Sequential oxidation/asymmetric aldol reaction of primary alcohols by resin-supported catalysts

Article abstract of DOI:10.1016/j.tetlet.2010.12.008

The sequential reaction including alcohol oxidation by TEMPO/Cu system and the asymmetric aldol reaction by peptide catalysis was realized using resin-supported catalysts. The step of oxidizing primary alcohols to the corresponding aldehydes could be dramatically enhanced through the introduction of triglycyl peptide to supported TEMPO and the method of pre-adsorbing a Cu-complex into resin beads.

Full text of DOI:10.1016/j.tetlet.2010.12.008

Tetrahedron Letters 52 (2011) 770–773
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sequential oxidation/asymmetric aldol reaction of primary alcohols
by resin-supported catalysts
⇑
Kengo Akagawa, Shota Takigawa, Erika Mano, Kazuaki Kudo
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The sequential reaction including alcohol oxidation by TEMPO/Cu system and the asymmetric aldol reac-
tion by peptide catalysis was realized using resin-supported catalysts. The step of oxidizing primary alco-
hols to the corresponding aldehydes could be dramatically enhanced through the introduction of triglycyl
peptide to supported TEMPO and the method of pre-adsorbing a Cu-complex into resin beads.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 October 2010
Revised 30 November 2010
Accepted 3 December 2010
Available online 8 December 2010
Keywords:
Sequential reaction
Asymmetric aldol reaction
Resin-supported catalyst
TEMPO oxidation
Peptide catalyst
The aldol reaction is one of the versatile C–C bond forming
methods, and its asymmetric variant is of great importance for syn-
thesizing biologically active compounds. Development of enantio-
selective aldol reactions is a constantly advancing field. To date, a
number of methods have been established, which include those
using chiral auxiliaries and chiral catalysts.2 Among them, the
direct asymmetric aldol (DAA) reaction between two carbonyl
compounds is synthetically advantageous, dispensing with the
complex using molecular oxygen as a terminal oxidant is notewor-
thy from the viewpoint of mild reaction conditions. However,
9
there is one problem that TEMPO reacts with a carbonyl compound
1
0
in the presence of an organo-amine catalyst. Concerning this, we
previously demonstrated that otherwise incompatible acidic and
basic catalysts could be used in a single flask without affecting
each other through the immobilization of the two kinds of cata-
1
1
1
lysts on separate resin beads. It is expected that TEMPO and an
amine-catalyst could also coexist by supporting them on different
resins, thus the DAA reaction starting from alcohols should be real-
ized. Here, we report the sequential oxidation/asymmetric aldol
reaction of primary alcohols by resin-supported catalysts.
3
preparation of enolate intermediates or their equivalents. Particu-
4
larly, after List et al. reported a proline-catalyzed reaction, organ-
ocatalytic DAA reactions have been extensively investigated
because of its operational simplicity, the stability of catalysts,
and ambient reaction conditions.5
As a model reaction, we chose benzyl alcohol 1a as a substrate
for the oxidation to aldehyde 2a by the TEMPO/Cu-system, and the
subsequent DAA reaction of 2a with acetone by organocatalysis to
afford product 3a in one pot (Table 1). As a catalyst for the DAA
reaction, tripeptide D-Pro-Tyr-Phe attached on polyethylenegly-
col–polystyrene (PEG–PS) resin was used according to our previous
study. TEMPO having 4-carboxy group was immobilized on amino-
terminated PEG–PS resin by conventional condensation. In the
presence of the two kinds of supported catalysts, along with cop-
In most organocatalytic DAA reactions, aldehydes are employed
as electrophiles. Aldehydes are sometimes chemically unstable and
less commercially available than primary alcohols. Therefore, if
aldehydes could be prepared from the corresponding primary alco-
hols in situ and subsequently used as substrates for DAA reactions,
6–8
it would be a practically useful methodology.
In such a reaction system, because both the oxidation catalyst
and the organocatalyst are in the same flask, an oxidizing agent
that works under mild reaction conditions is required in order
not to deteriorate the coexisting organocatalyst. Among various
methods of oxidizing alcohols to aldehydes, the reaction catalyzed
by 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and a copper
0
per(I) chloride and 2,2 -bipyridine, the oxidation of 1a to 2a was
performed under air. After 24 h, acetone and Tris–HCl buffer (pH
7.4) were added to the reaction mixture for conducting the asym-
metric aldol reaction. With the simple PEG–PS-supported TEMPO
catalyst, the oxidation of the alcohol was quite sluggish (entry 1).
This was presumably because the copper complex, which should
work cooperatively with TEMPO in the alcohol oxidation, was not
present around immobilized TEMPO in the reaction mixture. There
⇑
Corresponding author. Tel.: +81 3 5452 6357; fax: +81 3 5452 6359.
E-mail address: kkudo@iis.u-tokyo.ac.jp (K. Kudo).
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.008

K. Akagawa et al. / Tetrahedron Letters 52 (2011) 770–773
771
Table 1
Oxidation with TEMPO and copper salt followed by asymmetric aldol reaction with prolyl peptide in one-pot
Entry
(AA)
n
1a:2a:3a
ee (%) of 3a
1
2
3
4
—
Gly
93:2:5
94:1:5
82
80
80
82
84
82
82
82
(Gly)
(Gly)
(Gly)
(Gly)
(Leu)
(Phe)
2
3
3
5
89:1:10
63:7:30
78:4:18
95:1:4
89:1:10
80:3:17
(5)
(5)
a
5
6
7
8
3
3
a
Oxidation reaction was performed in DMF instead of in THF.
0
Scheme 1. Adsorption of CuCl and 2,2 -bipyridine in resin-supported catalysts.
are several reports claiming that a glycine-based peptide has an
ability to form a complex with a copper salt.12 Accordingly, glycine
residues were introduced between TEMPO and the PEG–PS resin to
locate the copper salt close to TEMPO moiety. Although the inser-
tion of one or two glycine(s) did not significantly improve the reac-
tivity (entries 2 and 3), triglycine tether brought about the
acceleration of the oxidation (entry 4). Introducing glycine penta-
mer or other amino-acid trimers were not as effective as triglycine
whereas only 0.3 mol equiv was entrapped in the simple TEMPO-
bound PEG–PS resin. This distinct affinity of the copper complex
toward the resins coincides with the different rate of the oxidation
catalyzed by the two types of immobilized TEMPO (Scheme 1, en-
tries 1 and 4).
With employing the above pre-adsorption method, the one-pot
sequential reaction was performed under optimized reaction con-
ditions (Table 2). For the asymmetric aldol reaction, catalyst 7 was
employed because of the slightly better catalytic performance
compared to catalyst 4. The benzyl alcohols having 2-nitro or 2-
chloro substituent were converted to aldol product 3 in good yield
and enantioselectivity (entries 1 and 4). The substrates having 3-
nitro or 4-nitro group also afforded the corresponding aldol prod-
ucts in an enantioselective manner although generated aldehyde 2
was not fully converted into aldol 3 in 24 h (entries 2 and 3). The
use of cyclohexanone instead of acetone resulted in the retarded
aldol reaction. Nevertheless, the reaction also proceeded enanti-
oselectively and the isolated yield based on consumed aldehyde
2 was good (entry 5).
(
entries 6–8). In all cases, the formation of 3a by the subsequent al-
dol reaction proceeded in an enantioselective manner, though the
conversions were low. The use of the buffer was critical for sup-
pressing the non-enantioselective background reaction caused by
0
2
,2 -bipyridine as a base. When non-supported TEMPO was em-
ployed under the same conditions, TEMPO was quickly consumed
to give the
data).
a-oxyaminated product of acetone (see Supplementary
Although the oxidation was enhanced by introducing the trigly-
cyl peptide, the reaction rate was still low. One possible reason is
insufficient incorporation of the copper salt to the triglycine-mod-
ified resin. Therefore, the resins were pretreated with DMF solution
One of the merits of supported catalysts is their reusability with
0
13
of an excess amount of copper(I) chloride and 2,2 -bipyridine
a simple operation. We next attempted to reuse the catalysts.
(
Scheme 1). After the resins were collected by filtration, washed,
Unfortunately, in the second use of the mixed catalyst system, se-
vere decrease in the reaction rate of the aldol reaction was ob-
served (1a:2a:3a = 0:52:48, 30% isolated yield of 3a with 84% ee).
This might be because the partial deterioration of catalyst 7 was
caused by the copper ion. Therefore, TEMPO catalyst 5 was re-
moved by filtration after the alcohol oxidation, and then catalyst
and dried, a black mixture of the beads was obtained. By employ-
ing this Cu-adsorbed catalyst, the rate of the oxidation of the alco-
hol was significantly enhanced. Gravimetric analysis indicated that
about 1 mol equiv of the copper complex per TEMPO was adsorbed
into the resin in the case of catalyst 5 having triglycyl tether,

7
72
K. Akagawa et al. / Tetrahedron Letters 52 (2011) 770–773
Table 2
One-pot two-step reaction using supported catalysts with pre-adsorption of Cu-complex
Entry
R1
R2
R3
Amount of 5 (mol %)
1:2:3
Isolated yield (%) of 3
ee (%) of 3
1
2
3
4
5
2-NO
3-NO
4-NO
2-Cl
2
2
2
H
H
H
H
H
H
H
H
20
10
10
10
10
0:13:87
0:58:42
0:56:44
0:14:86
6:73:21
73
39
44
75
18
85
73
70
73
a
b
2-NO
2
–(CH
2
3
) –
87
a
Diastereomeric ratio was anti/syn = 92:8.
Value of anti product.
b
Table 3
Reusability of supported catalysts for sequential two-step reaction
Entry
Reuse of catalysts
Conditions of oxidation
1a:2a:3a
Isolated yield (%) of 3a
ee (%) of 3a
1
2
3
4
5
6
7
8
1st use
2nd use
3rd use
4th use
5th use
6th use
7th use
8th use
Under air, 6 h
Under air, 6 h
Under air, 24 h
Under air, 24 h
4:0:96
6:2:92
14:2:84
15:1:84
7:2:91
3:5:92
10:0:90
10:0:90
78
73
76
71
80
74
76
75
87
89
88
89
89
88
90
88
Under O
Under O
Under O
Under O
2
2
2
2
, 24 h
, 24 h
, 24 h
, 24 h
7
and ethylenediaminetetraacetic acid (EDTA), a trapping agent for
oxidation and organocatalytic conversion of the resulting alde-
hydes is now under way in our laboratory.
1
4
the leached copper ion, were added to the filtrate to ensure the
subsequent DAA reaction. Recovered catalysts 5 and 7 were sub-
jected to the repeated use for the sequential reaction (Table 3).
Although the reactivity of the TEMPO-supported catalyst gradually
decreased, modification of the reaction conditions for the oxidation
successfully realized repetitive use of the catalysts, and aldol prod-
uct 3a could be obtained without a significant loss in yield and
enantioselectivity even after eight times of reuse.
Supplementary data
Supplementary data (preparation of catalysts, experimental
procedure, reaction between non-supported TEMPO and acetone)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.12.008.
In conclusion, the DAA reaction was attained utilizing primary
alcohols as starting materials by combining the two catalytic sys-
tems, the TEMPO/Cu-oxidation and the prolyl-peptide-based
organocatalysis. The resin-support made TEMPO and the prolyl
catalyst compatible in one-pot (Tables 1 and 2), and also made
the two kinds of catalysts easily separatable and reusable in the
method of adding them sequentially (Table 3). The key to success
of the present system was that the efficiency of the oxidation could
be dramatically improved both by introducing triglycine between
TEMPO and the resin and by the pre-adsorbing procedure. Further
investigation on other sequential reactions involving the alcohol
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