Resolution of 1-(2-naphthyl)ethanol by a combination of an enzyme-catalyzed kinetic resolution with a fluorous triphasic separative reaction

Article abstract of DOI:10.1021/ol026232f

(Matrix presented) Kinetic resolution of a fluorous ester rac-1 with Candida antarctica B lipase provided a mixture of enantioenriched alcohol (R)-2 and fluorous ester (S)-1. The mixture was subjected to a fluorous triphasic reaction to give both enantiom

Full text of DOI:10.1021/ol026232f

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2585-2587
Resolution of 1-(2-Naphthyl)ethanol by a
Combination of an Enzyme-Catalyzed
Kinetic Resolution with a Fluorous
Triphasic Separative Reaction
,§
Zhiyong Luo,† Sauda M. Swaleh,‡ Fritz Theil,‡ and Dennis P. Curran*
Fluorous Technologies, Inc., 970 William Pitt Way, Pittsburgh, PennsylVania 15238,
ASCA GmbH, Richard-Willsta¨tter-Strasse 12, 12489, Germany, and Department of
Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received May 23, 2002
ABSTRACT
Kinetic resolution of a fluorous ester rac-1 with Candida antarctica B lipase provided a mixture of enantioenriched alcohol (R)-2 and fluorous
ester (S)-1. The mixture was subjected to a fluorous triphasic reaction to give both enantiomers of 1-(2-naphthyl)ethanol 2 in high ee without
chromatographic separation or fluorous−organic liquid−liquid extractive purification.
Kinetic resolutions of racemates are often the cheapest and
most practical routes to enantiopure compounds, especially
when both enantiomers are desired.1 These resolutions
typically require at least three steps: (1) stereoselective
conversion of one of the enantiomers into a new chemical
product, (2) separation of the starting compound (ideally now
one enantiomer) from the new product (ideally the other),
and (3) conversion of the new product to the starting material
(or the reverse, depending on which product is desired). For
example, resolution of a racemic mixture of esters of sec-
ondary alcohols might involve enzyme-catalyzed enantio-
selective deacylation, separation of the resulting alcohol from
the ester, and deacylation of the remaining ester (or re-
acylation of the alcohol). As methods for enantioselective
reactions continue to improve, the separation step in the
process increasingly becomes the bottleneck.
Recently, Theil and co-workers reported the efficient and
enantioselective enzyme catalyzed acylation of 1-phenyl-
ethanol and several other alcohols with a fluorous acylating
agent.2 Repeated extractions with a fluorous solvent were
needed to separate the fluorous ester from the unreacted
alcohol, so this was an enantioselective fluorous tagging
reaction in need of an efficient separation. At about the same
time, Curran and co-workers reported an attractive resolution
of fluorous-tagged secondary alcohols by using a fluorous
triphasic reaction.3 But there are no good methods to
enantioselectively adorn secondary alcohols with fluorous
tags, so this was an efficient separation and detagging process
in search of an enantioselective reaction. We report here that
the combination of an enantioselective, enzyme-catalyzed
† Fluorous Technologies, Inc.
‡ ASCA GmbH.
§ University of Pittsburgh.
(1) (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and
Resolutions; Wiley: New York, 1981. (b) Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; John Wiley & Sons: New York,
1994; Chapter 7. (c) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18,
249. (d) Cook, G. R. Curr. Org. Chem. 2000, 4, 869.
(2) (a) Hungerhoff, B.; Sonnenschein, H.; Theil, F. Angew. Chem., Int.
Ed. Engl. 2001, 40, 2492. (b) Hungerhoff, B.; Sonenschein, S.; Theil, F. J.
Org. Chem. 2002, 67, 1781.
(3) Nakamura, H.; Linclau, B.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 10119.
10.1021/ol026232f CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/25/2002

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).
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Org. Lett., Vol. 4, No. 15, 2002

this erosion occurs, several control experiments were con-
ducted. A sample of racemic 1-(2-naphthyl)ethanol was
subjected to the same conditions as in Figure 1; however,
nothing was found in the NaOMe/MeOH receiving phase.
In contrast, when acetonitrile was used in place of methanol
as the source and receiving phases, a small amount (∼4%)
of the alcohol was transported through the fluorous phase
over the course of 3 days.3 We next repeated the triphasic
reaction by adding (S)-1 and (R)-2 to the source phase but
omitting NaOMe from the receiving phase. Only fluorous
ester (S)-1 was found in the receiving phase; alcohol (R)-2
could not be detected. These experiments do not provide a
convincing explanation for the loss of ee, but we decided
that the loss was too small to merit additional study.
enzyme-catalyzed deacylation reaction of a racemic fluorous
ester stereoselectively provides a mixture of the detagged
alcohol and the fluorous ester. Separation of the alcohol from
the ester and saponification of the ester are carried out
simultaneously in a triphasic process instead of sequentially.
The fluorous tag allows the ester to pass from one side to
the other, but back passage is blocked by tag removal. In
the end, the source side contains one enantiomer, the
receiving side contains the other enantiomer, and the residual
tag is in the middle. Time-consuming, solvent-intensive,
extractive or chromatographic separations are bypassed.
This example serves as a model for a new class of resolu-
tions that couple enzymatic (or chemical) addition or removal
of a fluorous tag with subsequent triphasic separation and
reaction.
To summarize, we have demonstrated for the first time
the utility of a fluorous triphasic reaction coupled with an
enzyme-catalyzed kinetic resolution of a racemic ester. An
OL026232F
Org. Lett., Vol. 4, No. 15, 2002
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