CHEMCATCHEM
COMMUNICATIONS
Compared with the wasteful and tedious isolation processes
for homogeneous catalysis, immobilizd catalysts have attracted
considerable attention owing to their recoverable and recycla-
ble properties.[9] Magnetic nanoparticles (MNPs), as a new type
of catalyst carrier, have several prominent advantages, such as
high surface/area ratio, unique magnetic properties, outstand-
ing dispersibility, chemical durability, and low toxicity.[10] In ad-
dition, magnetic separation renders the recovery of catalysts
from a reaction media much easier than by filtration or centri-
fugation. For these reasons, MNPs, as burgeoning catalyst carri-
ers, have tremendous potential for performing catalytic asym-
metric synthetic transformations in an economical and environ-
mentally friendly manner. Recently, we developed a series of
rosin-derived amino thiourea catalysts to effectively organoca-
talyze aza-Henry reactions with the in situ generation of N-Boc
imines Boc=tert-butoxycarbonyl).[11,12] In view of the current
needs in peptide research and the different (or even opposite)
pharmaceutical activities of individual enantiomers of the same
compound,[13] herein, we report a new MNP-supported bifunc-
tional rosin-derived tertiary amino thiourea catalyst for the ste-
reocontrolled synthesis of b-amino acids through an asymmet-
ric Mannich reaction with the in situ generation of N-Boc
imines.
amino thiourea catalyst L4 was fabricated and examined as
a catalyst for this stereocontrolled organocatalytic asymmetric
process during the elaboration of the optimal conditions.
Next, we further examined the optimal reaction conditions
for this Mannich reaction (Table 1). These results indicated that
changing the solvent had a significant effect on the enantiose-
lectivity of this transformation and the use of, for example,
THF and MeCN, significantly decreased the stereoselectivity
(Table 1, entries 1 and 2). Of the solvents that were examined,
toluene was the best in terms of chemical yield and enantiose-
lectivity (Table 1, entry 5). With the purpose of improving the
stereoselectivity, the reaction temperature was lowered further.
The best result was obtained without a significantly decrease
in yield (88% yield, 95% ee; Table 1, entry 7) for the reaction in
the presence of thiourea (1S,2S)-L4 at À158C; thiourea (1R,2R)-
L4 also exhibited superior catalytic activity, with an opposite
sense of asymmetric induction (85% yield, 91% ee; Table 1,
entry 10).
The results of experiments under the optimized conditions
that probed the scope of this reaction are summarized in
Table 2. Thus, the stereocontrolled catalytic Mannich reactions
of dibenzyl malonate with various N-Boc-protected imines that
were generated in situ from a variety of substituted a-amido
sulfones were examined. Except for an aliphatic substrate
(Table 2, entry 15), a variety of aromatic amido sulfones that
contained various types of substituents underwent the reac-
tion to afford the desired products with S or R configurations
with excellent enantioselectivities and high yields (R adducts:
90–96% ee, 80–92% yield; S adducts: 90–96% ee, 81–90%
yield; Table 2, entries 1–12). As expected, the reactions of het-
erocyclic amido sulfones also proceeded in excellent enantio-
A model reaction of dibenzyl malonate (1a) with a-amido
sulfone 2a was performed in the presence of various thiourea
catalysts at room temperature under different conditions (see
the Supporting Information, Table S1). Our initial investigations
began by screening a range of inorganic bases, either as solids
or aqueous solutions, to evaluate their influence on this cata-
lytic asymmetric process with rosin-derived tertiary amino thio-
urea catalyst (1S,2S)-L3 (15 mol%) at room temperature in tolu-
ene (see the Supporting Infor-
mation, Table S1, entries 1–9).
Table 2. Mannich-type reactions of dibenzyl malonate with N-Boc-protected imines that are generated in situ
from a-amido sulfones under the optimized conditions.[a]
We found that an inorganic
base was crucial for obtaining
high reaction efficiencies. We
found that the best result was
obtained when the reaction was
conducted with 1.0 equivalent
of K2CO3 in a biphasic solvent
(90% yield, 85% ee; see the
Entry
R
Product
Yield R/S [%][b]
ee R/S [%][c]
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3
3
3
3l
3m
3n
3o
88/85
80/81
80/83
85/83
90/85
83/86
90/86
85/90
81/81
92/86
85/86
80/82
88/90
81/85
05/08
95/91
95/91
90/90
92/92
93/92
95/91
96/94
93/94
91/90
95/96
90/90
93/92
92/90
93/93
n.d.
Supporting
Information,
2-naphthyl
4-MePh
4-MeOPh
4-ClPh
4-FPh
4-BrPh
3-ClPh
3-MeOPh
2-FPh
Table S1, entry 6). Interestingly,
when using the opposite config-
uration of tertiary amino thiour-
ea L3, a pair of opposite optical-
ly active b-amino carbonyl ad-
ducts were obtained with similar
yields and enantioselectivities
(see the Supporting Information,
Table S1, entry 7). Next, we
tested the effects of other cata-
lysts (see the Supporting Infor-
mation, Table S1, entries 10–12).
To further improve the recycla-
bility of these catalysts, MNP-
supported rosin-derived tertiary
9
10
11
12
13
14
15
2-BrPh
2-MeOPh
2-thiophenyl
2-furyl
cyclohexyl
[a] Unless otherwise stated, the reactions were performed with an a-amido sulfone (0.1 mmol), dibenzyl malo-
nate (1a, 0.2 mmol), and K2CO3 (1.0 equiv) in toluene (1.0 mL) and water (50 mL) at À158C for 48 h. [b] Yield of
isolated product. [c] The ee value was determined by HPLC and the configuration was assigned by comparison
of the HPLC data and specific rotation with literature data.[5b]
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