Trichlorosilyl triflate for enantioselective direct-type aldol reaction with chiral phosphine oxide

Article abstract of DOI:10.1016/j.tetlet.2011.03.095

Trichlorosilyl triflate, in the presence of a chiral Lewis base catalyst, provides an effective method for the enantioselective direct-type aldol reaction of aldehydes and ketones. A chiral Lewis base induces both the production and activation of trichlor

Full text of DOI:10.1016/j.tetlet.2011.03.095

Tetrahedron Letters 52 (2011) 2834–2836
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Tetrahedron Letters
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Trichlorosilyl triflate for enantioselective direct-type aldol reaction
with chiral phosphine oxide
Shunsuke Kotani a, , Shohei Aoki b, Masaharu Sugiura b, Makoto Nakajima b,
⇑
⇑
a Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, Japan
b Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Trichlorosilyl triflate, in the presence of a chiral Lewis base catalyst, provides an effective method for the
enantioselective direct-type aldol reaction of aldehydes and ketones. A chiral Lewis base induces both the
production and activation of trichlorosilyl enol ether, yielding an aldol product in good yield and with
high diastereo- and enantioselectivities.
Received 9 February 2011
Revised 11 March 2011
Accepted 20 March 2011
Available online 24 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Enantioselective catalysis
Lewis base
Phosphine oxide
Trichlorosilyl triflate
The chemistry of hypervalent silicon compounds has recently
attracted much attention because it offers the possibility to devel-
op organocatalyzed enantioselective reactions in the presence of
chiral Lewis bases by employing less toxic and environmentally
friendly compounds.1 The hypervalent silicon species formed by
a four-coordinated silicon atom and a chiral Lewis base enables
effective transformations in asymmetric synthesis, and several
enantioselective reactions via hypervalent silicon species have
been developed.2–5 We recently investigated the enantioselective
direct-type aldol reaction catalyzed by chiral phosphine oxides as
Lewis base catalysts.6,7 The hypervalent silicon species formed
from silicon tetrachloride and a chiral phosphine oxide mediated
the enantioselective transformation via the enolization-aldol reac-
tion process, giving the corresponding products in good yields and
stereoselectivities (Scheme 1).
R2CHO
O
O
OH
Lewis base (LB), SiCl4
R1
R1
R2
Amine
Work up
LB
LB
SiCl4
SiCl3
O
O
OSiCl3
R2
O
R2CHO
R1
R1
R1
Aldol reaction
Enolization
Scheme 1. Asymmetric aldol reaction using SiCl4 with chiral Lewis base.
In this transformation, a temperature in excess of 0 °C was re-
quired for the enolization of substrates due to the low silylating
activity of silicon tetrachloride. To promote the reaction at lower
temperatures, which improved the stereoselectivity,8 we screened
a considerable number of silyl reagents and found that trichlorosi-
lyl triflate strongly promoted the enantioselective direct-type aldol
reaction9–12 at low temperatures. Trichlorosilyl triflate is readily
prepared from commercially available and inexpensive trifluoro-
methanesulfonic acid and phenyltrichlorosilane.13,14 However, less
attention has been paid to trichlorosilyl triflate as a reagent in the
field of organic synthesis. Here, we report the first application of
trichlorosilyl triflate to the enantioselective direct-type aldol reac-
tion using a chiral phosphine oxide.
Initially, we examined the enantioselective aldol reaction of
cyclohexanone (1a) and benzaldehyde (2a) in the presence of
10 mol % (S)-BINAPO in dichloromethane (Table 1). As reported
previously,6 silicon tetrachloride promoted the enantioselective al-
dol reaction at 0 °C (entry 1), but the yield of the product 3a was
quite low when the reaction was performed at À40 °C (entry 2).
On the other hand, trichlorosilyl triflate effectively promoted the
reaction at À40 °C to afford the aldol adduct 3a with good diaste-
reo- and enantioselectivity (entry 3).15 Investigation of the solvent
⇑
Corresponding authors.
E-mail address: skotani@gpo.kumamoto-u.ac.jp (S. Kotani).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.095

S. Kotani et al. / Tetrahedron Letters 52 (2011) 2834–2836
2835
Table 1
Optimization of enantioselective aldol reaction with trichlorosilyl triflatea
Entry
Solvent
Amine
Yieldb (%)
syn:antic
eed (%) (anti)
1e,f
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
EtCN
iPr2NEt
81
4
15:85
28:72
8:92
24:76
11:89
89:11
—
54
80
84
69
82
47
—
2f
iPr2NEt
3
4
5
6
iPr2NEt
38
29
61
13
0
iPr2NEt
iPr2NEt
Toluene
THF
iPr2NEt
7
iPr2NEt
8
9
10
11
12g
13g,h
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
Et3N
21
30
35
66
72
76
24:76
90:10
54:46
10:90
14:86
7:93
79
54
69
83
82
83
2,6-Lutidine
Pempidine
cHex2NMe
cHex2NMe
cHex2NMe
Figure 1. Results of aldol reaction between 1a and 2a with several chiral phosphine
oxides.
a
Unless otherwise noted, the reactions were conducted by adding aldehyde 2a
(0.5 mmol) to a solution of ketone 1a (0.75 mmol), (S)-BINAPO (10 mol %), trichlo-
rosilyl triflate (1.0 mmol), and amine (5.0 mmol) in solvent (2 mL) at À40 °C. The
reactions were quenched with satd aq NaHCO3 after 2 h.
Table 2
Enantioselective aldol reaction of ketones 1 and aldehyde 2aa
2aa
b
Isolated yield.
c
Determined by 1H NMR.
d
Determined by HPLC.
The reaction was conducted at 0 °C.
SiCl4 was used instead of SiCl3OTf.
The reactions were quenched with aq KF/HCOOH.
e
f
g
h
Ketone 1a was added before addition of SiCl3OTf solution. See Supplementary
Entry
1
Ketone, 1
3
Yieldb (%)
76
syn:antic
eed (%) (anti)
data.
O
3a
7:93
83
effects (entries 4–7) revealed that propionitrile gave the best re-
sults, yielding the product 3a in 61% yield (entry 5). In toluene,
racemic syn-isomer was predominantly produced [13% yield, sy-
n:anti = 89:11, 47% ee (anti)](entry 6), while tetrahydrofuran gave
no product (entry 7). Then, to improve the product yield, the effect
of amines was carefully examined (entries 8–11). In the case of tri-
ethylamine or 2,6-lutidine, the yield was less than 30% (entries 8
and 9). In contrast, the sterically congested amines, such as pempi-
dine, tended to give good results (entry 10). We found that dic-
yclohexylmethylamine was the best for the reaction (entry 11).
Quenching the reaction mixture with aq KF/HCOOH instead of satd
aq NaHCO3 improved the yield of 3a by promoting desilylation of
the silylated aldol adduct (entry 12). Furthermore, small amounts
of the self-condensation product of ketone 1a were isolated as a
by-product. Modification of the reaction procedure (addition of Si-
Cl3OTf after ketone 1a), suppressed a formation of this by-product
to further improve both the yield and selectivity (entry 13).
With the optimal conditions in hand, the screening of catalysts
was investigated (Fig. 1). In the reactions of (S)-tol-BINAPO or (S)-
SEGPHOS dioxide (SEGPHOSO), the chemical and optical yields de-
creased. The higher Lewis basicities, due to the inductive effects of
substituents, may interrupt catalyst turnover. Interestingly, (R,R)-
DIOPO gave the corresponding aldol adduct in high yield (92%
yield), although the stereoselectivity was lower than that of
BINAPO.
, 1a
O
2
3
4
3b
3c
3d
72
85
82
50:50
11:89
3:97
63
72
83
, 1b
O
O
, 1c
O
, 1d
O
O
O
5e
6f
3e
3f
81
71
3:97
82
,
1e
O
73:27
83g
Ph
, 1f
a
Unless otherwise noted, the reactions were performed with ketone
(0.75 mmol) and aldehyde 2a (0.5 mmol), (S)-BINAPO (10 mol %), trichlorosilyl tri-
flate (1.0 mmol), and amine (5.0 mmol) in EtCN (2 mL) at À40 °C.
1
b
Isolated yield.
Determined by 1H NMR.
Determined by HPLC.
SiCl3OTf was added last.
c
d
e
f
The reaction mixture was stirred for 3 h before addition of aldehyde.
g
The ee of syn-isomer.
tivity (entries 4 and 5), In the latter case, the addition order of the
silyl triflate was changed to avoid coordination of this reagent to
the acetal group.17 Trichlorosilyl triflate promoted the reaction of
an acyclic ketone 1f, to give the syn-adduct with 83% ee (entry
6). It is noteworthy that trichlorosilyl triflate enabled the transfor-
mation of acyclic ketones, which silicon tetrachloride could not
activate at all.
Using BINAPO as a Lewis base catalyst, the enantioselective al-
dol reactions of various ketones 1 with benzaldehyde 2a were
examined (Table 2). Cyclopentanone (1b) reacted well to afford
the corresponding product in good yield and enantioselectivity,
but the diastereoselectivity diminished (entry 2). Generation of
the racemic syn-adduct implied that the non-catalyzed process
proceeded, which decreased both the diastereo- and enantioselec-
tivities.16 Heterocyclic ketone 1c also gave the corresponding prod-
uct in good yield and selectivity (entry 3). 4,4-Disubstituted
ketones (1d,e) afforded the products in high yield and stereoselec-
Direct-type aldol reactions were examined using 4,4-dimethyl-
cyclohexanone (1d) as the aldol donor along with several alde-
hydes 2 (Table 3). Although cinnamaldehyde, an
a,b-unsaturated
aldehyde (2b), was slightly less reactive compared with aromatic
aldehydes, good selectivity was observed (entry 2). 1-Naphthalde-

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S. Kotani et al. / Tetrahedron Letters 52 (2011) 2834–2836
2. For phosphoramide-catalyzed enantioselective aldol reactions of trichlrosilyl
Table 3
Enantioselective aldol reaction of ketone 1d and aldehydes 2a
enol ethers, (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem.
Soc. 1996, 118, 7404; (b) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am.
Chem. Soc. 1997, 119, 2333; (c) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.
Tetrahedron 1998, 54, 10389; (d) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T. J.
Org. Chem. 1998, 63, 918; (e) Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem.
Soc. 1998, 120, 12990; (f) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000,
33, 432; (g) Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000, 122, 8837;
(h) Denmark, S. E.; Pham, S. M.; Stavenger, R. A.; Su, X.; Wong, K.-T.;
Nishigaichi, Y. J. Org. Chem. 2006, 71, 3904; (i) Denmark, S. E.; Eklov, B. M.;
Yao, P. J.; Eastgate, M. D. J. Am. Chem. Soc. 2009, 131, 11770.
Entry
Aldehyde, R, 2
3
Yieldb (%)
syn:antic
eed (%) (anti)
3. For pyridine N-oxide-catalyzed enantioselective aldol reactions of trichlrosilyl
enol ethers, Nakajima, M.; Yokota, T.; Saito, M.; Hashimoto, S. Tetrahedron Lett.
2004, 45, 61.
1
Ph, 2a
3d
3g
3h
3i
3j
3k
3l
82
65
89
79
81
72
84
80
3:97
7:93
2:98
3:97
6:94
6:94
3:97
7:93
83
77
46
83
73
87
88
86
2e
3
PhCH@CH, 2b
1-Naphthyl, 2c
2-Naphthyl, 2d
4-MeOC6H4, 2e
4-NO2C6H4, 2f
4-BrC6H4, 2g
4-BrC6H4, 2g
4. For phosphine oxide-catalyzed enantioselective aldol reactions of trichlrosilyl
enol ethers, (a) Kotani, S.; Hashimoto, S.; Nakajima, M. Synlett 2006, 1116; (b)
Kotani, S.; Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122.
5. For recent papers for other applications of Lewis base to asymmetric aldol
reactions, see: (a) Denmark, S. E.; Heemstra, J. R., Jr. J. Am Chem. Soc. 2006, 128,
1038; (b) Denamrk, S. E.; Heemstra, J. R., Jr. J. Org. Chem. 2007, 72, 5668; (c)
Denmark, S. E.; Chung, W.-j. Angew. Chem., Int. Ed. 2008, 47, 1890; (d) Denmark,
S. E.; Chung, W.-j. J. Org. Chem. 2008, 73, 4582.
4e
5
6e
7e
8e,f
3m
a
Unless otherwise noted, the reactions were performed with ketone 1d
(0.75 mmol) and aldehyde 2 (0.5 mmol), (S)-BINAPO (10 mol %), trichlorosilyl tri-
flate (1.0 mmol), and amine (5.0 mmol) in EtCN (5 mL) at À40 °C.
6. Kotani, S.; Shimoda, Y.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2009, 50,
4602.
7. We have also demonstrated chiral phosphine oxides catalyze the reductive
aldol reaction, see: (a) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem.
Commun. 2008, 4309; (b) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani, S.; Nakajima,
M. Chem. Asian J. 2010, 5, 478.
b
Isolated yield.
c
Determined by 1H NMR.
Determined by HPLC.
For 4 h.
d
e
8. In the aldol reaction of trichlorosilyl enol ethers using BINAPO, more than 90%
ee was observed at À78 °C, see: Ref. 4.
f
The reaction was conducted with ketone 1e instead of 1d, and SiCl3OTf was
added last.
9. For reviews on direct aldol reaction, see: (a) Alcaide, B.; Almendros, P. Eur. J.
Org. Chem. 2002, 1595; (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102,
2187; (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570; (d) Notz, W.;
Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580; (e) Guillena, G.; Nájera,
C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (f) Mukherjee, S.; Yang,
J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
hyde (2c) dramatically decreased the enantioselectivity, whereas
2-napthaldehyde (2d) gave the corresponding product 3i in good
chemical and optical yields (entries 3 and 4). p-Anisaldehyde
(2e), having an electron-donating group, showed a reactivity
similar to that of benzaldehyde (2a), but the enantioselectivity
decreased slightly (entry 5). In contrast, aldehydes with electron-
withdrawing substituents (2f,g) resulted in higher enantioselectiv-
ities (up to 88% ee) (entries 6–8).
In conclusion, we have demonstrated the first use of trichloro-
silyl triflate as a trichlorosilyl reagent for enantioselective direct-
type aldol reactions of aldehydes and ketones catalyzed by chiral
Lewis bases. Further exploration of the effective silyl reagents
and their applications in organic synthesis are in progress.
10. For leading papers on direct asymmetric aldol reactions, see: (a) Yamada, Y. M.
A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1997, 36, 1871;
(b) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395; (c)
Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003; (d) Suzuki, T.; Yamagiwa,
N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R.
Tetrahedron Lett. 2001, 42, 4669.
11. For recent direct asymmetric aldol reactions, see: (a) Liu, J.; Yang, Z.; Wang, Z.;
Wang, F.; Chen, X.; Liu, X.; Feng, X.; Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130,
5654; (b) Luo, S.; Xu, H.; Zhang, L.; Li, J.; Cheng, J.-P. Org. Lett. 2008, 10, 653; (c)
Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas, C. F., III Org. Lett. 2008,
10, 1621; (d) Luo, S.; Xu, H.; Chen, L.; Cheng, J.-P. Org. Lett. 2008, 10, 1775; (e)
Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47,
2082; (f) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 17666; (g)
Baer, K.; Kraußer, M.; Burda, E.; Hummel, W.; Berkessel, A.; Gröger, H. Angew.
Chem., Int. Ed. 2009, 48, 9355; (h) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 18244; (i) Ube, H.; Shimada, N.;
Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858; (j) Daka, P.; Xu, Z.; Alexa, A.;
Wang, H. Chem. Commun. 2011, 47, 224.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
12. Trichlorosilyl triflate has been used for the preparation of trichlorosilyl enol
ether by Denmark et al., see: (a) Denmark, S. E.; Stavenger, R. A.; Winter, S. B.
D.; Wong, K.-T.; Barsanti, P. A. J. Org. Chem. 1998, 63, 9517; (b) Denmark, S. E.;
Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982.
13. Bassindale, A. R.; Stout, T. J. Organomet. Chem. 1984, 271, C1.
14. The dichloromethane solution of trichlorosilyl triflate was storable in
a
Supplementary data
refrigerator in a screw-top bottle. No loss of activity has been observed for a
month.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.095.
15. The yield of the aldol adduct at À78 °C was quite low and the
diastereoselectivity was comparable to that at À40 °C.
16. The reaction of 1b and 2a in the absence of BINAPO was completed within
5 min and the corresponding syn-isomer was produced predominantly (83%
yield, syn:anti = 85:15).
References and notes
17. 1-Boc-4-piperidone was less reactive, yielding the product in low chemical
yield and stereoselectivity (24% yield, syn:anti = 28:72, 33% ee (anti)).
1. For reviews on Lewis base organocatalysts, see: (a) Orito, Y.; Nakajima, M.
ˇ
´
Synthesis 2006, 1391; (b) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29;
(c) Denmark, S. E.; Beutner, G. L. Angew. Chem. 2008, 120, 1584; Angew. Chem.,
Int. Ed. 2008, 47, 1560.; (d) Benaglia, M.; Rossi, S. Org. Biomol. Chem. 2010, 8,
3824.