Novel enantioselective direct aldol-type reaction promoted by a chiral phosphine oxide as an organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2009.05.065

Chiral phosphine oxide successfully catalyzed the direct aldol-type reactions of cyclohexanone derivatives and benzaldehyde derivatives in high stereoselectivities. The reaction mechanism involves the in situ formation of trichlorosilyl enol ethers. The present reaction could be extended to the cross-aldol reactions between two aldehydes.

Full text of DOI:10.1016/j.tetlet.2009.05.065

Tetrahedron Letters 50 (2009) 4602–4605
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Novel enantioselective direct aldol-type reaction promoted by a chiral
phosphine oxide as an organocatalyst
Shunsuke Kotani a, Yasushi Shimoda b, Masaharu Sugiura b, Makoto Nakajima b,
*
a Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 862-0973, Japan
b Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral phosphine oxide successfully catalyzed the direct aldol-type reactions of cyclohexanone deriva-
tives and benzaldehyde derivatives in high stereoselectivities. The reaction mechanism involves the
in situ formation of trichlorosilyl enol ethers. The present reaction could be extended to the cross-aldol
reactions between two aldehydes.
Received 25 April 2009
Revised 18 May 2009
Accepted 21 May 2009
Available online 25 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The enantioselective aldol reaction is a powerful method for con-
structing one or two successive chiral carbon centers.1 Progress in
catalytic, enantioselective aldol reaction has been made by chiral Le-
wis acid-catalyzed reactions of trimethylsilyl enol ethers, which act
as aldol donors and are prepared from parent carbonyl compounds.
In the last decades, catalytic enantioselective direct aldol reactions,
which do not require masked enol ethers to be prepared beforehand
from ketones or esters (aldol donors), have attracted much attention
due to their simple manipulation and high atom economy.2 Two
types of direct aldol reactions have been reported: the reactions cat-
alyzed by chiral metal alkoxide complexes, which were initially re-
ported by Shibasaki,3,4 and the reactions involving enamine
process, which were pioneered by List and Barbas.5,6 Both strategies
have been extensively investigated, and are commonplace in the
development of asymmetric reactions.7 Herein, we report a novel
type of enantioselective direct aldol-type reaction, which employs
a new concept involving a silicate intermediate promoted by a chiral
phosphine oxide8 as an organocatalyst.9
We initially examined the aldol reaction of cyclohexanone and
benzaldehyde with tetrachlorosilane and diisopropylethylamine
in dichloromethane at rt using BINAPO (BINAP dioxide) as a cata-
lyst (Eq. 1). Benzaldehyde was slowly added to the mixture con-
taining all the other components at rt,12 which afforded the aldol
adduct with good anti-selectivity, but in low chemical and optical
yields (rt, 4 h, 30% yield, syn/anti = 1/5, 16% ee (anti)). Among the
various conditions surveyed, propionitrile was the solvent of
choice, and this gave the adduct in high yield with a good selectiv-
ity (rt, 1 h, 85% yield, syn/anti = 1/6, 51% ee (anti)). Decreasing the
reaction temperature gave a slightly better stereoselectivity (0 °C
2 h, 81% yield, syn/anti = 1/6, 54% ee (anti)).
ð1Þ
The aldol reaction of trichlorosilyl enol ethers developed by
Denmark, which likely proceeds via a six-membered transition
state involving hypervalent silicate, provides a high syn/anti selec-
tivity (diastereoselectivity) as reflected by the E/Z ratio of the enol
ether.10 We have demonstrated that chiral N-oxides or phosphine
oxides catalyze the aldol reaction of trichlorosilyl enol ethers to af-
ford the b-hydroxy carbonyl compounds in the high diastereo- and
enantioselectivities.11 To improve the efficiency, we envisaged an
in situ preparation of the enol ethers from the mother carbonyl
compounds. If trichlorosilyl enol ether is prepared from the corre-
sponding ketone and tetrachlorosilane in the presence of phos-
phine oxides, and the resulting enol ether is simultaneously
activated by phosphine oxide to react with aldehydes, then a direct
aldol-type reaction of two carbonyl compounds will be realized.
Table 1 summarizes the results obtained for the reaction of var-
ious ketones and benzaldehyde under the optimal conditions. The
reaction of cyclopentanone gave a similar selectivity, but with a
low yield due to dehydration (entry 2). 4,4-Disubstituted cyclo-
hexanones (entries 3 and 4) gave better stereoselectivities, espe-
cially the 4,4-ethylenedioxy group, which dramatically increased
the enantioselectivity (entry 4). Heterocyclic ketones also yielded
the adducts with good yields and selectivities without loss of reac-
tivities (entries 5–7). Pinacolone, an acyclic ketone, did not give the
corresponding adduct (entry 8).
Direct aldol-type reactions were examined using 4,4-(ethylene-
dioxy)cyclohexanone as an aldol donor and several other aldehydes
* Corresponding author. Tel.: +81 96 371 4680; fax: +81 96 362 7692.
E-mail address: nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.065

S. Kotani et al. / Tetrahedron Letters 50 (2009) 4602–4605
4603
Table 1
Enantioselective direct aldol-type reactions between various ketones and benzaldehyde catalyzed by BINAPO
BINAPO (10 mol %)
O
OH
Ph
O
OH
Ph
O
SiCl4 (1.5 equiv)
+
PhCHO
+
iPr2NEt (10 equiv)
EtCN, 0 ºC
syn-3
anti-3
2a
1
Entry
Ketone
Time (h)
3
Yielda (%)
syn/antib
% eec (anti)
1
2
Cyclohexanone (1a)
Cyclopentanone (1b)
2
2
3aa
3ba
81
58
1/6
1/5
54
53
O
3
4
5
6
7
4
6
6
6
3ca
3da
3ea
3fa
84
79
82
75
1/24
1/31
1/11
1/16
53
73
45
62
(1c)
O
O
O
(1d)
(1e)
O
S
O
O
(1f)
BocN
O
6
3ga
3ha
79
1/11
–
55
–
(1g)
8
Pinacolone (1h)
12
Trace
a
Isolated yields.
b
c
Determined by 1H-NMR and HPLC analyses.
Determined by HPLC analysis.
Table 2
Enantioselective direct aldol-type reactions between a ketone and various aldehydes catalyzed by BINAPO
O
O
OH
O
OH
BINAPO (10 mol%)
SiCl4 (1.5 equiv)
R
R
+
+
RCHO
iPr2NEt (10 equiv)
EtCN, 0 ºC
O
O
O
O
O
O
1d
2
syn-3
anti-3
Yielda (%)
Entry
R
Time (h)
3
syn/antib
% eec (anti)
1
2
3
4
5
6
7
8
Ph (2a)
6
6
6
6
6
6
6
12
3da
3db
3dc
3dd
3de
3df
79
69
74
62
54
93
53
Trace
1/31
1/38
1/19
1/45
1/46
1/38
1/6
73
71
64
61
65
63
51
—
4-MeOC6H4 (2b)
4-BrC6H4 (2c)
1-Naphthyl (2d)
2-Naphthyl (2e)
3,5-Me2C6H3 (2f)
PhCH@CH (2g)
PhCH2CH2 (2h)
3dg
3dh
—
a
Isolated yields.
b
c
Determined by 1H NMR and HPLC analyses.
Determined by HPLC analysis.
(Table 2). The aldol reactions of aromatic aldehydes gave similar
results to those in benzaldehyde (entries 3–6). Sterically hin-
dered aldehydes tended to give higher diastereoselectivities,
but slightly lower enantioselectivities (entries 4–6). Although
the reaction of cinnamaldehyde, a conjugated aldehyde, afforded
the product in modest chemical yield and selectivities, dihydro-
cinnamaldehyde did not afford the aldol adduct under these con-
ditions, which may be due to the formation of the corresponding
chlorohydrin.13
ether was confirmed by 1H NMR analysis for the reaction of cyclo-
hexanone with tetrachlorosilane, diisopropylethylamine, and
BINAPO in CD3CN.14 Interestingly, the intermediate was not gener-
ated in the absence of BINAPO, indicating that the Lewis base cat-
alyst plays an important role not only in the aldol process, but also
for enolate generation. It is hypothesized that trichlorosilyl enol
ethers generated in situ with the assistance of BINAPO subse-
quently react with the coexisting aldehyde via a six-membered
chair-like transition state to give the corresponding aldol adducts.
To elucidate the reaction mechanism, BINAPO-catalyzed aldol
reactions of the isolated trichlorosilyl enol ethers of cyclohexanone
with benzaldehyde were conducted (Eq. 2). The indirect and direct
methods gave comparable results (indirect method: 63%, syn/
anti = 1/8, 52% ee (anti); direct method: 85%, syn/anti = 1/6, 54%
ee (anti)). Moreover, in situ formation of the trichlorosilyl enol
ð2Þ

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S. Kotani et al. / Tetrahedron Letters 50 (2009) 4602–4605
Table 3
Enantioselective direct aldol-type reactions between various aldehydes
BINAPO (10 mol%)
SiCl4 (1.5 equiv)
O
OH OH
NaBH4
R1
R3CHO
+
H
R3
iPr2NEt (5 equiv)
EtCN, rt
MeOH
R1 R2
5
R2
rt, 30 min
4
2
Entry
Aldol donor (R1, R2)
Aldol acceptor (R3)
Time (h)
5
Yielda (%)
% eeb (anti)
1
2
3
4
5
6
7
8
Me, Me (4a)
–(CH2)3– (4b)
Me, Me (4a)
Me, Me (4a)
Me, Me (4a)
Me, Me (4a)
Me, Me (4a)
Me, nPr (4c)
Ph (2a)
Ph (2a)
0.5
0.5
0.5
0.5
2
2
24
4
5aa
5ba
5ab
5ac
5ad
5ae
5ah
5ca
87
80
99
86
71
94
16
80c
55
49
58
58
51
53
4-MeOC6H4 (2b)
4-BrC6H4 (2c)
1-Naphthyl (2d)
2-Naphthyl (2e)
PhCH2CH2 (2h)
Ph (2a)
63
49d, 45e
a
Isolated yields.
Determined by HPLC analysis.
dr = 2:1.
The ee of the major diastereomer.
The ee of the minor diastereomer.
b
c
d
e
M. Chem. Eur. J. 1998, 4, 1137–1141; (c) Mahrwald, R. Chem. Rev. 1999, 99,
1095–1120; (d) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39,
1352–1374; (e) Palomo, C.; Oiarbide, M.; García, J. M. Chem. Soc. Rev. 2004, 33,
65–75.
As mentioned above, aliphatic aldehydes showed little reactiv-
ity as electrophiles. Therefore, we next envisioned that aliphatic
aldehydes might act as good aldol donors via enolization by tetra-
chlorosilane with an amine base.15 Direct aldol-type reactions be-
tween two different aldehydes are classical C–C bond-forming
reactions in organic synthesis. However, few examples of enantio-
selective direct aldol reactions have been reported between alde-
hydes due to crucial side reactions, including self-aldol reactions,
dehydration, and multiple aldol reactions.16
Thus, we investigated the reaction between benzaldehyde and
isobutyraldehyde in the presence of BINAPO as an organocatalyst.17
The reaction was conducted similar to the case using ketones and
the aldol products were transformed to the corresponding diols by
NaBH4 reduction to facilitate isolation. Table 3 shows the results
for the reactions between various aldehydes. Although stereoselec-
tivities were modest, the reactions proceeded smoothly to afford the
corresponding adduct without any self-condensation in every case.
Finally, the diastereo- and enantioselective reaction of 2-methyl-
pentanal with benzaldehyde afforded the desired aldol adduct,
2. For reviews on direct aldol reaction, see: (a) Alcaide, B.; Almendros, P. Eur. J.
Org. Chem. 2002, 1595–1601; (b) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004,
37, 570–579; (c) Guillena, G.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry
2007, 18, 2249–2293.
3. (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int.
Ed. 1997, 36, 1871–1873; (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102,
2187–2210; (c) Shibasaki, M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269–279.
4. For related catalyses, see: (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003–12004; (b) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.;
Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetrahedron Lett. 2001, 42, 4669–
4671.
5. (a) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396; (b)
Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580–591; (c)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–
5569.
6. For related catalyses, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983–1986; (b) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808–1809; (c)
Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem., Int. Ed. 2005, 44,
3055–3057.
7. Although the substrates are limited to glycine Schiff bases, the aldol reactions
promoted by phase transfer catalysts have been reported, see: Ooi, T.;
Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41,
4542–4544.
which possessed an a-quaternary stereogenic center with moderate
stereoselectivity (entry 8).18
In summary, we have demonstrated a new concept for the asym-
metric direct aldol-type reactions between ketones and aldehydes
or between two aldehydes by using a chiral phosphine oxide, BINAP-
O as an organocatalyst. Further investigations, including improving
the enantioselectivity, extending the scope of the reaction, and
applying to natural product synthesis, are currently underway.
8. For chiral phosphine oxide-catalyzed reactions, see: (a) Nakajima, M.; Kotani,
S.; Ishizuka, T.; Hashimoto, S. Tetrahedron Lett. 2005, 46, 157–159; (b) Tokuoka,
E.; Kotani, S.; Matsunaga, H.; Ishizuka, T.; Hashimoto, S.; Nakajima, M.
Tetrahedron: Asymmetry 2005, 16, 2391–2392; (c) Nakanishi, K.; Kotani, S.;
Sugiura, M.; Nakajima, M. Tetrahedron 2008, 64, 6415–6419; (d) Simonini, V.;
Benaglia, M.; Benincori, T. Adv. Syn. Catal. 2008, 350, 561–564.
9. For recent reviews on related organocatalyses, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed 2004, 43, 5138–5175; (b) Pellissier, H. Tetrahedron 2007,
ˇ
´
63, 9267–9331; (c) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29–36;
(d) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638; (e)
MacMillan, D. W. C. Nature 2008, 455, 304–308.
Acknowledgments
10. (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 1996,
118, 7404–7405; (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33,
432–440.
11. (a) Nakajima, M.; Yokota, T.; Saito, M.; Hashimoto, S. Tetrahedron Lett. 2004, 45,
61–64; (b) Kotani, S.; Hashimoto, S.; Nakajima, M. Synlett 2006, 1116–1118; (c)
Kotani, S.; Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122–3132; (d)
Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309–
4311.
This work was partly supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Transformations
of Carbon Resources’ from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We thank Takasago Inter-
national Corporation for its generous gift of chiral phosphines.
12. Although adding tetrachlorosilane to the mixture of the other components
gave the same results, adding
stereoselectivities.
a ketone to the mixture decreased the
Supplementary data
13. For a discussion on the chlorohydrin formation, see: Denmark, S. E.; Beutner, G.
L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774–3789.
14. The signal of the olefin proton was observed at 5.28 ppm derived from
cyclohexanone. See Supplementary data.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.065.
15. Denmark reported that HMPA catalyzed the formation of the trichlorosilyl enol
ether of isobutyraldehyde with tetrachlorosilane and 2,4,6-trimethylpyridine,
see: Denmark, S. E.; Bui, T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5439–5444.
16. For recent reports on asymmetric cross-aldol reactions of aldehyde enolate
equivalents, see: (a) Denmark, S. E.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40,
References and notes
1. For recent reviews on enantioselective aldol reaction, see: (a) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357–389; (b) Gröger, H.; Vogl, E. M.; Shibasaki,

S. Kotani et al. / Tetrahedron Letters 50 (2009) 4602–4605
4605
4759–4762; (b) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
6798–6799; (c) Mase, N.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed. 2004,
43, 2420–2423; (d) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem., Int.
Ed. 2006, 45, 3814–3816; (e) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527–5529; (f) Kano, T.;
Yamaguchi, Y.; Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1738–
1740.
17. (R)-3,30-Dimethyl-2,20-biquinoline N,N0-dioxide catalyzed the reaction of
benzaldehyde and isobutyraldehyde with a similar stereoselectivity but with
lower chemical yield (2 h, 71%, 55% ee).
18. For a review on enantioselective construction of quaternary carbon centers,
see: (a) Corey, E. J.; Guzman-Perez, A. Angew, Chem., Int. Ed. 1998, 37, 388–401;
(b) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146; (c) Trost, B.
M.; Jiang, C. Synthesis 2006, 369–396.