Asymmetric Direct α-Hydroxylation of β-Oxo Esters
To test the scale-up potential of our methodology, 1m
was treated with CHP (1.25 equiv.) on a gram-quantity
scale under the same conditions of catalyst loading (5 mol-
%). Surprisingly, after only 30 h at –5 °C, the hydroxylation
product was obtained in 80% yield without any loss of
enantioselectivity (75% ee). The shorter reaction time was
ascribed to the intensive mixing conditions by high-speed
mechanical agitation (800 rpm).
Experimental Section
General Procedure for the Catalytic Enantioselective Hydroxylation
Reaction
1-Adamantyl 2-Hydroxy-1-oxoindan-2-carboxylate (3j): 1-Ad β-oxo
ester 1j (62.3 mg, 0.2 mmol) and catalyst Cn-23 (5.3 mg, 0.01 mmol,
5 mol-%) were added to a test tube equipped with a stirring bar
and dissolved in toluene (1 mL). Cumyl hydroperoxide (0.3 m in
toluene solution, 1.5 equiv., 1 mL) was added, and the resulting
mixture was cooled to –5 °C before precooled 50% K2HPO4 (aq.)
(1 mL) was added, and the reaction was stirred at this temperature
for 60 h. After completion of the reaction, the reaction mixture was
diluted with Et2O (10 mL), washed with water (3ϫ 5 mL), dried
with anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (silica gel; petroleum
ether/EtOAc, 10:1) to afford 3j (57.4 mg, 88% yield). 1H NMR
(400 MHz, CDCl3): δ = 7.79 (d, J = 7.6 Hz, 1 H), 7.65 (t, J =
7.4 Hz, 1 H), 7.50–7.37 (m, 2 H), 4.07 (s, 1 H), 3.66 (d, J = 17.1 Hz,
1 H), 3.22 (d, J = 17.1 Hz, 1 H), 2.08 (d, J = 25.9 Hz, 3 H), 1.96
(s, 6 H), 1.59 (s, 7 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
201.52, 170.24, 152.39, 135.85, 133.98, 127.92, 126.28, 125.05,
83.92, 80.53, 40.89, 39.58, 35.85, 30.79 ppm. HRMS (ES–): calcd.
for C20H21O4 [M – H]–, 325.1440; found 325.1453. [α]2D0 = 21.4 (c
= 1.08, CHCl3, 73% ee). The ee value was determined by HPLC
using a Chiralcel AD-H column [hexane/2-propanol (90:10)]; flow
rate = 1.0 mL/min; 254 nm; τmajor = 12.9 min, τminor = 21.3 min
(73% ee).
For the hydroxylation reaction to occur with the ob-
served selectivity, an enolate–PTC complex needs to be
formed, in which only the Si face of the enolate is available
for reaction. To this effect, three sites of interaction between
substrate and catalyst have to exist: (i) Coulombic interac-
tion (ion pairing); (ii) hydrogen bonding between the proton
of the hydroxy group at C-9 of the PTC and the ester group
of the substrate; (iii) π–π stacking of the benzyl moiety and
the aromatic portion of the substrate. A model of the transi-
tion state, depicted in Figure 1, may explain the importance
of the chiral secondary alcohol moiety at the C-9 position
of the alkaloid (Table 1, Entries 17–20). The last interaction
could explain the decrease in stereoselectivity, when 1n was
used as the substrate. The unfavorable effect is probably due
to the fact that the 3Ј-CF3 group of Cn-23 sterically repels
the aromatic ring of the enolate, bearing a substituent in
4 position (Table 3, Entry 5), which disturbs the π–π inter-
action. This activation model may also explain the dramatic
decrease in stereoselectivity, when Cn-16 (instead of Cn-23)
was used to catalyze the indanone derivatives bearing a sub-
stituent in 6-position (Table 3, Entries 2, 3, 6).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization of the prepared
compounds, copies of NMR spectra, and chiral HPLC spectra of
the hydroxylation products.
Acknowledgments
We would likely to thank the National Natural Science Foundation
of China (No. 20976022) and the State Key Laboratory of Fine
Chemicals for their support.
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Figure 1. Model of a possible transition-state of the reaction.
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Conclusions
We have developed the first enantioselective phase-trans-
fer-catalyzed direct oxidation of 1-Ad β-oxo esters with
commercially available CHP. Under mild conditions, high
selectivities were obtained for a range of substituted ind-
anone derivatives. Moreover, this new methodology was
successfully amplified to a gram-quantity scale. This
method should be of great value in terms of simplicity and
ready availability of the respective catalysts.
Eur. J. Org. Chem. 2010, 6525–6530
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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