Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.

Catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester-derived carbonyl ylides with alkene dipolarophiles.

Catalyzed cascade reactions that generate molecular complexity rapidly and in an enantioselective manner are attractive methods for asymmetric synthesis. In the present article, chiral rhodium catalysts are shown to effect such a transformation by using a range of 2-diazo-3,6-diketoesters with bicyclo[2.2.1]alkenes and styrenes as reaction partners. The reactions are likely to proceed by formation of a catalyst-complexed carbonyl ylide from the diazo compound, followed by intermolecular cycloaddition with the alkene dipolarophile. It was possible to obtain high levels of asymmetric induction [up to 89% enantiomeric excess (ee) and 92% ee for the two chiral catalysts investigated]. Enantioselectivity is not highly sensitive to substituent variation at the ketone that forms the ylide; however, branching does improve ee. Observations of dipolarophile-dependent enantiofacial selectivity in the cycloadditions indicate that the dipolarophile can be intimately involved in the enantiodiscrimination process.

Synthesis of unprotected and borane-protected cyclic phosphines using Ru- and Mo- based olefin metathesis catalysts.

Ru- and Mo-based catalysts can be used in ring closing metathesis (RCM) reactions to synthesise cyclic phosphines protected as their borane complexes. The compatibility of the Schrock Mo-catalyst and the N-heterocyclic carbene Ru-catalysts with this class of substrates is particularly noteworthy as asymmetric RCM (ARCM) is now emerging as a new tool for the preparation of homochiral phosphines. One of the key results is that the Mo-catalyst allows the ring closure of the unprotected diallylphenylphosphine with 95% conversion.

Catalytic enantioselective [3 + 2]-cycloadditions of diazoketone-derived aryl-substituted carbonyl ylides.

An evaluation of alpha-aryl-alpha-diazodiones in tandem carbonyl ylide formation-enantioselective [3 + 2]-cycloaddition reactions is described. Such substrates were designed to allow investigation of the electronic characteristics of the dipole upon asymmetric induction. Intramolecular cycloadditions (with a tethered alkene dipolarophile) were found to occur in good to quantitative yields, with a difference in ee exhibited by the two electronically different diazodiones 8 and 9. Intermolecular cycloadditions using diazodiones 12 and 13 with DMAD and arylacetylenes 16-18 again demonstrated that electronics play a key role in determining the outcome of the cycloaddition reactions. Enantioselectivities of up to 76% were observed.

Stereoselective 1,2-cis glycosylation of 2-O-allyl protected thioglycosides.

The technique of intramolecular aglycon delivery (IAD), whereby a glycosyl acceptor is temporarily appended to a hydroxyl group of a glycosyl donor is an attractive method that can allow the synthesis of 1,2-cis glycosides in an entirely stereoselective fashion. 2-O-Allyl protected thioglycoside donors are excellent substrates for IAD, and may be glycosylated stereoselectively through a three-step reaction sequence. This sequence consists of quantitative yielding allyl bond isomerisation, to produce vinyl ethers that can then undergo N-iodosuccinimide mediated tethering of the desired glycosyl acceptor, and subsequent intramolecular glycosylation, to yield either alpha-glucosides or beta-mannosides accordingly. Although attempted one-pot tethering and glycosylation is hampered by competitive intermolecular reaction with excess glycosyl acceptor, this problem can be simply overcome by the use of excess glycosyl donor. Allyl mediated IAD is a widely applicable practical alternative to other IAD approaches for the synthesis of beta-mannosides, that is equally applicable for alpha-gluco linkages. It is advantageous in terms of both simplicity of application and yield, and in addition has no requirement for cyclic 4,6-protection of the glycosyl donor.