R-amino acid derivatives are obtained as products.6 These
derivatives are of special interest for the synthesis of designer
peptides with specific conformational and biological proper-
ties7 and as building blocks of potential therapeutic agents
such as metabotropic glutamate receptor ligands.8
Although several examples of catalytic enantioselective
R-hydrazination of 1,3-dicarbonyl compounds have already
been reported,9-11 there are still challenging issues that need
to be addressed, particularly in the area of organocatalysis.
These challenges include enantioselectivity, substrate gen-
erality, efficiency and ease of catalyst preparation, catalyst
loading, and reaction time. Herein we describe our investiga-
tion of catalytic enantioselective R-hydrazination of 1,3-
dicarbonyl compounds using a newly developed chiral
squaramide catalyst. We report a wide substrate scope with
several examples of reactions that proceed at ambient
temperature and afford products in 93-96% ee.
To confirm the ability of squaramides to catalyze the
R-hydrazination reaction, a series of catalysts with various
substituents on the two vinylogous amide nitrogen atoms was
prepared and tested in the addition of ꢀ-ketoester 1a to
diethyl azodicarboxylate (2, Table 1). In this regard, the ease
of synthesis and the modular nature of chiral squaramides
facilitates the fine-tuning of their activity. It should be noted
that the catalysts shown in Figure 1 are all readily prepared,
in two to three steps from commercially available dimethyl
squarate.12 Catalyst 3a, which was highly effective in the
reported conjugate addition to nitroalkenes,3a did not function
Figure 1. Structures of Catalysts
well for the present transformation (entry 1). Catalyst 3b
bearing an amine derived from the pseudoenantiomeric
cinchona alkaloid also gave an unsatisfactory result but,
interestingly, a product enriched in the same enantiomer as
3a (entry 2). Other chiral moieties were examined, and we
were delighted to find that catalyst 3e possessing the (R,R)-
1,2-diaminocyclohexane unit successfully promoted the
reaction in high yield and high enantioselectivity (entry 5).
The poor reactivity seen with catalyst 3d (entry 4) is
consistent with the expectation that a bifunctional catalyst,
possessing a basic amino group, is required to promote the
reaction. The amino group in catalyst 3e serves to generate
the active nucleophilic anion, and the resulting ammonium
ion is expected to organize the transition state geometry
through additional hydrogen bonding.13 Further investigation
of the effect of the tertiary amino group led to the discovery
of another suitable catalyst, 3j, which contains a piperidinyl
group (entries 5-10). Evaluation of the effect of the left part
of the squaramide catalyst showed bis(trifluoromethyl)phenyl
group to be the superior substituent (entries 10-12).
(6) For recent reviews on the stereoselective synthesis of quaternary
R-amino acids, see: (a) Vogt, H.; Bra¨se, S. Org. Biol. Chem. 2007, 5, 406–
430. (b) Cativiela, C; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2007, 18, 569–623. (c) Cativiela, C.; Ordo´n˜ez, M. Tetrahedron: Asymmetry
2009, 20, 1–63
.
(7) (a) Gante, J. Angew. Chem., Int. Ed. 1994, 33, 1699–1720. (b)
Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. ReV. 2001, 101,
3131–3152
.
(8) For a review, see: Schoepp, D. D.; Jane, D. E.; Monn, J. A.
Neuropharmacology 1999, 38, 1431–1476
.
(9) For examples of Lewis acid catalysis, see: (a) Juhl, K.; Jørgensen,
K. A. J. Am. Chem. Soc. 2002, 124, 2420–2021. (b) Marigo, M.; Juhl, K.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367–1369. (c) Ma, S.;
Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen, G. Org. Lett.
2004, 6, 2193–2196. (d) Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-
Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem. Commun. 2005, 5115–
5117. (e) Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006,
17, 658–664. (f) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565–
`
4568. (g) Comelles, J.; Pericas, A.; Moreno-Man˜as, M.; Vallribera, A.;
Drudis-Sole´, G.; Lledos, A.; Parella, T.; Roglans, A.; Garc´ıa-Granda, S.;
Roces-Ferna´ndez, L. J. Org. Chem. 2007, 72, 2077–2087. (h) Mashiko, T.;
Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 11342–11343. (i) Mashiko, T.; Kumagai, N.;
Shibasaki, M. Org. Lett. 2008, 10, 2725–2728. (j) Hasegawa, Y.; Watanabe,
M.; Gridnev, I. D.; Ikariya, T. J. Am. Chem. Soc. 2008, 130, 2158–2159.
(k) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
14990–14999
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(10) For examples of H-bonding catalysis, see: (a) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120–8121. (b) Pihko, P. M.;
Pohjakallio, A. Synlett 2004, 2115–2118. (c) Liu, X.; Li, H.; Deng, L. Org.
Lett. 2005, 7, 167–169. (d) Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y.
Synlett 2006, 137–140. (e) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem.
Soc. 2006, 126, 16044–16045. (f) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett
2008, 2659–2662. (g) Jung, S. H.; Kim, D. Y. Tetrahedron Lett. 2008, 49,
5527–5530. (h) Mang, J. Y.; Kim, D. Y. Bull. Korean Chem. Soc. 2008,
Since 3e and 3j provided products with similar enanti-
oselectivities, they were investigated further to identify the
optimal catalyst. Comparison of the catalytic ability of both
catalysts by conducting the reactions at low temperature
indicated that 3j was superior to 3e (entries 13-16).
29, 2091–2092. (i) Liu, X.; Sun, B.; Deng, L. Synlett 2009, 1685–1689
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(11) For examples of ammonium and phosphonium salt catalysis, see:
(a) He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem., Int. Ed.
2008, 47, 9466–9468. (b) Lan, Q.; Wang, X.; He, R.; Ding, C.; Maruoka,
(13) For the discussion of a proposed mechanism of reactions using
related bifunctional thiourea catalysts, see: (a) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–
125. For a theoretical study, see: (b) Hamza, A.; Schubert, G.; Soo´s, T.;
Pa´pai, I. J. Am. Chem. Soc. 2006, 128, 13151–13160.
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.
(12) See Supporting Information for details.
Org. Lett., Vol. 12, No. 9, 2010
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