A sequential application of kinetic resolution and polymer-supported scavenging for the isolation of chiral secondary alcohols

Full text of DOI:10.1021/jo010529u

J . Org. Chem. 2001, 66, 5645-5648
5645
the case of kinetic resolution, the products need to be
separated to enable analysis of catalyst activity and
selectivity. Therefore, techniques that facilitate the sepa-
ration of kinetic resolution products without the need for
column chromatography are highly desirable.
A Sequ en tia l Ap p lica tion of Kin etic
Resolu tion a n d P olym er -Su p p or ted
Sca ven gin g for th e Isola tion of Ch ir a l
Secon d a r y Alcoh ols
The preparation of chiral sec-alcohols by catalytic
processes is a very active area of research because of their
importance as building blocks in asymmetric synthesis.2c
Kinetic resolution can be performed whereby a racemic
mixture of sec-alcohols is transformed into optically active
products (e.g., an ester and remaining alcohol) that can
be separated typically by column chromatography. To
circumvent the need for time-consuming column chro-
matography, esterification of sec-alcohols with succinic
anhydride followed by an acid-base extraction has been
reported.8 This principle has also been extended to the
conversion of alcohols to sulfate esters.9 It should be noted
that while these two methods are important, their scope
is limited to large-scale reactions. Furthermore, their
generality is hampered by the choice of effective acylating
agents. A soluble polymer scavenging approach of a
racemic trifluoroethyl carbonate through lipase-catalyzed
transesterification with poly(ethylene glycol) (PEG) has
also been reported.10 However, this methodology also
presents several limitations. First, a unique catalyst
accepting PEG is needed. Second, an elaborate synthetic
scheme to form each activated carbonate is required for
each new acyl donor. More recently, Vedejs has reported
a parallel kinetic resolution performed under triphasic
conditions.11 During this process, one of the enantiomers
reacts with a polymer-supported reagent enabling sepa-
ration of the enantiomers by filtration. To complement
these existing technologies, we present a method to
separate the products from the kinetic resolution of sec-
alcohols.
Armando Co´rdova, Martin R. Tremblay,
Bruce Clapham, and Kim D. J anda*
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La J olla, California 92037
kdjanda@scripps.edu
Received May 24, 2001
In tr od u ction
The preparation of enantiomerically pure or enan-
tioenriched organic compounds is of great importance.1
As such, the development of chemical and biochemical
catalysts for both enantioselective synthesis and the
kinetic resolution of racemates has advanced at an
accelerated pace.2-4 In particular, kinetic resolution is
important in asymmetric synthesis since it provides both
enantiomers of a compound. Developments in the areas
of combinatorial chemistry, catalytic antibodies, site-
directed mutagenesis, and directed evolution of biocata-
lysts have fueled the discovery and optimization of both
chemical and biological catalysts.5,6 As powerful as these
technologies have become, the catalyst discovery process
still faces a bottleneck centered around the analysis and
processing of both catalyst selectivity and activity.7 In
* To whom correspondence should be addressed. Tel: (858) 784-
2515. Fax: (858) 784-2595.
(1) (a) Chirality in Industry: The Commercial Manufacture and
Applications of Optically Active Compounds; Collins, A. D., Sheldrake,
G. N., Crosby, J ., Eds.; Wiley: Chichester, 1992. (b) Chirality in
Industry II: Developments in the Commercial Manufacture and
Applications of Optically Active Compounds; Collins, A. N., Sheldrake,
G. N., Crosby, J ., Eds.; Wiley: Chichester, 1997. (c) Sheldon, R. A.
Chirotechnology: Industrial Synthesis of Optically Active Compounds;
Dekker: New York, 1993.
(2) (a) Comprehensive Asymmetric Catalysis, Vol. I-III; J acobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999. (b)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994. (c) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH:
Weinheim, 1993. (d) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1059.
(3) (a) Spivey, A. C.; Maddaford, A.; Redgrave, A. J . Org. Prep. Proc.
Int. 2000, 32, 331. (b) Long, Y. O.; Paquette, L. A. Chemtracts 2000,
13, 9. (c) Yamada, T. Chemtracts 2000, 13, 9. (d) Vedejs, E.; Mackay,
J . A. Org. Lett. 2001, 3, 535. (e) Vedejs, E.; Daugulis, O. J . Am. Chem.
Soc. 1999, 121, 5813. (f) Fu, G. C. Acc. Chem. Res. 2000, 33, 412. (g)
Tao, B.; Lo, M. M.-C.; Fu, G. C. J . Am. Chem. Soc. 2001, 123, 353.
(4) (a) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Pergamon: Oxford, 1994. (b) Faber, K. Biotransformations
in Organic Chemistry, 3rd ed.; Springer: Berlin, 1997. (c) Schmid, A.;
Dordick, J . S.; Hauer, B.; Kiener, A.; Wubbolts, M.; Witholt, B. Nature
2001, 409, 258.
(5) (a) Liu, G.; Ellman, J . A. J . Org. Chem. 1995, 60, 7712. (b)
J andeleit, B.; Schaefer, D. J .; Powers, T. S.; Turner, H. W.; Weinberg,
W. H. Angew. Chem., Int. Ed. Engl. 1999, 38, 2494. (c) Sigman, M. S.;
J acobsen, E. N. J . Am Chem. Soc. 1998, 120, 4901. (d) Cole, B. M.;
Shimizu, K. D.; Krueger, C. A.; Harrity, J . P. A.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668. (e)
Francis, M. B.; J acobsen, E. N. Angew. Chem., Int. Ed. Engl. 1999,
38, 937.
Resu lts a n d Discu ssion
Our strategy features a simple two-step procedure that
combines both kinetic resolution and separation of the
products using a solid-phase scavenging or “fishing out”
procedure (Scheme 1).12 The strength of our method is
that the kinetic resolution can be performed with either
a polymer-supported enzyme or a polymer-supported
chemical catalyst.13,14 Thus, after removal of the catalyst
from the kinetically resolved mixture by filtration, the
(7) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 2001, 40, 284. and
references therein. (b) Harris, J . L.; Backes, B. J .; Leonetti, F.; Mahrus,
S.; Ellman, J . A.; Craik, C. S. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
7754. (c) Michels, P. C.; Khmelnitsky, Y. L.; Dordick, J . S.; Clarck, D.
S. Trends. Biotechnol. 1998, 16, 210.
(8) Gutman, A. L.; Brenner, D.; Boltanski, A. Tetrahedron: Asym-
metry 1993, 4, 839.
(9) Yamano, T.; Kikumoto, F.; Yamamoto, S.; Miwa, K.; Kawada,
M.; Ito, T.; Ikemoto, T.; Tomimatsu, K.; Mizuno, Y. Chem. Lett. 2000,
448.
(10) Whalen, L. J .; Morrow, S. J . Tetrahedron: Asymmetry 2000, 11,
1279.
(11) Vedejs, E.; Rozners, E. J . Am. Chem. Soc. 2001, 123, 2426.
(12) (a) Hodge, P. In Synthesis and Separations Using Functional
Polymers; Sherrington, D. C., Hodge, D., Eds. Wiley: New York, 1988.
(b) Seymor, E. S.; Fre´chet, J . M. J . Tetrahedron Lett. 1976, 17, 3669.
(c) Hori, M.; J anda, K. D. J . Org. Chem. 1998, 63, 889.
(13) Orrenius, C.; Mattson, A.; O¨ hrner, N.; Hult, K.; Norin, T.
Tetrahedron: Asymmetry 1994, 7, 1363.
(6) (a) Lerner, R. A.; Barbas, C. F., III; J anda, K. D. Harvey Lect.
1998, 92, 1. (b) Arnold, F. H. Nature 2001, 409, 253. (c) Altamirano,
M. M.; Blackburn, J . M.; Aguayo, C.; Fersht, A. R. Nature 2000, 403,
617. (d) Cane, D. E.; Walsh, C. T.; Khosla, C. Science 1998, 282, 63.
(e) Stemmer, W. D. Nature 1994, 370, 389.
(14) Clapham, B.; Cho, C.-W.; J anda, K. D. J . Org. Chem. 2001,
66, 868.
10.1021/jo010529u CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/11/2001

5646 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
Sch em e 1. Gen er a l Str a tegy for Isola tin g
Sch em e 2. Sep a r a tion of th e Ch ir a l Alcoh ol a n d
sec-Alcoh ols
Ester Usin g a Solid -P h a se Sca ven ger a
products obtained may be conveniently separated by
capture of the remaining alcohol with a suitable scaveng-
ing agent. To examine such an approach, a model
experiment was performed wherein (S)-1-phenylethanol
(R1 ) Ph, R2 ) Me, >99% ee) and its corresponding
enantiopure (R)-acetate (>99% ee) were reacted with a
series of resins under standard alcohol loading condi-
tions.15 Among the functionalized resins examined, poly-
mer-supported benzoyl chloride was found to be the best
scavenging resin due to the ease of attachment and
subsequent release of the captured (S)-1 alcohol (Scheme
2).16 Using this resin, all (S)-1 was removed from the
reaction mixture within 24 h and the two enantiomers
were separated by filtration. The polymer-bound alcohol
(S)-1 was released from the resin by hydrolysis in 41%
yield and >99% ee. The unbound ester was isolated from
the filtrate and hydrolyzed to the corresponding alcohol
(R)-1 in 42% yield, >99% ee. Furthermore, no scrambling
of the chiral information occurred during the loading of
alcohol (S)-1 in the presence of acetate (R)-1a .
a
Reagents and conditions: (a) Et3N, catalytic DMAP, CH2Cl2;
(b) physical separation by filtration; (c) KOH, MeOH.
to 7 mmol (gram-scale of racemic alcohols). Furthermore,
the scavenging resin could be recycled by treatment of
the polymer-bound carboxylic acid with oxalyl chloride.
Con clu sion
The separation procedure was applied to a series of
racemic sec-alcohols that were resolved using a polymer-
supported lipase13 (Table 1). Of note, the solid-supported
enzyme resolved the sec-alcohols and the enantioprefer-
ence was in accordance with literature reports (Table 1,
entries 1-9).13,17-19 Both the (S)- and (R)-enantiomers
were isolated in high ee and in greater than 95% purity
after the two-step reaction sequence, with yields of ∼40%
(50% theoretical). This methodology also proved useful
with a polymer-supported proline-based chemical catalyst
(Table 1, Entry 10), thus showing even greater utility of
our method. In this case, the same selectivity value (E )
3) was observed as previously reported.14 In addition, it
was determined (see Experimental Section) that the
combination of kinetic resolution with the “fishing out”
principle could be used to resolve racemic mixtures of up
The sequential application of a polymer-supported
catalyst and scavenging reagent provides a convenient
method for the isolation of chiral sec-alcohols. While we
have demonstrated this approach with secondary alco-
hols, we envision that this methodology could be ap-
plicable to other nucleophiles, such as secondary amines.20
Furthermore, because of its simplicity, the entire process
could be automated and, thus, utilized in the high-
throughput parallel screening of catalysts. Taken in this
context, valuable information such as enantiomeric ex-
cess, substrate specificity, solvent effects, and tempera-
ture dependence for both new and existing catalysts could
be quickly amassed.
Exp er im en ta l Section
Gen er a l Meth od s. Reagents were obtained from Sigma-
Aldrich Co. (Milwaukee, WI) and were used without purification.
Dry solvents (toluene, hexane) were provided in SureSeal bottles
and were handled under positive pressure of argon. Other
solvents were dried by distillation from sodium benzophenone
(THF) or from CaH2 (CH2Cl2). C. antarctica lipase B was
provided by Novo Nordisk A/S, Denmark. High loading carboxy-
polystyrene was purchased from Novabiochem Inc. (San Diego,
CA). Depending on the scale, polymer-assisted reactions were
(15) The scavenging step was assessed with as follows: (a) Ellman’s
DHP resin (Novabiochem): Thompson, L. A.; Ellman, J . A. Tetrahedron
Lett. 1994, 35, 9333. (b) Polystyrene diethylsilyl chloride (PS-DES
resin, Argonaut Technologies): Hu, Y.; Porco, J . A., J r.; Labadie, J .
W.; Gooding, O. W.; Trost, B. M. J . Org. Chem. 1998, 63, 4518.
(16) For references on the resin capture or “catch-and-release”
principle, see: (a) Keating, T. A.; Armstrong, R. W. J . Am. Chem. Soc.
1996, 118, 2574. (b) Brown, S. D.; Armstrong, R. W. J . Am. Chem.
Soc. 1996, 118, 6331.
(17) (a) Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Ba¨ckvall, J .-
E. J . Am. Chem. Soc. 1999, 121, 1645. (b) Co´rdova, A.; J anda, K. D. J .
Org. Chem. 2001, 66, 1906.
conducted in either
a scintillation vial or a peptide flask
(Chemglass Inc., Vineland, NJ ) and agitation was provided by
(18) Rakels, J . L. L.; Straathof, A. J . J .; Heijnen, J . J . Enzyme
Microb. Technol. 1993, 15, 1051.
(19) Chen, C.-S.; Wu, S.-H.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1987, 109, 2812.
(20) (a) Koeller, K. M.; Wong, C.-H. Nature 2001, 409, 232. (b)
Takayama, S.; Lee, S. T.; Hung, S.-C.; Wong, C.-H. Chem. Commun.
1999, 127.

Notes
J . Org. Chem., Vol. 66, No. 16, 2001 5647
Ta ble 1. En a n tioselectivity of Ca n d id a a n ta r ctica Lip a se B a n d th e P olym er -Su p p or ted P r olin e-Ba sed Ca ta lyst
Deter m in ed a fter th e “F ish in g ou t” Step a n d Clea va ge fr om th e P olym er Su p p or t
a
Fast reacting enantiomer. The absolute configuration was based on optical rotation, which were in accordance with those in the
literature.13,14,17 c ) ees/(ees + eep).18,19 c Determined by chiral HPLC on a Chiracel OD-H column (hexane/2-propanol mixtures, λ )
b
d
254 nm) after cleavage from the resin. Determined on the alcohol corresponding to the acetate formed, by chiral HPLC on a Chiracel
OD-H column. e E ) ln[(1 - ees )/(1 + ees/eep)]/ln[(1 + ees )/ (1 + ees/eep)].18,19 f See ref 14.
either a 360° LabQuake shaker (Barnstead/Thermolyne) or a
180° wrist-action shaker (MilliGen, Bedford, MA). Optical puri-
ties were determined by HPLC using a Chiracel OD-H column
(hexane/ 2-propanol mixtures, λ ) 254 nm). The structural
integrity of the compounds (Table 1, entries 1-10) and their
esters was determined by 1H NMR (400 MHz) and compared
with the literature.13,14,17
P r ep a r a tion of th e P olym er -Bou n d Ben zoyl Ch lor id e.
The benzoyl chloride scavenging resin was synthesized according
to the procedure of Hodge and co-workers21 and was used shortly
after its preparation.
En zym a tic Kin etic Resolu tion a n d Sca ven gin g P r oce-
d u r e in a P a r a llel F or m a t. The sec-alcohols (0.5 mmol) were
added to dry vials containing C. antarctica lipase B (10 mg) and
dry toluene (3 mL) was added. Vinyl acetate (1.5 mmol) was
added, and the vials were shaken (200 rpm) at room tempera-
ture. After ∼50% conversion (estimated by TLC), the lipase was
removed by filtration and washed with CH2Cl2. The solvent and
excess vinyl acetate were removed in vacuo. The conversion and
complete removal of the acylating agent were verified by 1H
NMR. The mixture was then dissolved in CH2Cl2 (2 mL) and
added to vials containing polymer-bound benzoyl chloride (2.3
equiv, acid chloride ∼1 mmol/g), Et3N (2 mmol), and catalytic
DMAP in CH2Cl2 (2 mL). The vials were rotated for 16-24 h at
room temperature while the removal of the alcohol from the
reaction mixture was monitored by TLC. After complete scav-
enging, the resin was isolated by filtration and washed with CH2-
Cl2. The filtrate was diluted with excess ether, washed with 1
N HCl, dried (MgSO4), and concentrated in vacuo to give the
pure acetate esters. The esters were then cleaved by hydrolysis
according to Orrenius et al.,13 and the ee and purity of the
corresponding alcohols were determined by chiral HPLC.13,14,17
The remaining resin, containing the other enantiomer, was
further washed with CH2Cl2, THF, and hexane. Thereafter, this
resin was added to vials containing THF (2 mL) and a 2.5% (w/
v) KOH/methanol solution (2 mL). The release of alcohol was
monitored by TLC and was complete within 12 h. The resin was
separated by filtration and washed with ether. The ether filtrate
was washed with 1 N HCl, and the alcohols were isolated and
analyzed as previously described.
Kin etic Resolu tion w ith a Ch em ica l Ca ta lyst a n d Sca v-
en gin g P r oced u r e. The kinetic resolution by the polymer-
supported chemical catalyst was performed according to our
previous work,14 and the scavenging procedure was the same
as for the enzyme catalyst (vide supra).
P r ep a r a tive-Sca le Rea ction . The racemic mixture of 1-phe-
nylethanol (870 mg; 7.13 mmol) was added to a dry vial
containing C. antarctica lipase B (200 mg), and then dry CH2-
Cl2 (5 mL) was added. Vinyl acetate (723 µL; 7.8 mmol) was
(21) Hodge, P.; Kemp, J .; Khoshdel, E.; Perry, G. M. React. Polym.
1985, 3, 299.

5648 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
added and the vial was shaken (200 rpm) at room temperature.
After ∼50% conversion (24 h), the lipase was removed by
filtration and washed with CH2Cl2. The solvent and excess vinyl
acetate were removed in vacuo. The conversion and complete
removal of the acylating agent were verified by 1H NMR. The
mixture (1.0 g; 3.5 mmol alcohol) was then dissolved in dry CH2-
Cl2 (10 mL) and added to a peptide flask containing swollen
polymer-bound benzoyl chloride (7 g; ∼1 mmol Cl/g) in 40 mL
of dry CH2Cl2 with Et3N (2 mL; 14 mmol) and catalytic DMAP
(243 mg; 0.04 M final concentration). The peptide flask was
agitated at room temperature until the alcohol was completely
removed from the reaction mixture. After complete scavenging
(∼24 h), the resin was isolated by filtration and washed with
CH2Cl2 (2 × 20 mL). The filtrate was washed with 1 N HCl,
dried (Na2SO4), and concentrated in vacuo to give 423 mg of the
pure acetate ester. The resin was further washed with THF (4
× 20 mL) and hexane (3 × 30 mL) and then dried under high
vacuum. The hydrolysis of both esters was performed as
described above to generate, in two distinct vials, 273 mg (32%
overall) of (R)-1-phenylethanol (96% ee) ((R)-1) and 292 mg (34%
overall) of (S)-1-phenylethanol (>99% ee) ((S)-1).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(Grant GM-56154), The Scripps Research Institute, and
The Skaggs Institute for Chemical Biology. A.C. is a
Skaggs postdoctoral fellow and acknowledges a fellow-
ship from the Wennergren Foundations, Sweden. M.R.T.
is a Skaggs postdoctoral fellow and acknowledges a
fellowship from the Natural Science and Engineering
Research Council of Canada. B.C. is a Skaggs postdoc-
toral fellow. The provision of enzyme by Novo Nordisk
A/S, Denmark is also gratefully acknowledged.
J O010529U