First example of a highly enantioselective catalytic protonation of silyl enol ethers using a novel Lewis acid-assisted Bronsted acid system

Full text of DOI:10.1021/ja962414r

12854
J. Am. Chem. Soc. 1996, 118, 12854-12855
Scheme 1. The General Outline for the Catalytic Cycle for
Enantioselective Protonation of Silyl Enol Ethers Using LBA
First Example of a Highly Enantioselective
Catalytic Protonation of Silyl Enol Ethers Using a
Novel Lewis Acid-Assisted Brønsted Acid System
Kazuaki Ishihara, Shingo Nakamura,
Masanobu Kaneeda, and Hisashi Yamamoto*
Graduate School of Engineering, Nagoya UniVersity
Furo-cho, Chikusa, Nagoya 464-01, Japan
ReceiVed July 15, 1996
Table 1. Chiral LBA-Catalyzed Enantioselective Protonation of 3a
The recent development of the enantioselective protonation
of enolates using stoichiometric or catalytic amounts of chiral
proton sources has been one of the most useful advances in
synthetic chemistry.1,2 In most of these reactions, metal enolates
are used under basic or neutral conditions. We recently reported
that an optically active binaphthol (BINOL)-tin tetrachloride
complex 1 is a highly effective chiral proton source for enantio-
selective protonation of a prochiral silyl enol ether, which is an
isolable synthetic equivalent of enol or enolate.3 We refer to
this activated proton source as a Lewis acid-assisted Brønsted
acid or LBA.3 We report here catalytic systems for the
enantioselective protonation of prochiral trimethylsilyl enol
ethers using a novel chiral LBA 2.2
chiral proton source,
mol %
SnCl4
(mol %)
time
(h)b
entry
ee (%)c
1d
2
3
(R)-BINOL-Me, 2
(R)-BINOL-Me, 5
(R)-BINOL, 5
(R)-BINOL-Me, 2
(R)-BINOL-Me, 2
(R)-BINOL-Me, 20
(R)-BINOL, 100
(R)-BINOL-Me, 100
110
110
110
50
50
16
1
82 (90)
83 (91)
73 (80)
82 (90)
90
0.5
0.5
2
2
1
0.2
0.2
4
5e
6d,f
7g,h
8g
0
100
100
88 (97)
89 (98)
a Unless otherwise noted, 3 (91% regioisomeric purity) was slowly
added dropwise at -80 °C to a solution of (R)-BINOL-Me, 5, and tin
tetrachloride in toluene to give 4 in a quantitative yield. b Addition time
of 3. c Determined by HPLC analysis; values in parentheses were
corrected for the regioisomeric purity of 3. d A 3:2 toluene-CH2Cl2
solvent was used. e Compound 3 (>99% regioisomeric purity) was used.
f The conversion was less than 48%. g See ref 3a for the procedure for
the stoichiometric reaction. h See ref 5.
The rationale for the catalytic cycle for enantioselective
protonation using LBA is outlined in Scheme 1. The catalytic
cycle presupposes the following: (1) after protonation of silyl
enol ethers with chiral LBA, the chiral proton source must be
regenerated by the transfer of a proton from the achiral proton
source while the achiral proton source is transformed to a silyl
ether by the transfer of a silyl group from silyl enol ether; (2)
tin tetrachloride must be predominantly coordinated to the chiral
proton source; (3) the reactivity of LBA generated from the
achiral proton source and tin tetrachloride must be much lower
than that of the chiral proton source or its LBA.
On the basis of the above working hypothesis, we realized
the LBA-catalyzed enantioselective protonation of trimethylsilyl
enol ether 3 derived from racemic 2-phenylcyclohexanone.
Representative results are summarized in Table 1. In the
presence of stoichiometric amounts of tin tetrachloride as a
Lewis acid and 2,6-dimethylphenol (5) as an achiral proton
source in toluene, the protonation of 3 with (R)-2-hydroxy-2′-
methoxy-1,1′-binaphthyl (BINOL-Me) (2-5 mol %) was ac-
celerated and controlled sterically to form ketone 4 with high
enantioselectivity (entries 1 and 2). Although a similar result
was observed with the catalytic use of (R)-BINOL, the resulting
enantioselectivity was only moderate (entry 3). Compound 5
was the most effective achiral proton source among a variety
of aromatic alcohols screened, including 2,4,6-trimethylphenol,
2,6-diethylphenol, 2,6-diisopropylphenol, and 4-bromo-2,6-
dimethylphenol. While tin tetrachloride efficiently promoted
protonation in substoichiometric quantities (entries 4 and 5),4
its use in less molar quantities than a chiral proton source
remarkably lowered the reactivity (entry 6). The stoichiometric
protonation of 3 with (R)-LBA 2 as well as (R)-LBA 1 gave 4
in excellent enantioselectivity (entries 7 and 8).5
To demonstrate that the scope of this strategy is not limited
to silyl enol ethers derived from 2-arylcyclohexanones, we
applied this catalytic system to ketene bis(trimethylsilyl) acetal
6 derived from racemic 2-phenylpropanoic acid (7). The results
are summarized in Table 2. The protonation of 6 with (R)-
BINOL-Me (10 mol %) in the presence of stoichiometric
amounts of tin tetrachloride and 5 exhibited moderate enanti-
oselectivity (entry 1). A high degree of enantioselectivity was
attained using catalytic amounts of (R)-BINOL-Me (10 mol %)
and tin tetrachloride (8 mol %) (entry 2).6 Tin tetrachloride
(4) Representative procedure for the enantioselective protonation of 3
catalyzed by (R)-2 (Table 1, entry 5): Under an argon atmosphere, to a
solution of 5 (41 mg, 0.33 mmol) in toluene (5 mL) were added a solution
of (R)-BINOL-Me (1 mL, 0.006 mmol, 6 mM) in toluene and a solution of
tin tetrachloride (0.15 mL, 0.15 mmol, 1 M) in dichloromethane. The mixture
was stirred at ambient temperature for 0.5 h. The solution was then cooled
to -80 °C, and a solution of 3 (0.9 mL, 0.3 mmol, 0.33 M) in toluene was
added dropwise along the wall of the flask over a period of 2 h. After
being stirred for a further 5 min, the mixture was poured into saturated
ammonium chloride, extracted with ether twice, dried over MgSO4, filtered,
and concentrated in Vacuo. Purification of the crude product by silica gel
chromatography (eluent 10:1 to 5:1 hexane-ethyl acetate) gave the pure
product 4 (47 mg, 89% yield) as a white solid. The enantiomeric excess
was determined to be 90% by HPLC analysis using a Daicel Chiral OD-H
column, 200:1 hexane-i-PrOH with detection at 210 nm (elution times
(1.0 mL/min flow) for the enantiomers of 22.7 (major, S) and 26.5 min
(minor, R)).
(1) For reviews of enantioselective protonations, see: (a) Duhamel, L.;
Duhamel, P.; Launay, J.-C.; Plaquevent, J.-C. Bull. Soc. Chim. Fr. 1984,
II-421. (b) Waldmann, H. Nachr. Chem. Tech. Lab. 1991, 39, 413.
(2) For recent studies on the catalytic enantioselective protonation of
enolates under basic conditions, see: (a) Fehr, C.; Stempf, I.; Galindo, J.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1044. (b) Fehr, C.; Galindo, J.
Angew. Chem., Int. Ed. Engl. 1994, 33, 1888. (c) Yanagisawa, A.; Kikuchi,
T.; Watanabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372.
(3) (a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994,
116, 11179. (b) Ishihara, K.; Nakamura, S.; Yamamoto, H. Croat. Chem.
Acta 1996, 69, 513.
(5) The increase in enantioselectivity for the protonation of 3 with (R)-1
compared to that in our original paper3a is due to the use of 3 (purified by
redistillation).
S0002-7863(96)02414-6 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 50, 1996 12855
Table 2. Chiral LBA-Catalyzed Enantioselective Protonation of 6a
1
Scheme 2. Tin Aryloxide Intermediates Predicted by H
NMR Analyses
chiral proton source,
mol %
SnCl4
(mol %)
time
(h)b
entry
ee (%)c
1
2
3
4
(R)-BINOL-Me, 10
(R)-BINOL-Me, 10
(R)-BINOL-Me, 5
(R)-BINOL, 5
110
8
4
1
1
2
2
68
94
80
22
4
a Unless otherwise noted, 6 was slowly added dropwise at -80 °C
to a solution of (R)-BINOL-Me, 5, and tin tetrachloride in toluene to
give 7 in a quantitative yield. b Addition time of 6. c Determined by
esterification with TMSCH2N2 and HPLC analysis.
Table 3. Comparison of the Reactivities of LBAs in the
Protonation of 3 to 4 at -78 °C
efficiently promotes the protonation of 6 with (R)-BINOL-Me
in less molar quantities than a chiral proton source, since 6 is
much more reactive than 3. In addition, (R)-BINOL-Me is far
superior to (R)-BINOL as a chiral proton source in the catalytic
protonation of 6 (entry 3 vs 4).
The procedures optimized for the catalytic enantioselective
protonations of 3 and 6 have been applied to the synthesis of
(-)-2-phenylcycloheptanone (8), (-)-2-(2-naphthyl)cyclohex-
anone (9),3a and (S)-(+)-ibuprofen (10).3a
conversion of
LBA
3 to 4 (%)b
(R)-2
5-SnCl4
SnCl4
100
17
0
c
a A reaction time of 5 min was employed. The reaction was
quenched with pyridine after 5 min since 3 was added to a solution of
a stoichiometric amount of LBA in toluene at -78 °C over 3 min.
b Determined by 1H NMR analysis of the crude products. c Blank test:
the experiment was performed without any proton sources.
respectively. The production of the silyl ether of 5 was
ascertained by 1H NMR analysis of the reaction mixture at -80
°C. The poor results observed with small amounts of tin
tetrachloride can be explained by unfavorable weak associations
between 2 and excess 5. Chelation between excess tin
tetrachloride per chiral proton source and 5 prevents the
deactivation of 2 and may promote proton transfer from 5 to
12. Nevertheless, 5-tin tetrachloride is not acidic enough to
react predominantly with 3 in the presence of (R)-LBA 2. The
reactivity of 2 is certainly much greater than that with 5-tin
tetrachloride in toluene (Table 3).
The catalytic cycle for the enantioselective protonation of 6
catalyzed by (R)-LBA 2 is rather simple, since excess tin
tetrachloride per chiral proton source is not added. In this case,
2 should be regenerated from intermediate 12 by acquiring a
proton and a chloride from 5 and chlorotrimethylsilane,
respectively. Considering the catalytic systems for both 3 and
6, the protonation of 3 with LBA 2 is the rate-determining step,
at least in the latter system, since the regeneration of chiral LBA
proceeds without participation of tin tetrachloride.
To the best of our knowledge, the catalytic protonations
described here are the first examples of the highly enantiose-
lectiVe protonation of silyl enol ethers in the presence of a
catalytic amount of chiral proton source. The proposed catalytic
cycles are supported by 1H NMR analytical data, which strongly
suggest the generation of chlorotrimethylsilane and tin aryloxide
intermediates 11 and 12 in situ. These and other possible
mechanisms are under further investigation, especially with
regard to the design of more highly enantioselective catalytic
systems.
The present study was prompted by our previous finding that
a small amount of (R)-BINOL, together with the corresponding
monosilyl ether, was observed by TLC, although the stoichio-
metric reaction of 3 with (R)-LBA 1 in toluene gave 4 in a
1
quantitative yield.11 The H NMR spectrum of the reaction
mixture in toluene-d8 at -80 °C exhibited two singlets for the
trimethylsilyl groups of the monosilyl ether of (R)-BINOL and
chlorotrimethylsilane at -0.26 and 0.16 ppm, respectively, at
a molar ratio of 85:15. On the other hand, the 1H NMR
spectrum of the reaction mixture of 3 and (R)-LBA 2 at -80
°C exhibited only one singlet for chlorotrimethylsilane. The
formation of chlorotrimethylsilane lead us to anticipate the
possibility of generating tin aryloxide intermediates 11 and 12
(Scheme 2).
The experimental results shown in Table 1 can be reasonably
explained by supposing that the tin aryloxide intermediate 12
is reconverted to (R)-LBA 2 by receiving a proton and a chloride
from 5 and chlorotrimethylsilane and/or tin tetrachloride,
(6) Representative procedure for the enantioselective protonation of 6
catalyzed by (R)-2 (Table 2, entry 2). The reaction was carried out similar
to that described in ref 4. The reaction mixture was poured into 1 N HCl
and extracted with ethyl acetate twice, dried over MgSO4, filtered, and
concentrated in Vacuo. Purification of the crude product by silica gel
chromatography (eluent 10:1 to 5:1 hexane-ethyl acetate and then ethyl
acetate alone) provided the pure product 7 (42 mg, 93% yield) as a white
solid. The enantiomeric excess was determined to be 94% by esterification
with TMSCH2N2 in methanol and HPLC analysis using a Daicel Chiral OJ
column, 9:1 hexane-i-PrOH with detection at 210 nm (elution times (1.0
mL/min flow) for the enantiomers: 10.7 (major, S) and 12.7 min (minor,
R)).
Acknowledgment. This study was supported in part by a Grant-
in-Aid for Scientific Study from the Ministry of Education, Science,
and Culture of the Japanese Government.
(7) The same reaction conditions with entry 2 in Table 1 were used.
(8) Values in parentheses were corrected for the regioisomeric purities
of silyl enol ethers.
(9) The same reaction conditions with entry 2 in Table 1 were used except
that tin tetrachloride concentration was reduced to 50 mol %.
(10) The same reaction conditions with entry 2 in Table 2 were used.
(11) The disilyl ether of (R)-BINOL was not observed at all. In fact, the
mixture of tin tetrachloride and the monosilyl ether of (R)-BINOL was less
reactive for 3 (-78 °C, 5 min; <21% conversion). Considering the steric
and electronic effects of the trimethylsilyl group, the rigid formation of
LBA from (R)-BINOL and tin tetrachloride should be rather difficult.
Supporting Information Available: Experimental procedures and
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JA962414R