K. Konigsberger et al. / Tetrahedron: Asymmetry 10 (1999) 679–687
687
3.15. Synthesis of (R)-2-hydroxy-2-methyl-3,3,3-trifluoropropionic acid [(R)-1a]
(
R)-2-Cyano-1,1,1-trifluoroprop-2-yl butyrate (R)-4b (211.8 g, 1.01 mol), water (400 mL) and HCl
19
conc. (400 mL) were stirred vigorously and heated under reflux for 8 h. At this point, F-NMR indicated
quantitative conversion to the product. Aqueous NaOH, 50% (w/w) (480 g) was added over 30 min at
or below 25°C to bring the pH to 4.8. tBME (1000 mL) was added and the mixture stirred vigorously
while adjusting the pH to 4.8 with 6 N HCl. The organic phase was discarded, and the aqueous phase
was washed once more with tBME (500 mL) at pH 4.8 as described above. After adjusting the pH of the
aqueous phase to 1 with 6 N HCl and extraction with tBME (2×500 mL), the combined organic layers
were concentrated to dryness (bath 30°C, vacuum ≤20 mmHg), at which point the product crystallized.
Heptane (500 mL) was added and removed in vacuo. The heptane treatment was repeated once, then
just enough heptane (approx. 180 mL) was added to allow slurrying of the crystalline material with a
mechanical stirrer. The slurry was cooled in an ice bath and stirred for 2 h. Filtration afforded (R)-2-
hydroxy-2-methyl-3,3,3-trifluoropropionic acid [(R)-1a] (134 g, 84%) as a white crystalline solid. Mp
2
2
1
06–110°C; [α]D +18.4 (c 2.55, CH OH); e.e. assayed by GC after derivatization as the methyl ester
3
with Cs CO /MeI/acetone: >99%.
2
3
Acknowledgements
The authors thank Altus Biologics Inc., Boehringer Mannheim Inc., and Amano Pharmaceuticals for
their generous donations of enzyme samples.
References
1
2
3
4
5
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(
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0
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1
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4
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