versions of this reaction reported in the literature are very
limited and are mostly based on metal catalysis.10 To the best
of our knowledge, the report by Ramachandran and co-
workers on the synthesis of glutamic acid derivatives employ-
ing allylic acetates under chiral phase transfer conditions was
the only example based on organic catalysis in the literature.11
As part of our research program toward the development of
practical asymmetric synthetic methods, we were interested
in developing organocatalytic asymmetric transformations
employing the MBH adducts.12
Scheme 2. Regioselectivity in the Substitution Reactions
Scheme 1. Conversions of the MBH Adducts
We began our investigation by choosing the reaction
between nitroethane 2a and MBH carbonates 1 as a model
reaction. A number of cinchona alkaloid-derived bifunc-
tional catalysts16 were examined, and the results are sum-
marized in Table 1. All the tertirary amineꢀthiourea
catalysts, cinchonidine-derived 4, quinine-derived 5, and
quinidine-based 6, were able to catalyze the regioselective
formation of the product 3 (Table 1, entries 1ꢀ3).17
However, quinine-derived tertiary amineꢀsulfonamide 7
was found to be ineffective (Table 1, entry 4). Variation of
the ester moiety in the MBH carbonates offered further
improvement; employment of the ethyl ester of the MBH
carbonate 1a-2 led to the formation of 3a in 96% yield and
93% ee (Table 1, entry 5). The solvent screening was
carried out(Table1, entries 7ꢀ13), andTHF wasidentified
as the solvent of choice for the subsequent reactions.
Having identified the optimal reaction conditions, we
then investigated the substrate scope (Table 2). The reac-
tion worked well for the MBH carbonates with differ-
ent aromatic moieties; very good yields and excellent
enantioselectivities were attainable, regardless of the
electronic nature and the substitution pattern of the
aryl groups (Table 2, entries 1ꢀ11). The relatively low
Nitroalkanes are valuable nucleophiles commonly used
in organic synthesis and have been extensively investigated
in asymmetric nucleophilic addition reactions.13 Although
the reactions between the MBH acetates and nitroalkanes
promoted by inorganic bases have been reported by Kim
and Basavaiah, respectively,14 a catalytic asymmetric ver-
sion of this reaction is unknown. Herein, we describe the
first regioselective asymmetric substitution of the MBH
adducts by nitroalkanes, catalyzed by cinchona alkaloid-
derived bifunctional catalysts.
For the allylic substitution of the MBH adducts, a
commonly accepted tandem SN20ꢀSN20 mechanism15 is
illustrated in Scheme 2. The nucleophilic catalyst (a tertiary
amine or phosphine) first adds to the MBH adduct in an
SN20 fashion, with the concurrent departure of the OR
group, which could be utilized to activate the nucleophile.
A second SN20 reaction then affords the final product,
regenerating the catalyst at the same time. In order to obtain
a product of type B (Scheme 1), we hypothesize that employ-
ment of a bifunctional nucleophilic catalyst with an appro-
priate Brønsted acid moiety may be a viable approach.
Following the initial SN20 reaction, the hydrogen bonding
interactions between the nucleophile and the Brønsted acid
moiety of the catalyst are expected to direct the subsequent
SN2 substitution, thus leading to products of type B.
(16) For selected examples of this type of catalysts, see: (a) Okino, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (b)
Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (c)
Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 6366. (d) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005,
7, 4293. (e) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y.
ꢀ
ꢀ
Synlett 2005, 603. (f) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org.
Lett. 2005, 7, 1967. (g) McCooey, S. H.; Connon, S. J. Angew. Chem., Int.
Ed. 2005, 44, 6367. (h) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun.
2005, 4481. (i) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y.
Angew. Chem., Int. Ed. 2009, 48, 7604. (j) Zhu, Q.; Lu, Y. Angew. Chem.,
Int. Ed. 2010, 49, 7753. (k) Zhong, F.; Chen, G.-Y.; Lu, Y. Org. Lett.
2011, 13, 82. (l) Liu, X.; Lu, Y. Org. Lett. 2010, 12, 5592. (m) Liu, X.; Lu,
Y. Org. Biomol. Chem. 2010, 8, 4063. (n) Zhu, Q.; Lu, Y. Org. Lett. 2009,
11, 1721. (o) Luo, J.; Xu, L.-W.; Hay, A. S. R.; Lu, Y. Org. Lett. 2009, 11,
437. (p) Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Commun. 2009, 2044.
For reviews, see:(q) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289. (r)
Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924. (s)
Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (t)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (u)
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (v) Yu, X.;
Wang, W. Chem.;Asian J. 2008, 3, 516. (w) Connon, S. J. Chem.
Commun. 2008, 2499.
(10) (a) Qiu, L.; Prashad, M.; Hu, B.; Prasad, K.; Repic, O.; Blacklock,
T. J.; Kwong, F. Y.; Kok, S. H. L.; Lee, H. W.; Chan, A. S.C. Proc.
Natl. Acad. Sci. U.S.A. 2007, 104, 16787. (b) Badkar, P. A.; Rath,
N. P.; Spilling, C. D. Org. Lett. 2007, 9, 3619. (c) Chen, C.-G.; Hou,
X.-L.; Pu, L. Org. Lett. 2009, 11, 2073. (d) Sibi, M. P.; Patil, K. Org.
Lett. 2005, 7, 1453.
(11) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.; Reddy,
M. V. R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005, 127, 13450.
(12) For our recent application of the MBH adducts in the asym-
metric [3 þ 2] annulation, see: Zhong, F.; Han, X.; Wang, Y.; Lu, Y.
Angew. Chem., Int. Ed. 2011, 50, 7837.
(13) For reviews on Henry reaction, see: (a) Boruwa, B.; Gogoi, N.;
Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006, 17, 3115. (b)
Palomo, C.; Oiarbide, M.; Laso, A Eur. J. Org. Chem. 2007, 2561.
(14) (a) Basavaiah, D.; Rao, J. S. Tetrahedron. Lett. 2004, 45, 1621.
(b) Kim, J. M.; Im, Y. J.; Kim, T. H.; Kim, J. N. Bull. Korean Chem. Soc.
2002, 23, 657.
(17) The reaction between 1a-2 and 2a in the presence of 20 mol %
C-9-OBz-quinidine at room temperature for two days did not yield any
desired product.
(15) (a) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett. 2004, 6,
1337.
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