Primary amine-metal lewis acid bifunctional catalysts: the application to asymmetric direct aldol reactions

Article abstract of DOI:10.1039/b912728c

The first example of metal Lewis acid-primary amine bifunctional cooperative catalyst derived from primary amino acids was developed, and it was found to catalyze aldol reactions of cyclic ketones highly efficiently with very good to excellent stereoselec

Full text of DOI:10.1039/b912728c

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Primary amine-metal Lewis acid bifunctional catalysts: the application
to asymmetric direct aldol reactionsw
Zhenghu Xu, Philias Daka and Hong Wang*
Received (in Berkeley, CA, USA) 2nd July 2009, Accepted 18th September 2009
First published as an Advance Article on the web 7th October 2009
DOI: 10.1039/b912728c
The first example of metal Lewis acid-primary amine bifunc-
tional cooperative catalyst derived from primary amino acids
was developed, and it was found to catalyze aldol reactions of
cyclic ketones highly efficiently with very good to excellent
stereoselectivities.
will act as a Lewis acid, and at the same time it will also serve to
assemble the molecule into a relatively rigid structure, a desired
property for bifunctional catalysts. Furthermore, the Lewis
acidity and the secondary structure for substrate interaction
can be easily tuned by introducing different metals.
Six tridentate ligands were prepared (Fig. 1). These ligands can
be readily obtained through coupling reactions of 2,6-diamino-
pyridine with natural amino acids (see ESIw for synthetic details).
We initially conducted metal screening with ligand 1a in the aldol
reaction of cyclohexanone with 4-nitrobenzaldehye in THF. While
all metal salts examined displayed activity (Table 1, entries 1–4),
Cu(SbF6)2 showed exceptionally good activity and high stereo-
selectivity. The aldol reaction was complete in only 12 h, and the
aldol product 5a was generated in 92% yield, 15:1 dr (anti/syn),
and 90% ee (anti). The different activities and selectivities observed
for different metals may arise from different Lewis acidities and
coordination geometries of the metals. Counter anion effect was
also observed: Cu(OTf)2 displayed lower activity and stereo-
selectivity relative to Cu(SbF6)2 (entries 1 and 2). Slightly better
results were obtained when neat conditions were applied (entry 5).
We then screened the ligands in conjunction with Cu(SbF6)2 under
neat conditions (entries 6–10). Excellent stereoselectivity (up
to 499:1 dr and 95% ee) and activity were observed for L-valine
derived catalysts (entries 5–8). As compared with L-valine-based
catalysts, catalysts derived from L-phenylalanine showed lower
stereoselectivity (entries 9 and 10). Among all the catalysts,
1c/Cu(SbF6)2 offered the best results (entry 10). In comparison
with the aldol reactions catalyzed by other metal Lewis acids
The direct asymmetric aldol reaction is one of the most important
C–C bond-forming reactions.1 In nature, it is catalyzed by
aldolases with excellent stereocontrol.2 Type I aldolase activates
the aldol donor by a primary amino group of lysine located at the
active site through an enamine mechanism, based on which the
enamine-based aminocatalysis was developed;3 in type II aldolase
a zinc cofactor is involved as a Lewis acid; several research groups
have mimicked this process by using metal complexes.4 We want
to take advantage of both types of aldolases and develop a novel
class of enamine (Lewis base)-metal Lewis acid bifunctional
catalysts with the intention to bridge the more traditional fruitful
transition metal catalysis with the newly established prosperous
aminocatalysis.
As compared with their secondary amine counterpart (proline),
which has been playing a major role in organocatalysis and has
been intensively investigated in the past few years,3 primary
amino acids have received much less attention.5 However,
primary amino acids and their derivatives have shown unique
selectivity and activity in organocatalysis as demonstrated by
recent studies on aldol and Mannich reactions.6 Although they
are currently of much narrower substrate scope and lower activity
than proline-based catalysts, primary amino acids have shown to
offer better results for many reactions.5,6 Herein, we wish to
report the first example of primary amine-metal Lewis acid
bifunctional catalysts derived from primary amino acids, and
their successful application to asymmetric direct aldol reactions.
The major challenge in developing Lewis acid–Lewis base
bifunctional catalysts lies in the acid–base self-quenching reaction
leading to catalyst-inactivation.7 To solve this problem, we tether
the primary amino acid to a tridentate ligand (Fig. 1), so that the
tridentate ligand will ‘‘trap’’ the incoming metal and prevent the
metal from coordinating to the amine. In this way, the metal and
the primary amine are brought in close proximity without
interacting with each other. This design principle has been
demonstrated in our proline-based enamine-metal Lewis acid
catalysts.8 The metal introduced into the chiral tridentate scaffold
Department of Chemistry and Biochemistry, Miami University,
Oxford, OH 45056. E-mail: wangh3@muohio.edu;
Fax: +1 (513)529-2824; Tel: +1 (513)529-2824
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, characterization data for all new compounds,
and HPLC data. See DOI: 10.1039/b912728c
Fig. 1 Structure of ligands and illustration of bifunctional catalyst.
Chem. Commun., 2009, 6825–6827 | 6825
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Table 1 Metal and ligand screeninga
Entry
Ligand
Metal
Solvent
T/h
Yield (%)e
Anti/synf
ee (%)g
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
2
3
4
1c
1c
1c
Cu(SbF6)2
Cu(OTf)2
Zn(OAc)2
Co(ClO4)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
THF
THF
THF
THF
neat
neat
neat
neat
neat
neat
neat
neat
neat
12
24
48
24
12
12
12
12
12
12
16
20
36
92
56
36
70
90
92
90
93
95
64
84
80
90
15/1
8/1
1/1.3
5/1
15/1
22/1
499/1h
499/1h
8/1
91
87
25/12
79
93
95
95
92
81
57
95
94
92
9
10
11b
12c
13d
5/1
16/1
20/1
20/1
a
The reactions were performed with 0.2 mmol of 4-nitrobenzaldehyde and 0.3 mL of cyclohexanone at room temperature in 0.6 mL THF; or
b
c
0.2 mmol of 4-nitrobenzaldehyde with 1 mL of cyclohexanone (neat). 5 Equiv. of H2O was added. 10 Equiv. of H2O was added. 10 Mol%
catalyst. Combined yield. Determined by H NMR. Determined by chiral HPLC. The syn diastereomer was not observed on 1H NMR.
d
e
f
1
g
h
requiring moist and air free,4 this reaction system is water and air
heterocyclic ketones reacted with both electron-rich and
tolerant. The aldol reaction proceeded smoothly in the presence of
water and air with slightly lower diastereoselectivities (entries 11
and 12). When lower catalyst loading was applied, longer reaction
time was required for the completion of the reaction (entry 13).
Ligand 1c/Cu(SbF6)2 was then selected for further investiga-
tion. Under the optimal conditions, the aldehyde scope of the
direct aldol reaction of cyclohexanone was evaluated (Table 2).
Not only were the reactive electron-deficient aldehydes excellent
substrates, giving 6/1 to 499/1 diastereoselectivity (anti/syn),
and 88–95% enantioselectivity (Table 2, entries 1–8), but
the unreactive electron-rich aldehydes also furnished the
aldol products 5 in good yields with high stereoselectivities
(8/1–12/1 dr, 83–90% ee) (entries 9–11).
electron-poor aldehydes and generated aldol products (6) in
high yields with excellent diastereoselectivities (10/1–46/1,
anti/syn) and very good enantioselectivities (87–94%) (entries
2–7). It is noteworthy that only 2.5 eq. of heterocyclic ketones
were used in these aldol reactions. However, the reactions of
cyclopentanone and acetone with 4-nitrobenzaldehyde lead to
the corresponding aldol products in lower diastereoselectivity
and enantioselectivity, respectively (entries 1 and 8).
In order to understand the nature of the catalysts, we have
conducted a series of reactions (Scheme 1). When free ligand
1a was solely used as the catalyst in the absence of a metal, no
reaction was detected. Addition of benzoic acid (20 mol%)
lead to less than only 5% of formation of the aldol product.
Cu(SbF6)2 alone cannot catalyze the aldol reaction. These data
are in striking contrast to the aldol reactions carried out with
1a/metal indicating that both ligand 1a and Cu(SbF6)2 are
essential for the aldol reaction to occur. It has been well accepted
that for primary amine catalyzed aldol reactions, the presence of
water is necessary to facilitate the formation of enamine leading
to the aldol product.5a,9 It is noteworthy that the aldol reactions
catalyzed by this bifunctional catalyst, even though water
tolerant (Table 1, entries 11 and 12), proceeded highly efficiently
in the absence of water. These data strongly support that this
primary amine-metal Lewis acid bifunctional catalyst function
cooperatively, and the aldol acceptors (aldehyde) are more
activated in this bifunctional catalytic system relative to those
in the primary amino acid-based (enamine-Brønsted acid)
organocatalytic system,5,6 showing the great potentials of these
catalysts. All the aldol reactions predominately generated the
anti aldol products with a (2S, 10R) configuration. We speculate
that the metal coordinates with the chelating ligand to form a
rigid chiral structure and acts as a Lewis acid to activate the
aldehyde; the primary amine reacts with cyclohexanone to form
an enamine; the enamine attacks the activated aldehyde from the
re-face to generate the products (Fig. 2).
Several other ketone donors were also investigated and
the results are summarized in Table 3. The six-membered
Table 2 Aldehyde scope of direct aldol reaction of cyclohexanonea
Entry R1
Product Yield (%)b Anti/sync ee (%)d
1
2
3
4
5
6
7
8
4-NO2C6H4
5a
5b
5c
5d
90
90
82
93
89
98
73
60
76
71
75
499/1e
20/1
499/1e
12/1
9/1
12/1
6/1
6/1
95
95
94
92
94
92
88
94
86
90
83
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-COOMeC6H4 5e
2,6-Cl2C6H3
4-ClC6H4
4-BrC6H4
C6H5
2-Naphthyl
4-MeC6H4
5f
5g
5h
5i
5j
5k
9
10
11
10/1
12/1
8/1
a
The reactions were performed with 0.2 mmol of aldehyde at room
b
temperature in 1 mL of cyclohexanone for 12–48 h. Combined
yield. Determined by 1H NMR. Determined by chiral HPLC.
e
c
d
1
The syn diastereomer was not observed on H NMR.
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Table 3 The aldol reaction of different ketone donorsa
Entry
R1
R2, R3
Product
Yield (%)c
Anti/synb
ee (%)d
1e
2
3
4
5
6
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
4-CNC6H4
2-Naphthyl
C6H5
–CH2CH2–
–CH2OCH2–
–CH2SCH2–
–CH2SCH2–
–CH2SCH2–
–CH2SCH2–
–CH2SCH2–
H, H
6a
6b
6c
6d
6e
6f
66
97
82
76
86
57
68
84
3/1
86
87
94
94
91
87
94
72
10/1
22/1
25/1
46/1
34/1
25/1
—
7
6g
6h
8e
4-NO2C6H4
a
b
The reactions were performed with 0.2 mmol of aldehyde and 0.5 mmol of ketone at room temperature in 1 mL of THF for 12–48 h. Determined
by 1H NMR. Combined yield. Determined by chiral HPLC. The reaction was performed with 0.2 mmol of aldehyde with 1 mL of ketone (neat).
c
d
e
Notes and references
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Scheme 1 Cooperative nature of the bifunctional enamine-metal
Lewis acid catalyst.
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Fig. 2 Proposed transition state.
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In summary, we have developed a novel class of primary
amine-based enamine-metal Lewis acid cooperative bifunc-
tional catalysts, and successfully applied them to asymmetric
direct aldol reactions. These catalysts are highly efficient in
catalyzing the aldol reaction of cyclic ketones with both
electron-rich and electron-poor aldehydes in very good to
excellent stereoselectivity. It is found that the coexistence of
the primary amine and metal Lewis acid is critical for the
reaction to occur. This catalytic system has the following
features: (1) it is the first example of bifunctional catalyst
combining metal Lewis-acid catalysis and primary amine
catalysis; (2) the catalysts’ structure can be easily tuned by
introducing different metals and/or different acyclic amino
acids; (3) the ligands are very simple and can be readily
prepared in large scales; (4) the reaction does not need an
inert atmosphere as required by most metal catalysis. Applica-
tion of these catalysts to Mannich reactions and Michael
reactions is underway.
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We thank Professor Mike Novak for useful discussions.
Financial support was provided by Miami University.
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Chem. Commun., 2009, 6825–6827 | 6827