A computational triage approach to the synthesis of novel difluorocyclopentenes and fluorinated cycloheptadienes using thermal rearrangements.

Electronic structure calculations have been used for the effective triage of substituent effects on difluorinated vinylcyclopropane precursors and their ability to undergo vinyl cyclopropane rearrangements (VCPR). Groups which effectively stabilised radicals, specifically heteroarenes, were found to result in the lowest energy barriers. Ten novel precursors were synthesised to test the accuracy of computational predictions; the most reactive species which contained heteroarenes underwent thermal rearrangements at room temperature to afford novel difluorocyclopentenes and fluorinated benzocycloheptadienes through competing VCPR and [3,3]-rearrangement pathways, respectively.

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease.

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

Evaluating the thermal vinylcyclopropane rearrangement (VCPR) as a practical method for the synthesis of difluorinated cyclopentenes: experimental and computational studies of rearrangement stereospecificity.

Vinyl cyclopropane rearrangement (VCPR) has been utilised to synthesise a difluorinated cyclopentene stereospecifically and under mild thermal conditions. Difluorocyclopropanation chemistry afforded ethyl 3-(1'(2'2'-difluoro-3'-phenyl)cyclopropyl) propenoate as all four stereoisomers (18a, 18b, 22a, 22b) (all racemic). The trans-E isomer (18a), prepared in 70 % yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99 %).

Single-step microwave-mediated synthesis of oxazoles and thiazoles from 3-oxetanone: a synthetic and computational study.

The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration.

Photophysical properties of platinum(II)-acetylide complexes: the effect of a strongly electron-accepting diimine ligand on excited-state structure.

The compounds [Pt(MesBIAN)(C[triple bond]CR)2] (R = C6H4-CN-p, 1; SiMe3, 2; C6H4-CF3-p, 3; C6H5, 4; C6H4-CH3-p 5) {MesBIAN = bis(mesitylimino)acenaphthene} have been synthesized; the X-ray crystal structure determinations of 4 and 5 and the starting material [Pt(MesBIAN)Cl2] are reported. Chemical oxidation of 4 with diiodine leads to generation of an intermediate platinum(IV) bis(acetylide) diiodide complex, which then couples and reductively eliminates the acetylide ligands as a diyne, leading to the generation of [Pt(MesBIAN)I2] 6. Compound 2 readily forms an adduct 2a with copper(I) chloride, in which the copper atom is bonded to the two acetylide triple bonds.

Bulky 4-phosphacyclohexanones: diastereoselective complexations, orthometallations and unprecedented [3.1.1]metallabicycles.

The 4-phosphacyclohexanones, 2,2,6,6-tetramethyl-1-phenyl-4-phosphorinanone (La), 1,2,6-triphenyl-4-phosphorinanone ((Ph)Lb), 1-cyclohexyl-2,6-diphenyl-4-phosphorinanone ((Cy)Lb) and 1-tert-butyl-2,6-diphenyl-4-phosphorinanone ((Bu)Lb) have been made by modifications of literature methods. Phosphines (R)Lb are each formed as mixtures of meso- and rac-diastereoisomers. Isomerically pure rac-(Ph)Lb, rac-(Cy)Lb and meso-(Bu)Lb can be isolated by recrystallisation from MeCN.