Development of a new Lewis base-tolerant chiral LBA and its application to catalytic asymmetric protonation reaction

Article abstract of DOI:10.1039/c0cc02492a

A new Lewis base-tolerant LBA (Lewis Acid Assisted Bronsted Acid) derived from La(OTf)₃ and (S)-HOP has been developed as a new chiral Bronsted acid. This acid has been successfully applied as a catalyst to asymmetric protonation reactions of silyl enol ethers of 2-substituted cyclic ketones.

Full text of DOI:10.1039/c0cc02492a

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Development of a new Lewis base-tolerant chiral LBA and its application
to catalytic asymmetric protonation reactionw
Cheol Hong Cheon,a Tatsushi Imahorib and Hisashi Yamamoto*a
Received 10th July 2010, Accepted 3rd August 2010
DOI: 10.1039/c0cc02492a
A new Lewis base-tolerant LBA (Lewis Acid Assisted Brønsted
Acid) derived from La(OTf)3 and (S)-HOP has been developed
as a new chiral Brønsted acid. This acid has been successfully
applied as a catalyst to asymmetric protonation reactions of silyl
enol ethers of 2-substituted cyclic ketones.
Chiral Brønsted acid catalysis has been one of the growing
fields in modern organic synthesis.1 Urea/thioureas,2 TADDOL,3
and phosphoric acids4 have been widely used as catalysts in
various asymmetric syntheses. Despite the recent progress in
asymmetric Brønsted acid catalysis, utility of these acids is
somewhat limited to reactive substrates due to their lower
reactivities compared to metal based Lewis acid catalysts.
Thus, the development of a new Brønsted acid with high
Scheme 1 Generation of chiral LBA from La(OTf)3 and (S)-HOP
reactivity is still one of the most urgent tasks in Brønsted acid
catalysis in order to extend the utility of these acids to more
general substrates.5
and its application to asymmetric protonation reaction.
activator in the presence of superstoichiometric amount of
2-propanol (eqn (1), Scheme 1). With this LBA in hand, we
attempted to apply this LBA as a catalyst to the asymmetric
protonation reaction12,13 of the silyl enol ether derived from
2-phenyl cyclohexanone. Among the metal triflates tested,14
La(OTf)3 was found to be the best choice of Lewis acid
activator;15 5 mol% of LBA derived from La(OTf)3 afforded
the desired protonation product in quantitative yield and 56%
enantiomeric excess (ee) (eqn (2)).
The combined acid system is an excellent method to increase
the reactivity of Brønsted acids.6 The coordination of a
Brønsted acid to a Lewis acid activator increases its acidity,
and thus increases its reactivity. Based on this idea, our group
has developed Lewis acid-assisted Brønsted acids (LBAs)
as strong chiral proton reagents and successfully applied
these LBAs as effective proton reagents for enantioselective
protonation7 and polyene cyclization8 reactions. Unfortunately,
however, the previous LBA systems,9 where SnCl4 and TiCl4
have been used as Lewis acid activators, have some limitations;
these LBAs have poor stability toward Lewis bases such as
moisture, alcohols and amines. Thus, highly anhydrous reaction
conditions are needed to maintain the reactivity of LBAs.
Furthermore, although a LBA has been used as a catalyst in
asymmetric protonation reaction with a bulky phenol as an
achiral Brønsted acid, poor stability of this LBA has rendered
catalytic systems almost unrealistic.10 Herein, we describe the
development of a new chiral LBA bearing remarkable stability
towards Lewis bases and its application as a catalyst
to asymmetric protonation reactions of silyl enol ethers of
2-substituted cyclic ketones.
Utilizing (S)-HOP and La(OTf)3 as a chiral ligand and a
Lewis acid activator, respectively, we further optimized the
reaction conditions in the protonation reaction (Table 1). As
expected, various alcohols could be used as achiral proton
Table 1 Optimization of reaction conditions
Entry Solvent
ROH (equiv.)
Time/h % Yielda ee (%)b
Chiral LBA was generated in situ from optically active
(S)-2-hydroxy-20-diphenylphosphino-1,10-binaphthyl ((S)-HOP)
as a chiral Brønsted acid11 and a metal triflate as a Lewis acid
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
THF
Hexanes MeOH (10)
Toluene MeOH (10)
i-PrOH (10)
MeOH (10)
EtOH (10)
t-BuOH (10)
CF3CH2OH (10) 36
PhOH (2)
MeOH (10)
MeOH (10)
24
18
24
48
93
97
76
94
30
96
93
53
56
68
8
18
Rac
Rac
68
32
ND
24
a Department of Chemistry, The University of Chicago,
5735 South Ellis Avenue, Chicago, Illinois 60615, USA.
E-mail: yamamoto@uchicago.edu; Fax: +1 773 702 0805;
Tel: +1 773 702 5059
12
48
48
48
36
b Priority Organization for Innovation and Excellence, Kumamoto
University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan
w Electronic supplementary information (ESI) available: Reaction
optimization and spectroscopic data for substrates. See DOI:
10.1039/c0cc02492a
Trace
52
a
b
Isolated yield after column chromatography separation. ee was
determined by HPLC analysis using chiral OD-H column.
c
6980 Chem. Commun., 2010, 46, 6980–6982
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sources in the protonation reaction with LBA, although both
reactivity and enantioselectivity showed a strong dependence
on the choice of achiral Brønsted acid (entries 1–5). Among
the alcohols examined, methanol gave the best enantio-
selectivity (entry 2). However, phenol was not able to be used
as achiral Brønsted acid presumably due to the small pKa
difference between the chiral Brønsted acid and phenol
(entry 6). Then, we further optimized solvents in protonation
reaction (entries 2, 7–10). Interestingly, the reactivity of LBA
in the protonation reaction displayed a strong dependence on
the solvent; the protonation reaction was significantly slow in
coordinating solvents, such as ether and THF, whereas the
protonation reaction is much faster in non-coordinating
halogenated solvents, such as CH2Cl2. Although CH2Cl2
and Et2O provided the protonation product in similar levels
of enantioselectivities, CH2Cl2 was chosen as the optimal
solvent because the reactivity of LBA significantly increased
in a non-coordinating halogenated solvent than a coordinating
solvent (entries 2 and 7).
However, even in the standard conditions, sometimes the
enantioselectivity fluctuated from 40 to 74% ee. We assumed
that this inconsistency in enantioselectivity might result from
the oxidation of the chiral Brønsted acid to the corresponding
phosphine oxide ligand ((S)-Ox-HOP) during the protonation
reaction. 31P NMR of the crude mixture providing low
enantioselectivity showed a new peak around 30 ppm, which
is corresponding to the corresponding phosphine oxide.18
Furthermore, LBA from (S)-Ox-HOP gave the protonation
product in quantitative yields but with much lower enantio-
selectivity (eqn (3)).19 In order to avoid the less-enantioselective
protonation reaction through LBA with the oxidized ligand,
(S)-Ox-HOP, the protonation reaction was carried out under
an argon atmosphere. To our delight, the protonation reaction
was reproducible without any fluctuation in enantioselectivity
(entry 6).
To further improve enantioselectivity of the protonation
reaction and understand the role of chiral and achiral
Brønsted acids, we carried out several control experiments
(Table 2). Interestingly, the MeOH activated by La(OTf)3 is
acidic enough to protonate the silyl enol ether (entry 1).
However, without any achiral Brønsted acid, no protonation
product was obtained even with stoichiometric amount of
La(OTf)3 and chiral Brønsted acid presumably due to poor
solubility of La(OTf)3 in CH2Cl2 in the absence of methanol
(entry 2). Furthermore, when methylated chiral Brønsted acid,
(S)-Me-HOP, was used instead of chiral Brønsted acid
(S)-HOP, still the protonation reaction proceeded but only
racemic product was obtained.16,17 These results suggested
that enantioselecitivity of the protonation reaction could be
increased by minimizing the protonation with the activated
methanol by La(OTf)3 and maximizing the protonation from
(S)-HOP activated by La(OTf)3. It is therefore expected that
increase in the ratio of ligand to metal would have a beneficial
effect on enantioselectivity presumably because (S)-HOP will
occupy the available sites on La(OTf)3, which decreases the
amount of methanol activated by La(OTf)3. To our delight,
increasing the ratio of ligand to metal indeed increased
enantioselectivity (entries 3–5).
ð3Þ
With these optimized conditions in hand, we next investigated
the generality and limitations of this protonation reaction
(Table 3). Various silyl enol ethers derived from 2-aryl
cycloalkanones gave the desired protonation products in
quantitative yields. However, enantioselectivity is strongly
dependent on the electronic and steric properties of the aryl
substituents. The silyl enol ethers carrying electron donating
groups at the para-position of the aryl substituents gave
almost the same levels of enantioselectivity (entries 1–3),
whereas electron withdrawing substituent at the para-position
of the aryl groups has deleterious effect on the enantio-
selectivity (entry 4). However, bulky aryl substituents had a
deleterious effect on the enantioselectivities; only moderate
enantioselectivities were obtained with cyclic ketones bearing
bulky aryl and ortho-substituted aryl groups (entries 5–7).
Furthermore, the ring size has an effect on enantioselectivity.
7-Membered ring silyl enol ethers provided the protonation
Table 2 Effect of ratio of (S)-HOP to La(OTf)3 on enantioselectivity
Entry
(S)-HOP (y mol%)
CH3OH (x equiv.)
L : Me
Time/h
% Yielda
ee (%)b
1
—
100
5
10
15
10
10
—
10
10
10
5
—
—
1 : 1
2 : 1
3 : 1
2 : 1
6
48
18
24
36
18
97
NR
94
95
94
96
ND
ND
68
74
73
2c
3
4
5
6d
75
a
b
Isolated yield after column chromatography separation. ee was determined by HPLC analysis using chiral OD-H column. La(OTf)3 was not
c
d
soluble in this condition. Reaction was carried out under an Ar atmosphere. L : M means the ratio of (S)-HOP to La(OTf)3.
e
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6980–6982 6981

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Table 3 Substrate scope
(b) H. Ishibashi, K. Ishihara and H. Yamamoto, Chem. Rec.,
2002, 2, 177.
7 For asymmetric protonation reactions with LBA, see:
(a) K. Ishihara, M. Kaneeda and H. Yamamoto, J. Am. Chem.
Soc., 1994, 116, 11179; (b) K. Ishihara, S. Nakamura, M. Kaneeda
and H. Yamamoto, J. Am. Chem. Soc., 1996, 118, 12874;
(c) K. Ishihara, Y. Ishida, S. Nakamura and H. Yamamoto,
Synlett, 1997, 758; (d) K. Ishihara, S. Nakamura and
H. Yamamoto, Croat. Chem. Acta, 1998, 69, 513;
(e) S. Nakamura, M. Kaneeda, K. Ishihara and H. Yamamoto,
J. Am. Chem. Soc., 2000, 122, 8120; (f) K. Ishihara, D. Nakashima,
Y. Hiraiwa and H. Yamamoto, J. Am. Chem. Soc., 2003, 125, 24;
(g) D. Nakashima and H. Yamamato, Synlett, 2006, 150.
8 For asymmetric polyene cyclization reactions with LBA, see:
(a) K. Ishihara, S. Nakamura and H. Yamamoto, J. Am. Chem.
Soc., 1999, 121, 4906; (b) S. Nakamura, K. Ishihara and
H. Yamamoto, J. Am. Chem. Soc., 2000, 122, 8131;
(c) K. Ishihara, H. Ishibashi and H. Yamamoto, J. Am. Chem.
Soc., 2001, 123, 1505; (d) K. Ishihara, H. Ishibashi and
H. Yamamoto, J. Am. Chem. Soc., 2002, 124, 3647;
(e) K. Kumazawa, H. Ishibashi, K. Ishihara and H. Yamamoto,
Org. Lett., 2004, 6, 2551; (f) H. Ishibashi, K. Ishihara and
H. Yamamoto, J. Am. Chem. Soc., 2004, 126, 11122;
(g) M. Uyanik, H. Ishibashi, K. Ishihara and H. Yamamoto,
Org. Lett., 2005, 7, 1601.
9 Other examples of LBAs derived from different metals, see:
(a) with Pd, see: M. Sugiura and T. Nakai, Angew. Chem., Int.
Ed. Engl., 1997, 36, 2366; (b) with Ag, see: A. Yanagisawa,
T. Touge and T. Arai, Angew. Chem., Int. Ed., 2005, 44, 1546.
10 Catalytic usage of LBA for protonation reaction in the presence of
stoichiometric amount of bulky phenol derivatives was reported,
see: ref. 7g.
11 Other chiral ligands were also investigated, see ESIw.
12 For reviews of asymmetric protonation reaction, see: (a) C. Fehr,
Angew. Chem., Int. Ed. Engl., 1996, 35, 2566; (b) J. T. Mohr,
A. Y. Hong and B. M. Stoltz, Nat. Chem., 2009, 1, 359.
13 For metal-free Brønsted acid catalyzed asymmetric protonation
reaction of silyl enol ethers, see: ref. 5b.
Entry
n
R
Time/h
% Yielda
ee (%)b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
2
Ph (1a)
18
18
18
18
12
18
12
16
18
97
96
94
96
95
92
95
93
96
75
72
70
52
42
54
32
54
34
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-ClC6H4 (1d)
2-MeOC6H4 (1e)
2-naphthyl (1f)
1-naphthyl (1g)
Ph (1h)
2-naphthyl (1i)
a
b
Isolated yield after column chromatography separation. ee was
determined by HPLC analysis using chiral column.
products in much lower enantioselectivity than those of
six-membered rings counterparts (entries 1, 6, 8, and 9).
In conclusion, we have developed a LBA derived from
(S)-HOP with La(OTf)3 as a Lewis acid activator. The LBA
is Lewis-base tolerant and was successfully applied to the
catalytic enantioselective protonation reaction of silyl enol
ether of 2-aryl cyclic ketones in the presence of a super-
stoichiometric amount of methanol. The enantioselectivity of
the protonation product was increased by decreasing the
amount of MeOH activated by La(OTf)3 and by preventing
oxidation of chiral Brønsted acid to the corresponding phos-
phine oxide ligand. Further application of this Lewis base
tolerant LBA is currently underway in our laboratory.
This research is supported by NIH (grant number:
GM086145-02S1) and Uehara Memorial Foundation for a
postdoctoral fellowship to T.I.
14 Various other Lewis acids were investigated in the same condition.
Yb(OTf)3 and Eu(OTf)3 provided the protonation product in 23,
20% ee, respectively, whereas Sc(OTf)3, In(OTf)3, Zn(OTf)2, and
Cu(OTf)2 provided only the racemic product. For more detailed
information, see ESIw.
15 For other applications of La(OTf)3 in organic reactions, see:
S. Kobayashi and I. Hachiya, J. Org. Chem., 1994, 59, 3590.
16 LBA derived from methylated (S)-HOP, (S)-Me-HOP, and
La(OTf)3 provided only racemic product in the protonation
reaction.
Notes and references
1 For a review of Brønsted acid catalysis, see: P. M. Pihko, Angew.
Chem., Int. Ed., 2004, 43, 2062.
2 For a review of hydrogen bond organic catalysis, see: A. G. Doyle
and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713.
3 Y. Huang, A. K. Unni, A. N. Thadani and V. H. Rawal, Nature,
2003, 424, 146.
17 The Yanagisawa group reported an excellent example of
asymmetric protonation reaction of silyl enol ethers through the
protonation with activated MeOH by chiral LBA, see: ref. 9b.
4 For reviews of chiral phosphoric acid catalysis, see:
(a) T. Akiyama, Chem. Rev., 2007, 107, 5744; (b) M. Tereda, Chem.
Commun., 2008, 4097.
5 Recent examples of reactivity enhancement in Brønsted acid
catalysis, see: (a) D. Nakashima and H. Yamamoto, J. Am. Chem.
Soc., 2006, 128, 9626; (b) C. H. Cheon and H. Yamamoto, J. Am.
Chem. Soc., 2008, 130, 9246.
6 For reviews of combined acids, see: (a) H. Yamamoto and
K. Futatsugi, Angew. Chem., Int. Ed., 2005, 44, 1924;
18 For a chemical shift in 31P NMR of (S)-HOP, see: W. Zhang and
M. Shi, Tetrahedron: Asymmetry, 2004, 15, 3467.
19 For more detailed information, see ESIw.
c
6982 Chem. Commun., 2010, 46, 6980–6982
This journal is The Royal Society of Chemistry 2010