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