DOI: 10.1002/anie.201006595
Asymmetric Catalysis
Highly Enantioselective Catalytic Benzoyloxylation of 3-Aryloxindoles
Using Chiral VAPOL Calcium Phosphate**
Zuhui Zhang, Wenhua Zheng, and Jon C. Antilla*
3-Hydroxy-2-oxindoles are structural motifs present in a
number of natural products and biologically active com-
pounds.[1,2] Among these molecules, 3-aryl-3-hydroxyoxin-
doles represent an important class of molecules that have
found broad applications in medicinal chemistry. One such
example is SM-130686 (Scheme 1), a compound exhibiting
Benzoyl peroxide (BPO) is a readily available oxylation
reagent, which has been known for decades.[11] Nonetheless,
asymmetric oxylation using BPO are very rare.[12] Herein, we
describe, to the best of our knowledge, the first example of a
highly enantioselective benzoyloxylation of an oxindole with
BPO catalyzed by a chiral calcium phosphate (Scheme 2).[13]
By comparison to published reports, this work provides access
to 3-hydroxyoxindole derivatives with the highest stereose-
lectivity to date.
Scheme 1. Structure of SM-130686.
Scheme 2. Enantioselective benzoyloxylation of oxindoles.
potent activity with respect to growth hormone release.[2a] The
absolute configuration of the hydroxy group at the C3
position was shown to further modulate the biological
activity.[2c] It is therefore of high importance to introduce
asymmetry at the C3 position with high enantiocontrol. To
date, only a limited number of approaches have been
reported, which outline the preparation of chiral 3-hydroxy-
2-oxindoles. One type of approach calls for the asymmetric
nucleophilic addition of organometallic reagents[3] or elec-
tron-rich reagents[4–6] to isatins. The second approach entails
asymmetric hydroxylation of 3-substituted 2-oxindoles.[7]
Despite these developments, the available methodologies
are often limited and a new methodology is highly desirable,
considering the importance of chiral 3-substituted oxindoles.
Since the independent reports by Akiyama and Terada in
2004,[8] chiral phosphoric acids have proven to be versatile
catalysts and have subsequently been applied to a variety of
transformations with high stereocontrol.[9] Moreover, the
alkali or alkaline earth derived salts of chiral phosphoric acids
have proven to be highly effective catalysts in several recent
reports.[10]
We began our investigation with 3-phenyloxindole 1a and
BPO as substrates, and toluene as the solvent, as a starting
point for optimization studies. Chiral phosphoric acids
purified by silica gel column chromatography, were then
screened. Catalysts H[P1], H[P4], and H[P6] (Table 1,
entries 1, 4, and 6) imparted meagre stereoselectivity.
H[P6], a VAPOL-derived phosphoric acid, proved to be the
best catalyst when TBME was the solvent (Table 1, entries 7–
9). The reverse selectivity was observed in DCM (Table 1,
entry 10).[14] To our delight, an upgrade to 99% ee was
obtained using diethyl ether (Table 1, entry 11). Interestingly,
H[P6] washed with 6n HCl exhibited poor catalytic efficiency
and enantioselectivity under the same conditions (Table 1,
entry 12). Correlation of this result to that of a recent report
by Ishihara and co-workers,[10a] showing a high abundance of
chiral phosphate salts in the absence of a final HCl wash of the
chiral phosphoric acid/salt mixture obtained by silica gel
purification, directed us to propose the active catalytic species
to be that of a chiral phosphate salt.[15] To identify the metal
counterion, several variants of P6 were prepared and
evaluated. Na[P6] and K[P6] afforded the product with no
selectivity (Table 1, entries 13 and 14). Ca[P6]2 and Sr[P6]2
both induced remarkably high selectivity (> 99%) (Table 1,
entries 15 and 16). Ba[P6]2 allowed for a significantly lower
enantioselectivity (7%) (Table 1, entry 17). Mg[P6]2 fur-
nished the product with 60% ee, but with the opposite
configuration (Table 1, entry 18), presumably due to a differ-
ence on coordination spheres compared to calcium.[16] To our
delight, excellent enantioselectivity (95%) is still observed
with Ca[P6]2, even when the catalyst loading is reduced to
0.10 mol% (Table 1, entry 22).
[*] Dr. Z. Zhang, Dr. W. Zheng, Prof. Dr. J. C. Antilla
Department of Chemistry, University of South Florida
4202 E. Fowler Avenue, CHE 205A, Tampa, FL 33620 (USA)
Fax: (+1)813-974-1733
E-mail: jantilla@usf.edu
[**] We thank the National Institutes of Health (NIH GM-082935) and
the National Science Foundation CAREER program (NSF-0847108)
for financial support. We also thank Matthew J. Kaplan for
preparation of the catalyst and helpful suggestions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 1135 –1138
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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