Enantioselective base-free phase-transfer reaction in water-rich solvent

Article abstract of DOI:10.1021/ja906821y

(Chemical Equation Presented) The development of enantioselective phase-transfer catalysis for preparing important natural products or physiologically active compounds is quite attractive and challenging in terms of environmental consciousness. Although q

Full text of DOI:10.1021/ja906821y

Published on Web 11/03/2009
Enantioselective Base-Free Phase-Transfer Reaction in Water-Rich Solvent
Rongjun He, Seiji Shirakawa, and Keiji Maruoka*
Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic Chemistry, Department of
Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received August 12, 2009; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1. Phase-Transfer Conjugate Addition of 3-Phenyloxindole
Enantioselective organocatalysis has emerged as a powerful and
promising synthetic field that is complementary to metal-catalyzed
transformations and has accelerated the development of new
methodologies for synthesizing diverse chiral molecules.1 The
operational simplicity, ready availability of catalysts, and low
toxicity associated with organocatalysis provides highly attractive
synthetic methods that would compete with ordinary biocatalyzed
approaches. However, although many biocatalyzed reactions pro-
ceed under neutral conditions in water, both organo- and metal-
catalyzed reactions generally require either acids or bases as reaction
promoters.1 Accordingly, as in biocatalyzed transformations, the
development of certain organocatalytic reactions that would proceed
in water under essentially neutral conditions without any promoters
is quite attractive and challenging in terms of environmental
consciousness. In this context, we are interested in the possibility
of developing an enantioselective conjugate addition of 3-substituted
oxindoles under neutral conditions in water-rich solvent in the
presence of certain chiral phase-transfer catalysts,2 since an
enantioselective conjugate addition of 3-substituted oxindoles to
Michael acceptors is currently one of the hot topics in catalytic
asymmetric synthesis,3,4 as oxindoles are important building blocks
in numerous natural alkaloids and in many pharmaceuticals.5 Very
recently, two enantioselective conjugate additions of 3-alkyloxin-
doles to nitroolefins by either an organocatalytic or organometallic
pathway have been independently reported,4 but the utility of
3-aryloxindoles as substrates for enantioselective conjugate additions
is still found to be difficult.3 Here we report a first example of this
project by demonstrating a hitherto-unknown enantioselective base-
free conjugate addition of 3-aryloxindoles to nitrostyrenes under
neutral conditions in water-rich solvent in the presence of optically
pure quaternary ammonium salts of type 1 as chiral bifunctional
phase-transfer catalysts.
Bu4NBr, and both aqueous K2CO3 and PhCO2K as mild bases work
well for the enantioselective conjugate addition of 2 with high
enantioselectivity (82-83% ee) (Scheme 1). Very surprisingly, we
discoVered that eVen without any basic additiVes, the reaction
proceeds smoothly in the presence of chiral phase-transfer catalyst
(S)-1b in 1:2 toluene/water at 0 °C for 2 h to furnish 3 with 90%
ee,7,8 implying the intervention of intermediary chiral ion pair 4.
Indeed, treatment of 2 with catalyst (S)-1b in 1:2 toluene/D2O at 5
°C for 2 h gave rise to deuterated d-2 in 88% yield with recovery
of 2 in 11% yield, indicating the facile enolization of 2 with the
aid of (S)-1b in water solvent (Scheme 2). In the absence of (S)-
1b or in the presence of Bu4NBr, none of the deuterated product
d-2 was formed. It should be noted that water is essential for the
promotion of the reaction, and the reaction in toluene without water
does not proceed at all. Since quaternary ammonium salts as phase-
transfer catalysts are generally belieVed to require base additiVes,6
the present reaction inVolVing catalyst (S)-1b solely without any
base is regarded as a rare example under essentially neutral
conditions. The enantioselective conjugate addition of 2 to ꢀ-ni-
trostyrene is also found to be catalyzed by (S)-1b in buffer solutions
in the pH range 6.8-7.2 (Scheme 1).9
Scheme 2. Deuteration of 3-Phenyloxindole 2
Conjugate addition of 3-phenyloxindole 2 to ꢀ-nitrostyrene
catalyzed by Bu4NBr as the phase-transfer catalyst proceeded
smoothly with aqueous K2CO3 in toluene at 0 °C for 10 min to
furnish the corresponding conjugate adduct rac-3 in 95% yield
(diastereomeric ratio ) 61:39) (Scheme 1). Use of aqueous PhCO2K
as a mild base, however, gave only 5% yield under phase-transfer
conditions with a much longer reaction time (24 h). In marked
contrast, our newly designed chiral bis(3,5-bis(trifluoromethyl)phe-
nyl)hydroxymethyl-substituted phase-transfer catalyst (S)-1b with
bifunctional properties exhibited a high reactivity compared with
With this information at hand, we further carried out the
enantioselective conjugate addition of 3-phenyloxindole 2 to
ꢀ-nitrostyrene under neutral conditions in water-rich solvent (10:1
water/toluene)10 in the presence of chiral phase-transfer catalyst
9
16620 J. AM. CHEM. SOC. 2009, 131, 16620–16621
10.1021/ja906821y CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Transformation of Conjugate Adduct 3
(S)-1b with both high diastereo- and enantioselectivity (Scheme
1). In contrast, chiral diphenylhydroxymethyl-substituted phase-
transfer catalyst (S)-1a, the structure of which was confirmed by
X-ray analysis,11 exhibited moderate enantioselectivity (40% ee).
Because methyl-protected (S)-1c showed only a low enantioselec-
tivity (-6% ee), the presence of hydroxy groups in catalyst (S)-1b
is crucially important, implying the bifunctional nature of this
catalyst.12,13
Other selected examples are listed in Scheme 3. 3-Phenyloxindole
possessing an electron-withdrawing chloro substituent gave higher
enantioselectivity, while introduction of an electron-donating meth-
oxy group resulted in the decrease of both the diastereo- and
enantioselectivity. 3-(ꢀ-naphthyl)oxindole, 3-benzothiophen-2-ylox-
indole, 1-(2-furyl)-2-nitroethene, and 1-nitro-4-phenyl-1-butene
exhibited good diastereoselectivity and high enantioselectivity. In
case of the 1-nitro-1-pentene substrate, high enantioselectivities were
observed for both diastereomers in spite of low diastereoselectivity.
Unfortunately, 3-methyloxindole gave low reactivity and selectiv-
ity.14
phase-transfer catalysts to realize various enantioselective base-
free organic transformations in water solvent under neutral condi-
tions. The results of these studies will be reported in due course.
Scheme 3. Selected Examples of Enantioselective Conjugate
Addition of 3-Substituted Oxindoles
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research from MEXT, Japan. We thank Dr. Xisheng
Wang and Dr. Takuya Hashimoto for X-ray analysis of (S)-1a.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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Importantly, both racemic and optically active conjugate adducts
derived from 3-aryloxindoles can be readily transformed into
valuable natural products and their analogues. For example, the
optically active conjugate adduct 3 (90% ee) was subjected to
catalytic hydrogenation over Pd/C in EtOAc/MeOH, removal of
the Boc protecting group with trifluoroacetic acid in CH2Cl2, and
treatment with LiAlH4 in THF (Scheme 4) to furnish the corre-
sponding cyclization product 6, which has a core structure similar
to those of many important natural products such as flustramines
and flustramides, etc.15 These natural product analogues might
possess important biological activity and hence are valuable for
drug discovery.
In conclusion, we have developed the enantioselective conjugate
addition of 3-aryloxindoles to ꢀ-nitrostyrene under neutral condi-
tions in water-rich solvent in the presence of chiral phase-transfer
catalyst (S)-1b without base additives. The reaction proceeds in a
highly diastereo- and enantioselective manner. We are continuing
to explore the enormous synthetic potential of chiral bifunctional
(7) The BF4- salt of (S)-1b showed results similar to those for the corresponding
bromide salt (97%, dr ) 92:8, 90% ee).
(8) For the stereochemical determination of 3, see the Supporting Information.
(9) Buffer solutions were prepared from NaH2PO4/Na2HPO4 by the Sigma-
Aldrich Buffer Reference Center.
(10) We used a small amount of toluene to dissolve solid 2, ꢀ-nitrostyrene, and
(S)-1.
(11) See the Supporting Information.
(12) Chiral 3,3′-diarylbinaphthyl-modified ammonium salts (ref 13) also exhibited
low enantioselectivity. For details, see the Supporting Information.
(13) (a) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc. 2007, 129,
1038. (b) Wang, Y.-G.; Kumano, T.; Kano, T.; Maruoka, K. Org. Lett.
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(14) Only a low yield (34%) was obtained after 24 h at 0 °C.
(15) (a) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Elsevier Science Ltd.:
Oxford, U.K., 1999; Vol. 13, p 163. (b) Kawasaki, T.; Shinada, M.; Ohzono,
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