Enantioselective aldol reactions of trichlorosilyl enol ethers catalyzed by the chiral phosphine oxide BINAPO

Article abstract of DOI:10.1055/s-2006-939725

The enantioselective aldol reactions of aldehydes with trichlorosilyl enol ethers catalyzed by chiral phosphine oxide BINAPO afforded the corresponding aldol adducts with high diastereo- and enantioselectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939725

1116
LETTER
Enantioselective Aldol Reactions of Trichlorosilyl Enol Ethers Catalyzed by
the Chiral Phosphine Oxide BINAPO
E
nantioselecti
h
ve Aldol Rea
u
ctions of
T
ri
n
c
hlorosilyl
E
s
nol
E
ther
u
ke Kotani,a Shunichi Hashimoto,b Makoto Nakajima*a
a
Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Kumamoto 862-0973, Japan
Fax +81(96)3627692; E-mail: nakajima@gpo.kumamoto-u.ac.jp
b
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan
Received 31 January 2006
phosphoramides3 or N-oxides,4b,5c which attack the silicon
atom to form a hypervalent silicate.13 The main advantage
of this type of aldol reaction is that the cyclic transition
state provides high syn/anti selectivity (diastereoselec-
tivity) reflected by the E/Z ratio of the enol ether, while
Lewis acid catalyzed aldol reactions that involve acyclic
transition states often produce syn-adducts predominantly
from both isomers of the enol ethers.
Abstract: The enantioselective aldol reactions of aldehydes with
trichlorosilyl enol ethers catalyzed by chiral phosphine oxide
BINAPO afforded the corresponding aldol adducts with high dia-
stereo- and enantioselectivities.
Key words: aldol reactions, asymmetric catalysis, Lewis bases,
phosphine oxides, stereoselectivity
Asymmetric organocatalysis methods1 utilizing neutral
Lewis bases have recently attracted considerable attention
because they have led to the emergence of new types of
chiral ligands based on phosphoramides,2,3 N-oxides,4,5
and sulfoxides.6 Phosphine oxide is highly polar and has a
relatively low Brønsted basicity.7 As a result, its reactivity
would be expected to be similar to those of Lewis bases.
Moreover, various types of chiral phosphine oxides can be
readily prepared by simple oxidation of commercially
available chiral phosphines. However, examples of the
application of chiral phosphine oxides to asymmetric or-
ganocatalysis are still limited. Quite recently, the enantio-
selective allylation of hydrazones, promoted by the chiral
phosphine oxide BINAPO (Figure 1) was reported by
Kobayashi, who demonstrated the first example of a chiral
phosphine oxide as a promoter, although more than
stoichiometric amounts of the Lewis base were required
for the reaction to proceed.8 We recently reported the first
example of a chiral phosphine oxide as a catalyst in the
enantioselective allylation of aldehydes9 and the ring-
opening of meso-epoxides.10 As part of our program on
developing BINAPO-catalyzed reactions, we report here-
in some enantioselective aldol reactions of trichlorosilyl
enol ethers to afford aldol adducts in high diastereo- and
enantioselectivities.
O
Ph
P
Ph
Ph
P
Ph
O
BINAPO
Figure 1
We first examined the aldol reaction of the trichlorosilyl
enol ether derived from cyclohexanone (1a) with benzal-
dehyde in the presence of 10 mol% of BINAPO in dichlo-
romethane at –78 °C. The corresponding aldol adduct was
obtained in moderate yield and the enantioselectivity of
the main product (anti-isomer) was high, though the dia-
stereoselectivity was unsatisfactory (Table 1, entry 1).
Since the aldol reaction might have been promoted by hy-
drogen chloride,3a produced by adventitious hydrolysis of
the trichlorosilyl enol ether, the addition of an acid scav-
enger was then investigated. As a result, the diastereo-
selectivity was dramatically increased, when 2-methyl-2-
butene or diisopropylethylamine were added to the reac-
tion mixture (Table 1, entries 2 and 3). The reaction rate
was significantly increased with diisopropylethylamine
(Table 1, entry 3), suggesting that the amine is not only an
acid scavenger but also promotes the aldol reaction.14
The asymmetric aldol reaction is one of the most powerful
methods for constructing two successive chiral carbon
centers.11,12 The development of asymmetric aldol reac-
tions is dominated by the use of chiral Lewis acid catalysts
to activate carbonyl compounds, however, aldol reactions
of trichlorosilyl enol ethers as aldol donors developed by
Denmark provided new opportunities for Lewis base cat-
alyzed aldol reactions.3a The aldol reaction of a trichloro-
silyl enol ether is catalyzed by neutral Lewis bases such as
Using diisopropylethylamine as an additive, we then in-
vestigated the aldol reaction of other trichlorosilyl enol
ethers with benzaldehyde. The enol ether derived from cy-
clopentanone also gave the anti-adduct as the major prod-
uct with moderate enantioselectivity (Table 1, entry 4).
Although the reactions of enol ethers derived from acyclic
ketones proceeded rather slowly, the enol ether derived
from pinacolone gave the best enantioselectivity of 95%
ee (Table 1, entry 5). It is noteworthy that anti-adducts
were predominantly produced from E-enol ethers and the
syn-adduct was predominantly produced from the Z-enol
SYNLETT 2006, No. 7, pp 1116–1118
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939725; Art ID: U01406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Aldol Reactions of Trichlorosilyl Enol Ethers
1117
R1
Table 1 Enantioselective Aldol Reactions of Trichlorosilyl Enol
Ethers 1a–e with Benzaldehyde Catalyzed by BINAPO
O
OH
R4
R4
Cl
O
L
R2
R3
O
Si
Cl
BINAPO
(10 mol%)
iPr2NEt
H
R1 R2
R3
L
O
OH
O
OH
L-L: BINAPO
(1.2 equiv)
+
+
PhCHO
1a–e
(1.2 equiv)
Ph
Ph
Figure 2 Plausible transition state
–78 °C
CH2Cl2
syn
anti
The results obtained from the reaction of various alde-
hydes with the enol ether derived from cyclohexanone are
summarized in Table 2. As is often observed in Lewis
base catalyzed aldol reactions, the addition of an uncon-
jugated aldehyde proceeded rather slowly, but the enan-
tioselectivity was high (Table 2, entry 1). High syn/anti
selectivities were obtained for reactions of sterically con-
gested aldehydes (Table 2, entries 3 and 4), although the
enantioselectivities decreased somewhat. Aldehydes with
electron-donating substituents gave slightly lower enan-
tioselectivities, while aldehydes with electron-deficient
substituents gave high stereoselectivities (Table 2, entries
7–9). The best result (syn/anti, 1:25, 96% ee) was ob-
tained for the reaction of 4-nitrobenzaldehyde.16
Entry Enol ether Time (h) Yield (%)a syn/antib ee [syn, anti] (%)b
1c
2
58
1:2.3
25, 86
OSiCl3
1a
1a
2d
3
1
96
94
94
1:13
1:14
1:17
53, 84
71, 87
74, 69
1a
0.25
0.25
4
OSiCl3
1b
Table 2 Enantioselective Aldol Reactions of 1a with Aldehydes
Catalyzed by BINAPO
5
6
6
8
51
62
–
95
OSiCl3
OSiCl3
tBu
BINAPO
(10 mol%)
iPr2NEt
1c
O
OH
O
OH
1:5.7
59, 74
(1.2 equiv)
R
R
+
+
RCHO
1a
–78 °C
CH2Cl2
Et
(1.2 equiv)
syn
anti
1de
Entry R
Time
(h)
Yield syn/antib ee of
7
12
51
4.5:1
75, 14
OSiCl3
(%)a
anti-isomer (%)b
Ph
1ef
1
2
3
4
5
6
7
8
9
PhCH2CH2
PhCH=CH
12
55
1:5.8
1:6.9
1:48
1:34
1:6.3
1:6.6
1:16
1:21
1:25
90
81
74
55
78
83
89
93
96
0.5
83
a Combined isolated yield.
b Determined by HPLC. Relative configurations of new compounds
were assigned on the basis of the splitting pattern of the hydroxyl-
bearing methine.
2,4,6-Me3C6H2 0.25 90
1-Naphthyl
4-MeOC6H4
4-MeC6H4
4-BrC6H4
0.25 97
0.25 96
0.25 92
0.25 98
0.25 87
0.25 90
c Reaction without i-Pr2NEt.
d Reaction with 2-methyl-2-butene instead of i-Pr2NEt.
e E/Z, 6.5:1.
f E/Z, 1:>10.
ether (Table 1, entries 3, 4, and 6 vs 7). To verify the ste-
reochemical relationship between the E/Z ratio and diaste-
reoselectivity, reactions of benzaldehyde with E- and Z-
enol ethers derived from heptanal were investigated
(Equation 1),15 which suggested that the reaction proceed-
ed via a chair-like six-membered transition state
(Figure 2), as proposed previously by Denmark.3
4-CF3C6H4
4-NO2C6H4
a Combined isolated yield.
b Determined by HPLC. Relative configurations of new compounds
were assigned on the basis of the splitting pattern of the hydroxyl-
bearing methine.
1) BINAPO (10 mol%)
iPr2NEt (1.2 equiv)
OMe OH
In conclusion, we have demonstrated the effectiveness of
BINAPO as a catalyst in the enantioselective aldol reac-
tions of trichlorosilyl enol ethers; the stereochemical out-
come suggests a six-membered chair-like transition state
involving hypervalent silicate. In the aldol reaction of the
trichlorosilyl enol ether derived from cyclohexanone,
R1
–78 °C, CH2Cl2
PhCHO
+
MeO
Ph
OSiCl3
R2
2) MeOH
R1 R2
R1 = C5H11, R2 = H
R1 = H, R2 = C5H11
Equation 1
Synlett 2006, No. 7, 1116–1118 © Thieme Stuttgart · New York

1118
S. Kotani et al.
LETTER
(7) The dipole moment of Ph3PO is 4.31 D and the pKa of its
conjugate acid is –2.1: (a) Smyth, C. P. J. Am. Chem. Soc.
1938, 60, 183. (b) Hadzi, D.; Klofutar, C.; Oblak, S. J.
Chem. Soc. A 1968, 905.
(8) Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew. Chem. Int.
Ed. 2004, 43, 6491.
(9) Nakajima, M.; Kotani, S.; Ishizuka, T.; Hashimoto, S.
Tetrahedron Lett. 2005, 46, 157.
(10) Tokuoka, E.; Kotani, S.; Matsunaga, H.; Ishizuka, T.;
Hashimoto, S.; Nakajima, M. Tetrahedron: Asymmetry
2005, 16, 2391.
sterically congested aldehydes favored high diastereose-
lectivities, while high enantioselectivities were obtained
with benzaldehydes with electron-deficient substituents.
The present reaction provides the first example of the use
of a chiral phosphine oxide as an organocatalyst for the
aldol reaction of an aldehyde. Further studies to enhance
enantioselectivity and to explore the mechanism are cur-
rently in progress.
Acknowledgment
(11) For reviews, see: (a) Nelson, S. G. Tetrahedron: Asymmetry
1998, 9, 357. (b) Gröger, H.; Vogl, E. M.; Shibasaki, M.
Chem. Eur. J. 1998, 4, 1137. (c) Mahrwald, R. Chem. Rev.
1999, 99, 1095. (d) Machajewski, T. D.; Wong, C.-H.
Angew. Chem. Int. Ed. 2000, 39, 1352. (e) Denmark, S. E.;
Fujimori, S. In Modern Aldol Reactions, Vol. 2; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, 2004, Chap. 7.
This work was partly supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and
Culture of Japan, the Novartis Foundation (Japan) for the Promo-
tion of Science, and the SUNBOR GRANT.
(12) Other recent examples of enantioselective aldol reactions:
(a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J.
Am. Chem. Soc. 1992, 114, 4418. (b) Sodeoka, M.; Ohrai,
K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648.
References and Notes
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(14) In the case of the allylation of allyltrichlorosilane catalyzed
by BINAPO, a combination of i-Pr2NEt and TBAI had a
beneficial effect on the reaction rate. In this aldol reaction,
the addition of TBAI promoted dehydration, thus decreasing
the yield of the aldol adduct [0.25 h, 75% yield, syn/
anti, 1:7.6, 44% ee(syn), 82% ee(anti)].
(15) E-Enol ether (E/Z, >20:1): 96% yield, syn/anti, 1:25, 28%
ee(syn), 12% ee(anti); Z-enol ether (E/Z, 1:4): 92% yield,
syn/anti, 3.8:1, 31% ee(syn), 13% ee(anti).
(16) Typical Procedure: To a stirred solution of (S)-BINAPO
(24.6 mg, 0.038 mmol), 4-nitrobenzaldehyde (57 mg, 0.38
mmol) and i-Pr2NEt (0.45 mmol) in CH2Cl2 (3.5 mL), enol
ether 1a in CH2Cl2 (0.9 M, 0.5 mL, 0.45 mmol) was added at
–78 °C under an argon atmosphere. The mixture was stirred
at the same temperature for 15 min. After quenching the
reaction with a sat. aq solution of NaHCO3 (2 mL), the
mixture was filtered though celite, and the aqueous layer was
extracted with CH2Cl2 (3 × 15 mL). The organic layer was
washed with brine (30 mL), dried over Na2SO4, and
concentrated. The crude material was purified by column
chromatography (silica gel, 5 g, hexane–EtOAc, 6:1) to give
the adduct as a syn/anti mixture (85 mg, 90% yield).
Stereoselectivities were determined by HPLC (Chiralpak
AD-H, hexane–i-PrOH, 4:1).
(6) (a) Massa, A.; Malkov, A. V.; Kočovský, P.; Scettri, A.
Tetrahedron Lett. 2003, 44, 7179. (b) Kobayashi, S.;
Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem. Soc.
2003, 125, 6610.
Synlett 2006, No. 7, 1116–1118 © Thieme Stuttgart · New York