Triphenylphosphine promoted addition of dimethyl acetylenedicarboxylate to 1,2-benzoquinones: facile synthesis of novel γ-spirolactones

The addition of dimethyl acetylenedicarboxylate to o-quinones in the presence of triphenylphosphine leading to highly functionalised γ-spirolactones is reported

Novel heterocyclic construction via dipolar cycloadditions to 1,2-dicarbonyl compounds

The reactivity of o-quinones and other 1,2-diones towards a variety of dipolar species viz-, nitrile oxides, carbonyl ylides, betaines and mesoionic compounds has been investigated. In most cases, these reactions occur with the participation of C=O group as the dipolarophile leading to the synthesis of novel heterocyclic compounds

Novel cycloaddition reactions of o-benzoquinones and related chemistry

o-Benzoquinone is a unique conjugated 1,2-dione that can exhibit diverse cycloaddition modes, participating either as carbodiene, heterodiene, dienophile or heterodienophile. With electron-rich dienes, benzodioxins are formed in excellent yields. Pentafulvenes including 6-vinylfulvenes normally give rise to bicyclo [2.2.2] adducts. Exceptions are observed with cycloalkylfulvenes where the fulvenes undergo rearrangement to cyclopentadiene derivatives prior to cycloaddition, resulting in benzodioxins. o-Benzoquinones participate as dipolarophiles on treatment with nitrile oxides and carbonyl ylides yielding highly oxygenated novel spiro compounds. Triphenylphosphine catalyzed addition of DMAD to o-benzoquinones afforded another class of novel spirolactones. The bicyclo [2.2.] octene diones derived fromo-benzoquinones undergo a number of synthetically useful transformations

Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors

Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta­[<i>b</i>]­benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure–activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation–initiation machinery (i.e., complex 5′-untranslated region UTR) relative to simple 5′UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds <b>74</b> and <b>76</b> were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol

Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926

The formation of the d-homocyclopamine ring system in IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective cyclopropanation followed by a stereoselective acid-catalyzed carbocation rearrangement. In order to perform large-scale cyclopropanation reactions, we developed new iodomethylzinc bis­(aryl)­phosphate reagents that were found to be both effective and safe. These soluble reagents can be prepared under mild conditions and are stable during the course of the reaction. Importantly, they have favorable energetics relative to other cyclopropanating agents such as EtZnCH₂I. Herein, we describe the process optimization studies that led to successful large-scale production of the d-homocyclopamine core necessary for IPI-926

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)‑γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (<b>26</b> or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors