Communications
complexes, the reaction intermediate for the S,S-selective
formation of oxindoles under the catalysis of
(DHQD)2PHAL is presumably an open conformation similar
to that described by Corey and Noe for osmium-catalyzed
asymmetric
dihydroxylation
(Scheme 2).[9]
With
the synthesis of biologically interesting analogues of suruga-
toxin has been attempted. We confirmed that 1i and 1j could
be converted smoothly into the corresponding oxindole aldol
adducts 3i and 3j, respectively, under the optimized reaction
conditions (Table 2, entries 24, 25, 27, and 28). Unfortunately,
however, the spirooxindole (R*,R*)-4k produced spontane-
ously in acceptable yields in the reaction of 1k with ethyl
trifluoropyruvate was obtained as a racemate as a result of a
retro-aldol reaction of the intermediate 3k caused by the
basicity of the benzylamino moiety (Table 2, entries 26 and
29).
In conclusion, we have developed an organocatalytic
enantioselective direct aldol-type reaction of oxindoles with
trifluoropyruvate. By employing suitable pseudoenantiomeric
cinchona alkaloids as catalysts, both enantiomers of the
trifluoromethylated oxindole products with two contiguous
asymmetric quaternary carbon centers can be obtained
selectively in one step. The CF3 group of the pyruvate is
essential to the success of the oxindole-aldol reaction.
Although the absolute configuration of the tertiary alcohol
center in (R,R)-3 is opposite to that of the equivalent center in
natural surugatoxin, we are confident that the total synthesis
of trifluoro-substituted surugatoxin will be possible by using
this strategy, as methodology for the inversion of tertiary
alcohols has been developed by Mukaiyama and co-work-
ers.[11] Studies toward the total synthesis of the trifluoro-
methyl analogue of surugatoxin and epimeric compounds are
ongoing.
Scheme 2. Conformation of the (DHQD)2PHAL catalyst and proposed
approximate structure of the substrate–catalyst complex for the S,S-
selective formation of adducts 3 in the aldol-type condensation of
oxindoles 1 with 2.
(DHQD)2PHAL in the open conformation, the deprotona-
tion of the oxindole is induced by the quinuclidine nitrogen
atom, and the resulting enoates might be stabilized in part
through hydrogen bonding and p stacking in the U-shaped
cleft of (DHQD)2PHAL. The Si face of the oxindole is
covered so effectively by the quinoline ring that trifluoropyr-
uvate approaches the Re face and is captured by the hydro-
gen-bonding network through the quinuclidine nitrogen
atom. Consequently, the S,S isomers 3 are produced predom-
inantly. The cinchona alkaloid may act as the catalytic base in
the first step of the mechanism, the deprotonation step, and as
the catalytic acid in the second step, the aldol reaction.
Further studies are required to fully elucidate the mechanistic
details of this direct aldol-type reaction of oxindoles
(Scheme 2).
As a preliminary investigation into the application of this
methodology to the preparation of biologically active mole-
cules, we examined the asymmetric direct aldol-type reaction
of substrates 1i–k with 3-aminoethyl substituents (Table 2,
entries 24–29) to form a core component of the trifluoro-
methyl analogue of surugatoxin. Surugatoxin[10] is a biologi-
cally active natural product isolated from the toxic Japanese
ivory shell, Babylonia japonica. It depresses orthodromic
transmission reversibly and antagonizes the depolarizing
action of carbachol on isolated rat superior cervical ganglia.
A total synthesis of racemic surugatoxin has been repor-
ted;[10b] however, neither an asymmetric total synthesis nor
Experimental Section
3a: 2 (54.0 mL, 0.40 mmol) was added slowly to a stirred mixture of 1a
(30.0 mg, 0.20 mmol) and (DHQD)2PHAL (15.8 mg, 0.020 mmol) in
Et2O (1.0 mL) at 08C. The resulting mixture was allowed to warm to
room temperature over 5 h, and was stirred at room temperature for
11 h. The Et2O solvent was then removed under reduced pressure,
and the residue was purified by column chromatography on silica gel
(AcOEt/n-hexane 1:4) to give (2S,3S)-3a (64.2 mg, 99%, d.r. 90:10,
95% ee) as a white solid. The minor diastereomer was obtained with
74% ee.
Received: July 24, 2007
Published online: October 2, 2007
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8666 –8669
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