Soluble polymer-bound ligand-accelerated catalysis: Asymmetric dihydroxylation

Full text of DOI:10.1021/ja9608095

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7632
J. Am. Chem. Soc. 1996, 118, 7632-7633
and lower enantioselectivity9 than had previously been obtained
with its solution phase counterpart.
Soluble Polymer-Bound Ligand-Accelerated
Catalysis: Asymmetric Dihydroxylation
The problems associated with LAC in which the ligand is
localized by attachment to an insoluble polymer can be
understood by considering the basic tenet upon which this
concept is based.10 By definition, the LAC phenomenon
requires that the addition of a ligand increases the reaction rate
of an already existing catalytic transformation. Both the ligand-
accelerated and the nonaccelerated reactions operate in solution
simultaneously and in competition with each other. Obviously,
if the ligand does not have equivalent access to all the reaction
compartments where the substrate, metal oxidant, and olefin
reside, the most fundamental requirement for a successful ligand
accelerated catalysis scenario is not met. For the present case,
this means that the chiral ligand resides only in the insoluble
phase, while the OsO4 and olefin are in solution and free to
react anywhere. In this situation the optimal LAC conditions
can probably never be achieved even when using a large excess
of the insoluble polymer-bound ligand.9
In an effort to circumvent the problems observed with
insoluble supports and LAC, yet provide the economical and
physical advantages (product isolation and reagent recovery)
that a polymeric support can offer, we have investigated the
potential of applying the soluble homopolymer MeO-PEG as a
suitable scaffold for the AD reaction. We report here the
synthesis of polyethylene glycol monomethyl ether bound
cinchona alkaloid ligands (Figure 1) and their successful use in
the LAC asymmetric dihydoxylation reaction of various olefins.
The synthesis of the MeO-PEG-bound dihydroquinidine
ligands is depicted in Scheme 1. The commercially available
hydroquinidine 5 was acylated using glutaric anhydride and
4-N,N′-dimethylaminopyridine (DMAP) to provide carboxylic
acid 6. This reaction, though simple, provides the linking unit
necessary for attachment to the homopolymer MeO-PEG or any
other amino or alcohol group. The coupling of acid 6 to
polyethylene glycol monomethyl ether and ethyl alcohol in the
presence of dicyclohexylcarbodiimide and DMAP produced the
homopolymer 2 and its simple diester homologue 3, respectively.
The chiral homopolymer 2 was the archetype used to examine
and compare all of the AD reactions investigated. The structural
similarity of 2 to the insoluble acrylonitrile ligand 1 allowed
for a direct comparison between soluble and insoluble supports
to be made,8a while contrasting the reactivity of ligands 2, 3,
and 4 in the AD reaction would delineate any effect that the
polyethylene glycol backbone may have on asymmetric induc-
tion. In addition, to standardize the comparisons between our
soluble ligand support and the insoluble ligand support, we used
the same conditions as reported for the 1-AD catalytic reaction.8a
The MeO-PEG-supported catalyst 2 is completely soluble in
an acetone-water mixture (v/v ) 10/1); thus the catalytic reaction
is completely homogeneous. Of greater note is that the reaction
is complete within the same time frame as that of its solution
counterpart with no decrease of yields or enantioselectivity
(Table 1). For this methodology to be useful, product isolation,
Hyunsoo Han and Kim D. Janda*
The Scripps Research Institute
Departments of Molecular Biology and Chemistry and
The Skaggs Institute of Chemical Biology
10550 North Torrey Pines Road
La Jolla, California 92037
ReceiVed March 12, 1996
Insoluble polymer-reagents and catalysts have achieved wide
recognition and acclaim.1 However, as successful as insoluble
reagent and catalyst supports have been there are limitations
associated with such species.2 An alternative to insoluble
polymer-bound reagents or catalysts is soluble polymer bound
ligands, reagents, or catalyst supports,3 the difference being that
reactions are carried out homogeneously and separation of the
homopolymer from reaction products can be achieved by taking
advantage of the properties of the polymer chain. We have
been interested in applying soluble polymers in the arena of
combinatorial synthesis. As such we recently introduced what
we term “liquid phase combinatorial synthesis” or LPCS.4 The
cornerstone of LPCS is a linear homopolymer [polyethylene
glycol monomethyl ether (MeO-PEG)] which serves a dual role
as both a terminal protecting group and a solublizing agent for
any compound(s) synthesized on the support. Using this
approach, we have synthesized combinatorial peptide, small
molecule,4 and peptidomimetic libraries.5
The ligand-accelerated catalytic (LAC) asymmetric dihy-
droxylation (AD) of olefins based on cinchona alkaloid ligands
was described by Sharpless in 1988;6 since this seminal report,
the AD reaction has been further developed to include applica-
tion to a wider range of olefins, improved enantiomeric
efficiency, and overall simplicity of operation.7 From the
standpoint of cost, ligand and/or metal recovery and recycling
are of prime interest because the cinchona alkaloid ligand and
osmium tetroxide are the most expensive components of the
procedure. In this regard, several groups have reported the
catalytic asymmetric dihydoxylation of olefins using insoluble
polymer bound cinchona alkaloid-ligands.8 While it was hoped
that this methodology would provide convenience and improve
the economics of the process, it was deemed less than satisfac-
tory because of increased reaction times, highly variable yields,
* To whom correspondence should be addressed.
(1) (a) Pittman, C. U. ComprehensiVe Organometallic Chemistry;
Wilkinson, G., Ed.; Pergamon Press: Oxford, 1982. (b) Mathur, N. C.;
Narang, C. K. Williams, R. E. Polymers as Aids in Organic Chemistry;
Academic Press: New York, 1980. (c) Frechet, J. M. J. Tetrahedron 1981,
37, 663. (d) Syntheses and Separations Using Functionalized Polymers;
Sherrington, D. C., Hodge, P., Eds.; Wiley: New York, 1988. (e)
Bergbreiter, D. E.; Blanton, J. R.; Chandran, R.; Hein, M. D.; Huang, K.-
J.; Treadwell, D. R.; Walker, S. A. J. Polym. Sci., Polym. Chem. Ed. 1989,
27, 4205.
(2) Barany, G.; Merrifield, R. B. In The Peptides, Gross, E., Meienhofer,
J., Eds.; Academic Press: New York, 1979; Vol. 2, p 1.
(3) (a) Bayer, E.; Schurig, V. Angew. Chem., Int. Ed. Engl. 1975, 14,
493. (b) Bayer, E.; Schurig, V. CHEMTECH 1976, 6, 212. (c) Bergbreiter,
D. E. ACS Symposium Series 1986, 308, 17. (d) Bergbreiter, D. E.;
Chandran, R. J. Am. Chem. Soc. 1987, 109, 174. (e) Bergbreiter, D. E.
CHEMTECH 1987, 17, 686. (f) Phelps, J. C.; Bergbreiter, D. E. Tetrahedron
Lett. 1989, 30, 3915. (g) Bergbreiter, D. E.; Walker, S. A. J. Org. Chem.
1989, 54, 2726. (i) Bergbreiter, D. E.; Morvant, M.; Chen, B. Tetrahedron
Lett. 1991, 32, 2731. (j) Doyle, M. P.; Eismont, M. Y.; Bergbreiter, D. E.;
Gray, H. N. J. Org. Chem. 1992, 57, 6103. (k) Bergbreiter, D. E.; Zhang,
L.; Mariagnanam, V. M. J. Am. Chem. Soc. 1993, 115, 9295.
(4) Han, H.; Wolfe, M. M.; Brenner, S.; Janda, K. D. Proc. Natl. Acad.
Sci. U.S.A. 1995, 92, 6419.
(5) Han, H.; Janda, K. D. J. Am. Chem. Soc. 1996, 118, 2539.
(6) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968.
(7) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 116, 2483.
(8) (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 3003.
(b) Pini, D.; Petri, A.; Nardi, A.; Rosini, C.; Salvadori, P. Tetrahedron Lett.
1991, 32, 5175. (c) Lohray, B. B.; Thomas, A.; Chihari, P.; Ahuja, J. R.;
Dhal, P. K. Tetrahedron Lett. 1992, 33, 5453. (d) Pini, D.; Petri, A.;
Salvadori, P. Tetrahedron: Asymmetry 1993, 4, 2351. (e) Lohray, B. B.;
Nandanan, E.; Bhushan, V. Tetrahedron Lett. 1994, 35, 6559. (f) Pini, D.;
Petri, A.; Salvadori, P. Tetrahedron 1994, 50, 11321. (g) Pini, D.; Petri,
A.; Salvadori, P. Tetrahedron Lett. 1995, 36, 1549. (h) Sung, E. C.; Roh,
E. J.; Lee, S.-G.; Kim, I. O. Tetrahedron: Asymmetry 1995, 6, 2687.
(9) A recent report by Salvadori and co-workers describes an insoluble
support that provides improved enantioselectivity. However, their system
still required long reaction times (24 h) and excess of polymeric ligand.
Furthermore, reaction yields were lower than observed under homogeneous
reaction conditions. Petri, A.; Pini, D.; Rapaccini, S.; Salvadori, P. Chirality
1995, 7, 580.
(10) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem. Int.
Ed. Engl. 1995, 34, 1059.
S0002-7863(96)00809-8 CCC: $12 00 © 1996 American Chemical Society

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Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7633
Table 1. Comparison of Catalytic Asymmetric Dihydroxylations
Using Ligands 1-4a
a
See 8a and references contained within for experimental details.
General conditions employed, N-methylmorpholine-N-oxide and acetone/
b
water (10/1, v/v) were used as the solvent system. Results from ref
c
8a. Entry two (2) was recycled a total of five times, the average yield
d
and ee for these five runs is listed here. Slow addition time for the
olefin.
In summary, we have demonstrated how a chiral ligand can
be integrated into a soluble polymeric species so that LAC can
operate in an unhindered manner on a polymer support. The
soluble polymer-bound ligand provides all the advantages that
an insoluble support can offer, while also being as effective as
a free ligand both in reactivity and selectivity. This new soluble
polymer bound-ligand system should be applicable to other
classes of AD ligands11 for improved enantioselectivity7 as well
as other enantioselective catalytic processes.12 We believe the
MeO-PEG polymer will not only be useful to the research
chemist but also for effecting the separation of catalyst from
product in homogeneous industrial applications.13 Finally
because of its desirable physical properties, this and other ligand
accelerated catalysts that are incorporated within liquid phase
supports may find use in automated high through-put synthetic
efforts.14
Figure 1. Various asymmetric dihydroxylation ligands.
Scheme 1a
Acknowledgment. We thank Professor K. B. Sharpless for his
helpful suggestions and critical reading of the manuscript. This work
was supported in part by The R. W. Johnson Pharmaceutical Research
Institute, The Scripps Research Institute, The Skaggs Institute of
Chemical Biology, and the A. P. Sloan Foundation.
a (a) TEA, DMAP, glutaric anhydride (60%); (b) DCC, DMAP, ROH
(95%).
separation, and recovery of the polymer bound ligand must be
straightforward and reliable. Upon completion of the AD
reaction, the entire mixture was diluted with methylene chloride,
dried (anhydrous sodium sulfate), and filtered. Diethyl ether
was added to the resulting mixture in order to precipitate MeO-
PEG-bound ligand (typically, the MeO-PEG-bound ligand was
recovered in >98% yield). The filtrate contained the dihy-
droxylated product.
The asymmetric dihydroxylation of a variety olefins by
ligands 1-4 is shown in Table 1. Immediately evident is the
fact that MeO-PEG-bound ligand 2 is more efficient than the
insoluble polymer bound ligand 1, both in its enantioselectivity
and reactivity (entries 1 and 2, Table 1). What is more, the
polymer-bound ligand 2 is easily recovered in near quantitative
fashion and recycled several times with no loss of reaction yield
or enantioselectivity (entry 3, Table 1). With all four olefins
tested, MeO-PEG-bound ligand 2 was as effective as free ligand
3 (compare entries 2 and 4, entries 6 and 7, entries 8 and 9,
and entries 10 and 11). These findings strongly suggest that
the MeO-PEG backbone does not influence or affect the
observed asymmetric induction (entry 5). Furthermore, these
findings provide direct support for our notion that for successful
polymer-bound LAC all components involved in the reaction
must be able to interact freely with each other in solution.
Supporting Information Available: Synthetic details and spectral
data for compounds 2, 3, and 6 and the general procedure for the
asymmetric dihdroxylation reaction (4 pages). See any current
masthead page for ordering and Internet access instructions.
JA9608095
(11) The (DHQD)2-PHAL ligand has been appended to MeO-PEG; this
new liquid phase ligand provides significantly greater enantioselectivity
(Han, H.; Janda, K. D. Unpublished results).
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Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima,
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