Encouraged by these results and our own laboratory’s
recent success in the construction of bispirooxindoles,3x we
designed a novel MichaelꢀHenry tandem process to con-
struct highly substituted carbocyclic 3,30-spirooxindole
core units from simple 3-substituted oxindoles and nitro-
styrenes, catalyzed by cinchona alkaloids (Figure 2).
Successfully executed, this strategy would allow four
consecutive stereocenters, including one quaternary spiro-
carbon center, to be set in a single step. Herein, we report
the realization of this goal with the organocatalytic synthe-
sis of a collection of spirocyclic-3,30-oxindoles in excellent
chemical and optical yield.
In an effort to identify a suitable catalyst for our
proposed transformation, those shown in Figure 3, includ-
ing several chiral tertiary amine derivatives (IꢀVII) and
Figure 2. Retrosynthetic analysis for the construction of spiro-
cyclo-3,3-oxindoles via a MichaelꢀHenry cascade reaction.
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Figure 3. Organocatalysts employed in the asymmetric Michaelꢀ
Henry cascade reaction.
those with thiourea moieties (VꢀVII), were evaluated in a
model reaction of oxindole derivatives 1aꢀd and nitro-
styrene 2a. Benzyl-protected catalyst II6 provided reaction
product 3a with a dr of 1:1:1 and an enantiomeric excess of
66% ee (Table 1, entry 2). The replacement of the benzyl
group by the sterically more demanding 9-anthracenyl-
methyl group (III) led to an improvement in selectivity.
Only two diastereomers (dr 1:3) with an enantiomeric
excess of 78% were obtained (entry 3), whereas use of
thiourea-containing catalyst V7 resulted in 1:4 dr and ꢀ43%
ee (entry 5). A Takemoto-type catalyst VI,8 containing a bis-
methylated cyclohexylamine functionality, provided prod-
uct 3a with a 1:3 diastereoselectivity and an enantiomeric
excess of 58% (entry 6). Use of VII,9 in which the amine
moiety is incorporated in a cyclic C5-tether, resulted in a
similar dr; however, the ee was increased to 78% (entry 7).
Encouraged by these results, further experiments were
undertaken to better understand the catalytic system.
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