A high-throughput screening protocol for fast evaluation of enantioselective catalysts

Article abstract of DOI:10.1021/jo025534s

A new high-throughput screening protocol that allows fast evaluation of enantioselective catalysts has been developed. The usefulness of norephedrine-derived β-amino alcohols as catalysts for the enantioselective alkylation of prochiral aldehydes has been determined by simultaneous screening of three representative substrates. GC analysis of the crude product mixture using a selectively modified cyclodextrin as the chiral stationary phase avoids timeconsuming workup procedures. The chemical yield, enantioselectivity, substrate specificity, and catalytic activity of the chiral catalysts as well as the induced absolute configuration have been determined in a single screening experiment and two short GC runs.

Full text of DOI:10.1021/jo025534s

J . Org. Chem. 2002, 67, 2727-2729
2727
A High -Th r ou gh p u t Scr een in g P r otocol for
F a st Eva lu a tion of En a n tioselective
Ca ta lysts
Christian Wolf* and Pili A. Hawes
F igu r e 1. Structure of catalysts 1 and 2.
Department of Chemistry, Georgetown University,
Washington, DC 20057
Sch em e 1. Mu ltisu bstr a te HTS Usin g Ald eh yd es
3-5
cw27@georgetown.edu
Received J anuary 18, 2002
Abstr a ct: A new high-throughput screening protocol that
allows fast evaluation of enantioselective catalysts has been
developed. The usefulness of norephedrine-derived â-amino
alcohols as catalysts for the enantioselective alkylation of
prochiral aldehydes has been determined by simultaneous
screening of three representative substrates. GC analysis
of the crude product mixture using a selectively modified
cyclodextrin as the chiral stationary phase avoids time-
consuming workup procedures. The chemical yield, enantio-
selectivity, substrate specificity, and catalytic activity of the
chiral catalysts as well as the induced absolute configuration
have been determined in a single screening experiment and
two short GC runs.
ephedrine, 1, and (1R,2S)-N-monobutylnorephedrine, 2,
as catalysts for the enantioselective alkylation of three
representative aldehydes, Figure 1.5 The development
and evaluation of â-amino alcohols that promote the
enantioselective alkylation of prochiral aldehydes using
organozinc reagents remains an active area of investiga-
tion.6 Chiral ligands used to date usually afford high
stereoselectivity only for certain types of aldehydes. A
fast and comprehensive screening protocol that is capable
of determining a catalyst’s applicability to linear, branched,
and aromatic aldehydes is most desirable for the develop-
ment of new catalysts.
Chiral catalysts 1 and 2 were synthesized from com-
mercially available (1R,2S)-norephedrine.7 Benzaldehyde,
3, cyclohexanecarboxaldehyde, 4, and hexanal, 5, were
chosen as substrates to represent different types of
aldehydes, i.e., linear and branched aliphatic as well as
aromatic aldehydes, Scheme 1. Racemic 1-phenylpro-
panol, 6, 1-cyclohexylpropanol, 7, and 3-octanol, 8, were
prepared via Grignard reaction from corresponding al-
dehydes 3-5, respectively, and used for GC method
development as well as references for mass spectrom-
etry.8 Comparison of MS data of each reference with MS
spectra obtained for the nonracemic alcohol mixtures of
our screening experiments allowed us to exclude coelution
of impurities during GC analysis. Thus, we were able to
(a) unequivocally identify products and (b) accurately
determine the enantiomeric excess of each alcohol from
the crude product mixture. Notably, our screening pro-
cedure avoids time-consuming purification steps.
Combinatorial chemistry provides a powerful tool for
the development of new enantioselective catalysts.1 Fast
identification of efficient catalysts and optimization of
reaction conditions require a high-throughput screening
(HTS) methodology that is capable of answering a variety
of questions.2 Recently, Welch et al. reported a fast HTS
protocol that utilizes HPLC-MS to evaluate yeast-medi-
ated enantioselective reductions of diaryl ketones.3 Kagan
et al. applied multisubstrate screening to evaluate the
asymmetric reduction of ketones using an oxazaboroli-
dine derived from (S)-diphenylproline.4 Herein, we report
a multisubstrate screening methodology using enantio-
selective GC-MS analysis. Our approach allows fast
determination of asymmetric induction, enantioselectiv-
ity, chemical yield, catalyst activity, and substrate speci-
ficity of a chiral catalyst by a single experiment. The HTS
protocol was developed using (1R,2S)-N,N′-dibutylnor-
(1) (a) 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, 1668-1671. (b) Gennari, C.; Nestler, H. P.; Piarulli, U.; Salom, B.
Liebigs Ann./ Recl 1997, 637-647. (c) Shimizu, K. D.; Cole, B. M.;
Krueger, C. A.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1704-1707. (d) Gennari, C.; Ceccarelli,
S.; Piarulli, U.; Montalbetti, C. A. G. N.; J ackson, R. F. W. J . Org.
Chem. 1998, 63, 5312-5313. (e) Ding, K.; Ishii, A.; Mikami, K. Angew.
Chem., Int. Ed. 1999, 38, 497-501. (f) Reetz, m. T.; Becker, M. H.;
Klein, H.-W.; Sto¨ckigt, D. Angew. Chem., Int. Ed. 1999, 38, 1758-
1761. (g) J andeleit, B.; Schaefer, D. J .; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. 1999, 38, 2494-2532. (h)
Reetz, M. T.; Ku¨hling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew.
Chem., Int. Ed. 2000, 39, 3891-3893. (i) Long, J .; Ding, K. Angew.
Chem., Int. Ed. 2001, 40, 544-547. (j) Mikami, K.; Angelaud, R.; Ding,
K.; Ishii, A.; Tanaka, A.; Sawada, N.; Kudo, K.; Senda, M. Chem. Eur.
J . 2001, 7, 730-737. (k) Chataigner, I.; Gennari, C.; Ongeri, S.; Piarulli,
U.; Ceccarelli, S. Chem. Eur. J . 2001, 7, 2628-2634.
GC analysis of the reaction mixture containing prochiral
aldehydes 3-5 and of the crude product mixture obtained
by enantioselective alkylation with diethyl zinc allowed
fast evaluation of norephedrine-derived catalysts 1 and
(5) (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J . Am. Chem.
Soc. 1989, 111, 4028-4036. (b) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49-69. (c) Soai, K.; Niwa, S. Chem. Rev. 1992,
92, 833-856.
(6) Tye, H. J . Chem. Soc., Perkin Trans. 1 2000, 275-298. Tye, H.;
Comina, P. J . J . Chem. Soc., Perkin Trans. 1 2001, 1729-1747 and
references therein.
(7) Soai, K.; Yokoyama, S.; Hayasaka, T. J . Org. Chem. 1991, 56,
4264-4268.
(8) Racemic alcohols 6-8 were prepared from aldehydes 3-5 using
ethylmagnesium chloride. Each alcohol was purified by flash chroma-
tography and identified by NMR spectroscopy.
(2) (a) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chem. Eur.
J . 1998, 4, 1885-1889. (b) Bein, T. Angew. Chem., Int. Ed. 1999, 38,
323-326. (c) Baumann, M.; Stu¨rmer, R.; Bornscheuer, U. T. Angew.
Chem., Int. Ed. 2001, 40, 4201-4204.
(3) Welch, C. J .; Grau, B.; Moore, J .; Mathre, D. J . J . Org. Chem.
2001, 66, 6836-6837.
(4) Gao, X.; Kagan, H. B. Chirality 1998, 10, 120-124.
10.1021/jo025534s CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

2728 J . Org. Chem., Vol. 67, No. 8, 2002
Notes
F igu r e 2. Gas chromatogram of the reaction mixure (left) and GC separation of a representative product mixture obtained by
multisubstrate HTS using (1R,2S)-1 as the catalyst (right).
Ta ble 1. Mu ltisu bstr a te Scr een in g Resu lts
2. Optimization of chromatographic conditions using
octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin9 as the
temp
% ee
% yield
run catalyst (°C) aldehyde ((3%)a configurationa ((3%)b
chiral stationary phase enabled us to separate aldehydes
3-5, naphthalene, and the enantiomers of alcohols 6-8
in a single run, Figure 2. GC analysis of the reaction
mixture containing the three aldehydes and naphthalene
as the internal standard provided individual response
factors for calculation of chemical yields.10 In addition,
the enantiomeric excess and absolute configuration of
chiral alcohols 6-8 were easily obtained from the same
run. No indication of coelution of impurities with enan-
tiomers of 6-8 was observed by GC-MS. Since aldehydes
3-5 were converted simultaneously, i.e., under identical
reaction conditions, comparison of the substrate specific-
ity and application spectrum of the catalyst was greatly
facilitated, vide infra. Thus, our HTS protocol provides
a comprehensive and time-efficient catalyst evaluation
that requires only one experiment and two short GC-MS
or GC-FID runs of less than 15 min.
1
1
1
1
1
1
2
2
2
0
0
0
25
25
25
25
25
25
3
4
5
3
4
5
3
4
5
91
97
84
92
95
83
71
46
43
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
97
96
88
99
1
2
3
97
97
>99c
93
98
a
Enantiomeric excess of alcohols 6-8 was determined by
enantioselective GC. Elution order of enantiomers of alcohols 6-8
using octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin as the
chiral stationary phase was determined according to the known
chiral induction of 1.5c Percent yields are calculated on the basis
b
of GC analysis using naphthalene as the internal standard.10 c No
starting material was detected.
Ta ble 2. In d ivid u a l Scr een in g Resu lts
Simultaneous screening of the enantioselective alky-
lation of aldehydes 3-5 revealed high enantioselectivity
and catalytic activity of (1R,2S)-1 for aldehydes 3 and 4,
Table 1. Alcohols (R)-6 and (R)-7 were obtained in almost
quantitative yields and ees above 90% at 0 °C. Conversion
of 5 to (R)-8 proceeded with only 84% ee and 88%
chemical yield due to incomplete aldehyde conversion at
0 °C after 16 h. Interestingly, the yield of 8 significantly
improved to 97% at room temperature without compro-
mising the enantioselectivity. The multisubstrate screen-
temp
% ee
% yield
run catalyst (°C) aldehyde ((3%)a configurationa ((3%)b
1
2
3
4
5
6
1
1
1
2
2
2
0
0
0
25
25
25
3
4
5
3
4
5
92
94
84
69
47
35
(R)
(R)
(R)
(R)
(R)
(R)
>99c
>99c
88
98
89
84
a
Enantiomeric excess of alcohols 6-8 was determined by
enantioselective GC. Elution order of enantiomers of alcohols 6-8
using octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin as the
chiral stationary phase was determined according to the known
chiral induction of 1.5c Percent yields are calculated on the basis
b
(9) Ko¨nig, W. A. J . High Resolut. Chromatogr. 1993, 16, 312-323.
(10) Individual response factors [area(aldehyde) × mg(standard)/
area(standard) × mg(aldehyde)] were determined for all three alde-
hydes by GC analysis of the reaction mixture. Determination of the
ratio of the area of each aldehyde to the area of naphthalene obtained
from a second GC run of the product mixture allowed calculation of
the remaining starting material. Dilution experiments revealed excel-
lent linearity of aldehyde responses over the concentration range
obtained in reaction and product mixtures. Total area % of side
products proved to be less than 2% in all cases. Thus, we were able to
calculate aldehyde conversion as well as the chemical yield. Calculation
of the yield using a standard solution of alcohols 6-8 and naphthalene
as the internal standard afforded similar results. However, reproduc-
ibility and precision were unsatisfactory since response factors of
alcohols 6-8 varied significantly from run to run.
of GC analysis using naphthalene as the internal standard.10 c No
starting material was detected.
ing results clearly show that (1R,2S)-1 exhibits a higher
enantioselectivity for aromatic and branched aliphatic
substrates than for linear aliphatic aldehydes. Most
importantly, our HTS protocol affords reproducible re-
sults that are in excellent agreement with data obtained
from individual screening experiments, Table 2. Enan-
tioselectivites and chemical yields obtained by both
screening procedures do not vary more than 3%.

Notes
Comparison of our screening results reveals superior
J . Org. Chem., Vol. 67, No. 8, 2002 2729
In summary, we have demonstrated that fast evalua-
tion of â-amino alcohols as catalysts for the enantiose-
lective alkylation of prochiral aldehydes using diethylzinc
can be accomplished by multisubstrate high-throughput
screening. The applicability of norephedrine-derived
catalysts toward linear, branched, and aromatic alde-
hydes has been determined by simultaneous screening
of representative substrates. GC analysis of the crude
product mixture using a selectively modified cyclodextrin
as the chiral stationary phase avoids time-consuming
workup procedures. Thus, the chemical yield, enantiose-
lectivity, substrate specificity, and catalytic activity of the
chiral catalysts as well as the induced absolute config-
uration have been determined in a single screening
experiment and two short GC runs using naphthalene
as the internal standard.
catalytic performance of â-amino alcohol 1 over 2, Table
1. Both catalysts promote formation of alcohols exhibiting
the (R)-configuration. Enantioselective alkylation of al-
dehydes 3-5 using catalyst (1R,2S)-2 proceeds with high
yields but only moderate ees at room temperature.
Results obtained for conversion of aldehydes 3 and 4 to
their corresponding alcohols by multisubstrate and in-
dividual screening are in very good agreement. However,
simultaneous screening somehow affords a higher enan-
tioselectivity and yield for the formation of (R)-8 from 5,
Table 2.
One might expect that the usefulness of multisubstrate
HTS as described herein would be limited to catalytic
reactions that do not exhibit autocatalysis or catalyst
poisoning by reaction products. However, it is well-known
that the enantioselective alkylation of aldehydes pro-
moted by â-amino alcohols is often accompanied by
autocatalysis and nonlinear effects.11 Nonchiral additives
have also been reported to affect the catalytic perfor-
mance of â-amino alcohols.12 The increase of yield and
enantioselectivity observed for conversion of hexanal in
the presence of benzaldehyde and cyclohexanecarboxal-
dehyde might result from some catalytic activity of (R)-
alkoxides formed during catalysis.13 Nevertheless, results
obtained using our HTS protocol are in very good agree-
ment with individual screening of each aldehyde. Simul-
taneous substrate screening as described herein is also
likely to be very useful for optimization of reaction
conditions and for evaluation of catalyst candidates for
a variety of other enantioselective reactions.
Exp er im en ta l Section
Chemicals were of reagent grade and purchased from Aldrich.
All reactions were carried out under a nitrogen atmosphere and
anhydrous conditions.
Gen er a l P r oced u r e for Scr een in g Ca ta lyst 1. A solution
of catalyst 1 (0.04 mmol, 9 mol %) and the aldehyde mixture
(0.47 mmol of all three aldehydes) in 2 mL of anhydrous hexanes
was stirred at room temperature for 20 min and then cooled to
0 °C. After 40 min, Et2Zn (1.1 mL, 1 M in hexanes) was added
dropwise. The solution was stirred for 16 h at 0 °C and quenched
with 5 mL of saturated NH4Cl. The aqueous layer was extracted
three times with CH2Cl2. The organic layers were combined and
used for GC analysis without further workup.
Gen er a l P r oced u r e for Scr een in g Ca ta lyst 2. A solution
containing 2 and diethylzinc was stirred at room temperature
for 40 min. After the solution was cooled to 0 °C, the aldehyde
mixture was added dropwise. The solution was allowed to come
to room temperature and stirred for 16 h. The workup procedure
described above was followed by GC analysis of the crude product
mixture.
(11) (a) Oguni, N.; Matsuda, Y.; Kaneko, T. J . Am. Chem. Soc. 1988,
110, 7877-7878. (b) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J .
Am. Chem. Soc. 1989, 111, 4028-4036. (c) Bolm, C.; Bienewald, F.;
Seger, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1657-1659. (d) Soai,
K.; Shibata, T. J . Synth. Org. Chem. J pn. 1997, 55, 994-1005. (e)
Shibata, T.; Hayase, T.; Yamamoto, J .; Soai, K. Tetrahedron: Asym-
metry 1997, 8, 1717-1719. (f) Avalos, M.; Babiano, R.; Cintas, P.;
J ime´nez, J . L.; Palacios, J . C. Tetrahedron: Asymmetry 1997, 8, 2997-
3017. (g) Shibata, T.; Takahashi, T.; Konishi, T.; Soai, K. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2458-2460. (h) Girard, C.; Kagan, H. B. Angew.
Chem., Int. Ed. 1998, 37, 2922-2959. (i) Kitamura, M.; Suga, S.; Oka,
H.; Noyori, R. J . Am. Chem. Soc. 1998, 120, 9800-9809. (j) Blackmond,
D. G. J . Am. Chem. Soc. 1998, 120, 13349-13353. (k) Soai, K.; Shibata,
T.; Sato, I. Acc. Chem. Res. 2000, 33, 382-390.
GC An a lysis. Aldehydes 3-5, naphthalene, and enantiomers
of alcohols 6-8 were separated by GC using octakis(6-O-methyl-
2,3-di-O-pentyl)-γ-cyclodextrin (60% in OV 1701, 30 m) as the
chiral stationary phase. Temperature program: 90 °C for 5 min,
then 7 °C/min to 115 °C. Enantioselectivity R: 1.02 (6), 1.02 (7),
1.04 (8).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for the synthesis of catalysts 1 and 2 and spectroscopic
data for 1 and 2 This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Vogl, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570-1577.
(13) Alkoxides are known to promote the enantioselective alkylation
of aldehydes with low enantioselectivity.
J O025534S