Figure 1. Kinetic resolution by enzymatic deacylation and fluorous triphasic reaction/separation.
reaction with a fluorous triphasic separative reaction of the
resulting product mixture indeed results in a practical and
efficient kinetic resolution process. The separation and
deacylation are combined, so the new process requires only
two steps rather than three.
To illustrate the new method, we chose to resolve rac-1-
(2-naphthyl)ethanol by enantioselective deacylation.4 Race-
mic ester 1 was readily prepared by acylation of 1-(2-
naphthyl)ethanol with 2H,2H,3H,3H-perfluoroundecanoyl
chloride.2,4 The process that resolves rac-1 into (S)-1 and
(R)-2 is shown in Figure 1.
The kinetic resolution of fluorous ester rac-1 was con-
ducted with Candida antarctica B lipase,4,5 and the reaction
was stopped when the conversion reached about 50%. The
lipase was removed by filtration, and the resulting crude
mixture containing ester (S)-1 and alcohol (R)-2 was used
for the fluorous triphasic reaction. In a control experiment,
ester 1 and alcohol 2 were separated by silica gel column
chromatography to give (R)-2 in 50% yield with >99% ee.
Saponification of ester (S)-1 with NaOMe gave alcohol (S)-2
in 50% yield with 91% ee.
In a typical triphasic experiment,3,6 a U-tube was charged
with FC-72 (perfluorohexanes), and the mixture obtained
from the kinetic resolution was added to the source phase
(MeOH/CHCl3). A solution of NaOMe/MeOH made up the
receiving phase. All three phases were gently stirred at room
temperature for 3 days. Evaporation of the source phase gave
alcohol (R)-2 with 89% ( 1% ee. Workup of the receiving
phase provided (S)-2 with 95% ( 2% ee. The yields of (R)-2
and (S)-2 were comparable to those obtained from silica gel
column chromatography followed by saponification (45%
and 48%, respectively). Methyl (3-perfluorooctyl)propionate
was isolated from the FC-72 phase.7
The ee of each enantiomer of the alcohol isolated from
the triphasic reaction was marginally lower (2-4%) than the
corresponding reference product. In an effort to identify how
(4) Swaleh, S. M.; Hungerhoff, B.; Sonnenschein, H.; Theil, F. Tetra-
hedron 2002, 58, 4085.
(6) Fluorous Triphasic Reactions. To an U-shape tube charged with
FC-72 (15 mL) was added a solution of the mixture of ester (S)-1, alcohol
(R)-2, and butyl ester 3 (116 mg) in MeOH/CHCl3 (6 mL, 5:1) to the
substrate side and NaOMe (0.2 mL, 25wt % in MeOH) in MeOH (6 mL)
to the reagent side. All three phases are gently stirred at room temperature
for 72 h. The source phase was taken up with a pipet and evaporated to
dryness. The residue was passed through a silica plug with 25% EtOAc/
hexanes to give (R)-2 (13 mg, 45% yield, 95 ( 1% ee). The receiving
phase was taken up and added to 1 N aqueous HCl. After extraction with
diethyl ether, the ether layer was dried over magnesium sulfate and
evaporated to dryness. The residue was passed through a silica plug with
25% EtOAc/hexanes to give (S)-2 (14 mg, 48% yield, 89 ( 2% ee). The
% ee was determined by chiral HPLC as mentioned above and was reported
as an average of the results from two triphasic reaction experiments.
(7) Due to its poor solubility in organic solvents, the recovery of methyl
(3-perfluorooctyl)propionate is moderate (about 50%) in these small-scale
experiments.
(5) Kinetic Resolution of rac-1. A solution of the racemic ester rac-1
(5 mmol) in acetonitrile (120 mL) was treated with n-butanol (20 mmol)
and C. antarctica B lipase (Chirazyme L-2, c.-f., lyo. from Roche
Diagnostics, Mannheim) (8.0 g). The reaction mixture was stirred at ambient
temperature until the conversion reached ca. 50% (estimated by TLC, 7
days). The lipase was removed by filtration and washed with acetone (2 ×
40 mL). The combined filtrates were evaporated under reduced pressure to
provide a mixture of ester (S)-1, alcohol (R)-2, and butyl ester 3 (butyl
2H,2H,3H,3H-perfluoroundecanoate). An aliquot of this mixture (116 mg)
was purified by silica gel column chromatography (15-30% EtOAc/hexane)
to give alcohol (R)-2 (16.0 mg, 50% yield, >99% ee) and ester (S)-1 (60
mg). Treatment of (S)-1 with NaOMe/MeOH at room temperature for 30
min to give (S)-2 (15 mg, 50% yield, 91% ee). The ee’s of (S)-2 and (R)-2
were determined by chiral HPLC (column: Chiralcel OJ, eluent: n-hexane/
2-propanol (9:1), flow rate: 1 mL/min, UV detection at 254 nm).
2586
Org. Lett., Vol. 4, No. 15, 2002