Catalytic enantioselective aldol-type reaction of β-ketosters with acetals

Article abstract of DOI:10.1002/anie.200705344

(Chemical Equation Presented) Two activations, one catalyst: By using cationic Pd and Pt complexes, a catalytic enantioselective aldol-type reaction of β-ketoesters with acetals has been developed (see scheme). The formation of metal enolates occurs under acidic conditions to allow the use of acetals as electrophiles to give the desired aldol products in high diastereoseletivity and enantioselectivity.

Full text of DOI:10.1002/anie.200705344

Communications
DOI: 10.1002/anie.200705344
Asymmetric Catalysis
Catalytic Enantioselective Aldol-type Reaction of b-Ketosters with
Acetals**
Natsuko Umebayashi, Yoshitaka Hamashima, Daisuke Hashizume, and Mikiko Sodeoka*
In memory of Yoshihiko Ito
Optically active b-oxycarbonyl compounds are useful inter-
mediates in synthetic organic chemistry and great efforts have
been devoted to the development of catalytic asymmetric
aldol reactions. Excellent methods have been developed with
secondary amines as well as chiral Lewis acids, whereby
ketones and their silyl derivatives react with aldehydes in a
highly enantioselective manner.[1] In contrast, readily enoliz-
able 1,3-dicarbonyl compounds, such as b-ketoesters and
malonates, have rarely been used as nucleophiles[2] because of
the insufficient nucleophilicity of the metal enolates of such
compounds; a plausible alternative explanation is that the
products are unstable and readily undergo retro-aldol reac-
tions (Scheme 1). Because of these general difficulties, there
are only a few examples of the synthesis of optically active b-
oxymalonates by using p-allyl Pd chemistry,[3] aldol reac-
tions,[4] and oxy-Michael reactions.[5] As for catalytic aldol
reactions of 1,3-dicarbonyl compounds, we recently reported
a catalytic asymmetric hydroxymethylation of b-ketoesters by
using paraformaldehyde as a C1 unit.[6,7] However, reactions
with less reactive aldehydes were difficult to perform (vide
infra), and we were unable to find literature precedent on
similar reactions.
Previously, we showed that chiral Pd enolates formed by
the reaction of chiral PdII–bisphosphine complexes 1 with b-
ketoesters were accompanied by the formation of a protic
acid (Scheme 1).[8] We envisaged that this proton might
activate acetals to give an oxonium intermediate, which would
undergo an aldol-type reaction with the b-ketoester. Since the
Scheme 1. Aldol-type reaction of b-ketoesters.
product is O protected, we expected that the undesired retro-
aldol reaction would be suppressed. The use of an acetal as a
synthetic equivalent of an aldehyde has been extensively
investigated in Lewis acid mediated or catalyzed aldol-type
reactions with silyl enolates.[9] In general, chiral induction is
hard to achieve in these reactions because the chiral Lewis
acid interacts only weakly with the prochiral electrophile
(Scheme 2). To our knowledge, an asymmetric version of this
type of reaction has not been reported. Herein, we disclose
the first example of a catalytic asymmetric aldol-type reaction
of acetals by using chiral PdII and PtII complexes, where the
chiral metal enolates of prochiral b-ketoesters are the key
intermediates.
We chose tert-butyl-2-oxo-cyclohexane carboxylate (2a)
and cinnamaldehyde diethyl acetal (3a)[10a] as model sub-
strates (Table 1). The reaction of 2a with 3a was carried out in
the presence of 10 mol% of Pd–binap complex 1a (binap =
2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl) in THF at 08C.
As expected, the desired aldol-type adduct 4aa was obtained
in excellent yield. To our delight, the enantioselectivity of the
product was excellent (98%), although the diastereoselectiv-
ity was insufficient (Table 1, entry 1). When the reaction was
carried out at À208C the diastereoselectivity was improved
(Table 1, entry 2). As shown in entry 3 in Table 1, the amounts
of the catalyst and the acetal used could be reduced. Careful
[*] N. Umebayashi, Dr. Y. Hamashima, Prof. M. Sodeoka
Synthetic Organic Chemistry Laboratory, RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
Fax: (+81)48-467-9373
E-mail: sodeoka@riken.jp
Dr. D. Hashizume
Molecular Characterization Team, RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
N. Umebayashi, Prof. M. Sodeoka
Graduate School of Science and Engineering
Saitama University
255 Shimo-okubo, Sakura-ku, Saitama 338-8570 (Japan)
[**] We thank Prof. Teiji Chihara of RIKEN for his generous support. This
work was supported by a Grant-in-Aid for the Encouragement of
Young Scientists (B) from JSPS (No. 18790005), a Grant-in-Aid for
Scientific Research on Priority Areas from MEXT (No. 19028065,
“Chemistry of Concerto Catalysis”), and Special Project Funding for
Basic Science from RIKEN.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Lewis acid catalyzed Mukaiyama-type aldol reaction with
acetals.
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Chemie
including methyl, allyl, and benzyl acetals,[10c–e] underwent the
Table 1: Optimization of the reaction conditions.
desired aldol-type reaction to give products at synthetically
useful levels (Table 2, entries 1–3). The ability to make aldol-
type products with allyl and benzyl groups is useful because
such groups can be easily removed. Reactions of other b-
ketoesters were also examined; for example, the reactions of
2b proceeded without difficulty, and the enantioselectivity
was again excellent (Table 2, entries 4 and 5). When the
reaction was carried out at À208C, the diastereoselectivity
was significantly improved without any loss in the efficiency
of the reaction (Table 2, entry 6).
Entry
1
3a
T
t
Yield
d.r.[a]
2.3:1
7.7:1 >99 >99
5.0:1
11:1
ee [%][b]
(mol%) (equiv)
[8C] [h] [%]
major minor
1
2
3
1a (10)
1a (10)
1a (5)
1c (10)
1a (5)
4
4
1.5
4
1.5
0
24 96
98
98
À20 24 61
0
0
0
3
85
12 58
64
99
72
99
95
34
95
As in the case of our Michael reaction,[8a,b] acyclic
substrate 2c was less reactive than the cyclic b-ketoesters.
The reactions of 2c with 3c and 3d did not go to completion,
and a color change of the reaction mixture was observed,
indicating decomposition of the catalyst (Table 2, entries 7
and 8). We speculated that the Pd complex tended to undergo
reduction by the alcohol, derived from the starting acetals,[11]
because the complexation of 2c with 1a was slow. To address
this issue, we examined the use of a PtII complex with the
expectation that it would give a Pt enolate, similar to the Pd
enolate, that would be more resistant to decomposition.[12,13]
Gratifyingly, in the presence of 10 mol% of Pt complex 5a,
the desired product 4cd was formed in 71% yield after
3 hours (Scheme 3). The reaction with 5b gave 4cd in better
4
5[c]
3
5.3:1
[a] The diastereomeric ratio was determined by comparing the integra-
tion values of the allylic methine protons in the 1H NMR spectrum of the
crude product mixture. [b] Enantioselectivity was determined by chiral
HPLC analysis. The numbers represent the enantiomeric excess of the
major and minor diastereomers. [c] 3a with cis configuration was used.
observation revealed that 3a was almost entirely consumed
after 3 hours, affording 4aa in 85% yield with a 5:1
diastereomeric ratio and almost perfect enantioselectivity
(major diastereomer: 99% ee; Table 1, entry 3). With a
bulkier complex such as 1c, high diastereoselectivity was
observed, although both the reaction rate and the enantiose-
lectivity decreased (Table 1, entry 4). An acetal with a cis
configured double bond[10b] underwent reaction to afford 4aa
with a trans configuration (Table 1, entry 5). The reaction
with 3a was chemoselective, and no 1,4-type adduct was
formed (vide infra). A control experiment revealed that an
aldol product was not formed in the reaction where cinna-
maldehyde was used in place of 3a.
We next examined the scope of the reaction by using the
optimized reaction conditions (Table 2). Other substrates,
Scheme 3. Aldol-type reactions of 2c with 3d by using Pt complexes.
Tf =trifluoromethanesulfonyl.
Table 2: Aldol-type reactions by using other substrates.
diastereoselectivity
and
excellent
enantioselectivity
(97% ee). Significant improvement in the diastereoselectivity
was observed in the reaction catalyzed by 5c. Finally, a better
stereoselectivity (d.r. = 14:1, 89% ee for major diastereomer)
was achieved when the reaction was carried out at À208C.
As shown in the Supporting Information, the relative and
absolute stereochemistry of the major diastereomers of
compounds 4aa and 4cd were unequivocally determined by
X-ray crystallographic analysis.[14] Taken together with our
previous results[8] it is likely that the observed absolute
stereochemistry arises from facial
Entry Ketoester Acetal Product
t
Yield
d.r.[a]
ee [%][b]
[h] [%]
major minor
1
2a
2a
2a
2b
2b
2b
2c
2c
3b
3c
3d
3a
3c
3c
3c
3d
4ab
4ac
4ad
4ba
4bc
4bc
4cc
4cd
3
3
3
3
1
1
3
3
43
70
71
86
86
82
41
22
4.2:1 >99 98
4.5:1 >99 92
2
3
4
5
5.2:1
3.2:1
2.2:1
6.3:1
4.5:1
3.6:1
99 99
99 98
98 98
selection of the metal enolate, and
that the relative stereochemistry is
biased by the geometry of the
6[c]
7[d]
8[d]
99 98
[e]
97
–
–
–
[e]
[e]
approaching
oxonium
ion
(Figure 1). This idea is in accord
with the fact that the enantioselec-
tivity is high, regardless of the
difference in the size of the acetals.
[a] The diastereomer ratio was determined by comparing the integration
ratio of the allylic methine protons in the 1H NMR spectrum of the crude
products. [b] Enantioselectivity was determined by chiral HPLC analysis.
The numbers represent the enantiomeric excess of the major and minor
diastereomers. [c] À208C. [d] 10 mol% 1a. [e] Not determined.
Figure 1. Proposed tran-
sition-state model.
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Communications
In the present reaction, conversion of the acetal into the
acetals as a coupling partner; basic conditions are unfavor-
able. Whereas a straightforward aldol reaction of b-ketoesters
with aldehydes hardly gives the corresponding product, the
present method affords the aldol-type product in good yield
with up to 99% ee. Thus, we have demonstrated the utility of
the metal enolates under acidic conditions, and additional
studies in this area are in progress.
oxonium ion by protonation is crucial. In fact, the reaction
efficiency was affected by the partial structure of the acetal
(Scheme 4). A substrate that gives an oxonium ion stabilized
Received: November 21, 2007
Revised: March 9, 2008
Published online: April 25, 2008
Keywords: b-ketoester · acetal · aldol reaction · palladium ·
.
platinum
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Scheme 4. Reactions using various acetals.
by an adjacent p system reacts with b-ketoesters, but a
product is not formed in the reaction with simple acetals. For
example, the reaction of 2a with the diethyl acetal of
hydrocinnamaldehyde catalyzed by 1a did not proceed,
even at room temperature. However, an acetal of benzalde-
hyde reacted with 2a under the standard conditions. Although
the chemical yield was less satisfactory, probably because of
steric repulsions, almost perfect enantioselectivity was ach-
ieved (major diastereomer: 99% ee). An acetal of a simple
a,b-unsaturated aldehyde was also available, and 4af was
obtained in 53% yield with 99% ee. In contrast, the reaction
of acrolein diethyl acetal (3g) was dramatically different, and
formal 1,4-addition product 4ag was obtained as a major
product.[15]
With regard to the reaction mechanism, alkylation of the
b-ketoester with a p-allyl Pd intermediate generated from Pd0
and 3 is also plausible.[3] If this were the case, the high
enantioselectivity that is observed would arise from the facial
selectivity of the chiral p-allyl Pd species, and not from the
chiral enolate. High selectivity should, therefore, be observed
in the reaction with malonate, but the reaction of dibenzyl
malonate with 3a gave the corresponding aldol-type product
in 55% yield with only 23% ee and a diene derived from b-
elimination of ethanol in 15% yield (see the Supporting
Information). These results suggest that the p-allyl Pd species
is not involved in the reaction.
In conclusion, we have developed a highly enantioselec-
tive aldol-type reaction of b-ketoesters with acetals. Our Pd
complex can act as an acid/base catalyst, and simultaneous
activation of both the nucleophile and the electrophile is
possible. Formation of the enolate under acidic conditions is
the key to the success of the reaction and allows the use of
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Chemie
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22; b) B. Byrne, L. M. Lafleur Lawter, K. J. Wengenroth, J. Org.
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M. Sodeoka, Org. Lett. 2006, 8, 4851 – 4854.
[12]We recently reported that the Pt–binap complex gave better
results in the addition reaction of b-ketoesters to paraformalde-
hyde. See, reference [6].
[13][Ni{( R)-segphos}](OTf)2 and [Cu{(S,S)-tert-Bu-box}](OTf)2 gave
poor results (11% yield and 0% ee after 45 h, 0% yield after
24 h, respectively).
[14]CCDC-662229 ( 4aa) and CCDC-677026 (4 cd) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
In the case of 4cd, X-ray analysis was carried out after the
conversion to the corresponding camphor derivative. Details of
the conversion and the crystallographic studies are described in
the Supporting Information.
[15]A similar methyl acetal was formed when a catalytic asymmetric
Michael reaction with acrolein was carried out in MeOH in the
presence of 1a. See reference [8b].
[11]We recently found that ethanol was oxidized in the presence of
À
1a to give a Pd H species, which underwent asymmetric
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