Enantioselective protonation of silyl enolates catalyzed by a Binap·AgF complex

Article abstract of DOI:10.1002/anie.200462325

Silver lining: A catalytic enantioselective protonation of trimethylsilyl enolates uses a binap/silver(I) fluoride complex as a chiral catalyst in a mixture of dichloromethane and methanol (see scheme). Various ketones with tertiary asymmetric carbon cent

Full text of DOI:10.1002/anie.200462325

Communications
Asymmetric Catalysis
have reported previously, various ratios of binap and AgF
were examined by 1H NMR spectroscopy and the 0.6:1
mixture was found to give the desired 1:1 complex without
formation of the unreactive 2:1 complex.[5]
Enantioselective Protonation of Silyl Enolates
Catalyzed by a Binap·AgF Complex**
Akira Yanagisawa,* Taichiro Touge, and Takayoshi Arai
Enantioselective protonation of prochiral enolates and enan-
tioselective alkylation of enolates are efficient methods to
prepare optically active carbonyl compounds with a tertiary
asymmetric carbon center at the a-position.[1,2] The catalytic
enantioselective protonation reactions of metal enolates
already reported are performed either under basic or under
acidic conditions. The method under basic conditions
involves, for example, the protonation of a reactive metal
enolate, such as lithium enolate, with a catalytic amount of a
chiral acid and an excess of an achiral acid.[3] In contrast, the
method under acidic conditions uses silyl enolates or ketene
silyl acetals as substrates which, in the presence of a chiral
Lewis acid or a chiral Brønsted acid catalyst, are converted
into optically active carbonyl compounds.[4] Binap·AgF is an
efficient chiral catalyst for the asymmetric aldol reaction of
silyl enolates[5] and also for the asymmetric allylation of
aldehydes with allylsilane.[6] Because the activation of a
trimethoxysilyl group by the fluoride ion is remarkable, we
envisioned that the silver fluoride complex could also act as a
chiral catalyst for the asymmetric protonation of silyl enolates
with an appropriate achiral proton source such as methanol.
We report here a new catalytic asymmetric protonation of
silyl enolates with methanol using binap·AgF as a chiral
catalyst [Eq. (1)].
We then studied the influence of the solvent on yield and
enantioselectivity (Table 1). Among the solvents tested, THF
or chlorinated hydrocarbons gave better enantioselctivities
Table 1: Optimization of the asymmetric protonation of the trimethylsilyl
enolate of 2-methyl-1-tetralone catalyzed by (R)-binap·AgF.[a]
Entry Solvent Proton
source
T [8C] t [h] Yield [%][b] ee [%] Config.[c]
1
2
3
4
5
6
7
MeOH MeOH
À20 16 26
20
38
30
13
26
38
56
60
62
14
34
S
S
S
S
S
S
S
S
S
S
R
THF
DMF
MeOH
MeOH
À40
À40
6
5
87
60
toluene MeOH
Et2O MeOH
À20 13 18
À40
6
74
CHCl3 MeOH
CH2Cl2 MeOH
À20 20 47
À20 20 68
À20 20 44
À20 36 72
À20 15 75
8[d] CH2Cl2 MeOH
9[d] CH2Cl2 MeOH
10
11
CH2Cl2 EtOH
CH2Cl2 iPrOH
À20
7
97
[a] Unless otherwise noted, the reaction was carried out with (R)-binap
(0.06 mmol), AgF (0.1 mmol), the trimethylsilyl enolate of 2-methyl-1-
tetralone (1 mmol), and the specified proton source (0.5 mL) in the
specified solvent (10 mL). [b] Yield of isolated product. [c] The enantio-
selectivity was determined by HPLC analysis on a chiral column (OD-H).
[d] MeOH (1 mL) and CH2Cl2 (20 mL) were used.
We initially examined the protonation of a 2-methyl-1-
tetralone-derived trimethylsilyl enolate with methanol to find
the optimal reaction conditions. We attempted the reaction
employing diverse ratios of binap and AgF at À208C and
found that a 0.6:1 mixture yielded a nonracemic product with
higher enantioselectivity than a 1:1 mixture [Eq. (2)]. As we
than methanol, and dichloromethane was the solvent of
choice. When the protonation was performed in a 20:1
mixture of dichloromethane and methanol, (S)-enriched 2-
methyl-1-tetralone was obtained with 56% ee (entry 7). A
further improvement in the enantiomeric ratio was achieved
when twice as much solvent was used (entries 8 and 9). We
also investigated the enantioselectivity of this catalytic
protonation with other achiral alcohols but methanol
proved most efficient (entries 7, 10, and 11).
This asymmetric protonation was applied to a variety of
trimethylsilyl enolates; the results with 2-methyl-1-tetralone
and related ketone derivatives are summarized in Table 2.
Both the 5-methoxy and the 2-ethyl derivatives gave good
optical purities similar to that of 2-methyl-1-tetralone
(entries 1–3). However, to our surprise, use of the 2,2,6-
trimethylcyclohexanone-derived silyl enolate resulted in a
[*] Prof. Dr. A. Yanagisawa, Dr. T. Arai
Department of Chemistry
Faculty of Science, Chiba University
Inage, Chiba 263-8522 (Japan)
Fax: (+81)43-290-2789
E-mail: ayanagi@faculty.chiba-u.jp
T. Touge
Graduate School of Science and Technology
Chiba University
Inage, Chiba 263-8522 (Japan)
[**] We gratefully acknowledge financial support from the Novartis
Foundation (Japan) for the Promotion of Science. We also thank
Takasago International Corporation for a generous gift of (R)-p-Tol-
binap.
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DOI: 10.1002/anie.200462325
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Angewandte
Chemie
Table 2: (R)-binap·AgF-catalyzed asymmetric protonation of various
high enantioselectivity of more than 80% ee (entry 4). In
trimethylsilyl enolates.[a]
general, simple ketones with no aromatic substituent at the a-
carbon lead to unsatisfactory results in the catalytic asym-
metric protonation under acidic conditions.[4b] Gratifyingly, a
quite high enantiomeric ratio was obtained with the silyl
enolate of 2-phenylcyclohexanone (entry 5), and the use of p-
Tol-binap with the same silyl enolate afforded 99% ee
(entry 6). 2-Arylcycloalkanones are also good substrates for
the present asymmetric protonation: for instance, the trime-
thylsilyl enolate of 2-phenylcycloheptanone showed high
enantioselectivity and reactivity (entry 7). As for p-methox-
yphenyl, p-tolyl, and 2-naphthyl derivatives, almost perfect
enantioselectivity was attained and R-enriched products were
formed essentially quantitatively in every case (entries 8–10).
The reaction mechanism has not been fully elucidated;
however, two mechanisms can be suggested for the catalytic
asymmetric protonation (Figure 1).[7] From the aforemen-
tioned fact that AgF obviously activates the trimethylsilyl
group of the substrates, the cyclic model A can be postulated
as an initial transition-state structure for the reaction. In this
assembly, the binap·AgF complex acts as a chiral Lewis acid
and MeOH coordinates to both the silver(i) complex and the
silyl enolate to form a six-membered cyclic structure, which is
further stabilized by the adjacent four-membered ring formed
by AgF and the trimethylsilyl group. As a probable catalytic
mechanism for the next stage, the binap·AgF complex is
regenerated from the assembly A accompanied by the
formation of the protonated product and methoxytrimethyl-
silane (route 1). However, an alternative mechanism
(route 2), which generates binap·AgOMe[8] and fluorotrime-
thylsilane from A by a transmetallation step, cannot be ruled
out. In the second cycle and thereafter, binap·AgOMe is
recycled and behaves as a chiral catalyst in the transition-state
structure B.
Entry
Trimethylsilyl
enolate
T [8C] t [h] Yield [%][b] ee [%] Config.[c]
1
2
À20
À20
36
48
72
82
62
67
S
S
3
À20
0
48
48
24
24
48
75
82
96
75
95
64
S
S
R
R
R
4
87[d]
98
5
À30
À30
À30
6[e]
7
99
97
8
9
À40
À40
À40
48
48
48
93
96
89
>99
R
R
R
>99
>99
10
[a] Unless otherwise noted, the reaction was carried out with (R)-binap
(0.06 mmol), AgF (0.1 mmol), the trimethylsilyl enolate (1 mmol), and
MeOH (1 mL) in anhydrous CH2Cl2 (20 mL). [b] Yield of isolated
product. [c] The enantioselectivity was determined by HPLC analysis
on a chiral column (OD-H). See Table 3 in the Experimental Section for
details. [d] The enantioselectivity was determined by GLC analysis on a
chiral column (G-TA). [e] (R)-p-Tol-binap was used.
In conclusion, we have developed a novel catalytic
asymmetric protonation system. The use of a binap·AgF
complex as the chiral catalyst and MeOH as the proton source
allows the synthesis of various nonracemic ketones with
enantioselectivities of up to 99% ee. Further studies on the
application of this protonation to other substrates and
extension of the present catalytic system to other
reactions are currently underway.
Experimental Section
Typical procedure for asymmetric protonation of trime-
thylsilyl enolates with methanol catalyzed by (R)-bina-
p·AgF.
Synthesis
of
(R)-2-phenylcyclohexanone[2a,4b,9]
(entry 5 in Table 2):
A
mixture of AgF (13.5 mg,
0.106 mmol) and (R)-binap (38.5 mg, 0.062 mmol) was
dissolved in anhydrous MeOH (1 mL) under argon in the
dark, and stirred at room temperature (208C) for 10 min.
After addition of anhydrous CH2Cl2 (20 mL) to the
solution, the mixture was stirred for another 10 min at
room temperature. (2-Phenylcyclohex-1-enyloxy)trime-
thylsilane (214.9 mg, 0.88 mmol) was added dropwise to
the resulting mixture at À788C. The mixture was stirred
for 24 h at À308C and then treated with saturated
aqueous NaHCO3 (10 mL). The aqueous layer was
extracted twice with diethyl ether (10 mL each), and the
Figure 1. Plausible reaction mechanisms for the asymmetric protonation catalyzed
by binap·AgF.
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Communications
combined organic extracts were washed with saturated brine (20 mL),
metry 2003, 14, 3851; d) L. Navarre, S. Darses, J.-P. Genet,
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Chem. 2004, 69, 5104; g) Y. Hamashima, H. Somei, Y. Shimura,
T. Tamura, M. Sodeoka, Org. Lett. 2004, 6, 1861; h) G. Liang, D.
Trauner, J. Am. Chem. Soc. 2004, 126, 9544.
dried with anhydrous Na2SO4, and concentrated in vacuo after
filtration. The residual crude product was purified by column
chromatography on silica gel (1/7 ethyl acetate/hexane as the
eluent) to give (R)-enriched 2-phenylcyclohexanone (146.5 mg,
96% yield) as a white solid.
Details on the products and the determination of their ee values
are listed in Table 3.
[3] A. Yanagisawa, T. Watanabe, T. Kikuchi, H. Yamamoto, J. Org.
Chem. 2000, 65, 2979.
[4] a) K. Ishihara, S. Nakamura, M. Kaneeda, H. Yamamoto, J. Am.
Chem. Soc. 1996, 118, 12854; b) S. Nakamura, M. Kaneeda, K.
Ishihara, H. Yamamoto, J. Am. Chem. Soc. 2000, 122, 8120.
Nakai et al. have reported an asymmetric protonation of silyl
enolates by water catalyzed by a chiral cationic Pd complex:
c) M. Sugiura, T. Nakai, Angew. Chem. 1997, 109, 2462; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2366.
[5] a) A. Yanagisawa, Y. Nakatsuka, K. Asakawa, H. Kageyama, H.
Yamamoto, Synlett 2001, 69; b) A. Yanagisawa, Y. Nakatsuka, K.
Asakawa, M. Wadamoto, H. Kageyama, H. Yamamoto, Bull.
Chem. Soc. Jpn. 2001, 74, 1477.
[6] A. Yanagisawa, H. Kageyama, Y. Nakatsuka, K. Asakawa, Y.
Matsumoto, H. Yamamoto, Angew. Chem. 1999, 111, 3916;
Angew. Chem. Int. Ed. 1999, 38, 3701.
[7] Another mechanism involving a transient silver enolate is also
possible.
[8] We attempted to generate binap·AgOMe in situ, without success.
[9] a) G. Berti, B. Macchia, F. Macchia, L. Menti, J. Chem. Soc. C
1971, 3371; b) Y. Nakamura, S. Takeuchi, Y. Ohgo, M. Yamaoka,
A. Yoshida, Tetrahedron 1999, 55, 4595.
[10] A. I. Meyers, D. R. Williams, G. W. Erickson, S. White, M.
Druelinger, J. Am. Chem. Soc. 1981, 103, 3081.
[11] The absolute configuration was assigned by analogy.
[12] A. P. G. Kieboom, H. Van Bekkum, Synthesis 1970, 476.
[13] a) P. J. Hattersley, I. M. Lockhart, M. Wright, J. Chem. Soc. C
1969, 217; b) M. Adamczyk, D. S. Watt, D. A. Netzel, J. Org.
Chem. 1984, 49, 4226; c) D. D. Pathak, H. Adams, C. White, J.
Chem. Soc. Chem. Commun. 1994, 733; d) K. Fuji, T. Kawabata,
A. Kuroda, T. Taga, J. Org. Chem. 1995, 60, 1914.
[14] a) M. B. Eleveld, H. Hogeveen, Tetrahedron Lett. 1986, 27, 631;
b) A. Yanagisawa, T. Kikuchi, T. Kuribayashi, H. Yamamoto,
Tetrahedron 1998, 54, 10253.
Table 3: HPLC analysis of the chiral ketone products.[a]
Entry Product
ee
hexane/
tminor tmajor
[min] [min]
[%]
iPrOH
1
(S)-3,4-dihydro-2-methyl-
62
99:1
20:1
12.3 13.3
24.9 18.9
naphthalen-1(2H)-one[2a,10]
2[b] (S)-3,4-dihydro-5-methoxy-
2-methylnaphthalen-1(2H)-
one[11,12]
67
3
(S)-2-ethyl-3,4-dihydro-
64
87
98
99:1
–
13.9 14.9
26.3 27.1
13.9 14.8
14.0 15.0
naphthalen-1(2H)-one[11,13]
4[c] (S)-2,2,6-trimethyl-
cyclohexanone[3,14]
5
(R)-2-phenylcyclo-
9:1
hexanone[2a, 4b,9]
6
99
97
9:1
20:1
7[d] (R)-2-phenylcyclo-
9.1
7.1
heptanone[4b,11,15]
8
9
(R)-2-(4-methoxyphenyl)-
cyclohexanone[4b,9b,16]
(R)-2-p-tolylcyclo-
>99
>99
>99
20:1
20:1
20:1
7.4
9.2
15.4 16.8
24.2 29.5
hexanone[4b,9b,16]
10
(R)-2-(naphthalen-2-yl)-
cyclohexanone[4b,9b,16]
[a] HPLC analysis: Chiralcel OD-H, Daicel Chemical Industries, Ltd., flow
rate=0.5 mLminÀ1 unless stated otherwise. The entry numbers are the
same as in Table 2. [b] Chiralcel OB, flow rate= 0.5 mLminÀ1. [c] GC
analysis on a chiral column (Chiraldex G-TA, Astec, 808C, 50 Pa).
[d] Chiralpak AS, flow rate=1.0 mLminÀ1
.
[15] M. W. Rathke, D. Vogiazoglou, J. Org. Chem. 1987, 52, 3697.
[16] K. Ishihara, M. Kaneeda, H. Yamamoto, J. Am. Chem. Soc. 1994,
116, 11179.
Received: October 16, 2004
Published online: January 11, 2005
Keywords: asymmetric catalysis · ketones · protonation · silver ·
.
silyl enolates
[1] Reviews: a) S. Hꢀnig, in Houben-Weyl: Methods of Organic
Chemistry, Vol. E21 (Eds.: G. Helmchen, R. W. Hoffmann, J.
Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, p. 3851; b) C.
Fehr, Angew. Chem. 1996, 108, 2726; Angew. Chem. Int. Ed.
Engl. 1996, 35, 2566; c) A. Yanagisawa, H. Yamamoto in
Comprehensive Asymmetric Catalysis III (Eds.: E. N. Jacobsen,
A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, p. 1295;
d) J. Eames, N. Weerasooriya, Tetrahedron: Asymmetry 2001, 12,
1; e) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840;
Angew. Chem. Int. Ed. 2001, 40, 3726; f) A. Yanagisawa, in
Comprehensive Asymmetric Catalysis, Suppl. 2 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg,
2004, p. 125.
[2] For notable recent examples of asymmetric protonation, see:
a) K. Ishihara, D. Nakashima, Y. Hiraiwa, H. Yamamoto, J. Am.
Chem. Soc. 2003, 125, 24; b) Y. Ohtsuka, T. Ikeno, T. Yamada,
Tetrahedron: Asymmetry 2003, 14, 967; c) G. Asensio, A.
Cuenca, N. Rodriguez, M. Medio-Simꢁn, Tetrahedron: Asym-
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