A novel chiral zirconium catalyst for enantioselective aldol and Mannich-type reactions. Catalytic activation of both aldehydes and imines using a similar chiral Lewis acid

Article abstract of DOI:10.1016/S0040-4020(00)01038-3

A novel zirconium catalyst has been developed for asymmetric aldol reaction of aldehydes with silyl enolates and asymmetric Mannich reactions of imines with silyl enolates. Similar types of catalysts have been successfully used in both reactions, and the

Full text of DOI:10.1016/S0040-4020(00)01038-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 861±866
A novel chiral zirconium catalyst for enantioselective aldol and
Mannich-type reactions. Catalytic activation of both aldehydes
and imines using a similar chiral Lewis acid
Shu Kobayashi,p Haruro Ishitani, Yasuhiro Yamashita, Masaharu Ueno and Haruka Shimizu
Å
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
Received 4 July 2000; accepted 14 August 2000
AbstractÐA novel zirconium catalyst has been developed for asymmetric aldol reaction of aldehydes with silyl enolates and asymmetric
Mannich reactions of imines with silyl enolates. Similar types of catalysts have been successfully used in both reactions, and the desired
products were obtained in high yields and high selectivities. For the sense of the chiral induction, reverse enantiofacial selectivities were
observed between aldol reactions and Mannich reactions. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
In this paper, we report examples of effective activations of
both aldehydes and imines using a similar chiral zirconium
catalyst (3).
Nucleophilic addition to carbonyl and related compounds,
which is one of major ®elds in organic chemistry, is often
used in many organic transformations. Generally, strong
nucleophiles attack carbonyls without the aids of activators.
On the other hand, in the reactions using rather weak
nucleophiles such as silanes and stannanes, Lewis acids
are often employed to activate aldehydes and imines.1±3
Recently, due to the increasing demands on asymmetric
synthesis, chiral Lewis acids have been focused for the
activation of aldehydes and imines, and catalytic enantio-
selective reactions using chiral Lewis acids for the synthesis
of versatile chiral building blocks have been intensively
studied.4 While several excellent chiral Lewis acids for
the activation of aldehydes have been reported, few
examples are known for the catalytic activation of imines
by chiral Lewis acids.5 This is partially because coordi-
nation forms are different between aldehydes±Lewis acids
complexes and imines±Lewis acids complexes. While
Lewis acids coordinate to aldehydes in syn direction to
the hydrogen atoms of the aldehydes (1),6 Lewis acids
coordinate to imines in syn (2a) or anti (2b) direction to
the hydrogen atoms of the imines (Scheme 1).7
1.1. Aldehyde activation (aldol reactions)
The Lewis acid-mediated aldol reactions of silyl enol ethers
with aldehydes (Mukaiyama aldol reaction) provide one of
the most convenient carbon±carbon bond-forming
methods.8 The ®rst catalytic asymmetric version of this
reaction using chiral tin (II) Lewis acids appeared in
1990,9 and after that, several ef®cient Lewis acid catalysts
based on boron, titanium, copper, etc., have been reported.10
While these highly selective reactions have been regarded
as one of the most ef®cient reactions for the preparation of
chiral b-hydroxy ketone and ester derivatives, temperatures
of 2788C and strict anhydrous conditions are required in
most cases.10±12
We have found that a chiral zirconium catalyst activated
aldehydes to create excellent asymmetric environments.13
In the presence of 10 mol% of a chiral zirconium catalyst
prepared from Zr(OtBu)4, ((R)-3,30-dibromo-1,10-bi-2-
naphthol (R)-3,30-BrBINOL), and propanol, benzaldehyde
reacted with 1-trimethylsiloxy-1-methoxy-2-methylpropene
Scheme 1. Activation of aldehydes and imines by Lewis acids.
Keywords: zirconium; aldehydes; imines; asymmetric catalysis.
* Corresponding author. Tel.: 181-3-5841-4790; fax: 181-3-5684-0634;
e-mail: skobayas@mol.f.u-tokyo.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01038-3

862
S. Kobayashi et al. / Tetrahedron 57 (2001) 861±866
Table 1. Catalytic asymmetric aldol reactions using 3
R1
R2
3
PrOH/mol (%)
Yield (%)
ee (%)
Me
Me
Me
Me
Me
H
OMe
OMe
OMe
OMe
OMe
SEt
3c
3d
3b
3a
3d
3d
20
20
20
20
50
50
94
97
62
49
89
81
78
89
44
38
97
92
asymmetric Mannich reactions using stoichiometric
amounts of chiral sources have already been reported,15,16
very little is known concerning catalytic asymmetric
versions.5 This is in contrast to the recent progress achieved
in catalytic enantioselective aldol reactions of aldehydes
with enolate components, especially silyl enolates
(Mukaiyama aldol reaction) as mentioned in the previous
section. While chiral Lewis acids have played leading roles
in these reactions, coordination forms are different (see
Introduction). In addition, it is assumed that most Lewis
acids would be trapped by basic nitrogen atoms of the start-
ing materials and/or products in Mannich reactions, and that
truly catalytic reactions would be dif®cult to perform. In
1997, we reported the ®rst example of truly catalytic
enantioselective Mannich reactions of imines with silyl
enolates using a novel zirconium catalyst prepared from
Zr(OtBu)4, (R)-6,60-dibromo-1,10-bi-2-naphthol ((R)-6,60-
BrBINOL), and N-methylimidazole (NMI).17
Scheme 2. Hydrolysis of the aldol adduct.
at 08C in toluene to afford the corresponding aldol adduct in
94% yield with 78% ee. In the absence of propanol, much
lower yield and enantiomeric excess were obtained. Other
BINOL derivatives were tested in the same system, and the
results are summarized in Table 1. When (R)-3,30-diiodo-
1,10-bi-2-naphthol ((R)-3,30-IBINOL) was used, the product
was obtained in 89% ee. It was also found that the amount of
propanol in¯uenced the selectivity. When 50 mol% of
propanol was used, the desired aldol adduct was obtained
in 89% yield with 97% ee. The absolute con®guration of the
aldol adduct was determined to be S by comparison of the
optical rotation of the corresponding carboxylic acid with
that in the literature (Scheme 2).14 When 1-ethylthio-1-
trimethylsiloxyethene was used instead of 1-trimethyl-
siloxy-1-methoxy-2-methylpropene under the similar
reaction conditions, the same high level of yield and
selectivity was obtained.
We used 10 mol% of chiral zirconium catalyst 3 in the
Mannich reaction of imine 4 with 1-trimethylsiloxy-1-
methoxy-2-methylpropene in toluene at 2458C. The
catalyst 3 was prepared from Zr(OtBu)4, (R)-3,30-BrBINOL,
and propanol, and was already shown to be effective in the
aldol reactions of silyl enol ethers with aldehydes. The
Mannich reaction proceeded smoothly to afford the corre-
sponding adduct in 99% yield with 69% ee. It is noted that
(R)-3,30-IBINOL gave lower selectivity in this reaction,
while (R)-3,30-ClBINOL gave the same level of the yield
and selectivity (Table 2). The absolute con®guration of the
adduct was determined to be R by comparison of the optical
rotation of the corresponding amino ester with that in the
literature (Scheme 3).18,19 It was interesting to ®nd that the
1.2. Imine activation (Mannich reactions)
Asymmetric Mannich reactions of imines with enolate
components provide useful routes for the synthesis of chiral
b-amino ketones or esters (Mannich bases),3 which are
versatile chiral building blocks for the synthesis of many
nitrogen-containing biologically important compounds
including b-amino acids, b-lactams, etc.3a While several
Table 2. Catalytic asymmetric Mannich reactions using 3
R1
R2
3
Additive
Yield (%)
ee (%)
Me
Me
Me
Me
Me
H
OMe
OMe
OMe
OMe
OMe
SEt
3c
3d
3b
3a
3c
3c
PrOH
PrOH
PrOH
PrOH
H2Oa
H2Oa
99
99
95
63
94
60
69
44
70
23
95
79
a As a solvent, THF was used instead of toluene, and molecular sieves 3A was added after the preparation of the catalyst (see Experimental).

S. Kobayashi et al. / Tetrahedron 57 (2001) 861±866
863
imines derived from aniline or 2-methoxyaniline were
used. The zirconium catalyst 3 coordinates to an imine to
form zirconium complex 6. A silyl enol ether attacks the
imine to produce 7, whose trimethylsilylated oxygen atom
attacks the zirconium center to afford the product along with
regeneration of the catalyst 3. The product was obtained as a
trimethylsilylated form without the acidic work-up.
Scheme 3. Conversion to free amine.
use of water as an additive instead of propanol greatly
improved the enantiomeric excess. Namely, when the
zirconium catalyst was prepared from Zr(OtBu)4, (R)-
3,30-BrBINOL, and water, imine 4 (R1ˆPh) reacted with
1-trimethylsiloxy-1-methoxy-2-methylpropene to afford
the corresponding adduct in 94% yield with 95% ee.
Ethylthio-1-trimethylsiloxyethene also reacted with imine
4 under the same reaction conditions to give the desired
adduct in 79% ee.
As for the sense of the chiral induction, reverse enantiofacial
selectivities were observed between aldol reactions and
Mannich reactions. While silyl enolates attack aldehydes
from the re-face of the aldehydes in aldol reactions, the
re-face of imines are shielded and silyl enolates are
expected to attack to the si-face of imines in Mannich reac-
tions. The reverse selectivities observed here would be
ascribed to the difference of the coordination form between
aldehydes±Lewis acids complexes and imines±Lewis acids
complexes, and it should be noted that such coordination
forms were well-controlled by using the similar zirconium
catalyst in these reactions.
1.3. Catalytic cycle
The assumed catalytic cycle of the asymmetric aldol
reaction is shown in Scheme 4. Catalyst 3 activates an
aldehyde, and a silyl enolate attacks the aldehyde to form
key intermediate 5. When no alcohol is present, it is thought
that the catalyst regeneration step (from 5 to 3) would be
slow, and when the reaction is quenched with water, 5 forms
a monotrimethylsilylated BINOL derivative detected by
GC-MS analysis. On the other hand, 5 immediately reacts
with an alcohol to regenerate the catalyst (3) along with
formation of the aldol adduct and an alcohol trimethylsilyl
ether.
2. Conclusion
We have developed a novel chiral zirconium catalyst which
can activate both aldehydes and imines successfully. While
catalytic asymmetric aldol reactions of aldehydes with silyl
enolates proceeded smoothly in high selectivities, catalytic
Mannich reactions of imines with silyl enolates are also
performed in high yields and high enantioselectivities by
using the similar types of the catalysts. Although both cata-
lysts are based on zirconium and BINOL derivatives, slight
modi®cations of ligands and reaction conditions were
needed to obtain the highest yields and selectivities. Lewis
acids activate both aldehydes and imines, but activation
On the other hand, a similar catalytic cycle is postulated in
the Mannich reactions (Scheme 5). The bidentate coordina-
tion of imines to the zirconium was proved to be essential,
since almost no chiral induction was observed when the
Scheme 4. Assumed catalytic cycle of the aldol reactions.

864
S. Kobayashi et al. / Tetrahedron 57 (2001) 861±866
Scheme 5. Assumed catalytic cycle of the Mannich reactions.
forms are different between them. It should be noted that the
similar catalysts were successfully used for the activation of
both aldehydes and imines, and that reverse enantiofacial
selectivities were observed between aldehyde additions and
imine additions. These results will be helpful to design
novel chiral catalysts for many other addition reactions of
carbonyl and related compounds.
3.2. A typical experimental procedure for asymmetric
aldol reactins
To a suspension of 3,30-IBINOL (24 mg, 0.044 mmol) in
toluene (0.5 ml) was added Zr(OtBu)4 (15.3 mg,
0.04 mmol) in toluene (1.0 ml) at room temperature. The
mixture was stirred for 30 min, and then propanol (20±
50 mol%) in toluene (1.0 ml) was added. After stirred for
30 min at this temperature, toluene solutions of an aldehyde
(0.4 mmol) and a silyl enol ether (0.48 mmol) were succes-
sively added at 08C. The mixture was stirred for 18 h, and
saturated NaHCO3 aq. was added to quench the reaction.
The aqueous layer was extracted with dichloromethane, and
the crude product was treated with THF-1N HCl (20:1) at
08C to hydrolyze a small amount of a silylated adduct. After
a usual work up, the crude adduct was chromatographed on
silica gel to give the desired adduct. The optical purity was
determined by chiral HPLC analysis.
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded on a JEOL JNM-
LA300, JNM-LA400, or JNM-LA500 spectrometer in
CDCl3 unless otherwise noted. Tetramethylsilane (TMS)
served as internal standard (dˆ0) for 1H NMR, and
CDCl3 was used as internal standard (dˆ77.0) for 13C
NMR. High-performance liquid chromatography was
carried out using following apparatuses; SHIMADZU LC-
10AT (liquid chromatograph), SHIMADZU SPD-10A (UV
detector), and SHIMADZU C-R6A Chromatopac. Column
chromatography was conducted on Silica gel 60 (Merck)
and preparative thin-layer chromatography was carried out
using Wakogel B-5F. Toluene was distilled and dried over
MS 4A. THF was distilled from Na±benzophenone. Propa-
nol was distilled in the presence of Mg, dried over MS 4A,
and stored under argon. All silyl enol ethers were prepared
according to the modi®ed House's procedure.20 BINOL
derivatives were prepared according to Snieckus'
methods.21
3.2.1. (S)-Methyl 3-hydroxy-2,2-dimethyl-3-phenylpro-
1
panoate. H NMR (CDCl3) d 1.12 (s, 3H), 1.15 (s, 3H),
3.73 (s, 3H), 4.90 (s, 1H), 7.25±7.36 (m, 5H). 13C NMR
(CDCl3) d 19.0, 23.1, 47.6, 52.1, 78.7, 127.6, 127.8,
139.9, 178.2. HPLC: Daicel Chiralcel OJ, hexane/i-
PrOHˆ9/1, ¯ow rateˆ0.5 ml/min: tRˆ18.3 min (S),
tRˆ22.0 min (R). Absolute con®guration was determined
after basic hydrolysis of the sample with 97% ee:
[a]D ˆ15.708 (c 2.49, MeOH) (lit.13a (R)-isomer;
25
24
[a]D ˆ27.18 (c 1.0, MeOH), lit.13b (R)-isomer; [a]D
24
ˆ
25.28 (c 0.98, MeOH)).
3.2.2. (R)-S-Ethyl 3-hydroxy-3-phenyl-propanethioate.

S. Kobayashi et al. / Tetrahedron 57 (2001) 861±866
865
1H NMR (CDCl3) d 1.26 (t. 3H, Jˆ7.4 Hz), 2.87±3.08 (m,
5H), 5.17 (dd, 1H, Jˆ3.7, 8.8 Hz), 7.10±7.36 (m, 5H). 13C
NMR (CDCl3) d 14.5, 23.4, 52.6, 70.8, 125.6, 127.8,
128.5, 142.3, 199.0. HPLC: Daicel Chiralcel OD,
hexane/iPrOHˆ19/1, ¯ow rateˆ0.8 ml/min: tRˆ12.1 min
uration assignment was made by comparison of the optical
rotation of N-free amino ester with that in the literature.19
3.4.1. (R)-Methyl 3-amino-2,2-dimethyl-3-phenylpropio-
nate. 1H NMR (CDCl3): d 1.20 (s, 3H), 1.25 (s, 3H), 3.65 (s,
3H), 3.87 (brs, 1H), 7.23±7.35 (m, 5H). 13C NMR (CDCl3):
d 20.6, 24.1, 52.0, 55.6, 127.3, 127.7, 127.9, 128.3, 176.9.
27
(S), tRˆ13.4 min (R). 92% ee: [a]D ˆ151.68 (c 0.67,
benzene) (lit.22 (S)-isomer; [a]D ˆ256.38(c 1.40, benzene,
28
26
Hydrochloride: [a]D ˆ134.6 (c 0.17, 1N HCl) (lit.19
92% ee)).
23
[a]D ˆ232.8 (c 1.1, 1N HCl)).
3.3. A typical experimental procedure for asymmetric
Mannich reactions
Acknowledgements
To 3,30-BrBINOL (20 mg, 0.044 mmol) in THF (0.5 ml)
was added Zr(OtBu)4 (15.3 mg, 0.04 mmol) in THF
(1.0 ml) solution at room temperature. The mixture was
stirred for 30 min. and then water (20 mol%) in THF
(1.0 ml) was added. After stirred for 30 min at this tempera-
ture, MS 3A (125 mg) and THF solutions of an imine
(0.4 mmol) and a silyl enol ether (0.48 mmol) were succes-
sively added at 08C. The mixture was stirred for 18 h, and
saturated NaHCO3 aq. was added to quench the reaction.
The aqueous layer was extracted with dichloromethane, and
the crude product was treated with THF-1N HCl (20:1) at
08C to remove the silyl group. After a usual work up, the
crude adduct was chromatographed on silica gel to give the
desired adduct. The optical purity was determined by chiral
HPLC analysis.
This work was partially supported by CREST, Japan
Science and Technology Corporation (JST), and a Grant-
in-Aid for Scienti®c Research from the Ministry of
Education, Science, Sports and Culture, Japan.
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