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mixture was cooled to 08C, then 1,3-benzodithiolylium tetrafluoro-
borate 13 (1 mmol, 1 equiv) was added and the mixture was stirred
overnight at 08C. Once the reaction was complete, an excess
volume of Et2O was added. The organic layer was separated and
the aqueous layer was extracted with Et2O (310 mL). The collect-
ed organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure at RT to prevent racemiza-
tion. The residue was then diluted in MeOH (2.5 mL), and NaBH4
(1.75 mmol, 1.75 equiv) was slowly added at 08C. After 1 h, the re-
action was quenched with water and the mixture was concentrat-
ed under reduced pressure. The residue was extracted with Et2O
(310 mL), dried over Na2SO4, and concentrated to give products
22a–d. The title compounds were isolated by flash column chro-
matography.
Scheme 7. Preparation of gem-difluorodiol 37. i) LiAlH4, THF, 08C, quant.; ii)
NaH, ClCH2OMe, THF, 80%; iii) DBH, PPHF, CH2Cl2, À708C, 27% (16% with
MOM); iv) NaH, BnBr, THF, 60%; v) H2, Pd(OH)2/C, AcOEt, quant.; vi) TFA,
CH2Cl2, then H2, Pd(OH)2/C, quant.
General procedure for the stereoselective alkylation with
catalyst 21
Aldehyde 19e (2.5 mmol, 2.5 equiv), l-camphorsulfonic acid
(0.4 mmol, 0.4 equiv) and cinchona catalyst 21 (0.2 mmol,
0.2 equiv) were dissolved in water/acetonitrile (1:1 v/v, 8 mL). The
mixture was cooled to 08C, then 1,3-benzodithiolylium tetrafluoro-
borate 13 (1 mmol, 1 equiv) was added and the reaction mixture
was stirred overnight at 08C. A saturated solution of NaHCO3
(5 mL) was added and the mixture was diluted with Et2O (20 mL).
The organic layer was separated and the aqueous layer was ex-
tracted with Et2O (315 mL). The collected organic layers were
washed with brine, dried over Na2SO4, and concentrated under re-
duced pressure at RT. The residue was then diluted in MeOH
(2.5 mL) and NaBH4 (1.75 mmol, 1.75 equiv) was added slowly at
08C. After 1 h, the reaction was quenched by adding water
(2.5 mL) and the mixture was concentrated under reduced pres-
sure. The residue was extracted with Et2O (315 mL), dried over
Na2SO4, and concentrated under reduced pressure. The title com-
pound 22e (90% yield, 83 %ee) was isolated by flash column chro-
matography (cyclohexane/EtOAc, 9:1).
Scheme 8. Preparation of (R)-(À)-difluoroarundic acid 40.
Alzheimer’s and Parkinson’s diseases[25a,b] as well as for its prop-
erties to attenuate retinal ganglion cell death.[25c] Compound
ent-28ac (ee 90%), was obtained by the reaction shown in
Scheme 2 with the catalyst ent-20 in 75% overall yield.[26] The
difluorination, successive deprotection through the use of
Pd(OH)2 on carbon under hydrogen,[27] and oxidation to acid,
gave 40 in 40% overall yield.
General procedure for the difluorination
Precautions must be taken to exclude moisture from the reaction
media. DBH (0.1 mmol, 1 equiv) was dissolved in anhydrous di-
chloromethane (1 mL) under an inert atmosphere. The mixture was
cooled to À708C, then PPHF (4 mmol, 40 equiv HF) was added, fol-
lowed by the portionwise addition of benzodithioladduct 25, 26,
or 27 (0.1 mmol,1 equiv). The reaction mixture became deep-red
and was stirred for 1 h at À708C. Upon completion, the mixture
was diluted with dichloromethane, filtered through a short plug of
basic alumina, and the solvent was removed under reduced pres-
Conclusion
We have described a simple and effective methodology for the
preparation of highly functionalized enantioenriched gem-di-
fluorinated building blocks that could be useful in medicinal
and biological chemistry. The introduction of a stereogenic
center occurs using a simple organocatalytic methodology,
and using commercially available starting materials. We have
applied this method to the synthesis of difluoroarundic acid.
Other biologically active molecules can be effectively accessed
by using this methodology.
1
sure. The crude mixture was analyzed by H NMR spectroscopy to
determine the yield of the reaction [1,4-diacetylbenzene
(0.05 mmol) was used as internal standard], then the product was
purified by flash chromatography.
Acknowledgements
Bologna University, Fondazione Del Monte, and the European
Commission through the projects FP7-PEOPLE-238434, (Bio-
ChemLig) and FP7-201431 (CATAFLU.OR) are acknowledged for
financial support. S.S., M.C., and V. L.-C. acknowledge BioChem-
Lig FP7-PEOPLE-238434 for PhD and Postdoctoral fellowships.
Dr. Enrico Emer, Dr. C. M. Wilson, and Luca Mengozzi are ac-
knowledged for proofreading.
Experimental Section
General procedure for the stereoselective alkylation with
catalyst 20
Aldehyde 19a–d (2.5 mmol, 2.5 equiv) and catalyst 20 (0.2 mmol,
0.2 equiv) were dissolved in water/acetonitrile (1:1 v/v, 8 mL). The
Chem. Eur. J. 2015, 21, 13689 – 13695
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