Titanium tetrachloride and chiral aliphatic alcohol as a new Lewis acid assisted chiral Br?nsted acid for the enantioselective protonation of silyl enol ether

Article abstract of DOI:10.1055/s-2005-922782

A complex of TiCl₄ and a chiral alcohol serves as highly reactive Lewis acid assisted chiral Br?nsted acid (chiral LBA) for the enantioselective protonation of silyl enol ethers. Interestingly, the enantioselectivity depends on the preparation conditions of chiral LBA. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922782

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50
CLUSTER
Titanium Tetrachloride and Chiral Aliphatic Alcohol as a New Lewis Acid
Assisted Chiral Brønsted Acid for the Enantioselective Protonation of Silyl
Enol Ether
N
D
ew Lewis
A
cid
A
a
ssistedCh
i
s
nsted
A
ci
u
d
f
or the Ena
k
ntioselective
e
Protonation Nakashima, Hisashi Yamamoto*
Department of Chemistry, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA
Fax +1(773)7020805; E-mail: yamamoto@uchicago.edu
Received 31 October 2005
Initially, we suspected the dissociation of HCl from
·TiCl due to the higher Lewis acidity of TiCl being the
Abstract: A complex of TiCl and a chiral alcohol serves as highly
reactive Lewis acid assisted chiral Brønsted acid (chiral LBA) for
the enantioselective protonation of silyl enol ethers. Interestingly,
4
1
4
4
reason that 1·TiCl revealed lower enantioselectivity than
4
the enantioselectivity depends on the preparation conditions of 1·SnCl . However, unexpectedly, the enantioselectivity
4
chiral LBA.
was increased to 40% ee (R) when chiral LBA 1·TiCl was
4
prepared at –78 °C over a period of 1 hour. The prepara-
Key words: protonations, asymmetric synthesis, alcohols, titanium
tion time 1·TiCl was then extended even further, and the
4
results are summarized in Scheme 2. As the preparation
time was extended for 15 minutes, 1 hour and 3 hours, the
enantioselectivity was increased to 14%, 40% and 54% ee
The design and synthesis of chiral, strong Brønsted acids
are relatively difficult. Therefore, the enhancement of
acidity of a chiral proton source like a chiral alcohol by the
complexation with a Lewis acid is one of the most effi-
cient methods to get a strong chiral Brønsted acid. We
refer to this activated chiral proton source by Lewis acid
as a Lewis acid assisted chiral Brønsted acid (chiral LBA).
Based on this idea, we have already reported several chiral
(
R), respectively. When the preparation of 1·TiCl was
4
done over 5 hours, the enantioselectivity was decreased to
2
7% ee (R).
Ph
LBA: (R)-BINOL·SnCl , (R,R)-2-alkoxy-1,2-diarylethan-
OSiMe3
Ph
O
4
MeO
OH1 (1.1 equiv)
ol·SnCl and optically active ortho-alkoxyphenol·SnCl ,
Lewis Acid (1.1 equiv)
Ph
4
4
1
for the enantioselective protonation of silyl enol ethers
CH2Cl2
2
and the enantioselective polyene cyclization. Both enan-
tioselectivity and reactivity can be controlled by changing
the structure of the chiral Brønsted acid and, in fact, high
enantioselectivity can be realized. The reactivity of this
system still needs to be improved. In order to tune the
acidity of chiral LBAs, it is obviously desirable that other
Lewis acids can be utilized. Herein we describe the unique
property of a new chiral LBA, which is prepared from
–78 °C, 1 h
Lewis Acid: SnCl4
TiCl4
~70% yield, 69% ee (R)
>99% yield, 14% ee (R)
Scheme 1 Enantioselective protonation using chiral LBA.
TiCl and a chiral alcohol.
4
First, we tried the enantioselective protonation of silyl
enol ether derived from 2-phenylcyclohexanone using
chiral LBA (1.1 equiv), which is prepared in situ from
commercially available (R)-2-phenyl-2-methoxyethanol
(
1) with SnCl or TiCl at –78 °C for 15 minutes in
4 4
CH Cl . After 1 hour at –78 °C, the reaction with SnCl
2
2
4
gave a 69% ee (R) product in about 70% yield with start-
ing silyl enol ether remaining. In contrast, the reaction
with TiCl proceeded completely and gave a 14% ee (R)
4
product in quantitative yield (Scheme 1). It was note-
worthy that the reactivity of chiral LBA 1·TiCl was
4
higher than that of 1·SnCl4.
Scheme 2 Preparation time vs. ee of product (the numbers in the
graph indicate the ee of product).
SYNLETT 2006, No. 1, pp 0150–0152
Advanced online publication: 16.12.2005
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DOI: 10.1055/s-2005-922782; Art ID: Y07805ST
©
Georg Thieme Verlag Stuttgart · New York

CLUSTER
Lewis Acid Assisted Chiral Brønsted Acid for Enantioselective Protonation
151
Figure 1 The relationship between ee of 1 and ee of product (the
numbers in the graph indicate the ee of the product).
Table 1 Effect of Ratio of 1 and TiCl a
4
OSiMe3
Ph
1 (X equiv)
O
Lewis Acid (Y equiv)
Ph
CH2Cl2
–78 °C, 1 h
Scheme 3 Preparation temperature vs. ee of product (the numbers
>99% yield
in the graph indicate the ee of product).
Entry
TiCl (equiv)
1 (equiv)
2.2
ee of product (% ee)
4
1
2
1.1
1.1
2.2
racemic
68
The preparation temperature was also considered
1.1
(
Scheme 3) since this factor also affects the enantioselec-
tivity. As the temperature was increased, the enantioselec-
tivity was initially increased and then eventually
3
1.1
11
a
3
,4
Reaction conditions: silyl enol ether (0.1 mmol), CH Cl (1.5 mL).
2 2
decreased.
After optimization, we found the 1·TiCl gave the optimal
4
enantioselectivity 68% ee (R) when 1·TiCl was prepared
at 0 °C for 30 minutes (Scheme 2).
4
5
,6
obtained when (R)-2-cyclohexyl-2-methoxyethanol was
used (entry 2 in Table 2). This result indicated that in this
TiCl4 (1.1 equiv)
optically active 2-methoxy-2-alkylethanol·TiCl system
4
1
(1.1 equiv)
"chiral LBA"
p-p interaction between the chiral Brønsted acid and silyl
enol ether does not exist as shown in our previous cases.1g
Using a bulky aryl group is not effective for increasing the
enantioselectivity (entry 4 in Table 2). This is because 2-
methoxy-2-arylethanol was converted to 2-chloro-2-
arylethanol during the preparation of chiral LBA. After
the reaction, about 70% of the chiral alcohol was changed
to 2-chloro-2-arylethanol.
CH2Cl2 (1 mL)
0
°C, 30 min
O
OSiMe3
Ph
Ph
CH2Cl2 (0.5 mL)
–78 °C, 1 h
(0.1 mmol)
>
6
99% yield
8% ee (R)
Scheme 4 Optimized condition.
Table 2 Screening of Chiral Brønsted Acidsa
R
These phenomena can be explained as follows: due to the
strong aggregation of TiCl , it needs longer time or higher
MeO
OH (1.1 equiv)
4
OSiMe3
Ph
O
TiCl4 (1.1 equiv)
temperature to prepare the desired complex of 1 and
Ph
TiCl . However, the enantioselectivity is finally decreased
by the dissociation of HCl from 1·TiCl4.
2 2
CH Cl
4
–78 °C, 1 h
>
99% yield
The linear relationship between ee of 1 and ee of the
product was observed (Figure 1). The enantioselectivity is
Entry
R
ee of product (% ee)
affected by the ratio of 1 and TiCl (Table 1). In con-
sideration of these results and the X-ray analysis of 2-
4
1
2
3
4
Ph (1)
68
methoxyethanol·Ti(Oi-Pr)Cl reported by professor Han-
3
Cyclohexyl
Benzyl
Mesityl
67
7
Mou Gau and colleagues, it is suggested that 1·TiCl is
4
46
also a 1:1 complex as shown in our previous chiral
1
,2
LBA.
racemic
Using the optimized preparation condition (0 °C, 30 min),
various optically active 2-methoxy-2-alkylethanols were
investigated. Interestingly, a 67% ee (R) product was
a
The reaction conditions: silyl enol ether (0.1 mmol), CH Cl
1.5 mL).
2
2
(
Synlett 2006, No. 1, 150–152 © Thieme Stuttgart · New York

1
52
D. Nakashima, H. Yamamoto
CLUSTER
In the case of SnCl , it was ascertained that the reaction
(2) (a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem.
Soc. 1999, 121, 4906. (b) Nakamura, S.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131.
4
did not occur via the tin enolate which is generated from
1
a,8
transmetallation of silyl enol ether with SnCl4. In the
(c) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem.
9
TiCl case, we could not rule out that possibility. There-
4
Soc. 2001, 123, 1505. (d) Ishihara, K.; Ishibashi, H.;
Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647.
(e) Kumazawa, K.; Ishibashi, H.; Ishihara, K.; Yamamoto,
H. Org. Lett. 2004, 6, 2551. (f) Ishibashi, H.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 11122.
fore, we considered two possible mechanisms: one is that
silyl enol ether is protonated by the proton of 1·TiCl4
intermolecularly, and the other is intramolecular proton
transfer in the titanium enolate.
(
g) Uyanik, M.; Ishibashi, H.; Ishihara, K.; Yamamoto, H.
In summary, although enantioselectivity was still not high
Org. Lett. 2005, 7, 1601.
enough, new chiral LBA prepared from TiCl and chiral
4
(3) When the preparation temperature was higher than –20 °C, a
small amount of 2-chloro-2-phenylethanol was observed.
(4) The concentration of the reaction also affects the
enantioselectivity [40% ee (R) in Scheme 2, 34% ee (R) in
Scheme 3 (preparation conditions: –78 °C, 1 h)].
2
-methoxy-2-alkylethanol showed high reactivity. Thus
we have confirmed the importance of the preparation
conditions of chiral LBA for the enantioselectivity.
(
5) General Procedure for Enantioselective Protonation of
Silyl Enol Ether Derived from 2-Phenylcyclohexanone.
To a solution of 1 (16 mL, 0.11 mmol) in CH Cl (1 mL) was
Acknowledgment
2
2
Financial support for this project has been provided by SORST,
Japan Science and Technology (JST).
added a 1.0 M solution of TiCl in CH Cl (110 mL, 0.11
4
2
2
mmol) dropwise at 0 °C under nitrogen. After being stirred
for 30 min at 0 °C, the solution was cooled to –78 °C and a
solution of freshly prepared silyl enol ether (24.6 mg, 0.1
mmol) in CH Cl (0.5 mL) was added dropwise along the
References and Notes
2
2
wall of the flask over a 5 min period. After the solution was
stirred for 1 h at –78 °C, the reaction was quenched with sat.
(
1) (a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem.
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aq NaHCO , extracted with Et O twice, dried over anhyd
3
2
MgSO , filtered and concentrated. Purification of the crude
12874. (c) Ishihara, K.; Ishida, Y.; Nakamura, S.;
4
product by column chromatography on silica gel (eluent:
Yamamoto, H. Synlett 1997, 758. (d) Ishihara, K.;
Nakamura, S.; Yamamoto, H. Croat. Chem. Acta 1998, 69,
hexane–Et O) provided 2-phenylcyclohexanone in
2
quantitative yield. The ee values were determined by
analytical HPLC (OD-H, hexane–i-PrOH, 99.5:0.5).
5
13. (e) Nakamura, S.; Kaneeda, M.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8120.
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002, 2, 177. (g) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 24.
(
6) The reaction gave a 65% ee (R) product when 1·TiCl was
(
2
4
prepared at 0 °C for 15 min.
7) Lee, C.-S.; Kuo, C.-N.; Shao, M.-Y.; Gau, H.-M. Inorg.
Chem. Acta 1999, 285, 254.
(
(
(
8) Nakamura, E.; Kuwajima, I. Chem. Lett. 1983, 59.
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Synlett 2006, No. 1, 150–152 © Thieme Stuttgart · New York