Intramolecular Buchwald-Hartwig N-arylation of bicyclic hydrazines: practical access to spiro[indoline-2,3'-piperidines].

In recent years, spirocycles have been the focus of medicinal chemistry, and several drugs or drug candidates incorporating these "non-planar" chemical motifs have been developed. Herein, an unusual intramolecular Buchwald-Hartwig N-arylation of bicyclic hydrazines is described. This key reaction gives access to various spiro[indoline-2,3'-piperidine] derivatives after reductive cleavage of a nitrogen-nitrogen bond. Following this strategy, unprecedented spiro compounds can be obtained in up to 42% yields over 5 steps. Our approach widens the chemical space of spirocycles and may be useful to explore new avenues of research in drug discovery.

An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.

Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.

Conformational arm-wrestling: battles for stereochemical control in benzamides bearing matched and mismatched chiral 2- and 6-substituents.

The orientation of a tertiary amide group adjacent to an aromatic ring may be governed by the stereochemistry of an adjacent chiral substituent. With a chiral substituent in both ortho positions, matched/mismatched pairs of isomers result. Evidence for matched stereochemistry is provided by the clean NMR spectra of single conformers, while mismatching gives poor or unexpected selectivities in the formation of chiral substituents, or mixtures of amide conformers. Attempts to use the match-mismatch effect to select for racemic pairs of enantiomeric substituents, and hence develop a "racemate-sequestering" reagent, are described, along with the use of "matching" to scavenge a single enantiomer of a diamine from material of incomplete enantiomeric purity.

A convergent approach to huperzine A and analogues.

We describe a concise and convergent synthesis of (rac)-5-methoxy-6-azatricyclco[7.3.1.0(2,7)]trideca-2(7),3,5,11-tetraen-13-ol, which has the basic ring system of huperzine A, a potent inhibitor of acetylcholinesterase. We also describe the synthesis of the novel system 5-methoxy-6-azatricyclo[7.2.2.0(2,7)]trideca-2(7),3,5-trien-10-one and a series of related systems.

Carbolithiation of aromatic rings: cyclohexadienes from N-aroyl-2,2,6,6-tetramethylpiperidines.

Benzamides whose nitrogen atom is part of a 2,2,6,6-tetramethylpiperidine ring are dearomatised by alkyllithiums, which attack them regioselectively to yield, after electrophilic quench, substituted cyclohexadienes.