philes, which regioselectively affords 1-(3-hydroxy-2-oxoin-
dolin-3-yl) pentane-2,4-dione and 3-hydroxy-3-(4-hydroxy-2-
oxopent-3-enyl)-4, 4-dimethyl-dihydrofuran-2ACTHNUTRGENUG(N 3H)-one de-
rivatives with moderate to high optical purities. Further-
more, this method provides a facile access to enantioen-
riched oxygen-containing spirooxindoles[14j,15] and spirobu-
tyrolactones from simple commercial available starting ma-
terials.
To test our hypothesis on the tertiary-amine-promoted C-
Figure 1. Screened catalysts.
1
aldol reaction of 1,3-dicarbonyl compounds, 1,4-
diazabicyclo[2.2.2]octane (DABCO) was initially employed
ACHTUNGTRENNUNG
to catalyze the reaction between acetylacetone and different
aldol reaction acceptors (Table 1). When p-nitrobenzalde-
Inspired by the initial results, we then examined the asym-
metric catalytic ability of chiral tertiary-amine or tertiary-
amine–thiourea catalysts (Figure 1). To our delight, the
aldol reaction of isatin (3a) and acetylacetone (1a) proceed-
ed smoothly in the presence of 5 mol% of quinine (6a) in
EtOAc at room temperature, regioselectively giving the de-
sired compound 5a as the only product in 45% yield, albeit
with 21% ee (Table 2, entry 1). Better results were obtained
Table 1. The screening of aldol reaction acceptors.[a]
2/3
Catalyst
Yield of Yield of
4 [%][c]
5 [%][c]
Table 2. Catalyst screening and optimization of reaction conditions.[a]
1
2
3
4
5
6
7
p-nitrobenzaldehyde (2a)
1,2-cyclohexanedione (2b)
2,2,2-trifluoroacetophenone (2c) DABCO
methyl pyruvate (2d)
ethyl benzoylformate (2e)
isatin (3a)
DABCO
DABCO
22
–
–
–
–
–
–
–
–
–
–
24
–
[b]
[b]
DABCO
DABCO
DABCO
Catalyst
Solvent
T [8C]
Yield [%][b]
ee [%][c]
3a
pyrrolidine 42
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
6a
6b
6c
6d
6e
6 f
6g
6g
6g
6g
6g
6g
6g
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
THF
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
À10
45
52
66
87
45
94
93
91
95
86
59
98
70
21
41[f]
45
[a] The reactions were carried out with 1 (0.15 mmol), 2 or 3 (0.1 mmol),
and catalyst (20 mol%) in EtOAc (0.5 mL) at RT for 1d. [b] Unstable
product was obtained. [c] Isolated yield.
47
49
49
62[f]
57[f]
71[f]
64[f]
53[f]
74[f]
93[f]
hyde (2a) was subjected to the reaction conditions, only
Knoevenagel condensation occurred, affording the corre-
sponding a,b-enone 4 in 22% yield (Table 1, entry 1). Subse-
quently, more sterically congested active ketones were ex-
amined to evaluate the steric and electrophilic effects of the
acceptors (Table 1, entries 2–6). 2,2,2-Trifluoroacetophenone
(2c), methyl pyruvate (2d), and ethyl benzoylformate (2e)
failed to give either compound 4 or 5 (Table 1, entries 3–5),
while 1,2-cyclohexanedione (2b) led to an unstable complex
under the same reaction conditions (Table 1, entry 2). Grati-
fyingly, the reaction between isatin (3a) and acetylacetone
(1a) promoted by DABCO showed excellent C-1 regioselec-
tivity, which afforded 3-hydroxy-3-(4-hydroxy-2-oxopent-3-
enyl)indolin-2-one (5a) as the only product, albeit in low
yield (24%, Table 1, entry 6). To evaluate the influence of
the catalyst, pyrrolidine was then employed to promote the
reaction between isatin and acetylacetone. However, only
the Knoevenagel condensation product was obtained
(Table 1, entry 7). It is indicated that controlling the C-1 re-
gioselectivity of 1,3-dicarbonyl compounds in the direct
aldol reaction can be achieved through substrate and cata-
lyst design. Up to now, only few examples were reported on
substrate-dependent regioselectivity in organocatalysis.[16]
CH3CN
toluene
THF
THF
[a] Unless otherwise noted, the reactions were carried out with 1a
(1 mmol), 3a (0.1 mmol), and catalyst (5 mol%) in solvent (0.5 mL) at
RT for 2d. [b] Isolated yield. [c] Determined by chiral HPLC. [d] 3 ꢁ MS
(100 mg) was added. [e] 1a (3 mmol), 3a (0.1 mmol), catalyst (20 mol%),
and 3 ꢁ MS (100 mg) were added in solvent (0.5 mL) at À108C for 5d.
[f] Opposite configuration was obtained.
when tertiary-amine–thioureas[3a] were used as catalysts
(Table 2, entries 2–7). The screening studies revealed that
6g was the most promising catalyst, affording 5a in good
yield and promising enantioselectivity (Table 2, entry 7,
93%, 62% ee). Optimization of the reaction conditions indi-
cated that performing the reaction in THF gave the highest
enantioselectivity (Table 2, entry 9), while the addition of
3 ꢁ molecular sieves was found necessary to improve the
enantiocontrol. Finally, the highest enantioselectivity was
obtained with sacrificing the chemical yield by decreasing
the reaction temperature to À108C (Table 2, entry 13, 70%,
93% ee).
&
2
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Chem. Eur. J. 0000, 00, 0 – 0
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