Enantioselective Synthesis of [b]-Annulated Azepane Scaffolds

Cyclopenta-, benzo-, and cyclohepta[b]-annulated azepane scaffolds were prepared in two steps from optically active cyclic α-allyl-β-oxoesters. The first step was ruthenium-catalyzed olefin cross metathesis with acrylonitrile. The second step was palladium-catalyzed dihydrogenation which consists of three consecutive processes: The hydrogenation of the C−C double and C−N triple bonds was followed by the reductive amination via the iminium ion formed in situ from the primary amino function and the endocyclic carbonyl group. This last step gave, stereoselectively, the annulated azepanes with relative trans-configuration. The amino function and the ester group define two points for further diversification of the scaffolds. The trifluoroacetyl derivatives allowed to establish the enantiopurity of the products to be 97–98 % ee by GLC on a chiral phase. The relative trans-configurations and in one case also the absolute (R,R)-configuration was established by X-ray crystallography.     

Electrochemistry and Spin-Crossover Behavior of Fluorinated Terpyridine-Based Co(II) and Fe(II) Complexes

Due to their ability to form stable molecular complexes that have tailor-made properties, terpyridine ligands are of great interest in chemistry and material science. In this regard, we prepared two terpyridine ligands with two different fluorinated phenyl rings on the backbone. The corresponding Co^II and Fe^II complexes were synthesized and characterized by single-crystal X-ray structural analysis, electrochemistry and temperature-dependent SQUID magnetometry. Single crystal X-ray diffraction analyses at 100 K of these complexes revealed Co−N and Fe−N bond lengths that are typical of low spin Co^II and Fe^II centers. The metal centers are coordinated in an octahedral fashion and the fluorinated phenyl rings on the backbone are twisted out of the plane of the terpyridine unit. The complexes were investigated with cyclic voltammetry and UV/Vis-NIR spectroelectrochemistry. All complexes show a reversible oxidation and several reduction processes. Temperature dependent SQUID magnetometry revealed a gradual thermal SCO behavior in two of the complexes, while EPR spectroscopy provided further insights on the electronic structure of the metal complexes, as well as site of reduction.     

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

Glycogen synthase kinase‐3 (GSK‐3) regulates multiple cellular processes in diabetes, oncology, and neurology. N‐(3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(3‐chloro‐4‐methoxyphenyl)oxazole‐4‐carboxamide (PF‐04802367 or PF‐367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK‐3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF‐367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF‐367 is ideal for discovery of radiopharmaceuticals for GSK‐3 in the central nervous system. A ¹¹C‐isotopologue of PF‐367 was synthesized and preliminary PET imaging studies in non‐human primates confirmed that we have overcome the two major obstacles for imaging GSK‐3, namely, reasonable brain permeability and displaceable binding.     

Gold(I)‐Catalyzed N‐Desulfonylative Amination versus N‐to‐O 1,5‐Sulfonyl Migration: A Versatile Approach to 1‐Azabicycloalkanes

Valuable 1‐azabicycloalkane derivatives have been synthesized through a novel gold(I)‐catalyzed desulfonylative cyclization strategy. An ammoniumation reaction of ynones substituted at the 1‐position with an N‐sulfonyl azacycle took place in the presence of a gold cation by intramolecular cyclization of the disubstituted sulfonamide moiety onto the triple bond. Depending on the size of the heterocyclic ring and substitution of the substrates, two unprecedented forms of nucleophilic attack on the sulfonyl group were exploited, that is, a N‐desulfonylation in the presence of an external protic O nucleophile (37–87 %, 10 examples) and a unique N‐to‐O 1,5‐sulfonyl migration (60–98 %, 9 examples).     

A Germylene Stabilized by Homoconjugation

The synthesis of a bicyclic germylene from the reaction of a germole dianion with hafnocene dichloride is reported. This germylene is stabilized by a homoconjugative interaction of the dicoordinated germanium atom with a remote C=C double bond. First reactivity studies revealed its nucleophilic character and resulted in the synthesis of bimetallic hafnium/iron and hafnium/tungsten complexes with a germylene group linker.     

Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9‐membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate‐processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine‐binding proteins.     

Vehicle routing problems with time windows and multiple service workers: a systematic comparison between ACO and GRASP

This paper systematically compares an ant colony optimization (ACO) and a greedy randomized adaptive search procedure (GRASP) metaheuristic. Both are used to solve the vehicle routing problem with time windows and multiple service workers. In order to keep the results comparable, the same route construction heuristic and local search procedures are used. It is shown that ACO clearly outperforms GRASP in the problem under study. Additionally, new globally best results for the used benchmark problems are presented.