Stephen P. Watson

A convenient procedure for the solution phase preparation of 2-aminothiazole combinatorial libraries

Abstract A convenient procedure for the solution phase preparation of 2-aminothiazole combinatorial libraries is described. The library preparation is simple, practical, and effective, generating compounds based around a known pharmacophore in high yield and purity. Furthermore, the procedure tolerates a diverse range of functionality in its substrates and is notable in allowing the preparation of compounds containing both free acids and bases without recourse to protection.

The brucine N-oxide-promoted asymmetric Pauson–Khand reaction

The brucine N-oxide-mediated asymmetric Pauson–Khand reaction has been further investigated. It was found that the best levels of enantioselection were obtained with substituted propargylic alcohol complexes. The studies also revealed that when acetone or 1,2-dimethoxyethane is used as the reaction solvent, enhanced levels of enantioselectivity, up to an enantiomeric ratio of 11:89, are achieved.

A photolabile carbamate based dual linker analytical construct for facile monitoring of solid phase chemistry: ‘TLC’ for solid phase?

Abstract A dual linker analytical construct based on a photolabile carbamate is described. Photochemical cleavage from the solid support can be effected to afford an analytical fragment, containing the substrate, which is sensitised to electrospray mass spectrometry. We believe this simple construct now renders all substrates visible to high throughput mass specroscopic analysis.

Tetrazole NK1 receptor antagonists: The identification of an exceptionally potent orally active antiemetic compound

Abstract The medicinal chemistry strategy is described which led to the identification of GR205171, an orally active non-peptide neurokinin-1 receptor antagonist that is the most potent broad-spectrum antiemetic agent reported to date.

SOLID PHASE SYNTHESIS OF 5-AMINOPYRAZOLES AND DERIVATIVES

Abstract The development of a novel solid phase synthesis of some 5-aminopyrazoles and derivatives is described. Reaction of hydrazines with solid supported β-keto-nitrile (1) affords 5-aminopyrazoles (2) the amino group of which is readily acylated or sulphonylated. Generation of the solid supported β-keto-nitrile (1) is non trivial and represents a key step in the overall synthesis.

Preparation and reaction of desymmetrised cobalt alkyne complexes

Prochiral alkyne hexacarbonyl dicobalt complexes are desymmetrised directly with brucine N-oxide in the presence of a phosphine or phosphite ligand to produce the corresponding phosphorus-containing pentacarbonyl complex with appreciable enantiomeric excess. In Pauson–Khand reactions, it is found that the enantiomeric integrity of the desymmetrised complex is conserved in the cyclopentenone product. Moreover, the major enantiomer obtained in these reactions is opposite to that from a direct brucine N-oxide promoted Pauson–Khand reaction, allowing the preparation of either enantiomeric cyclopentenone in enriched form from a single source of chirality.

Rapid reaction scanning of solid phase chemistry using resins incocorporating analytical constructs

Abstract Two analytical constructs, based on orthogonally cleavable linkers, are reported which facilitate the mass spectral analysis of solid phase chemistry. The chemical compatibility and orthogonality of the linkers were established in a parallel reaction study using contructs prepared specifically for the purpose.

Solid phase synthesis of 5-aminopyrazoles and derivatives part II

Abstract A new synthesis of 5-amino pyrazoles on a solid support via in situ generation of a resin bound aldehyde nitrile is described. The synthesis is more versatile and efficient than the method that we had previously described and the new route yields complementary structures.

A novel palladium(0) catalysed tandem 1,3-allyl shift and Heck arylation

Abstract On treatment with Pd(PPh 3 ) 4 allyl vinyl ether (1) undergoes a Pd(0) catalysed 1,3 oxygen to carbon allyl shift to afford α-allyl ketone (2). In the presence of both Pd(PPh 3 ) 4 and base the allyl vinyl ether undergoes a Pd(0) catalysed tandem 1,3 allyl shift and intramolecular Heck arylation to give the spiro indane (3). Mechanistic investigations suggest that the 1,3-allyl shift proceeds via a π-allyl palladium intermediate.

A Convenient Synthesis of 2-Butyl-4(5)-chloro-1H-imidazole-5(4)-carboxaldehyde

Abstract A Convenient Synthesis of 2-Butyl-4(5)-chloro-1H-imidazole-5(4)-carboxaldehyde, starting from 2-butyl imidazole, has been developed.