High asymmetric induction with β-turn-derived palladium phosphine complexes

Article abstract of DOI:10.1021/ol035097j

(Matrix presented) Work toward the development of a bisphosphine ligand system for the palladium-catalyzed addition to cyclic allyl acetates is reported. A parallel approach using phosphine-containing amino acids in conjunction with natural amino acids wa

Full text of DOI:10.1021/ol035097j

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3069-3072
High Asymmetric Induction with
â-Turn-Derived Palladium Phosphine
Complexes
Scott J. Greenfield, Anton Agarkov, and Scott R. Gilbertson*
Department of Chemistry, Washington UniVersity, One Brookings DriVe,
Campus 1134, Saint Louis, Missouri 63130-4899
srg@wuchem.wust.edu
Received June 16, 2003
ABSTRACT
Work toward the development of a bisphosphine ligand system for the palladium-catalyzed addition to cyclic allyl acetates is reported. A
parallel approach using phosphine-containing amino acids in conjunction with natural amino acids was used to develop a selective ligand
system. The ligand system was examined while attached to the polymer support as well as in solution. Selectivites with the difficult substrate
3-acetoxycyclopentene of up to 95% ee are reported.
The parallel synthesis of phosphine ligands requires the use
of reactions that proceed in good yield and with high
selectivity. Our group has been involved in the development
of parallel methods for the discovery of asymmetric catalysts.
One of the approaches taken is based on solid-phase peptide
synthesis.1-8 Such an approach allows for the rapid develop-
ment of selective catalysts for specific reactions or individual
substrates. The utilization of solid-phase peptide chemistry
in the synthesis of phosphine ligands requires the synthesis
of phosphine-containing amino acids and the development
of a system that allows for protection and deprotection of
the phosphine moiety. We have reported such a system and
have synthesized peptide-based phosphine ligands.1-4 In
addition, these ligands have been coordinated to rhodium
and palladium and used in hydrogenation and allylation
reactions.6,7 While our initial results illustrated the feasibility
of the approach, they provided catalysts with good but lower
than desired selectivity. This paper reports the development
of a peptide-based bisphosphine ligand that provides state
of the art selectivity for the reaction of 3-acetoxycyclopentene
with nucleophiles (Scheme 1 n ) 1).
In the original design of peptide-based ligands, a sequence
was chosen that was expected to form a â-turn secondary
structure. Miller has used â-turn structures in the develop-
ment of asymmetric acylation catalysts.9-12 The plan was to
use the ability to easily modify the amino acids on either
end of the turn as the elements of diversity. That approach
proved to be flawed in that, upon chelation, the metal is
(1) Gilbertson, S. R.; Chen, G.; McLoughlin, M. J. Am. Chem. Soc. 1994,
116, 4481-4482.
(2) Gilbertson, S. R.; Wang, X. J. Org. Chem. 1996, 61, 434-435.
(3) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 37, 6475-6478.
(4) Gilbertson, S. R.; Wang, X.; Hoge, G. S.; Klug, C. A.; Schaefer, J.
Organometallics 1996, 15, 4678-4680.
(9) Copeland, G. T.; Jarvao, E. R.; Miller, S. J. J. Org. Chem. 1998, 63,
6784.
(10) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 4306-
4307.
(11) Jarvo, E. R.; Copland, G. T.; Papaioannou, N.; Bonitatebus, P. J.;
Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643.
(12) Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.;
Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629.
(5) Gilbertson, S. R.; Chen, G.; Kao, J.; Beatty, A.; Campana, C. F. J.
Org. Chem. 1997, 62, 5557-5566.
(6) Gilbertson, S. R.; Wang, X. Tetrahedron 1999, 11609-11619.
(7) Gilbertson, S. R.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc.
2000, 122, 6522-6523.
(8) Agardov, A.; Uffman, E. W.; Gilbertson, S. R. Org. Lett. 2003, 5,
2091-2094.
10.1021/ol035097j CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/26/2003

Scheme 1
Scheme 2
positioned away from the carboxyl and amino ends of the
turn and toward the residues critical for turn formation,
proline and the D-amino acid (Figure 1). In an attempt to
phine sulfide. Ester hydrolysis and exchange of Boc for Fmoc
protection provided the desired amino acid in high yield.
This method makes a wide variety of phosphine amino acids
available. For the purposes of this study, a series of
diaromatic phosphine amino acids were synthesized (Table
1) and examined.
Table 1.
yielda,b
yielda,b
entry
Ar
of 7
of 8
1
2
3
4
5
6
7
8
phenyl
75% (7a ) 80% (8a )
43% (7b) 43% (8b)
55% (7c) 61% (8c)
73% (7d ) 73% (8d )
40% (7e) 63% (8e)
73% (7f) 65% (8f)
1-naphthyl
2-naphthyl
3,5-xylene
mesityl
phenyl, 1-naphthylc
3,5-di-tert-butyl-4-methoxy phenyl 70% (7g) 95% (8g)
2,5-xylene 66% (7h ) 40% (8h )
a Isolated yields. b Products were enantiomerically pure as determined
by chiral HPLC. c Two diastereomers were separated by column chroma-
tography.
Figure 1.
exert direct control over the environment at the face of the
transition metal, different turn-forming amino acids were
placed in the critical i + 1 and i + 2 positions (4). A variety
of hydroxyproline derivatives were examined along with
different D-serine derivatives (3). In general, these changes
resulted in a decrease in reactivity and selectivity. Another
approach to influence the catalytic selectivity would be to
make changes to the aromatic groups on the phosphine.
While possible using the original synthesis of phosphine
amino acids, the synthesis of a variety of amino acids would
require a considerable amount of work.1 To overcome this
limitation, a new route to phosphine-containing amino acids
had to be developed.13
With these phosphine amino acids in hand, a library was
synthesized using the aromatic groups on the phosphine as
the source of diversity. Table 2 contains the results from
the study of a small library of â-turn-type peptides with
various aromatic groups attached to the phosphine moiety.
The starting point for the library was Ac-D-Phg-Pps-Pro-D-
Ala-Pps-D-Leu-support, a sequence that provided moderate
success in an earlier study. In general, it appears that when
the phosphine next to proline was larger, the catalyst provided
higher selectivity. There also appears to be a preference for
symmetrical groups on the phosphine, with 3,5-dimethyl-
substituted phenyl providing the highest selectivity (entries
5 and 6). The library also contains examples where the
phosphine amino acid was chiral at phosphorus, as well as
at the R-carbon. These examples provided some of the lowest
selectivities in the study (entries 16-19).
The new route utilizes chemistry developed by Knochel
(Scheme 2).14,15 Commercially available iodo amino ester
(5) was metalated with zinc and, following transmetalation
with copper, was reacted with a chloro dialkyl or diaryl-
phosphine. The phosphine was then protected as the phos-
After determining the “best” phosphine-containing amino
acids for the ligand, the other amino acids in the sequence
were examined (Table 3). The turn-forming motif was
retained by maintaining Pro or Oic and a D-amino acid at
the critical i + 1 and i + 2 positions. Substitution of amino
(13) Greenfield, S. J.; Gilbertson, S. R. Synthesis 2001, 2337-2340.
(14) Langer, F.; Puntener, K.; Sturmer, R.; Knochel, P. Tetrahedron:
Asymmetry 1997, 8, 715-738.
(15) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390-2392.
3070
Org. Lett., Vol. 5, No. 17, 2003

Following the optimization of the ligand system, the
reaction conditions were examined. Upon examination of a
number of solvents (DMF, THF, acetone, benzene, aceto-
nitrile), acetonitrile was found to be the solvent that provided
the highest selectivity with the polymer bound catalyst. At
0 °C in acetonitrile, ligand 32 provided the product in 95%
yield and 88% ee.
Table 2 a
The synthesis of peptides on solid support generally
provides products of high purity. However, there was concern
that small amounts of impurities could, upon coordination
to the metal, provide catalysts with significantly greater
activity and poorer selectivity than the desired catalyst. To
test this concern, the best ligand (32) was synthesized in
solution and purified by chromatography (compound 39).
Reaction of peptide 39 in acetonitrile provided a catalyst that
gave the addition product with comparable yield and
selectivity to the reaction in acetonitrile when the catalyst is
immobilized on the synthesis support (90% yield and 85%
ee vs 91% yield and 86% ee). Further study of the conditions
revealed that when the catalyst is dissolved in solution, the
best solvent appears to be THF rather than acetonitrile.
Reaction in THF at 0 °C provided the product in good yield
and with excellent selectivity (Table 4, entry 6, 91% yield,
entry
compd
R
R′
yieldb
eec
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Ph
Ph
76
78
86
93
88
96
91
86
93
88
91
93
85
91
91
88
91
88
68
67
20
55
31
77
81
64
15
64
17
57
28
70
73
59
55
14
32
30
2,5-xyl
2,5-xyl
Ph
3,5-xyl
3,5-xyl
Ph
1-nap
1-nap
Ph
1-nap
2-nap
2-nap
2-nap
Ph
2,5-xyl
Ph
2,5-xyl
3,5-xyl
Ph
3,5-xyl
1-nap
Ph
1-nap
2-nap
1-nap
2-nap
Ph
2-nap
1-nap/Ph
Ph/1-nap
1-nap/Ph
Ph/1-Nap
1-nap/Ph
Ph/1-nap
Ph/1-nap
1-nap/Ph
Table 4. Boc-D-Phg-Xps-Pro-D-Val-Pps-D-Leu-OMe
a All ligands where synthesized and screened on the Synphase system
from Mimotopes. Reactions were run between 0 °C and rt using N,O-
bis(trimethylsilyl)acetamide, TBAF, and dimethylmalonate. b Isolated yield.
c Enantiomeric excess was determined by 1H NMR analysis using [Eu(hfc)3]
shift reagent.
acids away from the metal had a negligible effect on the
selectivity of the catalyst, while substitution of D-Val in the
i + 1 position increased the selectivity slightly (88% ee).
entry
solvent
temp (°C)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
toluene
acetone
CH3CN
THF
THF
THF
THF
DMF
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0
-20
-30
-45
82
89
91
90
92
91
90
85
92
88
89
88
85
90
95
92
89
85
Table 3
a All reactions were run using N,O-bis(trimethylsilyl)acetamide, TBAF,
eee (%)
and dimethylmalonate. b Isolated yield. c Enantiomeric excess was deter-
compd
Www
Xxx
Yyy
Zzz
1
mined by H NMR using [Eu(hfc)3] shift reagent.
1
2
3
4
5
6
7
8
32
33
34
35
36
37
38
18
D-Phg
D-Phg
D-Ala
D-Phg
D-Phg
D-Ala
D-Phg
D-Phg
Pro
Oic
Pro
Pro
Pro
Pro
Pro
Pro
D-Val
D-Ala
D-Ala
D-Ala
D-Ala
D-Ala
D-Tle
D-Ala
D-Leu
D-Leu
D-Phg
D-Ala
D-Phg
D-Ala
D-Leu
D-Leu
86
79
82
82
81
79
42
81
95% ee). This selectiVity is comparable to that of the best
ligands known for this reaction.16-22
(16) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne,
M. R. J. Am. Chem. Soc. 2000, 122, 7905-7920.
(17) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.
(18) Trost, B. M.; Bunt, R. C. Angew. Chem, Int. Ed. Engl. 1996, 35,
99-102.
(19) Trost, B. M. In Catalytic Asymmetric Synthesis; Ojima, T., Ed.;
Wiley-VCH: New York, 2000; p 593.
(20) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919-
2920.
a Xps represents phosphine amino acid with 3,5-xylene on phosphine.
b Pps represents phosphine amino acid with phenyl on phosphine. c All
reactions were run between 0 °C and rt using N,O-bis(trimethylsilyl)ac-
etamide, TBAF, and dimethylmalonate. d Isolated yield. e Enantiomeric
excess was determined by 1H NMR analysis using [Eu(hfc)3] shift reagent.
Org. Lett., Vol. 5, No. 17, 2003
3071

Scheme 3
When the best ligand for 3-acetoxycyclopentene, Boc-D-
paper, along with our previous paper,8 illustrates the need
for methods that allow the rapid synthesis of diverse ligand
sets. In the case of palladium-catalyzed allylation with cyclic
substrates, when peptide-based ligands are used, â-turn
secondary structure is critical for obtaining high selectivity.
On the other hand, in the case of desymmetrization of meso
diols, such a secondary structure provided poor selectivity.
The example in Scheme 3 illustrates this as well. Simply
changing from the cyclopentenyl system to a cyclohexenyl
system requires new optimization of the ligand system.
Consequently, the ability to rapidly synthesized diverse
collections of ligands is important to accessing what Knowles
originally viewed as a strength of catalysis with phosphine-
transition metal complexes, that the ligand metal complex
can be tuned for a reaction.
Phg-Xps-Pro-D-Val-Pps-D-Leu-OMe, was used with the
3-acetoxycyclohexene, the selectivity was 76% ee with the
ligand on support and 81% ee with the ligand in solution.
Minimal optimization of this system ultimately provided Ac-
Gly-Xps-Pro-D-Ala-Xps-Gly-NH2 (40) as the best ligand for
this system (83% ee on support and 88% ee in solution,
Scheme 3).
Reaction of acyclic allyl acetates resulted in low selectivi-
ties. Examination of models suggests that the palladium
peptide complex may not be able to accommodate the
extended allyl system obtained upon oxidative addition of
the allyl acetate. We are currently synthesizing and studying
isolated palladium complexes in an attempt to better under-
stand the origins of selectivity with this system.
In his original paper, on the rhodium-catalyzed hydrogena-
tion by chiral phosphine rhodium complexes, Knowles states
that phosphine complexes have “the advantage that the
structure of the catalyst ligands can be varied according to
the particular unsaturated substrates in order to achieve
maximum asymmetric yield”.23 Since that original paper,
hundreds of chiral phosphines have been synthesized but
there have been no general methods developed to facilitate
the synthesis and screening of phosphine complexes. This
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: Experimental pro-
cedures and characterization of compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. 1998, 37, 3047-
3050.
(22) Gilbertson, S. R.; Xie, D. Angew. Chem. 1999, 38, 2750-2752.
(23) Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 22, 1445-
1446.
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Org. Lett., Vol. 5, No. 17, 2003