Rapid, Catalytic Hydrolysis of Methionine-Containing Dipeptides by a Dinuclear Palladium(II) Complex Having Thiolate Bridging Ligands

The dinuclear complex
(Me4N)2[Pd2(μ-SPh)2Cl4]
is solvolyzed upon reaction with AgClO4·H2O
in acetone. The
X-ray crystal structure of
(Ph4As)2[Pd2(μ-SPh)2Cl4]
showed that this dinuclear complex is bridged by two
thiolate
ligands with Cl- ions occupying terminal sites on the
palladium(II) atoms. The dinuclear solvolyzed
species
[Pd2(μ-SPh)2(sol)4](ClO4)2,
in which sol is H2O or acetone, binds to methionine side
chains in AcMet-X, where
X is Gly, Ala, Leu, Phe, or Val. It then catalyzes hydrolysis of
the amide bond involving the carboxyl group of
methionine. No prior activation of the amide bond is required for
hydrolysis. Dipeptides with regular amide
bonds are hydrolyzed in nonaqueous solvents, under mild conditions.
The reactions were followed by 1H NMR
spectroscopy. Turnover was achieved with the following
N-acetylated dipeptides:  AcMet-Gly, AcMet-Val, AcMet-Phe, and AcMet-Ala. One equivalent of
[Pd2(μ-SPh)2(sol)4](ClO4)2
cleaves 6−14 equiv of dipeptide. The turnover
number depends on the steric bulk of the leaving amino acid.
Hydrolysis kinetics were studied for AcMet-Gly,
AcMet-Ala, AcMet-Val, AcMet-Phe, and AcMet-Leu. The reaction
proceeds very rapidly, with a half-life of
less than 7 min for AcMet-Ala at 50 °C. The half-lives at 40
°C for most of the dipeptides are shorter than 30
min. Because the rate of the reaction also depends on the volume
of the leaving amino acid, the catalyst is
potentially sequence-selective. The effects of temperature on the
hydrolysis of AcMet-Ala were also studied.
This study is a step toward the use of transition-metal complexes
as reagents for the hydrolysis of lipophillic
peptides and proteins.