Aryl to Aryl Palladium Migration in the Heck and Suzuki Coupling of o-Halobiaryls

A novel 1,4-palladium migration between the o- and o‘-positions of biaryls has been observed in organopalladium intermediates derived from o-halobiaryls. The organopalladium intermediates generated by this migration have been trapped either by a Heck reaction employing ethyl acrylate or by Suzuki cross-coupling using arylboronic acids. This palladium migration can be activated or deactivated by choosing the appropriate reaction conditions. Chemical and computational evidence supports the presence of an equilibrium that correlates with the C−H acidity of the available arene positions

Identification of a small molecule yeast TORC1 inhibitor with a flow cytometry-based multiplex screen

TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high throughput flow cytometry multiplexed screen using five GFPtagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in an analogous manner to rapamycin. We have shown that CID 3528206 inhibited yeast cell growth, and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC50s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors

New approaches to heterocycles and carbocycles

The electrophilic cyclization of functionally-substituted alkynes is a very promising route to an extraordinary range of medicinally interesting, functionally-substituted heterocycles and carbocycles. For instance, a variety of substituted isocoumarins and alpha-pyrones are readily prepared in excellent yields under very mild reaction conditions by the reaction of o-(Ialkynyl)benzoates and (Z)-2-alken-4-ynoates with ICl, I2, PhSeCl, p-O2NC6 H4SCl, and HI. This methodology accommodates various alkynyl esters and has been successfully extended to the synthesis of polycyclic aromatic and biaryl compounds.;Electrophilic cyclization of o-(1-alkynyl)benzamides with ICl, I2, and NBS, affords a variety of substituted isoindolin-1-ones in good to excellent yields. In a few cases, substituted isoquinolin-1-ones were obtained as the major product instead. This methodology accommodates various alkynyl amides and functional groups, and has been successfully extended to heterocyclic starting materials. This chemistry has been successfully applied to the formal synthesis of a biologically interesting alkaloid cepharanone B.;A variety of substituted polycyclic aromatics are readily prepared in good to excellent yields under very mild reaction conditions by the reaction of 2-(1-alkynyl)biphenyls with ICl, I2, NBS, and p-O 2NC6H4SCl. This methodology readily accommodates various functional groups and has been successfully extended to systems containing a variety of polycyclic and heterocyclic rings.;The coupling of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles, either catalyzed by AUCl3 or induced by an electrophile, provides highly substituted furans in good to excellent yields under very mild reaction conditions. Various nucleophiles, including functionalized alcohols, H2O, carboxylic acids, 1,3-diketones and electron-rich arenes, and a range of cyclic and acyclic 2-(1-alkynyl)-2-alken-1-ones readily participate in these cyclizations. Iodine, NIS, and PhSeCl have proven successful as electrophiles in this process. The resulting iodine-containing furans can be readily elaborated to more complex products using known organopalladium chemistry.</p

Palladium-Catalyzed Domino Heck/Aryne Carbopalladation/C–H Functionalization: Synthesis of Heterocycle-Fused 9,10-Dihydrophenanthrenes

A novel palladium-catalyzed domino Heck/aryne carbopalladation/C–H functionalization reaction using in situ generated arynes has been developed in which three new C–C bonds and a carbon quaternary center are formed. This methodology affords moderate to excellent yields of heterocycle-fused 9,10-dihydrophenanthrenes

Synthesis of 9,10-Phenanthrenes via Palladium-Catalyzed Aryne Annulation by <i>o</i>‑Halostyrenes and Formal Synthesis of (±)-Tylophorine

A novel palladium-catalyzed annulation reaction of in situ generated arynes and <i>o</i>-halostyrenes has been developed. This methodology affords moderate to excellent yields of substituted phenanthrenes and is tolerant of a variety of functional groups such as nitrile, ester, amide, and ketone. This annulation chemistry has been successfully applied to the formal total synthesis of a biologically active alkaloid (±)-tylophorine

Regio- and Stereoselective Synthesis of Cyclic Imidates via Electrophilic Cyclization of 2‑(1-Alkynyl)benzamides. A Correction

The electrophilic cyclization of 2-(1-alkynyl)­benzamides affords high yields of cyclic imidates, instead of the previously reported isoindolin-1-ones, where cyclization proceeds on the oxygen of the carbonyl group rather than the nitrogen of the amide functionality. X-ray crystallography and spectroscopic techniques have been used to characterize the products. A correction is hereby provided in order to rectify the previous misassignment of structure

Regio- and Stereoselective Synthesis of Cyclic Imidates via Electrophilic Cyclization of 2‑(1-Alkynyl)benzamides. A Correction

The electrophilic cyclization of 2-(1-alkynyl)­benzamides affords high yields of cyclic imidates, instead of the previously reported isoindolin-1-ones, where cyclization proceeds on the oxygen of the carbonyl group rather than the nitrogen of the amide functionality. X-ray crystallography and spectroscopic techniques have been used to characterize the products. A correction is hereby provided in order to rectify the previous misassignment of structure