Trichlorosilyl triflate-mediated enantioselective directed cross-aldol reaction between ketones using a chiral phosphine oxide as an organocatalyst

Article abstract of DOI:10.1039/c2cc31543b

Trichlorosilyl triflate-promoted directed cross-aldol reaction between ketones in the presence of a chiral phosphine oxide as an organocatalyst is described. This is the first enantioselective cross-aldol reaction between simple ketones with good enantioselectivity.

Full text of DOI:10.1039/c2cc31543b

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Trichlorosilyl triflate-mediated enantioselective directed cross-aldol
reaction between ketones using a chiral phosphine oxide as an
organocatalystwz
Shohei Aoki,a Shunsuke Kotani,*b Masaharu Sugiuraa and Makoto Nakajima*a
Received 29th February 2012, Accepted 10th April 2012
DOI: 10.1039/c2cc31543b
Trichlorosilyl triflate-promoted directed cross-aldol reaction
between ketones in the presence of a chiral phosphine oxide as an
organocatalyst is described. This is the first enantioselective cross-
aldol reaction between simple ketones with good enantioselectivity.
Enantioselective construction of tetra-substituted stereogenic
centers is a remarkable challenge for stereoselective syntheses.1
One of the common methodologies for generating a tetra-
Scheme 1 Cross-aldol reaction between two different ketones.
We have recently demonstrated that trichlorosilyl triflate
substituted chiral center is applying the aldol addition to
mediated direct-type enantioselective aldol reaction occurs
ketones, resulting in a formation of b-hydroxy carbonyl
between aldehydes and ketones in the presence of chiral
phosphine oxide, BINAP dioxide (BINAPO).10,11 In our previous
compounds with a tetra-substituted chiral carbon.2 However,
the enantioselective aldol reaction between ketones is still a
studies, quenching a reaction with deuterium oxide in the absence
challenging issue, because the aldol reaction of ketone acceptors
of an aldehyde was found to give the a-deuterized ketone. This
observation implied the complete transformation of ketones into
has two main difficulties compared to that of aldehydes as follows:
(1) ketones are less reactive than aldehydes; (2) enantio-facial
the silyl enol ether in the reaction media, leading us to believe that
selection of ketones is more difficult than that of aldehydes, due
addition of different ketones may allow the cross-aldol reaction to
to both the smaller steric and electronic differences between the
proceed between two ketones (Scheme 1). Here, we report the
two substituents adjacent to carbonyl carbon. Recent progress in
the enantioselective aldol reactions between two ketones addressed
these problems, but the applicable substrates were still limited
first enantioselective aldol reaction of two different simple
ketones 1 (Fig. 1) using trichlorosilyl triflate12 and a chiral
phosphine oxide 2 (Fig. 2).
Initially, using acetone (1a) and acetophenone (1b) as
to pyruvates,3 isatin derivatives,4 and others.5 The first
enantioselective aldol addition to simple ketones was reported
substrates, the cross-aldol reaction was examined (Scheme 2).
After the treatment of 1a with trichlorosilyl triflate (2.0 eq.) and
diisopropylethylamine (10 eq.) in the presence of BINAPO (2a)
in propionitrile, 1b was added to the mixture.13 The desired
cross-aldol product 3ab was obtained in 85% yield with good
by Denmark in 2002, who used highly reactive trichlorosilyl
ketene acetals as the aldol donors in the presence of a chiral
Lewis base catalyst.6,7 In 2003, Shibasaki and Kanai developed
chiral copper-catalyzed enantioselective Mukaiyama-type aldol
addition of silyl ketene acetals to ketones.8 The direct-type aldol
reaction between different simple ketones is extremely difficult
because the precise recognition of aldol donors and acceptors is
enantioselectivity (74% ee). When the addition order of ketones
1a and 1b was inverted, the aldol adduct 3ba was obtained in
75% yield. This indicates that interconversion between the silyl
required. There is just one report by Tanabe in 1997, who achieved
enol ether and the ketone acceptor was suppressed under the
the direct-type aldol reaction of two simple ketones using a
TiCl4–Bu3N system, quantitatively but not enantioselectively.9
a Graduate School of Pharmaceutical Sciences, Kumamoto University,
5-1 Oe-honmachi, Chuo-ku, Kumamoto, Japan.
E-mail: nakajima@gpo.kumamoto-u.ac.jp; Fax: +81-963627692
b Priority Organization for Innovation and Excellence,
Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto,
Japan. E-mail: skotani@gpo.kumamoto-u.ac.jp
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details for the enantioselective aldol reaction, spectroscopic data for
new compounds, HPLC data for the aldol products. See DOI:
10.1039/c2cc31543b
Fig. 1 Ketones used in this study.
c
5524 Chem. Commun., 2012, 48, 5524–5526
This journal is The Royal Society of Chemistry 2012

Table 1 Optimization for the cross-aldol reaction between 1a and 1ba
Entry Solvent Amine (eq.)
Catalyst Time/h Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
EtCN iPr2NEt (10)
CH2Cl2 iPr2NEt (10)
iPrCN iPr2NEt (10)
iPrCN Et3N (10)
2a
2a
2a
2a
3
24
3
3
3
3
3
3
24
6
85
44
87
5
74
78
76
72
71
74
73
80
83
77
74
74
38
—
iPrCN 2,6-Lutidine (10) 2a
2
iPrCN Bu3N (10)
iPrCN Pempidine (10) 2a
2a
58
78
85
88
80
72
43
36
10
iPrCN iPr2NEt (5)
iPrCN iPr2NEt (5)
iPrCN iPr2NEt (5)
iPrCN iPr2NEt (5)
iPrCN iPr2NEt (5)
iPrCN iPr2NEt (5)
iPrCN iPr2NEt (5)
2a
2a
2b
2c
2d
2e
9d
10
11
12
13
14
Fig. 2 Chiral phosphine oxide catalysts used in this study.
6
3
24
Ph3POe 24
a
Unless otherwise noted, all reactions were carried out with ketone 1a
(0.5 mmol), ketone 1b (1.0 mmol), trichlorosilyl triflate (1.0 mmol),
iPr2NEt, and a catalyst 2 (0.05 mmol) in a solvent (5 mL) at ꢀ60 1C.
b
c
Yield of the isolated product after column chromatography. Ee was
d
determined by HPLC analysis. The reaction was carried out at ꢀ78 1C.
e
Triphenylphosphine oxide (20 mol%) was used.
oxide, a monodentate catalyst was not effective indicating that
bisphosphine oxide moieties on the catalyst were essential for
the cross-aldol reaction between ketones (entry 14).
Scheme 2 Directed cross-aldol reaction between 1a and 1b.
Using the phosphine oxide 2a as an organocatalyst, the
cross-aldol reactions between various types of ketones were
conducted (Scheme 3). 2-Butanone (1c) required a higher
temperature (ꢀ60 1C) to produce the product 3cb. In the
conditions realizing a directed cross-aldol reaction between
ketones.
To optimize the reaction conditions, we then screened the
solvent for the cross-aldol reaction of ketone 1a as an aldol donor
and 1b as an aldol acceptor (Table 1). Dichloromethane promoted
self-aldol reaction of 1a, decreasing the yield of the aldol adduct 3ab,
despite the improved enantioselectivity (entry 2). Isobutyronitrile
slightly improved both the chemical and optical yields in
comparison with propionitrile (entry 3).14 Using isobutyronitrile
as the solvent, the effect of amines was investigated (entries 3–7).
Although nearly the same enantioselectivities were observed,
triethylamine and 2,6-lutidine appear to suppress the aldol trans-
formation (entries 4 and 5). On the other hand, sterically congested
amines such as tributylamine and pempidine afforded the cross-
aldol product 3ab in good yield with high enantioselectivity
(entries 6 and 7).15 Among the amines tested, diisopropylethyl-
amine was the best for this reaction (entry 3). Decreasing
the amount of diisopropylethylamine and lowering the reaction
temperature slightly improved the enantioselectivity (entries 8
and 9). Furthermore, use of five equivalents of diisopropylethyl-
amine at ꢀ78 1C gave the best enantioselectivity (83% ee),
though the reaction time was prolonged (entry 9).
The reactions of ketones 1a and 1b in the presence of
various chiral phosphine oxides shown in Fig. 2 were performed
(entries 10–13). Tol-BINAPO (2b) and SEGPHOS dioxide
(SEGPHSO, 2c) gave similar results to BINAPO (2a) (entries 10
and 11), whereas the decrease in the yield was observed when
H8-BINAPO (2d) was used (entry 12). DIOPO (2e), bearing a
dioxolane skeleton as a chiral backbone, afforded low
chemical and optical yields (entry 13). Triphenylphosphine
Scheme 3 Enantioselective cross-aldol reaction.
Chem. Commun., 2012, 48, 5524–5526 5525
c
This journal is The Royal Society of Chemistry 2012

reaction of cyclic ketones 1d–f as an aldol donor, the diastereo-
selectivity was induced. Cyclopentanone (1d) bearing a 5-membered
ring slightly decreased enantioselectivity (product 3db), while cyclo-
hexanones 1e and 1f with 6-membered rings provided good
diastereo- and enantioselectivities.16,17
2008, 14, 8079–8081; (d) N. Hara, S. Nakamura, N. Shibata and
T. Toru, Chem.–Eur. J., 2009, 15, 6790–6793; (e) Q. Guo,
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9460–9464.
5 For other examples of enantioselective aldol addition to ketones,
see: (a) J. Liu, Z. Yang, Z. Wang, F. Wang, X. Chen, X. Liu,
X. Feng, Z. Su and C. Hu, J. Am. Chem. Soc., 2008, 130,
5654–5655; (b) T. Yoshino, H. Morimoto, G. Lu, S. Matsunaga
and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 17082–17083;
(c) W.-B. Chen, Z.-J. Wu, J. Hu, L.-F. Cun, X.-M. Zhang and
W.-C. Yuan, Org. Lett., 2011, 13, 2472–2475.
6 For reviews on Lewis base organocatalysts, see: (a) S. E. Denmark
and G. L. Beutner, Angew. Chem., 2008, 120, 1584–1663 (Angew.
Chem., Int. Ed., 2008, 47, 1560–1638); (b) Y. Orito and M. Nakajima,
Synthesis, 2006, 1391–1401; (c) A. V. Malkov and P. Kocovsky,
Eur. J. Org. Chem., 2007, 29–36; (d) M. Benaglia and S. Rossi,
Org. Biomol. Chem., 2010, 8, 3824–3830.
7 (a) S. E. Denmark and Y. Fan, J. Am. Chem. Soc., 2002, 124,
4233–4235; (b) S. E. Denmark, Y. Fan and M. D. Eastgate, J. Org.
Chem., 2005, 70, 5235–5248.
8 (a) K. Oisaki, Y. Suto, M. Kanai and M. Shibasaki, J. Am. Chem.
Soc., 2003, 125, 5644–5645; (b) K. Oisaki, D. Zhao, Y. Suto,
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9 (a) Y. Yoshida, R. Hayashi, H. Sumihara and Y. Tanabe, Tetrahedron
Lett., 1997, 38, 8727–8730; (b) Y. Yoshida, N. Matsumoto,
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Using cyclohexanone (1e) as an aldol donor, the aldol
acceptor was investigated. p-Methoxyacetophenone (1g) bearing
an electron-donating group afforded the corresponding aldol
product 3eg with good stereoselectivity. In the reaction of
p-bromoacetophenone (1h) bearing an electron-withdrawing
group, a similar result was obtained. Propiophenone (1i) gave the
decreased reactivity and diastereoselectivity but good enantio-
selectivity was observed (product 3ei). Benzylacetone (1j), having
small steric difference between both the methyl and methylene
substituents on the carbonyl carbon, provided good diastereo-
and enantioselectivities, though further improvement was required
(product 3ej).
In summary, we have developed the first phosphine oxide-
catalyzed enantioselective directed cross-aldol reaction between
simple ketones. The present method provided b-hydroxy carbonyl
compounds bearing a tetra-substituted chiral carbon with good
enantioselectivity. Detailed mechanistic studies, further improve-
ment of the stereoselectivity, and application to other important
carbon–carbon bond-forming reactions are currently under
investigation.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
10 S. Kotani, S. Aoki, M. Sugiura and M. Nakajima, Tetrahedron
Lett., 2011, 52, 2834–2836.
11 For other examples of phosphine oxide-catalyzed aldol reactions,
see: (a) M. Nakajima, S. Kotani, T. Ishizuka and S. Hashimoto,
Tetrahedron Lett., 2005, 46, 157–159; (b) S. Kotani, S. Hashimoto
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3122–3132; (d) M. Sugiura, N. Sato, S. Kotani and
M. Nakajima, Chem. Commun., 2008, 4309–4311; (e) Y. Shimoda,
T. Tando, S. Kotani, M. Sugiura and M. Nakajima,
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Y. Shimoda, M. Sugiura and M. Nakajima, Tetrahedron Lett.,
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Notes and references
1 For reviews of stereoselective construction of tetra-substituted
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2 For reviews of enantioselective addition to ketones, see:
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3 For enantioselective direct aldol reactions of ketones with a-keto
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13 SiCl4 did not effectively promote the enolization of ketone acting
an aldol donor, leading to production of undesired aldol adducts
(3ab; 17% yield, 3aa; 10% yield, 3bb; 9% yield, 3ba; 12% yield).
14 Isobutyronitrile possesses lower nucleophilicity and/or Lewis basi-
city than propionitrile, due to its steric hindrance and may not
deactivate trichlorosilyl triflate.
15 Amines also have the nucleophilicities and Lewis basicities. There-
fore, a sterically congested amine gave good results without
deactivating trichlorosilyl triflate.
16 For the enantiomeric excesses of minor isomers, see ESIz.
17 The relative configurations of diastereomers (3db, 3eb, 3fb, 3eg, 3eh
and 3ei) were tentatively assigned according to the literature, see:
E. Ghera and S. Shoua, J. Org. Chem., 1972, 37, 1292–1298.
4 For enantioselective direct aldol reactions of ketones with isatin
derivatives, see: (a) G. Luppi, P. G. Cozzi, M. Monari, B. Kaptein,
Q. B. Broxterman and C. Tomasini, J. Org. Chem., 2005, 70,
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c
5526 Chem. Commun., 2012, 48, 5524–5526
This journal is The Royal Society of Chemistry 2012