Robert John Watson

An enantioselective synthesis of sulphonamide hydroxamic acids as matrix metalloproteinase inhibitors

A high yielding and enantioselective synthesis of α-substituted hydroxamic acids as inhibitors of matrix metalloproteinases is described.

Synthesis and structure–activity relationships of guanine analogues as phosphodiesterase 7 (PDE7) inhibitors

The synthesis of a novel series of guanine analogues is reported. The compounds have been assessed in vitro and some analogues have been found to be inhibitors of phosphodiesterase type 7 (PDE7).

A Simple and Efficient Procedure for the Preparation of Chiral 2-Oxazolidinones from α-Amino Acids

Abstract A modified procedure for the title transformation is described which avoids: (i) a potentially hazardous borane reduction step, and (ii) the intermediacy of water soluble amino alcohols.

A concise synthesis of the novel antibiotic aranorosin

Abstract A short synthesis of the novel antibiotic aranorosin is described which employs a novel hypervalent iodine-mediated oxidative hydroxylation of a tyrosinal derivative in the key step. A similar procedure was employed to prepare 6′-epiaranorosin, and hence establish the stereochemistry of the natural compound.

The total synthesis of the diepoxycyclohexanone antibiotic aranorosin and novel synthetic analogues

A short synthesis of the novel antibiotic aranorosin in chiral form is described which employs (i) a novel hypervalent iodine-mediated oxidative hydroxylation of a tyrosinal derivative and (ii) a stereocontrolled cis-bisepoxidation in the key steps. A similar procedure was employed to prepare 6′-epiaranorosin, and hence establish the stereochemistry of the natural compound, and to prepare novel aranorosin analogues. An organometallic route is described which gives desamidoaranorosin.

An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat

Abstract A considerably shortened synthesis of the broad spectrum matrix metalloproteinase (MMP) inhibitor marimastat has been achieved by a direct hydroxylamino ring opening of a key acetonide intermediate.

Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease

The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

Structure of a model for the aranorosin nucleus

The structure of a synthetic model system, 2-hydroxy-6,7;9,10-cis,cis-diepoxy-1-oxaspiro[4.5]decan-8-one, C 9 H 10 O 5 , for the spirocyclic headgroup of the natural product aranorosin has been determined and shown to possess the natural product stereochemistry. Two crystallographically independent molecules cocrystallize in a centrosymmetric space group. The syn arrangement of the diepoxides and the lactol O atom about the cyclohexanone ring has been confirmed in both molecules. The cyclohexanone ring adopts a boat conformation with the carbonyl O atom anti to the lactol O atom

Organometallic additions to protected quinone bis-epoxides and quinone monoacetals: synthesis of the aranorosin nucleus

The addition reactions of organometallic reagents to monoprotected quinone bis-epoxides 7 and quinone monoacetals 5 provide a route to the highly oxygenated cyclohexanols 2 and 3; the application of this methodology to the preparation of the aranorosin analogue 4 is described.