the a-isothiocyanato imide, activated by a Lewis base, with
subsequent cyclization to lead to the generation of a 3,3’-
thiopyrrolidonyl spirooxindole, which can then be oxidized to
the 3,3’-pyrrolidonyl spirooxindole in a single transformation
(Scheme 2). On the basis of our recent success in enantiose-
lective organocatalysis using rosin-derived bifunctional thio-
urea catalysts developed in our group,[12,13] we surmised that
this kind of organocatalyst would be suitable for catalyzing
the asymmetric Michael/cyclization sequence through double
activation.
and with a slightly higher d.r. value, but in a relatively low
product yield resulted (entry 3). The widely used catalyst
L4[14] exhibited poor catalytic activity, and furnished the
product with relatively low diastereoselectivity despite its
excellent enantioselective control (entry 4). Notably, the
other enatiomer of the product could also be accessed with
the same excellent ee and d.r. values, as well as yield when L2
was used (entry 2). When the catalyst loading was reduced to
10 mol% and 5 mol%, the same excellent results were
obtained, but 36 hours were needed for completeion of the
reaction when 5 mol% catalyst was used (entries 5 and 6). L1
at a 10 mol% loading was selected for further studies in terms
of efficiency.
With the established optimal reaction conditions, a variety
of 3,3’-thiopyrrolidonyl spirooxindole compounds were syn-
thesized and the results are summarized in Scheme 3. Various
N-protecting groups of the methyleneindolinone having
different electronic and steric parameters were tolerated,
and gave the corresponding compounds in excellent yield,
good to excellent diastereoselectivity, and excellent enantio-
selectivity (3a–3 f). Both electron-donating and electron-
withdrawing substituents at different positions on the aro-
matic ring afforded the products in greater than 99% ee,
excellent d.r. values, and good to excellent yields (3g–3q).
An increase of the steric hindrance introduced by a bulkier
ester group did not affect the enantioselectivity, but decreased
the d.r. value of the products and the activity of the reactions,
as a longer time was needed to complete the reaction (3r and
3s). Notably, when the nitrogen atom of methyleneindolinone
was replaced by a sulfur or oxygen atom the reaction
proceeded smoothly, thus providing the product 3t with
greater than 99% ee and moderate distereoselectivity, and the
product 3u with moderate enantioselectivity and excellent
distereoselectivity. In addition to a-isothiocyanato imide,
methyl isothiocyanato acetate was also shown to be the
suitable substrate in the reaction (3v). Furthermore, the
spirooxindole 3w having three contiguous stereocenters,
including two spiro-quaternary chiral centers, was constructed
using this catalytic system and a-isothiocyanato lactone as the
reactant; the product was isolated with excellent stereo-
seletivity and in good yield. The absolute and relative
configurations of the spirooxindoles were unambiguously
determined by X-ray crystallography (see the Supporting
Information).
Scheme 2. Strategy for the construction of the 3,3’-pyrrolidonyl spiroox-
indole scaffold using a bifunctional chiral catalyst. PG=protecting
group.
To begin our initial investigation, several bifunctional
thiourea catalysts (15 mol% catalyst) were screened to
evaluate their ability to promote the Michael/cyclization
reaction sequence of methyleneindolinone (1a) with the a-
isothiocyanato imide 2a at room temperature in CH2Cl2
(Table 1). Gratifyingly, the rosin-derived tertiary amine
thiourea catalyst L1 gave the desired product with greater
than 99% ee, 10:1 d.r., and 99% yield (entry 1). The catalyst
L3 afforded 3a in almost the same excellent enatioselectivity
Table 1: Studies and optimization of the reaction parameters.[a]
On the basis of our experimental results and recent
studies,[15] we have proposed a possible model to explain the
stereochemistry of the Michael/cyclization reaction sequence
(Scheme 4). The electron-deficient methyleneindolinone is
activated by hydrogen bonds involving the carbonyl group in
the indolinone and the thiourea hydrogen atoms of the
catalyst, and the a-isothiocyanato imide is enolized by
deprotonation at its a-carbon atom by the tertiary amine.
The Re face of the enolate is exposed to the methyleneindo-
linone and the Si face of the Michael acceptor is approached
by the incoming nucleophile. Subsequent nucleophilic attack
of the stabilized carbon anion onto the electron-defficient
carbon atom of the a-isothiocyanato imide leads to the 3R,
4’R, 5’R-configured spirooxindole product, which is in keep-
ing with the experimental results.
Entry
Cat. (mol%)
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
L1 (15)
L2 (15)
L3 (15)
L4 (15)
L1 (10)
L1 (5)
3
3
12
>72
5
36
99
99
81
80
99
99
10:1
14:1
11:1
6:1
10:1
10:1
>99
>À99
95
95
>99
>99
[a] The reaction was performed at RT on 0.1 mmol scale with 1a
(1.1 equiv), 2a (1.0 equiv), and catalyst in 1 mL CH2Cl2. [b] Yield of
isolated product as a mixture of diastereoisomers. [c] Determined by
1H NMR spectroscopic analysis. [d] Determined by HPLC analysis on a
chiral stationary phase.
Angew. Chem. Int. Ed. 2011, 50, 9124 –9127
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9125