Enantioselective protonation of α-hetero carboxylic acid-derived ketene disilyl acetals under chiral ionic Bronsted acid catalysis

Article abstract of DOI:10.1039/c4cc06081d

Highly enantioselective protonation of α-halo and alkoxy carboxylic acid-derived ketene disilyl acetals is achieved by using P-spiro chiral diaminodioxaphosphonium barfate as a Bronsted acid catalyst, where the enantiofacial discrimination by the catalyst mainly stems from the recognition of the electronic difference between two substituents on the ketene disilyl acetal.

Full text of DOI:10.1039/c4cc06081d

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Enantioselective protonation of a-hetero
carboxylic acid-derived ketene disilyl acetals
under chiral ionic Brønsted acid catalysis†
Daisuke Uraguchi,a Tomohito Kizu,a Yuki Ohiraa and Takashi Ooi*ab
Cite this: Chem. Commun., 2014,
50, 13489
Received 4th August 2014,
Accepted 8th September 2014
DOI: 10.1039/c4cc06081d
www.rsc.org/chemcomm
Highly enantioselective protonation of a-halo and alkoxy carboxylic
acid-derived ketene disilyl acetals is achieved by using P-spiro chiral
diaminodioxaphosphonium barfate as a Brønsted acid catalyst, where
the enantiofacial discrimination by the catalyst mainly stems from the
recognition of the electronic difference between two substituents
on the ketene disilyl acetal.
Catalytic enantioselective protonation of prochiral enolates and
their equivalents is one of the simplest and most straightforward
processes for the construction of a tertiary stereogenic carbon
center at the a-position of a carbonyl functionality.1 An overview of
the existing systems reveals the uniqueness of the asymmetric
protonation of silyl-masked enolates in terms of geometric integ-
rity of the substrate and non-dependence of their reactivity on the
pKa value of the parent enolate.2–9 However, protocols that enable
a high level of stereocontrol are largely limited to silyl enolates
derived from a-tertiary cyclic ketones and a-aryl carboxylic acids.
Fig. 1 P-Spiro chiral diaminodioxaphosphonium barfate 1 (BArF = [3,5-
(CF3)2C6H3]4B).
Thus, the development of versatile enantioselective catalysis to ketene disilyl acetals prepared from other carboxylic acids
applicable to other structural classes of silyl enolates is in high bearing a-heteroatoms such as halogen atoms with particular
demand. In these situations, we recently realized the first catalytic interest in the effect of the structural difference between a planar
enantioselective protonation of ketene disilyl acetals derived from phthaloyl imide group and a spherical halogen atom on the facial
a-hetero-substituted carboxylic acids, namely N-phthaloyl a-amino selectivity. Here, we report the preliminary results of our investigations
acids, by virtue of the prominent proton-transfer ability of P-spiro on enantioselective protonation of a-halo and alkoxy carboxylic
diaminodioxaphosphonium barfate of type 1ÁHBArF (Fig. 1).10–13 acid-derived ketene disilyl acetals under the catalysis of chiral phos-
This chiral ionic Brønsted acid catalyst delivered a proton pre- phonium barfate 1ÁHBArF.14,15 Highly si-face-selective proton delivery
dominantly from the si-face of the enolate probably through was revealed to be a general trend for a variety of hetero-substituted
effective recognition of the terminal substituents, phthaloyl imide ketene disilyl acetals, thereby demonstrating the importance of the
and alkyl moieties. As part of our continuous efforts in eliciting the electronic bias of the terminal substituents rather than their steric
full potential of the catalysis exerted by 1ÁHBArF in this mode of nature in the present enantiofacial discrimination.
stereoselective protonation reactions, we pursued its application
We chose a-bromo hydrocinnamic acid-derived ketene disilyl
acetal 2a as a model substrate and subjected it to protonation with
2,6-dimethylphenol (stoichiometric proton source) in the presence
of 2 mol% each of chiral phosphonium barfate 1ÁHBArF and
2,6-di-tert-butylpyridine in toluene at À40 1C. The aim of this
inaugural exploration, considering the structural feature of 1ÁHBArF
consisting of tetraaryl and biaryl subunits, was to objectively evaluate
the necessity of incorporating a chiral binaphthyl core into both
these components for obtaining a synthetically satisfactory level
a Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied
Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho
B2-3(611), Chikusa, Nagoya 464-8603, Japan. E-mail: tooi@apchem.nagoya-u.ac.jp;
Fax: +81-(0)52-789-3338; Tel: +81-(0)52-789-4501
b CREST, Japan Science and Technology Agency (JST), Chikusa, Nagoya 464-8603,
Japan
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of 2 and 3. See DOI: 10.1039/c4cc06081d
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Table 1 Optimization of the catalyst structurea
Table 2 Substrate generalitya
Time (h) Yieldb (%) eec (%)
3
Entry
1
Time (h)
Yieldb (%)
eec (%)
Entry X, R (2)
1
2
3
4
5
1a
1b
1c
1d
1e
26
24
21
26
63
99
99
99
99
99
89
75
93
92
83
1
2
3
4
5
6
7
8
Br, Me (2b)
Br, Et (2c)
Br, Me(CH2)5 (2d)
Br, Me2CHCH2 (2e)
I, Bn (2f)
I, Me(CH2)5 (2g)
Cl, Bn (2h)
Cl, Me(CH2)5 (2i)
F, Bn (2j)
F, Me(CH2)5 (2k)
BnO, Me (2l)
BnO, Ph (2m)
BnO, 4-MeOC6H4 (2n) 26
2-NaphCH2O, Ph (2o) 27
24
23
22
24
26
25
24
26
27
22
24
20
87
92
93
90
92
99
86
92
93
90
86
99
93
92
89
92
93
85
93
90
87
90
88
92
95
89
89
91
3bd
3c
3d
3e
3f d
3g
a
Reactions were conducted with 0.1 mmol of 2a, 0.11 mmol of 2,6-Me2-
phenol, 2 mol% of 2,6-tBu2-pyridine, and 2 mol% of 1ÁHBArF in toluene
3hd
3i
b
c
at À40 1C. Isolated yields were indicated. Enantiomeric excesses of
3a were determined by chiral stationary phase HPLC as its methyl ester,
which was obtained by treatment of 3a with Me3SiCHQN2 in benzene/
MeOH at rt. Absolute stereochemistry of 3a was determined to be R by
comparison of specific rotation with the literature value.16
9
3jd
3kd
3ld
3md
3n
3o
10
11
12
13e
14
a
Unless otherwise noted, reactions were performed with 0.1 mmol of 2,
0.11 mmol of 2,6-Me2-phenol, 2 mol% of 2,6-tBu2-pyridine, and 2 mol%
of enantioselectivity (Table 1). When the reaction was implemented
b
with 1aÁHBArF comprising two binaphthyl-based subunits as a of 1cÁHBArF in toluene at À40 1C. Isolated yields were reported.
c
Enantiomeric excesses of 3 were determined by chiral stationary phase
Brønsted acid catalyst, the parent a-bromo hydrocinnamic acid (3a)
HPLC after being converted into the corresponding esters, see the ESI
d
was obtained quantitatively, and the enantiomeric excess was
for further details. Absolute configurations were determined to be R
determined to be 89% ee after derivatization to the corresponding by comparison of optical rotations with literature data, see the ESI for
details. Stereochemistries of other carboxylic acids were assigned by
analogy. Reaction temperature was À20 1C.
methyl ester by treatment with trimethylsilyldiazomethane
(entry 1). The observed high enantioselectivity reflects the ability
e
of the catalyst to discriminate the enantiofaces of prochiral 2a
The observed insensitivity of enantioselectivity to the size of a
hetero substituent prompted us to clarify the most important factor
for precise enantiofacial discrimination at the proton transfer
stage. Judging from the scope of this 1cÁHBArF-catalyzed protocol,
electronic bias of the terminal substituents plays a more crucial
role than their steric features. Therefore, pseudo-symmetric
ketene disilyl acetal 2p with minimal steric difference between
the terminal substituents was prepared for assessing the validity of
our assumption (Scheme 1). Actual exposure of 2p to the optimized
conditions led to the quantitative formation of the corresponding
a-benzyloxy carboxylic acid 3p with 47% ee. Moreover, the enantio-
meric excess of 3p was significantly enhanced when using
1aÁHBArF as the catalyst. These results clearly show that chiral
phosphonium ion 1ÁH is indeed capable of appreciating the
electronic propensity of the two terminal substituents on 2.
In conclusion, we have achieved a catalytic, highly enantio-
selective protonation of a-halo and alkoxy carboxylic acid-derived
ketene disilyl acetals for the first time based on the utilization
of the prominent proton-transfer and stereocontrolling abilities
through the recognition of the steric or electronic difference
between the bromide and alkyl substituents. While replacement
of the binaphthyl moiety of the tetraaryl component with an
achiral biphenyl structure (1bÁHBArF) impaired the enantio-
selectivity, a simple biphenyl was found to be superior in serving
as a biaryl subunit (entries 2 and 3). We then modified the
peripheral aryls of the tetraaryl subunit for examining the effect on
the selectivity; this revealed that the introduction of 4-substituted
phenyl groups slightly decreased the stereoselectivity irrespective of
their electronic properties (entries 4 and 5).
Having identified the catalyst structure suitable for effecting
the present asymmetric protonation reaction, we surveyed the
substrate generality (Table 2). Under the catalysis of 1cÁHBArF,
enantiofaces of a series of bromo-substituted ketene disilyl
acetals with linear alkyl chains were precisely discriminated
and the parent a-bromo alkanoic acids were isolated with high
enantioselectivities (entries 1–3). The steric demand of the alkyl
substituent afforded a subtle effect on the degree of facial
selectivity, as seen in the reaction with the substrate having an
isobutyl group (entry 4). It was of interest that the asymmetric
protonation of other a-halo carboxylic acid-derived ketene disilyl
acetals also proceeded generally with good to high enantioselec-
tivities, indicating that the identity of the halogen atom had a
marginal effect on the stereochemical outcome (entries 5–10).
Furthermore, the present system tolerated the incorporation of
not only simply spherical halogen atoms but also alkoxy groups
as hetero substituents on ketene disilyl acetals, thus offering
facile access to enantioenriched O-protected lactic acid and
mandelic acid derivatives (entries 11–14).
Scheme 1 Enantioselective protonation of pseudo-symmetric ketene
disilyl acetal 2p.
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(c) K. Ishihara, D. Nakashima, Y. Hiraiwa and H. Yamamoto,
J. Am. Chem. Soc., 2003, 125, 24.
of appropriately modified P-spiro diaminodioxaphosphonium
barfates 1ÁHBArF. The origin of the stereoselectivity most likely
resides in the recognition of the difference in the electronic
attributes of the terminal substituents of the ketene disilyl
acetal by the chiral phosphonium ion. We believe that the
present study underscores the synthetic potential of this class
of chiral ionic Brønsted acid catalysts.
This work was supported by the NEXT program, CREST-JST,
a Grant-in-Aid for Scientific Research on Innovative Areas
‘‘Advanced Molecular Transformations by Organocatalysts’’
from MEXT, the Program for Leading Graduate Schools ‘‘Integrative
Graduate Education and Research Program in Green Natural
Sciences’’ in Nagoya University, the Asahi Glass foundation,
and Grants of JSPS for Scientific Research. T.K. acknowledges
JSPS for financial support.
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