Catalysis with phosphine-containing amino acids in various "turn" motifs

Article abstract of DOI:10.1021/jo049103g

We have been actively involved in the development of parallel approaches for the discovery of phosphine ligands. Our approach has been based on the incorporation of phosphine-containing amino acids into peptide sequences that are designed to have stable secondary structures. We have examined helical and turn secondary structures and have reported that alkylation of cyclopentenyl acetate with dimethylmalonate can be catalyzed in high enantiomeric excess (ee) with a β-turn-based ligand. The importance of the peptide secondary structure was demonstrated through the synthesis of a series of peptide ligands where the nature of the turn-forming residues was probed. Additionally, other turn-forming units and a variety of different phosphine-containing amino acids have been examined for their ability to control the selectivity of the allylation reaction. This paper reports the results obtained through the examination of different turn motifs as well as different phosphine substitutions on the "best" turn sequence, Pps-Pro-D-Xxx-Pps.

Full text of DOI:10.1021/jo049103g

Catalysis with Phosphine-Containing Amino Acids in Various
“Turn” Motifs
Anton Agarkov,† Scott J. Greenfield,† Takahiro Ohishi,† Scott E. Collibee,† and
Scott R. Gilbertson*,‡
Department of Chemistry, Washington University, One Brookings Drive,
Saint Louis, Missouri 63130-4899, and Chemical Biology Program, Pharmacology and Toxicology,
The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0650
srgilber@utmb.edu
Received May 27, 2004
We have been actively involved in the development of parallel approaches for the discovery of
phosphine ligands. Our approach has been based on the incorporation of phosphine-containing amino
acids into peptide sequences that are designed to have stable secondary structures. We have
examined helical and turn secondary structures and have reported that alkylation of cyclopentenyl
acetate with dimethylmalonate can be catalyzed in high enantiomeric excess (ee) with a â-turn-
based ligand. The importance of the peptide secondary structure was demonstrated through the
synthesis of a series of peptide ligands where the nature of the turn-forming residues was probed.
Additionally, other turn-forming units and a variety of different phosphine-containing amino acids
have been examined for their ability to control the selectivity of the allylation reaction. This paper
reports the results obtained through the examination of different turn motifs as well as different
phosphine substitutions on the "best" turn sequence, Pps-Pro-D-Xxx-Pps.
Introduction
We have utilized phosphine containing â-turn peptide
secondary structures to control the selectivity of pal-
ladium-catalyzed allylation. [It is important to note that
â-turn structures have been use successfully in asym-
metric nucleophilic catalysis by Miller.9-12 That work
represents an excellent example of the power of using
peptide chemistry in assembly and screening of libraries
of catalysts for asymmetric catalysis.] Figure 1 illustrates
where substitutions have been made on the â-turn
systems. A series of peptides were synthesized containing
a variety of different phosphine-containing amino acids
(Ra). Libraries were screened where the stereochemistry
and properties of the residues at the ends of the peptide
FIGURE 1. Boxed sections will be varied, and the resulting
ligands will be screened for selective catalysis.
were varied (Rd and Re), and turns containing derivates
of proline, where the 4-position has different substituents
(Rb), were also examined. A third variation where a
variety of different D-amino acids (Rc) were used was
tested. In addition to these modifications of the basic Pps-
turn-Pps motif, several different turn-forming elements
have been tested including cyclic peptides.
Importance of â-Turn Secondary Structure. Our
initial goal was to synthesize libraries of peptide-based
phosphine ligands. These libraries were based on the
known â-turn-forming unit proline-D-amino acid.13,14
Prior to the synthesis of the libraries, a single peptide
was synthesized (2), characterized, and tested for its
ability to catalyze the desired reaction (Scheme 1). At
that time, a study of three different solvents was per-
formed as well. This first experiment provided a peptide
† Washington University.
‡ The University of Texas Medical Branch.
(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. Tetrahedron 1999, 11609-11619.
(5) Gilbertson, S. R.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc.
2000, 122, 6522-6523.
(6) Gilbertson, S. R. In Progress in Inorganic Chemistry; Karlen, K.
D., Ed.; John Wiley & Sons: New York, 2001; Vol. 50, pp 433-471.
(7) Greenfield, S. J.; Gilbertson, S. R. Synthesis 2001, 2337-2340.
(8) Greenfield, S. J.; Agarkov, A.; Gilbertson, S. R. Org. Lett. 2003,
5, 3069-3072.
(9) Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T.
E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629.
(10) Sculimbrene, B., R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
10125-10126.
(11) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134-
2136.
(12) Sculimbrene, B., R.; Morgan, A., J.; Miller, S. J. J. Am. Chem.
Soc. 2002, 124.
(13) Imperiali, B.; Kapoor, T. M. Tetrahedron 1993, 49, 3501-3510.
(14) Imperiali, B.; Fisher, S. L.; Moats, R. A.; Prins, T. J. J. Am.
Chem. Soc. 1992, 114, 3182-3188.
10.1021/jo049103g CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/21/2004
J. Org. Chem. 2004, 69, 8077-8085
8077

Agarkov et al.
SCHEME 1
that catalyzed the alkylation of cyclopentenyl acetate in
61% ee when acetonitrile was used as the solvent. This
promising initial result was obtained while the catalyst
was attached to the support on which it was synthesized.
This is significant since the goal was to screen the library
members while they were attached to the polymer
support.
quite good, with one ligand giving 80% ee, there was no
substitution at the sites of diversity that provided a clear
advantage over most other substitutions.
At this time, it was decided to determine if the
phosphine-turn-phosphine motif was responsible for the
observed selectivity or if any random sequence containing
chiral amino acids with phosphine in their side chain
would provide similar selectivity. A second 40-member
library was synthesized that contained more severe
alterations to the sequences (exact sequences are pro-
vided in the Supporting Information). The most signifi-
cant trend observed with this library was introducing
changes that disrupted the turn-forming unit. This was
done by deleting or substituting Gly for either proline or
the D-amino acid (Figure 4, red box). A second significant
change was positioning a single amino acid between the
phosphine amino acids and the â-turn (Figure 4, yellow
box). These two sets of substitutions were the only
changes in the basic ligand that consistently gave selec-
tivities below 30% ee. In the initial library the majority
of the substitutions made were on the ends of the peptide
and not at the turn where the transition metal appears
to be facing. As can be seen in Figure 4, the most
significant substitutions are at the turn. With that in
mind, a series of changes at the turn section were
performed.
Ultimately, it is important that results obtained with
the complexes attached to the polymer support correlate
to results obtained with the complexes in solution.
Without this it would not be possible to study the
structure of the successful catalysts and make decisions
as to how to focus the next libraries. In the case of the
â-turn derived ligands, this correlation was observed.
Upon removal of the most selective ligands from the
polymer support it was found that their selectivity in
solution was nearly the same as when they are im-
mobilized (80% ee on support 85% ee in solution). This
indicates that in the case of short structured peptides,
groups of complexes can be screened while they are
attached to the resin on which they are synthesized.
Substitutions at Proline. Given the relatively small
effect observed when making changes at end of the turn
structure, it was decided to make a series of changes at
the turn-forming residues. The MOM- and TBDMS-
protected derivatives of hydroxyproline (8-11) were
introduced instead of proline in the i+1 position. Ad-
ditional diversity was generated by removal of the
Next, a library of 96 ligands was synthesized (see the
Supporting Information for sequences) and screened for
its members’ ability to selectively catalyze this allylation
reaction (see Figure 3). The library was designed to have
the basic phosphine-turn-phosphine motif with the ele-
ments of diversity being the amino acids on either end
of the sequence and the side chain of the D-amino acid
(Figure 2 Rc, Rd, and Re). The structural features that
were varied in this initial library were adding and then
varying amino acids at the N-terminus, the substitution
of amino acids other than Gly at the C-terminal end of
the peptide, and substitution of D-amino acids other than
D-Ala next to the proline. The basic sequence examined
in the library was Ac-Xxx-Pps-Pro-D-Yyy-Pps-Zzz-Rink.
Amino acids placed in the Xxx and Zzz locations were
Ala, Gly, Phe, Glu, Cys, Ser, Lys, and Tyr as well as Phg,
His, and Trp at the Xxx position only. The amino acids
placed at the critical turn-forming position Yyy were
D-Ala, D-Phe, D-Val, D-Leu, D-Met, D-Phg, and Gly.
Palladium was coordinated to these ligands, and catalysis
was performed. Initially, the ligands were screened while
attached to the polymer support on which they were
synthesized. The selectivities obtained with this library
ranged from 34% ee for the lowest to 80% ee in the case
of the highest selectivity. There were 77 members of the
library that gave 60% ee or greater selectivity. While the
selectivities obtained with these supported ligands were
FIGURE 2. Pro-D-amino acid dimer the first libraries were
based on.
8078 J. Org. Chem., Vol. 69, No. 23, 2004

Catalysis with Phosphine-Containing Amino Acids
FIGURE 3. Results from the first 96-member library synthesized, based on the Pps-Pro-D-amino acid-Pps motif. The identity of
the library members is reported in the Supporting Information
FIGURE 4. Results from the library where some members differed from the basic phosphine-turn-phosphine motif. The identity
of the library members is reported in the Supporting Information.
t-BuMe2Si groups with fluoride anion after completion
of solid-phase peptide synthesis (12, 13). Screening of the
resulting six peptides was conducted in two separate
experiments. In every case but one, catalysis with these
ligands resulted in a decrease in selectivity. The best
selectivity was achieved with unprotected trans-Hyp (12),
which was the same ee obtained using the original
peptide 7. Since peptide 12 represents the least signifi-
cant perturbation from the base ligand 7 it appears that
for this reaction changes at this site will not result in
greater selectivity (Figure 5).
in a conformation where it is in the vicinity of the proline
and the D-amino acid. This makes the interaction of the
substrate with these residues important in determining
the selectivity of the product. Because the orientation of
the metal is toward the turn (Figure 7), two other motifs
known to form turn-type structures were examined. Since
this is the important region of the peptide other turn-
forming units may alter the specificity of the catalyst
with different substrates. It has been shown by Gellman
that homochiral depsipeptides, which contain L-acids,
tend to form â-turn and hairpin secondary structures.15,16
Different “Turn”-Forming Motifs. Our initial work,
examining the use of peptides that possess the Pro-D-
Xxx sequence between the two phosphine ligands, dem-
onstrated that upon coordination the metal is presented
(15) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc.
1994, 116, 4105-4106.
(16) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc.
1996, 118, 6975-6985.
J. Org. Chem, Vol. 69, No. 23, 2004 8079

Agarkov et al.
FIGURE 6. Heterochiral dinipecotic acid peptide ligand Ac-
Ala-Pps-R-Nip-S-Nip-Pps-Ala-NH2.
SCHEME 3
FIGURE 5. Selectives observed in reaction (1) with different
proline derivatives.
SCHEME 2
With this in mind we decided to examine what level of
selectivity we would obtain with a peptide motif that
positioned Pps on either side of this element. Ac-Ala-
Pps-(R)-Nip-(S)-Nip-Pps-Ala-NH2 (31) (Figure 6) was
chosen as a model peptide on the basis of Gellman’s
studies.18-22 The peptide (31) was synthesized on solid
support by the standard Fmoc protocol, and the crude
peptide was purified by preparative HPLC to afford 31
as a white solid.
The reaction of two allyl substrates and dimethyl-
malonate were examined by the TBAF/BSA method
developed in our laboratory. The reaction with cyclopen-
tenyl acetate was found to give poor selectivity (24% ee).
However, catalyst 31 gave 63% ee in the reaction with
diphenylallyl acetate 32 (Scheme 3). In the Pro-D-Yyy
system (6), linear allyl acetates such as 1,3-diphenylallyl
acetate do not undergo catalytic alkylation. Presumably
this is due to the pocket formed by the turn being too
small to accommodate the extended palladium complex.
The Nip-Nip â-turn is more open and the metal is farther
away from the two residues forming the turn. Therefore,
this ligand allows the formation of the extended pal-
ladium allyl complex and consequently is an active
catalyst for linear allyl acetates such as diphenylallyl
acetate.
As can be seen in Figure 7, the gross structure of the
three types of turning forming sequences we have exam-
ined is significantly different. The (R)-Nip-(S)-Nip se-
quence (36) is significantly more open than the sequence
Pro-D-amino acid turn (34) originally examined. As a
consequence, substrates that will not fit into the pocket
of 34 are catalyzed by the palladium complex 36. While
the static structure of 35 resembles the structure of 34,
the substitution of an ester for an amide apparently
alters either the structure or its stability significantly
since palladium complexes of 35 catalyze the allylation
reaction with no selectivity. Given the relatively low
selectivity obtained in the allylation with cyclopentenyl
acetate and 1,3-diphenylallyl acetate, we decided not to
investigate the use of either prolactyl turns or the Pps-
(R)-Nip-(S)-Nip-Pps systems further in the allylation
reaction.
Additionally, the Gellman laboratory has shown that
heterochiral dinipecotic acid segments promote anti-
parallel sheet interactions.17-22 Given that we have been
able to use the â-turn secondary structure to control the
selectivity of palladium-catalyzed allylations we decided
to examine these sequences.
The possibility of using depsipeptides in asymmetric
catalysis was investigated. Dimers of proline and glycolic,
lactic, and leucic acids were prepared (Scheme 2) and
incorporated into the middle of amino acid tetramers.
This collection of peptides contained homochiral and
heterochiral sequences (Table 1, entries 1-6). In addition,
three peptides with racemic diphenylphosphinoserines
were prepared. The resulting nine depsipeptides were
tested as ligands in the palladium-catalyzed alkylation
of cyclopentenyl acetate. The palladium catalysts made
from the nine depsipeptides catalyzed the alyllation with
high conversion but provided racemic product. As a
control, two examples of analogous peptide sequences,
where the Pro-ester linkage was replaced with an amide
(Table 1, entries 10 and 11), were tested. In both cases,
those examples provided selectivites comparable to what
we have obtained with other Pps-Pro-D-Xxx-Pps peptides.
Apparently, the planar amide bond generates a signifi-
cantly different environment than the ester bond and is
at least partially responsible for the selectivities we
observe in the Pro-D-Xxx systems.
As noted above, the heterochiral dinipecotic acids
segments promote antiparallel sheet interactions.17,21
(17) Chung, Y. J.; Christianson, L. A.; Stanger, H. E.; Powell, D.
R.; Gellman, S. H. J. Am. Chem. Soc. 1998, 120, 10555-10556.
(18) Huck, B. R.; Fisk, J. D.; Guzei, I. A.; Carlson, H. A.; Gellman,
S. H. J. Am. Chem. Soc. 2003, 125, 9035-9037.
(19) Huck, B. R.; Fisk, J. D.; Gellman, S. H. Org. Lett. 2000, 2, 2607-
2610.
(20) Arnold, U.; Hinderaker, M. P.; Nilsson, B. L.; Huck, B. R.;
Gellman, S. H.; Raines, R. T. J. Am. Chem. Soc. 2002, 124, 8522-
8523.
(21) Chung, Y. J.; Huck, B. R.; Christianson, L. A.; Stanger, H. E.;
Krauthauser, S.; Powell, D. R.; Gillman, S. H. J. Am. Chem. Soc. 2000,
122, 3995-4004.
(22) Lai, J. R.; Huck, B. R.; Weisblum, B.; Gellman, S. H. Biochem-
istry 2002, 41, 12835-12842.
8080 J. Org. Chem., Vol. 69, No. 23, 2004

Catalysis with Phosphine-Containing Amino Acids
FIGURE 7. Space-filling representations of the three turn-based phosphine-palladium catalysts.
TABLE 1. Hydroxy acids in the i+2 Position
Cyclic Peptide Ligands. In an attempt to optimize
the selectivity of the initial â-turn system, we decided to
test a series of cyclic peptides that contain the basic Pps-
Pro-D-Xxx-Pps sequence. A small six-member library was
synthesized to examine the possibility of improving the
existing selectivity by using more rigid cyclic structures
(Figure 8). The cyclic peptides contained glutamic acid
in the first position coupled to the same six amino acid
J. Org. Chem, Vol. 69, No. 23, 2004 8081

Agarkov et al.
FIGURE 8. Three cyclic peptides examined and their open-chain analogues.
SCHEME 4
TABLE 2. Results for Cyclic Peptides
sequence that form the â-turn motif. The peptides were
prepared using quasi-orthogonally Dmab-protected de-
rivatives of glutamic acid (Scheme 4). The Dmab group
is practical because it is stable toward 20% piperidine in
DMF, the conditions for Fmoc deprotection, but can be
removed using 2% hydrazine in DMF. The cyclization
was done using the R-carboxyl group (L- and D-Glu; 37
and 38) and the γ-carboxyl group (L-Glu; 39) of glutamic
acid. To monitor the cyclization step and for comparison
with the cyclic counterparts, corresponding linear ana-
logues (40-42) were prepared as well.
The peptides were used as ligands for the palladium-
catalyzed reaction of cyclopeny acetate and dimethyl
malonate anion. All reactions proceeded to completion
and gave similar ee’s (Table 2). It is interesting to note
that the three cyclic peptides tested gave lower selectivi-
ties than the corresponding “linear” peptide. Presumably,
this is due to the cyclic constraint altering the structure
of the turn-forming residues.
The examined cyclic structures were rather flexible.
A plan to synthesize smaller more rigid cyclic peptides
failed due to the inability to systematically synthesize
small libraries. It is known that the rate of cyclization of
short peptide sequences is dependent on the stereochem-
istry of the residues. While it is possible to synthesize
individual peptides, this problem prevents the synthesis
of small cyclic peptides in a parallel manner.
Modification of the Phosphine Amino Acid: Sub-
stitution at the â-Carbon. The phosphine group is
attached to the peptide by a CH2 group (â-carbon), which
can be used to introduce another source of chirality to
the system. Replacement of one of the hydrogens of this
CH2 group with an alkyl or aryl group will position a
chiral center next to the phosphine and potentially
control the conformation of the metal ligand complex.
These new chiral centers can either complement or cancel
the existing chirality conferred by the peptide. With this
issue in mind all eight possible diastereomeric combina-
tions were synthesized and screened for their ability to
8082 J. Org. Chem., Vol. 69, No. 23, 2004

Catalysis with Phosphine-Containing Amino Acids
TABLE 3. Pps(â-Ph) vs Pps for the Reaction of Cyclopentenyl Substrate
a ee, %; positive values correspond to the R-enantiomer (shown), negative to the S-enantiomer.
TABLE 4. Ligand 51 in the Reaction with Other
Substrates
tigated. The other location that can be modified in these
ligands is at the other groups attached to the phosphine.
Our best route to the required amino acids allows for the
facile synthesis of amino acids with a wide variety of
different alkyl and aryl groups attached to phosphorus.7
With these phosphine amino acids in hand, a library was
synthesized using the aromatic groups on the phosphine
as the source of diversity. Table 5 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 pro-
vided moderate success previously. In general, it appears
that when the phosphine next to proline is larger, the
catalyst provides higher selectivity. There also appears
to be a preference for symmetrical groups on the phos-
phine, 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. These examples provided some of
the lowest selectivities in the study (entries 16-19).
control the selectivity of the allylation reaction (Table 3).
The results for this experiment varied dramatically. Out
of eight new ligands (46-3), six gave the opposite
enantiomer as the major product in low ee (46-50 and
52). The only sequence to provide high selectivity (51)
was with Pps(â-S-Ph) in the i position and Pps in the
i+3 position.
After determining the “best” phosphine containing
amino acids for the ligand, the other amino acids in the
sequence were examined (Table 6). 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 acids away from the metal had a
negligible effect on the selectivity of the catalyst, while
substitution of D-Val in the i+2 position increased the
selectivity slightly (86% ee).
Following the optimization of the ligand system, the
reaction conditions were examined. Upon examining a
number of solvents (DMF, THF, acetone, benzene, and
acetonitrile), acetonitrile was found to be the solvent that
provided the highest selectivity with the polymer bound
catalyst. At 0 °C in acetonitrile, ligand 76 provided the
product in 95% yield and 88% ee.
Since the palladium complex of peptide 51 catalyzed
the reaction with cyclopentenyl acetate with good selec-
tivity, it was tested on three other substrates (54, 55,
and 56) to determine if it may be more selective with
these molecules than the standard ligand 7 (Table 4). The
conversion at 16 h with ligand 51 was lower than those
obtained with 7. This could be due to an increase in the
steric congestion around the metal. In the case of cyclic
substrates 55 and 56, the selectivities were lower than
those obtained with ligand 7. However, with the very
difficult substrate 1-methylbut-2-enyl acetate (54) the
selectivity was slightly higher (53% ee vs 48% ee). While
the substitution of a phenyl group on the methylene next
to the phosphine influenced the reaction selectivity, in
most cases it resulted in lower selectivity than was
obtained with the parent ligand 7.
Modification of the Phosphine Amino Acid: Sub-
stitution at Phosphorus. The decrease in selectivity
observed with ligands possessing a group on the â-carbon
indicates that substitutions in this area of the ligand can
have a significant effect on the catalyst. With this in
mind, a different modification at this region was inves-
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 signifi-
cantly greater activity and poorer selectivity than the
desired catalyst. To test this concern, the best ligand (76)
J. Org. Chem, Vol. 69, No. 23, 2004 8083

Agarkov et al.
SCHEME 5
TABLE 5. Catalysis with Various Phosphine Amino
Acidsa
TABLE 6. Ac-Www-Xpsa-Xxx-Yyy-Ppsb-Zzz Support
compd
Www
Xxx
Yyy
Zzz
eee (%)
1
2
3
4
5
6
7
8
76
77
78
79
80
81
82
62
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
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 at 0 °C to rt using N,O-
bis(trimethylsilyl)acetamide, TBAF, and dimethyl malonate. d Iso-
lated yield. e Enantiomeric excess was determined by 1H NMR
analysis using [Eu(hfc)3] shift reagent.
TABLE 7. Boc-D-Phg-Xps-Pro-D-Val-Pps-D-Leu-OMe (83)
entry
compd
R
R′
yieldb (%)
eec (%)
1
2
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
Ph
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
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
4
5
3,5-xyl
3,5-xyl
Ph
1-Nap
1-Nap
Ph
1-Nap
2-Nap
2-Nap
2-Nap
Ph
1-Nap/Ph
Ph/1-Nap
Ph/1-Nap
1-Nap/Ph
6
7
8
9
10
11
12
13
14
15
16
17
18
19
entry
solvent
T (°C)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
toluene
acetone
CH3CN
THF
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0
82
89
91
90
92
91
90
85
92
88
89
88
85
90
95
92
89
85
THF
THF
-20
THF
-30
-45
a All ligands where synthesized and screened on the Synphase
system from Mimotopes. Reactions were run at 0 °C to 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.
DMF
a All reactions were run using N,O-bis(trimethylsilyl)acetamide,
TBAF, and dimethyl malonate. b Isolated yield. c Enantiomeric
excess was determined by1H NMR using [Eu(hfc)3] shift reagent.
selectivity is comparable to the best ligands known for this
reaction.23-29
was synthesized in solution and purified by chromatog-
raphy (83). Reaction of peptide 83 in acetonitrile provided
a catalyst that gave the addition product with comparable
yield and selectivity to the reaction in acetonitrile when
the catalyst was immobilized on the synthesis support
(90% yield, 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 7, entry 6, 91% yield, 95% ee). This
(23) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.;
Gagne, M. R. J. Am. Chem. Soc. 2000, 122, 7905-7920.
(24) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.
(25) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 99-102.
(26) Trost, B. M. In Catalytic Asymmetric Synthesis; Ojima, T., Ed.;
Wiley-VCH: New York, 2000; p 593.
(27) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919-
2920.
(28) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. 1998, 37, 3047-
3050.
8084 J. Org. Chem., Vol. 69, No. 23, 2004

Catalysis with Phosphine-Containing Amino Acids
When the best ligand for 3-acetoxycyclopentene, Boc-
D-Phg-Xps-Pro-D-Val-Pps-D-Leu-OMe, was used with the
3-acetoxycyclohexene (55), the selectivity was 76% ee
with the ligand on support and 81% ee with the ligand
in solution. Minimal optimization of this system ulti-
mately provided Ac-Gly-Xps-Pro-D-Ala-Xps-Gly-NH2 (84)
as the best ligand for this system (83% ee on support and
88% ee in solution, Scheme 5).
is tenuous at best. The precise nature of the ligand’s
secondary structure is not certain, but it is clear that
some secondary structure is necessary for selective
catalysis. In situations where the secondary structure
elements are varied, a profound change in catalyst
selectivity is observed. Moving the metal-binding units
one amino acid from the turn-forming residues decreases
the observed selectivity to nearly zero. The replacement
of the Pro-D-amino acid sequence with other dimers that
are known to form turns also significantly decreases the
catalysis selectivity. The simple substitution of an ester
for an amide at the proline also results in a change from
nearly 80% ee to zero. Clearly, the amide between the
proline and the D-amino acid, which is remote to the
metal in a through bond sense, has a profound effect on
the selectivity of the transition metal. This along with
structural work has led to a model that positions the
metal near the turn-forming residues of proline and the
D-amino acid.
Conclusion
In his original paper on the rhodium-catalyzed hydro-
genation 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”.30 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. Our work 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. The example in Scheme 5 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
synthesize 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.
In addition to providing a facile approach for the
synthesis of new ligands, a peptide-based approach to
ligand synthesis provides an opportunity to use peptide
secondary structure to control catalyst selectivity. While
we have been successful applying the principles devel-
oped for the control and formation of â-turn secondary
structures and using them in the development of asym-
metric catalysts, it is important to note that given the
large size of the phosphine side chains and the con-
straints that are imposed by coordination of a transition
metal, the connection of our work to peptide folding issues
The combination of the turn-forming residues and the
groups on phosphorus provide a pocket. We are currently
attempting to develop these types of ligands for other
reactions such as the Heck reaction and metal-catalyzed
cycloisomerizations. Additionally, systems that combine
phosphines with other metal-binding groups are being
developed.
Acknowledgment. This work was supported by
NIH Grant No. R01 GM56490. We acknowledge the
support of the Robert A. Welch Foundatio,n and Mimo-
topes, A Fisher Scientific Company, is acknowledged for
materials support. KANEKA Corp. of Japan is acknowl-
edged for support of Dr. Ohishi. We also gratefully
acknowledge the Washington University High-Resolu-
tion NMR Facility, partially supported by NIH Grant
Nos. RR02004, RR05018, and RR07155, and the Wash-
ington University Mass Spectrometry Resource Center,
partially supported by Grant No. NIHRR00954, for their
assistance. Professor Samuel Gellman and Dr. Bayard
Huck are acknowledged for communication of the
procedure for the resolution of racemic nipecotic acid.
Supporting Information Available: Complete experi-
mental details, compound characterization, identity of library
members, and methods for the analysis of product enantio-
meric purity. This material is available free of charge via the
Internet at http://pubs.acs.org.
(29) Gilbertson, S. R.; Xie, D. Angew. Chem., Int. Ed. 1999, 38,
2750-2752.
(30) Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 22,
1445-1446.
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