Tetrahedron Letters 48 (2007) 985–987
Resin-supported acid- and base-catalyzed one-pot
sequential reaction including an enantioselective step
Kengo Akagawa, Seiji Sakamoto and Kazuaki Kudo*
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
Received 13 November 2006; revised 30 November 2006; accepted 4 December 2006
Available online 22 December 2006
Abstract—One-pot sequential acidic deacetalization and basic enantioselective aldol reaction were realized using Amberlite IR-120
(H+-form) and a resin-supported peptide catalyst, and the reusability of the catalysts was demonstrated.
Ó 2006 Elsevier Ltd. All rights reserved.
Biosynthesis in the cells of living organisms goes
through multistep enzymatic reactions to convert a
starting material into the final product, without separa-
tion of intermediates. The reactions in biosynthesis are
highly specific and selective. One of the current trends
in organic synthesis is an emulation of nature, that is,
the development of sequential reactions using multiple
catalysts in a single reaction vessel.1 In such a reaction
system, it is very important that any two catalysts
should not be reactive with each other. Otherwise, cata-
lytic activity might be lost due to mutual deactivation.
For example, acid catalysts are usually incompatible
with base catalysts because these two catalysts form a
salt. In this regard, several one-pot sequential reactions
using both acid and base catalysts, suitably designed to
avoid neutralization, have appeared. A pioneering
example in this field is a one-pot deacetalization/intra-
molecular aldol condensation using a mixture of cation-
and anion-exchange resins, reported by Stowell and
Hauck, Jr. in 1981.2 It took almost two decades before
other examples emerged in succession. These were either
sol–gel matrix encapsulated acid/base reagents,3 acidic/
basic layered clays,4 star-shaped polymers having
acidic/basic core sites,5 or mesoporous silica concomi-
tantly bifunctionalized by acids and bases.6 However,
all of these precedents gave either achiral or racemic
products and none of them has succeeded in emulating
nature’s stereoselectivity in reactions.
aldol reaction in aqueous media.7 In this reaction, the
catalytic cycle is supposed to proceed under basic condi-
tions through the formation of a chiral enamine, just
like class I aldolase. As the peptide catalyst is supported
on polymer resin, it is expected that the combination of
this resin with solid-supported strong acids such as
cation-exchange resins8 would promote successive trans-
formation from the acetal to the aldol product in a stereo-
selective manner via the intermediacy of the aldehyde.
In this Letter, we report the first enantioselective succes-
sive acid- and base-catalyzed reactions on solid supports
in a single reaction vessel.
The hydrolysis of 4-nitrobenzaldehyde dimethyl acetal
followed by aldol reaction with acetone was attempted
(Table 1). Commercially available Amberlite IR-120
(H+-form) was used as an acid catalyst. This resin is a
divinylbenzene-crosslinked partially sulfonated gel-type
polystyrene. As a base catalyst, PEG–PS resin-sup-
ported proline was employed. The reaction was per-
formed in H2O/acetone/THF = 1:1:1 (v/v/v) at room
temperature in the presence of 20 mol % of resin-sup-
ported proline and Amberlite (entry 1). After 20 h, the
1
reaction mixture was analyzed by H NMR and shown
to contain the starting acetal, 4-nitrobenzaldehyde, and
the corresponding aldol product with acetone in a ratio
of 4:9:87. This means that both the hydrolysis of the
acetal and the subsequent aldol reaction proceeded
smoothly. The degree of dehydration of the aldol prod-
uct was almost negligible. This is in stark contrast to the
results previously reported for a one-pot sequential
deacetalization/aldol condensation.1b,2,4,6 This might
be due to the milder reaction conditions used in the
On the other hand, we have previously reported on the
polymer supported peptide catalyzed direct asymmetric
*
Corresponding author. Tel.: +81 3 5452 6357; fax: +81 3 5452
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.008