Formation of ArF from LPdAr(F): Catalytic Conversion of Aryl Triflates to Aryl Fluorides

Despite increasing pharmaceutical importance, fluorinated aromatic organic molecules remain difficult to synthesize. Present methods require either harsh reaction conditions or highly specialized reagents, making the preparation of complex fluoroarenes challenging. Thus, the development of general methods for their preparation that overcome the limitations of those techniques currently in use is of great interest. We have prepared [LPd(II)Ar(F)] complexes, where L is a biaryl monophosphine ligand and Ar is an aryl group, and identified conditions under which reductive elimination occurs to form an Ar-F bond. On the basis of these results, we have developed a catalytic process that converts aryl bromides and aryl triflates into the corresponding fluorinated arenes by using simple fluoride salts. We expect this method to allow the introduction of fluorine atoms into advanced, highly functionalized intermediates.National Institutes of Health (U.S.) (Grant GM46059)Merck & Co., Inc.Boehringer Ingelheim PharmaceuticalsBASFNational Science Foundation (U.S.) (Grant CHE 9808061)National Institutes of Health (U.S.) (Grant DBI 9729592

Pinolide, a New Nonenolide Produced by Didymella pinodes, the Causal Agent of Ascochyta Blight on Pisum sativum

An aggressive isolate of Didymella pinodes isolated from pea (Pisum sativum) produced four different metabolites in vitro. The metabolites isolated from the culture filtrates were characterized by spectroscopic and optical methods. A new nonenolide, named pinolide, was isolated and characterized as (2S*,7R*,8S*,5E,9R*)-2,7,8-trihydroxy-9-propy1-5-nonen-9-olide. Pinolidoxin, the main toxin produced by D. pinodes, was also isolated together with two other closely related nonenolides, identified as herbarumin II and 2-epi-herbarumin II. Herbarumin II and 2-epi-herbarumin II have been previously isolated from the fungi Phoma herbarum and Paraphaeosphaeria recurvifoliae, respectively, but described here to be isolated for the first time from D. pinodes. When tested on leaves of the host plant and other legumes and weeds, pinolidoxin was phytotoxic in all of the plant species, whereas the other three nonenolides did not produce any symptoms. The importance of the stereochemistry of the hydroxy group at C-7 on phytotoxicity also is discussed

GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis

Adaptive changes in lysosomal capacity are driven by the transcription factors TFEB and TFE3 in response to increased autophagic flux and endolysosomal stress, yet the molecular details of their activation are unclear. LC3 and GABARAP members of the ATG8 protein family are required for selective autophagy and sensing perturbation within the endolysosomal system. Here, we show that during the conjugation of ATG8 to single membranes (CASM), Parkin-dependent mitophagy, and Salmonella-induced xenophagy, the membrane conjugation of GABARAP, but not LC3, is required for activation of TFEB/TFE3 to control lysosomal capacity. GABARAP directly binds to a previously unidentified LC3-interacting motif (LIR) in the FLCN/FNIP tumor suppressor complex and mediates sequestration to GABARAP-conjugated membrane compartments. This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. Thus, the GABARAP-FLCN/FNIP-TFEB axis serves as a molecular sensor that coordinates lysosomal homeostasis with perturbations and cargo flux within the autophagy-lysosomal network