical framework.11 Accordingly, we examined
several R groups and found that enantioselectivity of the
Diels–Alder reaction was also sensitive to the structure of the
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡Electronic supplementary information (ESI) available: Experimental
procedures and characterization of new compounds. CCDC reference
numbers 897988 & 897989. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob26674a
9134 | Org. Biomol. Chem., 2012, 10, 9134–9136
This journal is © The Royal Society of Chemistry 2012

Table 1 Evaluation of catalysts for nitroalkene Diels–Alder reactiona,b
Table 2 Nitroalkene Diels–Alder reaction with different dienesa,b
Entry
Ar
Yieldc (%)
erd
1e
2
Ph
77
80
38
80
67
30 : 70
65 : 35
66 : 34
64 : 36
69 : 31
4-F–Ph
4-Cl–Ph
4-Cl–Ph
3-Cl–Ph
3
4f
5
Entry
Catalyst
R
Yieldd (%)
ere
1
2
—
1
—
<5
70
—
64 : 36
a Reaction conditions: diene (0.4 mmol) and nitroethylene (0.2 mmol) in
the presence of 10 mol% of catalyst in CH2Cl2 (0.7 mL). b The absolute
stereochemistry of the 4-Cl substituted product (Table 2, entries 3 and 4)
was established by X-ray analysis. The rest were assigned by analogy.13
c Yield of isolated products. d Determined by chiral HPLC analysis.
e (P)-5 was used. f (M)-1 was used.
3f
4
2
3
84
70
38 : 62
59.5 : 40.5
5
6
4
5
70
77
67 : 33
70 : 30
Notes and references
1 Selected references: (a) J. N. Payette and H. Yamamoto, Angew. Chem.,
Int. Ed., 2009, 48, 8060; (b) E. P. Balskus and E. Jacobsen, Science,
2007, 317, 1736; (c) S. A. Snyder and E. J. Corey, J. Am. Chem. Soc.,
2006, 128, 740; (d) R. M. Wilson, W. S. Jen and D. W. C. MacMillan,
J. Am. Chem. Soc., 2005, 127, 11616; (e) E. J. Corey, T. Shibata and
T. W. Lee, J. Am. Chem. Soc., 2002, 124, 3808. For selected reviews of
asymmetric Diels–Alder reactions, see: (f) A. Erkkilä, I. Majander and
P. M. Pihko, Chem. Rev., 2007, 107, 5416; (g) E. J. Corey, Angew.
Chem., Int. Ed., 2002, 41, 1650.
2 Selected references: (a) N. Çelebi-Ölçüm, D. H. Ess, V. Aviyente and
K. N. Houk, J. Am. Chem. Soc., 2007, 129, 4528; (b) S. E. Denmark,
B. S. Kesler and Y.-C. Moon, J. Org. Chem., 1992, 57, 4912.
3 N. Takenaka, R. S. Sarangthem and S. K. Seerla, Org. Lett., 2007, 9,
2819.
a Reaction conditions: diene (0.4 mmol) and nitroethylene (0.2 mmol) in
the presence of 10 mol% of catalyst in CH2Cl2 (0.7 mL). b The absolute
stereochemistry of the 4-Cl substituted product (Table 2, entries 3 and 4)
was established by X-ray analysis. The rest were assigned by analogy.13
c −X = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. d Yield of isolated
products. e Determined by chiral HPLC analysis. f (P)-catalyst was used.
4 Selected references: (a) L.-Y. Wu, G. Bencivenni, M. Mancinelli,
A. Mazzanti, G. Bartoli and P. Melchiorre, Angew. Chem., Int. Ed., 2009,
48, 7196; (b) D.-Q. Xu, A.-B. Xia, S.-P. Luo, J. Tang, S. Zhang,
J.-R. Jiang and Z.-Y. Xu, Angew. Chem., Int. Ed., 2009, 48, 3821;
(c) H. Sundén, R. Rios, Y. Xu, L. Eriksson and A. Córdova, Adv. Synth.
Catal., 2007, 349, 2549; (d) R. Thayumanavan, B. Dhevalapally,
K. Sakthivel, F. Tanaka and C. F. Barbas, III, Tetrahedron Lett., 2002, 43,
3817.
5 K. J. Bartelson, R. P. Singh, B. M. Foxman and L. Deng, Chem. Sci.,
2011, 2, 1940.
6 Selected references: (a) F. Li, S. S. Tartakoff and S. L. Castle, J. Am.
Chem. Soc., 2009, 131, 6674; (b) T. Mugishima, M. Tsuda, Y. Kasai,
H. Ishiyama, E. Fukushi, J. Kawabata, M. Watanabe, K. Akao and
J. Kobayashi, J. Org. Chem., 2005, 70, 9430.
R substitution (Table 1, entries 3–6). Using catalyst 5, we carried
out a short screening of different dienes to obtain some idea
regarding the potential scope of this protocol. We were glad to
find that other dienes were tolerated well (Table 2, entries 2–5).
However, the reason for the low yield obtained with the
4-Cl-substituted diene (entry 3) was not immediately clear to us
since all of those dienes are equally reactive under the thermal
reaction condition (i.e., without a catalyst). We hypothesized that
there might be steric repulsion between 4-Cl-substitution and the
catalyst in the transition state, and thus we tested the sterically
less demanding catalyst 1. We were pleased to find that it gave
the product in high yield (entry 4).
In conclusion, we successfully demonstrated that the nitro-
alkene Diels–Alder reaction can be rendered enantio- and
periselective by chiral hydrogen bond donor catalysts. This rep-
resents, to our knowledge, the first asymmetric catalytic nitro-
alkene Diels–Alder reaction by LUMO-lowering catalysis.
Further optimizations of the catalyst structures and substrate
scope study are currently undertaken and will be reported in due
course.
7 Selected reference: S. Ranganathan, D. Ranganathan and A. K. Mehrotra,
J. Am. Chem. Soc., 1974, 96, 5261.
8 The Diels–Alder reaction of cyclopentadiene and 2-chloroacrylonitrile
followed by ring opening, see: E. J. Corey, N. M. Weinshenker,
T. K. Schaaf and W. Huber, J. Am. Chem. Soc., 1969, 91, 5675.
9 Selected references: (a) Y. Fujiwara and G. C. Fu, J. Am. Chem. Soc.,
2011, 133, 12293; (b) X. Han, Y. Wang, F. Zhong and Y. Lu, J. Am.
Chem. Soc., 2011, 133, 1726; (c) H. Xiao, Z. Chai, C.-W. Zheng,
Y.-Q. Yang, W. Liu, J.-K. Zhang and G. Zhao, Angew. Chem., Int. Ed.,
2010, 49, 4467; (d) B. J. Cowen and S. J. Miller, J. Am. Chem. Soc.,
2007, 129, 10988; (e) P.-C. Chiang, J. Kaeobamrung and J. W. Bode,
J. Am. Chem. Soc., 2007, 129, 3520; (f) J. E. Wilson and G. C. Fu,
Angew. Chem., Int. Ed., 2006, 45, 1426; (g) H. M. L. Davies,
B. Xiang, N. Kong and D. G. Stafford, J. Am. Chem. Soc., 2001, 123,
7461.
This work was supported by the Florida Department of
Health (07KN-12) and the National Science Foundation
(CHE-1152850). The mass spectrometer used was financed by
the National Science Foundation (CHE-0946858).
10 Selected reviews: (a) X. Yu and W. Wang, Chem. Asian J., 2008, 3,
516; (b) A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107,
5713; (c) M. S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed.,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9134–9136 | 9135

2006, 45, 1520; (d) Y. Takemoto, Org. Biomol. Chem., 2005, 3,
4299.
accordance with stereocontrol by steric bias. See: W. Adam, U. Jacob and
M. Prein, J. Chem. Soc., Chem. Commun., 1995, 839–840.
11 N. Takenaka, J. Chen, B. Captain, R. S. Sarangthem and
A. Chandrakumar, J. Am. Chem. Soc., 2010, 132, 4536.
12 5,5-Disubstituted plane-nonsymmetric cyclopentadienes are known to
undergo the Diels–Alder reaction with high π-facial selectivity in
13 For assignment of the absolute stereochemistry of the product, and the
proposed transition state models; see: ESI‡ for detail. Correspondence
regarding the X-ray data should be addressed to Professor Burjor
Captain, University of Miami.
9136 | Org. Biomol. Chem., 2012, 10, 9134–9136
This journal is © The Royal Society of Chemistry 2012