C O M M U N I C A T I O N S
Table 2. Substrate Generalitya
aphosphonium barfate 1·HBArF was prepared from 1 in quantita-
tive yield through protonation and anion-exchange processes.16
The catalytic performance of 1·HBArF as a chiral proton was
evaluated in the enantioselective protonation of ketene disilyl acetal
3, which can be conveniently prepared from the corresponding
R-amino acid and purified by standard silica gel column chroma-
tography (Table 1). The initial trial was carried out with alanine-
derived ketene disilyl acetal 3a in the presence of 1a·HBArF (1
mol %) and 2,6-di-tert-butylpyridine (5, 2 mol %)17 in toluene,
using 2,6-dimethylphenol (6) as a stoichiometric proton source
(entry 1). As expected, the reaction was completed in 20 min at 0
°C, and N-phthaloylalanine (4a) was isolated quantitatively. After
treatment of 4a with Ag2O/MeI at room temperature, the enantio-
meric excess of the methyl ester thus obtained was determined to
be 66% by HPLC analysis. We then examined the substituent (Ar)
effect of the catalyst on the stereoselectivity and found that the
use of 1b·HBArF having a phenyl group led to a significant
enhancement in the enantioselectivity (entry 2). Interestingly, critical
selectivity improvement was attained by replacing the nonsubsti-
tuted binaphthyl subunit with the sterically less demanding biphenyl
structure (1c·HBArF) (entry 3), and performing the reaction at a
lower temperature (-20 °C) allowed for even more rigorous
enantiofacial control, affording 4a with 97% ee (entry 4). Here it
is important to note that the protonation of 3a under the influence
of a stoichiometric amount of 1c·HBArF gave 4a quantitatively
with 96% ee, which suggests that a proton is directly transferred
from the chiral diaminodioxaphosphonium cation 1c·H.18
entry
R
3
time (h)
ee (%)b
4
1
MeCH2
3b
3c
3d
3e
3f
3g
3h
2
4
10
5
20
6
18
95
95
90
94
94
90
93
4b
4c
4d
4e
4f
4g
4h
2
Me(CH2)3
3c
4
Me2CHCH2
MeO(CH2)2
PhCH2
p-ClC6H4CH2
p-MeOC6H4CH2
5
6c
7
a Unless otherwise noted, reactions were conducted on a 0.1 mmol
scale with 1 mol % 1c·HBArF in 1.0 mL of toluene at -20 °C. b The
enantiomeric excess of the methyl ester of 4 was analyzed by use of
chiral HPLC. c The reaction was performed at 0 °C.
Scheme 2. Deprotection-Reprotection Sequence
In conclusion, we have developed chiral P-spiro diaminodiox-
aphosphonium barfates, and their unique reactivity and selectivity
as chiral protons have been revealed through the establishment of
highly enantioselective protonation of R-amino acid-derived ketene
disilyl acetals. This study not only adds to the body of research on
catalytic asymmetric protonation of enolates but also offers
unprecedented opportunities for the molecular design of this class
of chiral organic cations as well as for the development of related
applications.
Table 1. Optimization of Reaction Conditions for
1·HBArF-Catalyzed Asymmetric Protonation of Ketene Disilyl
Acetal 3aa
entry
1
temp (°C)
time (h)
ee (%)b
Acknowledgment. This work was supported by the Global COE
Program in Chemistry of Nagoya University, Grants for Scientific
Research from JSPS, and the Mitsubishi Foundation.
1
2
3
4
1a
1b
1c
1c
0
0
0
0.3
0.3
0.3
1
66
85
93
97
-20
Supporting Information Available: Representative experimental
procedures, spectral and analytical data for all new compounds, and
crystallographic data for 1a and 1b (CIF). This material is available
a Reactions were performed with 0.1 mmol of 3a, 0.11 mmol of 6, 2
mol % 5, and 1 mol % 1·HBArF in 1.0 mL of toluene. b The
enantiomeric excess of 4a was determined by chiral stationary phase
HPLC after derivatization to the corresponding methyl ester.
References
After the optimized conditions had been established, the substrate
generality was investigated, and selected examples are summarized
in Table 2. Ketene disilyl acetals 3 with various alkyl side chains,
including branched and functionalized ones, were well-accom-
modated, and although the reactivity was strongly affected by the
steric hindrance of 3, excellent enantioselectivities were uniformly
observed (entries 1-4).19 The present system was also applicable
to substrates with benzylic substituents having different electronic
properties, which were transformed to the parent N-protected
R-amino acids with high levels of enantiocontrol (entries 5-7).
These results demonstrate that this new protocol represents a unique
approach for overcoming the challenges inherent in the asymmetric
synthesis of R-amino acids by catalytic enantioselective protonation.
The phthaloyl moiety of the methyl ester of 4 was easily
removed upon exposure to hydrazine monohydrate in methanol
without any loss of enantiomeric purity; this was confirmed by
HPLC analysis after consecutive nitrogen reprotection, as
exemplified in Scheme 2.
(1) (a) Matsushita, H.; Noguchi, M.; Saburi, M.; Yoshikawa, S. Bull. Chem.
Soc. Jpn. 1975, 48, 3715. (b) Matsushita, H.; Noguchi, M.; Yoshikawa, S.
Chem. Lett. 1975, 1313. (c) Matsushita, H.; Tsujino, Y.; Noguchi, M.;
Yoshikawa, S. Bull. Chem. Soc. Jpn. 1976, 49, 3629. (d) Matsushita, H.;
Tsujino, Y.; Noguchi, M.; Saburi, M.; Yoshikawa, D. Bull. Chem. Soc.
Jpn. 1978, 51, 862.
(2) (a) Duhamel, L. C. R. Acad. Sci. 1976, 282C, 125. (b) Duhamel, L.;
Plaquevent, J.-C. Tetrahedron Lett. 1977, 18, 2285. (c) Duhamel,
L.; Plaquevent, J.-C. J. Am. Chem. Soc. 1978, 100, 7415. (d) Duhamel,
L.; Plaquevant, J.-C. Tetrahedron Lett. 1980, 21, 2521.
(3) For reviews, see: (a) Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett
1997, 411. (b) Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry 2001,
12, 1. (c) Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron:
Asymmetry 2004, 15, 3653. (d) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M.
Nat. Chem. 2009, 1, 359.
(4) For examples of the utilization of a stoichiometric amount of a chiral proton
source, see: (a) Cavelier, F.; Gomez, S.; Jacquier, R.; Verducci, J.
Tetrahedron: Asymmetry 1993, 4, 2501. (b) Cavelier, F.; Gomez, S.;
Jacquier, R.; Verducci, J. Tetrahedron Lett. 1994, 35, 2891. (c) Ishihara,
K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179.
(5) (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem.
Soc. 1996, 118, 12854. (b) Nakamura, S.; Kaneeda, M.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8120. (c) Ishihara, K.;
Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125,
24.
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J. AM. CHEM. SOC. VOL. 132, NO. 35, 2010 12241