Preparation of N-Isopropylidene-N'-2-Nitrobenzenesulfonyl Hydrazine (IPNBSH) and Its Use in Palladium-catalyzed Synthesis of Monoalkyl Diazenes. Synthesis of 9-Allylanthracene

An oven-dried 1-L, two-necked, round-bottomed flask, equipped with a 3 cm football-shaped stir bar, a rubber septum and inert gas inlet connected to a manifold, is charged with o-nitrobenzenesulfonyl hydrazide (1) (Note 1) (20.0 g, shaped stir bar, a rubber septum and inert gas inlet connected to a manifold, is charged with o-nitrobenzenesulfonyl hydrazide (1) (Note 1) (20.0 g, 92.1 mmol, 1 equiv) under an argon atmosphere. Acetone (Note 2) (300 mL) is added via cannula and the resulting solution stirred at room temperature (24 °C). After 10 min, TLC (Note 3) analysis of the reaction mixture indicated full conversion of the starting material (hexanes:ethyl acetate = 1:2; Rf[subscript SM] = 0.2, Rf[subscript product] = 0.5, visualized with ceric ammonium molybdate). Aliquots of the solution are transferred to a 500-mL onenecked flask and the solvent is removed with a rotary evaporator (200 mmHg, 40 °C) to afford a yellow powder. Hexanes (100 mL), acetone (20 mL), and a 3-cm football-shaped stir bar are added and the suspension stirred for 10 min at room temperature. The white solid is collected by vacuum filtration (40 mm, Büchner funnel with fritted disc, medium porosity) and washed with hexanes (2 × 60 mL, 24 °C). The white solid is then transferred to a 250-mL flask and dried in vacuo (7 mmHg, 24 °C) for 24 h to afford N-isopropylideneN'-2-nitrobenzenesulfonyl hydrazine (2) (Note 4) (22.5 g, 87.4 mmol, 95%) as an off-white solid

Selective Metal-Site-Guided Arylation of Proteins

We describe palladium-mediated S-arylation that exploits natural metal-binding motifs to ensure high site selectivity for a proximal reactive residue. This allows the chemical identification not only of proteins that bind metals but also the environment of the metal-binding site itself through proteomic analysis of arylation sites. The transformation is easy to perform under standard conditions, does not require the isolation of a reactive Ar–Pd complex, is broad in scope, and is applicable in cell lysates as well as to covalent inhibition/modulation of metal-dependent enzymatic activity

Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide

It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (<b>1</b>) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of <b>1</b> to be assessed. The acquired biodata show that <b>1</b> is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI₅₀ values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that <b>1</b> causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue