Design and Optimization of Phosphine Oxazoline Ligands
J. Am. Chem. Soc., Vol. 120, No. 36, 1998 9181
Applications of high-throughput methods in catalysis research
have emerged more slowly than in biotechnology and pharma-
ceutical development.12 There are several reasons for this,
including the following. First, catalysis is a less common event
than, for instance, binding of small molecules to a biological
target, so the hit rate in completely random screens for catalytic
activities is less. Incidentally, it follows that small focused
libraries of potential catalysts can be more useful than large
random collections of compounds wherein most have few
properties suitable for catalytic activities. Second, catalysis in
nonbiological systems tends to be hard to detect. High-
throughput assays for biological interactions are much better
developed than for organometallic systems. Third, impurities
tend to have more serious detrimental effects in studies of
catalysis, compared with assays to detect simple binding, hence
quality control is more important.
Figure 2. Principle of divergent ligand syntheses.
ligand synthesis, a large amount of a key optically pure material
is produced, then used to prepare many ligands (Figure 2).
Members of the ligand set formed may be structurally similar,
but that is not problematic because small changes can have
relatively large effects on the outcome of asymmetric reactions.
The concept of divergent ligand syntheses is usually not
emphasized, though it frequently emerges as a factor in well-
designed approaches to asymmetric catalysts. For instance,
Jacobsen’s ligands for asymmetric epoxidation22-26 and other
processes27-33 were developed by combining relatively expen-
sive or less accessible optically active diamines and a variety
of readily available salicylaldehyde derivatives. It would be
wrong to claim that divergent ligand synthesis is the best strategy
for every situation; in fact, it is preferable to obtain ligands
directly from commercially available sources, as in the Sharpless
epoxidation,34,35 or in a few synthetic steps, as for bisoxazo-
lines.36 However, such straightforward access to good molecular
architectures for asymmetric coordinating groups is relatively
rare. In cases where there is no such convenient strategy,
divergent routes to well-designed systems are an attractive
option.
This paper highlights divergent, solution-phase syntheses of
ligands for generation of focused libraries. It describes how
these ligands were used to produce libraries of catalysts in array
formats and how data was collected via an automated screen.
The novel phosphine oxazoline systems 1 were selected as a
test case. High-throughput methods have been used to evaluate
and optimize application of these ligands. This study facilitated
comparison of ligands 1 with the known systems 2.36-42
Our group is interested in improving the efficiency of
asymmetric catalyst discovery and optimization. Evaluation of
the arguments presented above led us to conclude that parallel
syntheses of catalyst systems coupled with high-throughput
automated screens were likely to be the most generally ap-
plicable approach.
Generation of the numbers of ligands necessary for screening
libraries of catalysts is a challenging problem. We believe that
solution-phase syntheses of the required ligands will be the most
desirable approach in the majority of situations, for two reasons.
First, it is difficult to attain the chemical and optical purities
required for reproducible and interpretable studies of asymmetric
catalysis via solid-phase syntheses of ligands, particularly for
sensitive molecules like phosphines. Second, small focused
libraries of catalysts are likely to be more useful than large
random libraries, for the reasons discussed above. The number
of ligands that must be prepared for focused libraries is
manageable, whereas solution-phase synthesis of hundreds or
thousands of ligands is impractical. Consequently, solution-
phase work has been the focus of our first publications in this
area.12-14 Meanwhile, other groups have concentrated on solid-
phase syntheses of ligands as a basis for library development.15-17
Work is in progress to couple these efforts with split and mix
methodologies,18 and the result is likely to be an extremely
elegant demonstration of truly combinatorial syntheses and
screens for catalysis.19 However, the reactions studied in
conjunction with solid-phase syntheses of ligands are selected
from a limited number of possibilities. This is because nearly20
all the chiral ligands prepared via solid-phase syntheses so far
have been peptidic systems, and the range of catalytic processes
that can be mediated with peptide-based ligands is limited.
The task of making a ligand set for screening in small focused
libraries is facilitated by a divergent approach.21 In a divergent
(22) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J.
Am. Chem. Soc. 1991, 113, 7063.
(23) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801.
(24) Jacobsen, E. N.; Zhang, W.; Gu¨ler, M. L. J. Am. Chem. Soc. 1991,
113, 6703.
(25) Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett.
1995, 36, 5457.
(26) Brandes, B. D.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5123.
(27) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993,
115, 5326.
(28) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. Engl. 1995, 34, 676.
(29) Mart´ınez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J.
Am. Chem. Soc. 1995, 117, 5897.
(30) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117,
5889.
(31) O’Connor, K. J.; Wey, S.-J.; Burrows, C. J. Tetrahedron Lett. 1992,
33, 1001.
(12) Burgess, K.; Porte, A. M. In AdVances in Catalytic Processes; Doyle,
M. P., Ed.; JAI Press: Greenwich, CT, 1997; Vol. 2, p 69.
(13) Burgess, K.; Lim, H.-J.; Porte, A. M.; Sulikowski, G. A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 220.
(14) Burgess, K.; Moye-Sherman, D.; Porte, A. M. In Molecular DiVersity
and Combinatorial Chemistry; Chaiken, I. M., Janda, K. D., Eds.; American
Chemical Society: Washington, DC, 1996; p 128.
(15) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 36, 6475.
(16) 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.
(17) 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.
(18) Francis, M. B.; Finney, N. S.; Jacobsen, E. N. J. Am. Chem. Soc.
1996, 118, 8983.
(32) Fukuda, T.; Katsuki, T. SYNLETT 1995, 825.
(33) Lam, F.; Xu, J. X.; Chan, K. S. J. Org. Chem. 1996, 61, 8414.
(34) Pfenninger, A. Synthesis 1986, 89.
(35) Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin,
V. S.; Taktani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Pure Appl.
Chem. 1983, 55, 589.
(36) Pfaltz, A. Acta Chem. Scand. 1996, 50, 189.
(37) Dawson, G. J.; Frost, C. G.; Williams, J. M. J. Tetrahedron Lett.
1993, 34, 3149.
(38) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
(39) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.;
Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523.
(40) Matt, P. V.; Loiseleur, O.; Koch, G.; Pfaltz, A. Tetrahedron 1994,
5, 573.
(41) Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994,
35, 8595.
(42) Koch, G.; Lloyd-Jones, G. C.; Loiseleur, O.; Pfaltz, A.; Pretot, R.;
Schaffner, S.; Schnider, P.; Matt, P. v. Recl. TraV. Chim. Pays-Bas 1995,
114, 206.
(19) Jacobsen, E. Conference on Combinatorial Approaches to Chemistry
and Biology, Cambridge, U.K., July 1997.
(20) Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712.
(21) Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050.