Ruthenium Half-Sandwich Complexes as Protein Kinase Inhibitors: An <i>N</i>-Succinimidyl Ester for Rapid Derivatizations of the Cyclopentadienyl Moiety

Cyclopentadienyl half-sandwich ruthenium complexes have been demonstrated to be promising scaffolds as protein kinase inhibitors. In order to rapidly identify derivatives which display modified pharmacological properties, we developed the synthesis of an organoruthenium compound bearing an N-succinimidyl ester at the cyclopentadienyl moiety. The quenching of this activated ester with a library of primary amines, followed by testing of the resulting amide library, led to the identification of organometallic Pim-1 and GSK-3 inhibitors with improved potencies and kinase selectivities

Ruthenium Half-Sandwich Complexes as Protein Kinase Inhibitors: An <i>N</i>-Succinimidyl Ester for Rapid Derivatizations of the Cyclopentadienyl Moiety

Cyclopentadienyl half-sandwich ruthenium complexes have been demonstrated to be promising scaffolds as protein kinase inhibitors. In order to rapidly identify derivatives which display modified pharmacological properties, we developed the synthesis of an organoruthenium compound bearing an N-succinimidyl ester at the cyclopentadienyl moiety. The quenching of this activated ester with a library of primary amines, followed by testing of the resulting amide library, led to the identification of organometallic Pim-1 and GSK-3 inhibitors with improved potencies and kinase selectivities

An Extremely Stable and Orthogonal DNA Base Pair with a Simplified Three-Carbon Backbone

A nucleotide C3HQ with a minimal three-carbon backbone displays unprecedented pairing strength and orthogonality in a homopair C3HQ:C3HQ in the presence of one equivalent of Cu2+. The pairing stability in DNA even exceeds the related base pair having the regular 2‘-deoxyribose backbone. This discovery of a synergy between an artificial backbone and base-pairing scheme opens new avenues for the economical design of modified oligonucleotides with tailored properties

Improved Phosphoramidite Building Blocks for the Synthesis of the Simplified Nucleic Acid GNA

An improved synthesis of glycol nucleic acids is reported using new phosphoramidite building blocks in which the exocyclic amino groups of adenine and guanine are protected as N-dimethylformamidines, whereas the amino group of cytosine is protected via an acetamide. Besides a more rapid synthesis with higher yields, these phosphoramidites allow the use of a quicker deprotection procedure in the subsequent solid-phase synthesis of GNA oligonucleotides

Ruthenium Complexes as Protein Kinase Inhibitors

Replacing complex natural products with simple metal complexes could lead to a new class of metallopharmaceuticals in which the metal center plays mainly a structural role. A strategy is introduced for the creation of ruthenium complex-based protein kinase inhibitors 1 (X = CO or CH2), morphed out of the class of indolocarbazole inhibitors with the alkaloid staurosporine as its most prominent member

Reductive Labilization of a Cyclometalating Ligand Applied to Auxiliary-Mediated Asymmetric Coordination Chemistry

(4S)-4-Isopropyl-2-(3-nitrophenyl)-4,5-dihydrooxazole ((S)-Phox) is introduced as a novel chiral auxiliary for the asymmetric synthesis of ruthenium polypyridyl complexes. A simply accessible (S)-Phox-bearing precursor serves as the starting point for diastereoselective coordination chemistry: The stereogenic carbon atom of the cyclometalating auxiliary controls the spatial arrangement of incoming 1,10-phenanthrolines during ligand substitution reactions (ratio Λ:Δ up to 14:1), and further precipitation affords diastereopure compounds. In the following key step, the labilization of the auxiliary ligand is achieved by reduction, thus permitting its replacement against a third polypyridyl ligand with complete retention of the configuration at the metal center (er > 99:1) under mildly acidic conditions, in contrast with previously developed systems that require strong acid. On the basis of results of NMR experiments and X-ray analysis obtained for intermediate compounds, mechanistic considerations for the formation of diastereomeric complexes were made, revealing a Δ → Λ isomerization as the reason for the observed limitations in selectivity optimization. This work expands the pool of methods available for the asymmetric synthesis of tris-heteroleptic ruthenium polypyridyl complexes and additionally may serve as an inspiration for the synthesis of other nonracemic octahedral chiral-at-metal compounds

Reductive Labilization of a Cyclometalating Ligand Applied to Auxiliary-Mediated Asymmetric Coordination Chemistry

(4<i>S</i>)-4-Isopropyl-2-(3-nitrophenyl)-4,5-dihydrooxazole ((<i>S</i>)-<b>Phox</b>) is introduced as a novel chiral auxiliary for the asymmetric synthesis of ruthenium polypyridyl complexes. A simply accessible (<i>S</i>)-<b>Phox</b>-bearing precursor serves as the starting point for diastereoselective coordination chemistry: The stereogenic carbon atom of the cyclometalating auxiliary controls the spatial arrangement of incoming 1,10-phenanthrolines during ligand substitution reactions (ratio Λ:Δ up to 14:1), and further precipitation affords diastereopure compounds. In the following key step, the labilization of the auxiliary ligand is achieved by reduction, thus permitting its replacement against a third polypyridyl ligand with complete retention of the configuration at the metal center (er > 99:1) under mildly acidic conditions, in contrast with previously developed systems that require strong acid. On the basis of results of NMR experiments and X-ray analysis obtained for intermediate compounds, mechanistic considerations for the formation of diastereomeric complexes were made, revealing a Δ → Λ isomerization as the reason for the observed limitations in selectivity optimization. This work expands the pool of methods available for the asymmetric synthesis of tris-heteroleptic ruthenium polypyridyl complexes and additionally may serve as an inspiration for the synthesis of other nonracemic octahedral chiral-at-metal compounds

A Simple Glycol Nucleic Acid

A glycol nucleic acid (GNA) with an acyclic propylene glycol phosphodiester backbone forms stable antiparallel duplexes following the Watson−Crick base pairing rules

Ruthenium Complexes as Protein Kinase Inhibitors

Replacing complex natural products with simple metal complexes could lead to a new class of metallopharmaceuticals in which the metal center plays mainly a structural role. A strategy is introduced for the creation of ruthenium complex-based protein kinase inhibitors 1 (X = CO or CH2), morphed out of the class of indolocarbazole inhibitors with the alkaloid staurosporine as its most prominent member

Deracemization of Chiral-at-Ruthenium Catalyst by Diastereoselective Dynamic Resolution

In this work, we introduce an auxiliary-mediated deracemization protocol in the synthesis of a non-C2-symmetric chiral-at-ruthenium catalyst bearing two cyclometalated 7-methyl-1,7-phenanthrolinium heterocycles, a CO ligand, and an additional labile MeCN ligand. Upon coordination of a monodentate chiral oxazoline ligand as chiral auxiliary, the racemic complex mixture is transformed into a single diastereomer in quantitative yield via a diastereoselective dynamic resolution process. After removal of the oxazoline ligand under acidic conditions, enantiomerically pure complexes (>20:1 er) with a Δ- and Λ-configuration were obtained. An application of the chiral-at-ruthenium catalyst to an enantioselective ring-closing C­(sp3)-H amidation of a 1,2,4-dioxazol-5-one to the corresponding chiral γ-lactam is demonstrated