Organocatalytic Stereoselective Direct Aldol Reaction of Trifluoroethyl Thioesters
uct was purified by column chromatography with different
reaction. Further studies and applications of the
methodology to other transformations are currently
underway.
hexane:ethyl acetate mixture as eluant (see below) to afford
the pure aldol adducts. Yields and ee for each reaction are
indicated in the Tables. The syn:anti ratio was determined
by 1H NMR spectroscopy on the crude product; the enantio-
meric excess was determined by HPLC on a chiral station-
ary phase. (S)-tetra-Me-BITIOPO was quantitatively recov-
ered by further elution with 10% MeOH in CH2Cl2.
Experimental Section
General Remarks
Supporting Information
All reactions were carried out in oven-dried glassware with
magnetic stirring under a nitrogen atmosphere, unless other-
wise stated. Dry solvents were purchased and stored under
nitrogen over molecular sieves (bottles with crown caps).
Reactions were monitored by analytical thin-layer chroma-
tography (TLC) using silica gel 60 F254 pre-coated glass
plates (0.25 mm thickness) and visualized using UV light or
phosphomolybdic acid. Proton NMR spectra were recorded
on spectrometers operating at 200, 300 or 500 MHz, respec-
tively. Proton chemical shifts are reported in ppm (d) with
the solvent reference relative to tetramethylsilane (TMS)
employed as the internal standard (CDCl3 d =7.26 ppm).
13C NMR spectra were recorded on 300 or 500 MHz spec-
trometers operating at 75 and 125 MHz, respectively, with
complete proton decoupling. Carbon chemical shifts are re-
ported in ppm (d) relative to TMS with the respective sol-
vent resonance as the internal standard (CDCl3, d=
77.0 ppm). Optical rotations were obtained on a polarimeter
at 589 nm using a 5-mL cell with a length of 1 dm. HPLC
for ee determinations was performed under the conditions
reported below.
1H NMR spectra and HPLC chromatograms of chiral prod-
ucts, synthesis of activated thioesters, and experimental de-
tails of the direct aldol condensation are available in the
Supporting Information.
Acknowledgements
Financial support by MIUR – PRIN (Nuovi metodi catalitici
stereoselettivi e sintesi stereoselettiva di molecole funzionali)
is gratefully acknowledged. The authors thank Chemi S.p.A
for the generous gift of (S)-tetramethyl-BITIOPO. T.B.
thanks the Dipartimento di Chimica Organica e Industriale
for hospitality.
References
Mass spectra (MS) were performed at CIGA (Centro In-
terdipartimentale Grandi Apparecchiature), with mass spec-
trometer APEX II & Xmass software (Bruker Daltonics).
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Typical Procedure of Enantioselective Direct Aldol
Reactions between Thioesters and Aldehydes
To a stirred solution of (S)-tetra-Me-BITIOPO (0.1 or 0.2
equiv.) in the chosen solvent (2 mL), the thioester (2 equiv.)
and diisopropylethylanime (10 equiv.) were added. The mix-
ture was then cooled to the chosen temperature and freshly
distilled tetrachlorosilane (1.5 equiv.) was added dropwise
via syringe. After 15 min, freshly distilled aldehyde (1
equiv.) was added. The mixture was stirred for 5 h (if the op-
erating temperature is 08C) or 12 h (if the operating temper-
ature is À258C), then the same amount of tetrachlorosilane
(1.5 equiv.) was added.
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For the example reported in Table 3, entry 1, the quanti-
ties are: (S)-tetra-Me-BITIOPO (0.1 equiv, 0.03 mmol,
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18.7 mg); thioester
4 (2 equiv., 0.60 mmol, 140.5 mg);
DIPEA (10 equiv, 3 mmol, 513 mL) tetrachlorosilane
(1.5 equiv., 0.45 mmol, 52 mL); benzaldehyde (1 equiv.,
0.30 mmol, 30 mL). After the indicated reaction time the re-
action was quenched by the addition of a saturated aqueous
solution of NaHCO3 (3 mL). The mixture was allowed to
warm up to room temperature and stirred for 30 min, then
water (5 mL) and ethyl acetate (15 mL) were added. The or-
ganic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate (15 mL). The combined organic
layers were washed with saturated NH4Cl solution (10 mL)
and brine (10 mL), dried over Na2SO4, filtered, and concen-
trated under vacuum at room temperature. The crude prod-
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2008, 10, 3405.
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Adv. Synth. Catal. 2011, 353, 848 – 854
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