Bioconjugates of Enantiomerically Pure Organopalladium Compounds by Metal‐Assisted Positional Selective Transesterifications at Palladium Enolates

Abstract

The synthesis of enantiomerically pure palladatricyclo[4.1.0.0(2,4)]heptanes and their modification by an unprecedented and very efficient positional selective transesterification is described. The mild reaction conditions are most probably based on an acceleration of the transesterification due to assistance by the metal. This novel approach allows straightforward access to a large number of structurally diverse organometallic complexes. The functional groups on the newly installed ester moieties were modified by using standard peptide synthesis protocols, Sonogashira reactions, and nucleophilic substitution reactions. The cellular uptake of these organometallic species was traced by confocal microscopy and their biological activity was evaluated by using different cell lines. Inhibition of cell growth and induction of apoptotic cell death by these novel palladium heterocycles are equivalent to Cisplatin.

A Highly Diastereoselective Recognition Process as the Basis for the Resolution of Palladatricyclo[4.1.0.02,4]heptanes

“…Overall, this unprecedented aggregation phenomenon forms the basis of the easy separation of the two diastereomers of 3 by column chromatography. As the stereochemically pure products can be functionalized by another positional selective transesterification, this use of the readily available (−)-menthol auxiliary can easily be embedded into longer synthetic sequences of more complex enantiopure organopalladium compounds …”

“…In the context of the biological applications of the PTHs, it is crucial to use enantiomerically pure compounds, and the diastereoselective dimerization process described here will allow this for similar palladacycles as well. As the stereodifferentiation for other metal centers with similar coordination geometries should be similar, this principle should be extendable to other organometallic compounds.…”

“…As the stereochemically pure products can be functionalized by another positional selective transesterification, this use of the readily available (−)-menthol auxiliary can easily be embedded into longer synthetic sequences of more complex enantiopure organopalladium compounds. 5 In the context of the biological applications of the PTHs, 5 it is crucial to use enantiomerically pure compounds, and the diastereoselective dimerization process described here will allow this for similar palladacycles as well. As the stereodifferentiation for other metal centers with similar coordination geometries should be similar, this principle should be extendable to other organometallic compounds.…”

“…By transesterification of rac-1 with commercially available (1R,2S,5R)-(−)-menthol, 4 the easily separable, enantiomerically pure diastereomers 3a,b were obtained in high yields up to a gram scale (Scheme 2). 5 Most remarkably, the separation succeeded with a normal silica gel column: 3a eluted first, followed by 3b. The relative configuration of the known stereocenters in the (−)-menthol unit and the four stereocenters in the PdTH framework could be assigned for both diastereomers by two independent crystal structure analyses, one of each diastereomer of 3.…”

“…For an easier access to nonracemic chiral palladacycles, we turned our focus to classical chiral resolution strategies. By transesterification of rac - 1 with commercially available (1 R ,2 S ,5 R )-(−)-menthol, the easily separable, enantiomerically pure diastereomers 3a , b were obtained in high yields up to a gram scale (Scheme ) …”