Catalytic asymmetric aldol reaction of ketones and aldehydes using chiral calcium alkoxides

Article abstract of DOI:10.1016/S0040-4039(01)00819-X

A chiral hydrobenzoin/Ca complex catalyzes the reaction of acetophenone and aliphatic aldehydes to give the corresponding aldol products in up to 91% ee.

Full text of DOI:10.1016/S0040-4039(01)00819-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4669–4671
Catalytic asymmetric aldol reaction of ketones and aldehydes
using chiral calcium alkoxides
Takeyuki Suzuki,a,b Noriyuki Yamagiwa,a,b Yoshimi Matsuo,b Shigeru Sakamoto,c
Kentaro Yamaguchi,c Masakatsu Shibasakia and Ryoji Noyorib,*
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bDepartment of Chemistry and Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
cChemical Analysis Center, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 24 March 2001; accepted 1 May 2001
Abstract—A chiral hydrobenzoin/Ca complex catalyzes the reaction of acetophenone and aliphatic aldehydes to give the
corresponding aldol products in up to 91% ee. © 2001 Elsevier Science Ltd. All rights reserved.
The asymmetric aldol reaction is useful for constructing
chiral organic frameworks.1 Although the direct cata-
lytic asymmetric reaction between unmodified ketones
and aldehydes is highly desirable, there are only a few
examples of synthetically meaningful reactions.2–6 Cer-
tain antibodies catalyze the reaction of acetone and
aromatic aldehydes giving the aldol products,3 and
proline (30–40 mol%) catalyzes an enantioselective
reaction of acetone or hydroxyacetone and aldehydes
(>25:1 mol ratio).4 Metal-based catalysts are more prac-
tical. Shibasaki reported that a chiral heteropolymetal-
lic catalyst (3–8 mol%) consisting of La, Li, and
binaphthol, with the aid of KN[Si(CH3)3]2 and H2O,
promotes the reaction of aromatic or aliphatic ketones
and aldehydes (typically a 5:1 mol ratio) to afford the
aldols in 30–93% ee in moderate to good yield.5a,c The
enantioselectivity is lowered by decreasing the bulkiness
of the aldehyde substrates. More recently, Trost devel-
oped chiral semi-crown/Zn catalysts that promote the
reaction of acetophenone and bulky aldehydes (10:1
mol ratio; 10 mol% catalyst) with high enantioselectiv-
ity, but in moderate yield.6 As such, there is still much
room for improvement of the synthetic efficiency. The
current problem in the direct aldol reaction is three-
fold: (1) there are few efficient chiral catalysts giving a
high turnover number and frequency; (2) the thermody-
namic balance between the starting carbonyl com-
pounds and the condensation products does not always
Scheme 1. Asymmetric aldol reaction between acetophenone and aliphatic aldehydes.
Keywords: asymmetric aldol reaction; chiral Ca catalyst; CSI-MS; direct aldol reaction; hydrobenzoins.
* Corresponding author. Tel.: +81 52 789 2956; fax: +81 52 783 4177; e-mail: noyori@chem3.chem.nagoya-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00819-X

4670
T. Suzuki et al. / Tetrahedron Letters 42 (2001) 4669–4671
favor the product formation;7 and (3) aldehyde sub-
strates giving high enantioselectivity are limited. We
report a new protocol using a simple diol-modified Ca
catalyst that gives chiral aldol products with reasonable
enantiomeric excess (Scheme 1).
none and alkanal 2e gave the cross-aldol in only 13%
yield and 15% ee, along with the self-aldol products of
2e.
The asymmetric bias is generated kinetically in the
reaction of an aldehyde and an in situ-formed ketone
enolate in the chiral hydrobenzoin/Ca template.
Because of the reversibility of the direct ketone/alde-
hyde aldol reaction, however, the prolonged exposure
of the chiral product to the reaction conditions signifi-
cantly decreased the product enantiomeric excess. For
example, reaction of 1 and 2a under standard condi-
tions afforded (R)-3a with the highest enantiomeric
excess (92%) after 30 min (4% yield), then 89% ee after
20 h (74% yield), and 85% ee after 40 h (84% yield).
Excess ketonic substrate, typically 10 mol equiv., was
crucial for obtaining the aldol product in a reasonable
chemical yield (>70%) and with a satisfactory enan-
tiomeric excess, where most of the excess ketone (90%)
was recovered by distillation. The reaction using an
equimolar mixture of 1 and 2a at −20°C for 163 h gave
(R)-3a in only 20% yield with 77% ee. Thus, this direct
catalytic asymmetric aldol reaction still has the inher-
ent, insoluble problem. The aldol (S)-3c (89% ee)
retards the reaction of 1 and 2a catalyzed by an (S,S)-
or (R,R)-5a-based Ca complex but does not greatly
affect the enantioselectivity.
When a mixture of acetophenone (1), pivalaldehyde
(2a), and
a
catalyst system prepared from
Ca[N{Si(CH3)3}2]2(thf)2
(4a),8
(S,S)-hydrobenzoin
[(S,S)-5a],9 and KSCN (1:3:1 mol ratio)10 in a 4:1
C2H5CN–THF mixed solvent (1:2a:Ca=1000:100:3 mol
ratio) was allowed to stand at −20°C for 20 h, (R)-3-
hydroxy-4,4-dimethyl-1-phenylpentan-1-one
[(R)-3a]
was obtained in 74% yield with 89% ee. The reaction
without KSCN gave (R)-3a in 66% yield and 73% ee.
Ca[N{Si(CH3)3}2]2(dme) (4b)8 could also be used in
place of 4a.
Table 1 shows some examples of the direct asymmetric
aldol reaction between the aromatic ketone 1 and
aliphatic aldehydes 2 using the (S,S)-5/Ca catalysts.
The reaction of aldehydes possessing a tertiary alkyl
group gave the aldol products in good yield with 87–
91% ee. The reactivity of the Ca catalyst is several times
higher than those of the known catalyst systems.5a–c,6
The aldol 3a was obtained even with only 1 mol% of
the Ca catalyst, albeit with a lower enantiomeric excess
(82%). A gram-scale reaction of 2a was performed
without special techniques.11 This method allowed for
the synthesis of (R)-3c in 76% yield with 91% ee, which
serves as a synthetic intermediate for epothilone A.5c
Aldehydes with a secondary alkyl group can also be
used as acceptors of the chiral enolate, although the
extent of enantioselectivity is less satisfactory. As anti-
cipated from the literature,5c,6 the reaction of acetophe-
There is a notable nonlinear relationship12 between the
enantiomeric excess of the chiral source 5 and aldol
product. For example, when the reaction of 1 and 2a
was conducted with the catalyst formed from 4a and
(S,S)-5a in 50% ee, the aldol (R)-3a was obtained in
84% ee.
Table 1. Asymmetric aldol reaction of acetophenone and aldehydes catalyzed by a chiral Ca complexa
Aldehyde
Diol in cat.
Time (h)
Aldol product
eec (%)
No.
R
No.
Yieldb (%)
Config.d
2a
2a
2a
2a
2b
2c
2d
2d
2e
t-C4H9
t-C4H9
t-C4H9
t-C4H9
C6H5CH2C(CH3)2
C6H5CH2OCH2C(CH3)2
cyclo-C6H11
cyclo-C6H11
C6H5CH2CH2
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5b
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5b
(S,S)-5a
20
22f
20g
16
24
24
20
10
14
3a
3a
3a
3a
3b
3c
3d
3d
3e
74
87
79
70
75
76
88
71
13
89
86
82
89
87
91
66
69
15
Re
R
R
R
Rh
Ri
Rj
R
Sk
a Unless otherwise stated, the reaction was conducted at −20°C using 5.20 mmol of acetophenone and 0.520 mmol of an aldehyde in 4:1
C2H5CN–THF mixed solvent (0.21 M) containing 3 mol% of the catalyst.
b Isolated yield.
c The ee was determined by chiral HPLC (Chiralpak AS).
d The absolute configurations of 3a, 3b, 3d, 3e were determined by the sign of optical rotation of products. The absolute configuration of 3c was
determined by the sign of optical rotation of the corresponding b-hydroxy esters after Baeyer–Villiger oxidation of 3c.5c
e [h]1D6 +73.2° (c 1.38, CHCl3);13a 89% ee.
f Reaction using 344 mmol of 1 and 35 mmol of 2a aldehyde in 4:1 C2H5CN–THF mixed solvent (0.44 M).
g Reaction using 1 mol% of the catalyst (3.0 M).
h [h]2D3 +56.8° (c 1.18, CHCl3);13b 87% ee.
i [h]2D3 +53.3° (c 2.36, CHCl3); 91% ee.
j [h]2D1 +44.2° (c 2.22, CHCl3);13a 66% ee.
k [h]2D2 +2.32° (c 0.34, CHCl3);13a 15% ee.

T. Suzuki et al. / Tetrahedron Letters 42 (2001) 4669–4671
4671
Although the detailed structure of alkaline earth cata-
lysts remains unclear, coldspray ionization mass spec-
trometry (CSI-MS)14 provided useful information
regarding the atomic constitution of the chiral Ca
alkoxides. The sample prepared from 4a and 3 equiv. of
(S,S)-5a [H2(HB)] gave the CSI-MS data, demonstrat-
ing that the major species is oligomeric. The eminent
peak at m/z 1922 corresponds to [Ca5H9(HB)8O]+. This
assignment is consistent with the result obtained with
the di-p-methoxy auxiliary (S,S)-5b15 [H2(HB*)], where
the major peak is shifted to m/z 2402 due to
[Ca5H9(HB*)8O]+. The Ca complex formed from 4a, 3
equiv. of H2(HB), and 1 equiv. of KSCN in a 4:1
C2H5CN–THF mixture gave a spectrum that exhibits a
III, C. F. J. Am. Chem. Soc. 1998, 120, 2768–2779; (b)
Zhong, G.; Lerner, R. A.; Barbas, III, C. F. Angew.
Chem., Int. Ed. 1999, 38, 3738–3741.
4. (a) List, B.; Lerner, R. A.; Barbas, III, C. F. J. Am.
Chem. Soc. 2000, 122, 2395–2396; (b) Notz, W.; List, B.
J. Am. Chem. Soc. 2000, 122, 7386–7387.
5. (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.;
Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36,
1871–1873; (b) Yamada, Y. M. A.; Shibasaki, M. Tetra-
hedron Lett. 1998, 39, 5561–5564; (c) Yoshikawa, N.;
Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1999, 121, 4168–4178. For the synthesis
of either syn- or anti-a,b-dihydroxy ketones, see: (d)
Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.;
Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 2466–2467.
6. Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003–12004.
7. Heathcock, C. H. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp. 133–179.
strong
peak
at
m/z
2019
due
to
[Ca5KH9(HB)8O(SCN)]+. These results indicate that
Ca, HB, and KSCN contribute to the formation of the
highly aggregated chiral complex. Despite the C2-sym-
metry of the auxiliary, (S,S)-5, the Ca complex has a
high degree of complexity. Although the less aggregated
Ca species might be responsible for the asymmetric
aldol reaction, such oligomeric catalysts must partici-
pate directly or indirectly in the asymmetric reaction in
view of significant asymmetric amplification.
8. Westerhausen, M. Inorg. Chem. 1991, 30, 96–101.
9. Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59,
8302–8303.
10. No reaction occurred with a 1:1:1 mixture of 4a, (S,S)-
5a, and KSCN.
In summary, the newly devised Ca complexes catalyze
the asymmetric aldol reaction of acetophenone and
aliphatic aldehydes directly without structural modifica-
tion. The properties of the Ca catalysts are further
modifiable, hopefully, leading to more efficient cata-
lysts, because various chiral hydrobenzoin derivatives
are available.9,15 Although the catalytic utility of Ca
salts has not been extensively explored,16 this environ-
mentally benign and abundant alkaline earth metal
might be useful for contemporary organic synthesis.
11. Experimental procedure: A solution of 4a (671 mg, 3.13
mmol) in THF (16 mL) was added to a stirred solution of
(S,S)-5a (671 mg, 3.13 mmol) and KSCN (101 mg, 1.04
mmol) in C2H5CN (63 mL) over 30 min at room temper-
ature. The mixture was stirred overnight at room temper-
ature and the insoluble materials were removed by
filtration. Compounds 1 (40.0 mL, 344 mmol) and 2a
(3.80 mL, 35.0 mmol) were added to this catalyst solution
(3 mol%) at −20°C, and the mixture was stirred at −20°C
for 22 h. Then 1 M aqueous HCl was added. The mixture
was extracted with ether and washed with aqueous
NaHCO3 and brine. The organic layer was dried over
Na2SO4, concentrated under reduced pressure, and dis-
tilled (50°C/2 mmHg) to afford 1 (33.7 g, 90% recovery).
The residue was subjected to silica-gel column chro-
matography (12:1 hexane–ether) to give (R)-3a (6.26 g,
87% yield, 86% ee) and (S,S)-5a (610 mg, 91% recovery).
12. (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed.
1998, 37, 2922–2959; (b) Oguni, N.; Matsuda, Y.;
Kaneko, T. J. Am. Chem. Soc. 1988, 110, 7877–7878; (c)
Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am.
Chem. Soc. 1989, 111, 4028–4036; (d) Noyori, R.; Suga,
S.; Oka, H.; Kitamura, M. Chem. Rec. 2001, 1, 85–100;
(e) Soai, K.; Shibata, T. In Catalytic Asymmetric Synthe-
sis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
Chapter 9.
Acknowledgements
This work was supported by the Ministry of Education,
Culture, Sports, Science, and Technology of Japan
(Grant No. 07CE2004).
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