Parallel approach to selective catalysts for palladium-catalyzed desymmetrization of 2,4-cyclopentenediol

Article abstract of DOI:10.1021/ol034548x

(Matrix presented) Work toward the development of a bis-phosphine ligand system for the palladium-catalyzed desymmetrization of meso-diols is reported. A parallel approach using phosphine-containing amino acids and a "representational search" was taken to

Full text of DOI:10.1021/ol034548x

ORGANIC
LETTERS
2
003
Vol. 5, No. 12
091-2094
Parallel Approach to Selective Catalysts
for Palladium-Catalyzed
2
Desymmetrization of
2,4-Cyclopentenediol
Anton Agarkov, Eric W. Uffman, and Scott R. Gilbertson*
Department of Chemistry, Washington UniVersity, One Brookings DriVe,
Campus Box 1134, Saint Louis, Missouri 63130-4899
srg@wuchem.wustl.edu
Received March 28, 2003
ABSTRACT
Work toward the development of a bis-phosphine ligand system for the palladium-catalyzed desymmetrization of meso-diols is reported. A
parallel approach using phosphine-containing amino acids and a “representational search” was taken to find a polymer-supported catalyst
system. The selectivities reported are comparable to many other polymer-bound asymmetric catalysts.
The palladium-catalyzed desymmetrization of meso-diols is
formally an intramolecular allylic substitution reaction of a
meso-substrate with two enantiotopic leaving groups (Scheme
number of successful attempts to perform this reaction in
8-10
an asymmetric manner.
Given this, we decided to develop
a selective catalyst for this transformation using the parallel
synthesis of prospective ligands. In this paper, we report the
development of a support-bound ligand that provides the
desymmetrization product with moderate to good selectivity.
1). The reaction was developed in the Trost lab and has been
While this reaction is an example of an asymmetric
palladium-catalyzed allyl substitution, it differs from standard
Scheme 1
(
2) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed. Engl. 1992,
1, 228-230.
3) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1991, 113,
317-6318.
4) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc.
992, 114, 9327-9343.
5) Trost, B. M.; Breit, B.; Organ, M. G. Tetrahedron Lett. 1994, 35,
817-5820.
6) Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J. W. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2386-2388.
3
6
1
5
(
(
(
(
successfully used in the synthesis of natural products.1-7
Other than the Trost work, there have only been a select
(
7) Trost, B. M.; Zambrano, J. L.; Richter, W. Synlett 2001, 907-909.
(
8) Lee, S.; Lim, C. W.; Song, C. E.; Kim, K. M.; Jun, C. H. J. Org.
Chem. 1999, 64, 4445-4451.
(9) Lim, C. W.; Lee, S. Tetrahedron 2000, 56, 5131-5136.
(10) Trost, B. M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339-1341.
(
1) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115,
4
44-458.
1
0.1021/ol034548x CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003

intermolecular examples in the enantiodetermining step. In
typical palladium-catalyzed intermolecular asymmetric al-
lylations, the enantioselectivity is set by the attack of the
nucleophile on one of two different carbons of a palladium
allyl complex (4).11-18 In this reaction, the asymmetric
induction takes place during the formation of the allylic
complex when one of the two enantiotopic carbamates is
lost to form the intermediate palladium complex (7 vs 7′).
The subsequent attack of the internal nucleophile provides
the product. This fundamental difference in the origin of
selectivity appeared to provide an excellent test for the ability
to use a parallel approach in the development of selective
catalysts. Such an approach has been taken for a select
number of reactions.1
tempted to catalyze the desymmetrization reaction with
palladium complexes based on this type of structural format.
A sequence that had been quite selective in the intermolecular
addition, Ac-D-Phg-L-Pps-Pro-D-Val-L-Pps-D-Tle-[support]
(Pps represents an amino acid containing diphenylphosphine
in its side chain), was used to optimize the reaction
conditions, including palladium source, solvent, and additive.
The reaction conditions that ultimately gave the best selectiv-
ity with this ligand proved to be Pd
2
(dba)
2
3
‚CHCl as the
palladium source, THF as the solvent, and tetrabutylammo-
nium fluoride (TBAF) added as a base (37% ee). Examina-
tion of other sequences designed to be â-turns resulted in
similar selectivities.
9-28
On the basis of the moderate selectivities obtained with
turn motifs, sequences that were not expected to form a
particular secondary structure were tested. A sequence with
the two phosphine-containing amino acids separated by a
single amino acid resulted in selectivity equal to that of the
best â-turn formats. This is different than the case of
intermolecular allylations, which appear to require a stable
secondary structure for high selectivity. It was decided to
attempt to optimize the [Pps-(amino acid)-Pps] motif for this
reaction.
With the assumption that the most significant residue in
such a sequence would be the one between the two
phosphine-containing amino acids, seven ligands, where this
amino acid was varied, were synthesized and screened. A
significant difference between proline and the other amino
acids tested was observed, with proline giving 47% ee
Figure 1. Two different enantiodeterming steps.
(Figure 2). While replacement of D-Phe for L-Phe and D-Val
for L-Val had little effect on the selectivity, replacement of
L-Pro with D-Pro resulted in a significant decrease in
selectivity. On the basis of these results, the Pps-Pro-Pps-
Gly tetramer was accepted as the scaffold of choice for future
optimization.
In previous work on palladium-catalyzed addition of
malonate to cyclic allyl acetates, we have found that
phosphine-containing â-turn peptide motifs can be useful in
selective palladium-catalyzed allylations.2 Initially, we at-
9
(
(
11) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-422.
12) Trost, B. M. In Catalytic Asym. Synthesis; Ojima, T., Ed.; Wiley-
VCH: New York, 2000; p 593.
13) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.
2
1
17) Williams, J. M. J. Synlett 1996, 705-710.
Synthesis; Wiley & Sons: New York, 1995.
19) Gilbertson, S. R. In Prog. Inorg. Chem.; Karlen, K. D., Ed.; John
Wiley & Sons: New York, 2001; Vol. 50, pp 433-471.
20) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chem. Eur. J.
(
(
1
998, 4, 1885-1889.
(
(
(
(
21) Hoveyda, A. H. Chem. Biol. 1998, 5, R187-R191.
22) Reetz, M. T. Angew. Chem., Int. Ed. 2002, 41, 1335-1338.
23) Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284-310.
24) Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. Engl. 1999, 38, 2494-2532.
25) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. J. Am. Chem. Soc.
002, 124.
(
2
(
26) Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
Figure 2.
1
0125-10126.
(27) Jarvo, E. R.; Copland, G. T.; Papaioannou, N.; Bonitatebus, P. J.;
Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643.
(
28) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 4306-
To provide additional sites of diversity, two amino acids
where attached to each end of the tetramer. The general
structure of the template is shown in Figure 3. This structure
4
307.
(29) Gilbertson, S. R.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc.
2
000, 122, 6522-6523.
2092
Org. Lett., Vol. 5, No. 12, 2003

Figure 3. Positions are numbered on the basis of â-turn peptides.
We currently do not know the secondary structure of these peptides.
possesses six positions at which it can be optimized. Changes
in the i and i + 2 positions can be made by using different
phosphorus-containing amino acids. In the study reported
here, this site was held constant. Commercially available
amino acids were used to modify the other positions. Since
proline appears to be the optimal type of amino acid in
position i + 1, a variety of proline derivatives were tested
in that position.
To avoid the screening of all possible ligands, a “repre-
sentational search”, where each of the six positions was
successively optimized by varying amino acids at a given
position while keeping all other subunits constant, was
employed.30 After the optimal amino acid was found for a
particular position, it was held constant in the subsequent
experiments. The advantage of such an approach is that a
much smaller number of ligands need to be tested. The
disadvantage is that the “best” ligand identified could be a
local maximum. Possible refinements of this strategy would
be to choose a different starting point, changing the order
of the optimization or after going through all positions going
back to the first one and trying to optimize it again.
The i - 1 and i + 4 positions were the next to be tuned.
To avoid screening through both L- and D-isomers of each
amino acid, three peptides were prepared. One, Ac-Phe-Pps-
Pro-Pps-Gly-Phe-[support], had L-Phe in the i - 1 and i +
Figure 4. Optimization in the i + 4 position of [D-Val-Pps-Pro-
Pps-Gly-[i + 4]-support]. (a) All reactions where run at rt overnight.
In select cases, isolated yields of the products where obtained (60-
70%). Selectivities were determined by HPLC on Chiralpak AD,
using 2-propanol/hexane ) 1:5, 1.0 mL/min, UV 204 nm. On the
basis of repetitive runs using different samples of the same peptide
sequence, the selectivities have been found to vary by (2%.
It is interesting to note that this reaction appears to be
more sensitive to substitution of various amino acids than
our previous systems based on â-turn structures. In those
systems substitutions at the ends of the peptides did not have
a significant effect on the catalyst’s selectivity. With a few
exceptions, it appears that amino acids with sterically bulky
side chains give the best results. However tert-Leu afforded
5
5% ee vs 68% ee obtained with Leu. In the cases of
extremely large side chains, the catalyst’s structure may be
more significantly altered, leading to a decrease in selectivity.
After finding the optimal amino acids for the i + 4
position, with D-Val in that position, the same 24 amino acids
were tested in the i - 1 position (Figure 5). Interestingly,
the substitution in this position caused a much smaller
fluctuation in the selectivity. Three amino acids, D-Asp-
(OtBu), D-Phg, and D-Val, afforded 68% ee.
Again, methionine and histidine provided the lowest ees,
which is probably due to some negative interaction between
the metal and these amino acids’ side chains. All other acids
afforded selectivities between 61 and 68% ee. Surprisingly,
even D-Pro in this position gave good selectivity (65% ee).
The best peptide in this library was removed from the
support and tested for its ability to perform selective catalysis.
Catalysis with the palladium complex of Ac-Val-D-Pps-D-
Pro-D-Pps-Gly-Leu-NHMe in solution provided the same
selectivity (68% ee) as its enantiomer while attached to a
solid support. As expected, the opposite enantiomer was the
major product.
In what might be considered a second-generation optimi-
zation, seven different amino acids were checked as alterna-
tives to proline in the i + 1 position. Three commercially
available (Pip, Oic, Tic) cyclic amino acids and four
derivatives of hydroxyproline were examined (Scheme 2).
Octahydroindole-2-carboxylic acid (Oic) gave the best
selectivity (76% ee), and MOM-protected cis-hydroxyproline
4
positions; another, Ac-D-Phe-Pps-Pro-Pps-Gly-D-Phe-[sup-
port], had D-Phe, and a third, Ac-Gly-Pps-Pro-Pps-Gly-Gly-
support], had Gly in those positions. The peptide with L-Phe
[
afforded 50% ee, and the peptide with Gly gave 54% ee.
Both of these selectivities were lower than the 61% ee
obtained with D-Phe in these positions. Because of this result,
only D-amino acids were tested in the i - 1 and i + 4
positions.
D-Valine was chosen as a fixed i - 1 subunit, and different
amino acids were tested in the i + 4 position (Figure 4).
Out of 24 amino acids, D-leucine gave the highest ee (68%).
Alanine and cyclohexylalanine were the second best amino
acids, affording 65% ee. Only methionine and histidine
afforded selectivities below 40% ee.
(
30) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin 1999; Vol. 3, p 1389.
Org. Lett., Vol. 5, No. 12, 2003
2093

Scheme 2
Figure 5. Optimization in the i - 1 position [Ac-[i - 1]-Pps-
Pro-Pps-Gly-D-Leu-support. (a) All reactions where run at rt
overnight. In select cases, isolated yields of the products where
obtained (60-70%). Selectivities were determined by HPLC on
Chiralpak AD, using 2-propanol/hexane ) 1:5, 1.0 mL/min, UV
204 nm. Based on repetitive runs using different samples of the
same peptide sequence the selectivities have been found to very
by ( 2%.
gave the second highest (74% ee). In the case of cis-
hydroxyproline, TBDMS-protected hydroxyl group caused
a 21% drop in ee compared to MOM. Both derivatives of
trans-Hyp afforded results similar to proline, while the six-
member analogues, Pip and Tic, provided considerably
poorer selectivities.
the complex immobilized on support and with it in solution,
we are continuing to study these ligands in solution to
optimize the reaction conditions for homogeneous catalysts.
To determine the origin of selectivity, the structure of the
ligand metal complex is also being examined.
In the last set of experiments, the importance of glycine
in the i + 3 position was examined [Ac-D-Val-Pps-Pro-Pps-
Gly-D-Val-support]. Four new peptides were synthesized,
with alanine and phenylalanine replacing Gly. All substitu-
tions had a detrimental effect on the selectivity. Substitution
with the L-isomers afforded only a slight decrease in
selectivity, but the members containing D-isomers gave
significantly lower selectivity.
At this point, the representational search was completed.
The new scaffold was found through screening 75 ligands,
with Ac-D-Val-Pps-Oic-Pps-Gly-D-Leu-NH-peptide identified
as the most selective catalyst for the desymmetrization of 1.
While good correlation was observed between catalysis with
Acknowledgment. This work was supported by NIH R01
GM56490. We also gratefully acknowledge the Washington
University High-Resolution NMR Facility, partially sup-
ported by NIH 1S10R02004, and the Washington University
Mass Spectrometry Resource Center, partially supported by
NIHRR00954, for their assistance.
Supporting Information Available: Spectral data for all
new compounds, experimental procedures, and tables or
selectivities of each library. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL034548X
2094
Org. Lett., Vol. 5, No. 12, 2003