Dearg S. Brown

Substitution reactions of 2-benzenesulphonyl cyclic ethers with carbon nucleophiles

Abstract Direct substitution of 2-benzenesulphonyl cyclic ethers was studied using a variety of carbon nucleophiles. These nucleophiles included organozinc reagents (derived from aryl, vinyl and alkynyl Grignard reagents) or silyl enol ethers, silyl ketene acetals, allylsilanes and trimethylsilylcyanide in the presence of aluminum chloride. A general selectivity for the formation of the trans-product was observed using 6-subsitituted sulphones.

CHIRAL ALUMINIUM COMPLEXES AS PHOSPHO-TRANSFER CATALYSTS

Abstract Readily accessible, chiral complexes of aluminium are effective and enantioselective catalysts for the phospho-aldol reaction under aerobic conditions.

a palladium catalysed cascade cyclisation-friedel-crafts alkylation approach to angularly fused ring systems

Abstract Pd(0) catalysed bis- and tris-cyclisation reactions involving aryl-or vinyl-iodides and terminating in Tonnai Friedel-Crafts alkylation of aryl and heteroaryl rings occur regio- and stereo-specifically in good yield.

Substitution reactions of 2-phenylsulphonyl-piperidines and -pyrrolidines with carbon nucleophiles : synthesis of the pyrrolidine alkaloids norruspoline and ruspolinone

Abstract Several 2-phenylsulphonyl-piperidines and -pyrrolidines were prepared from the corresponding N-acyl aminals by treatment with benzenesulphinic acid. On reaction with various carbon nucleophiles these sulphones gave good yields of substitution products. Typical nucleophiles used in these studies were organometallic reagents derived from Grignard reagents and zinc halide together with silyl enol ethers, silyl ketene acetals, allylsilanes and trimethylsilyl cyanide in the presence of a Lewis acid. These methods were employed in the synthesis of two natural product alkaloids; Norruspoline (38) and Ruspolinone (40).

Use of 2-phenylsulphonyl cyclic ethers in the preparation of tetrahydropyran and tetrahydrofuran acetals and in some glycosidation reactions

Abstract 2-Phenylsulphonyl cyclic ethers undergo facile displacement of the sulphonyl group by alcohols, in the presence of magnesium bromide etherate and sodium bicarbonate in tetrahydrofuran, to give goodyields of the corresponding acetals.

Preparation of cyclic ether acetals from 2-benzenesulphonylderivatives: a new mild glycosidation procedure

Abstract Several alcohols ranging from hindered to those containing chemicallysensitive groups react with 2-benzenesulphonyl cyclic ethers in the presence of magnesium bromide etherate and sodium bicarbonate to give good yields of the corresponding acetals.

Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules

A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.

Direct substitution of 2-benzenesulphonyl cyclic ethers using organozinc reagents

Abstract 2-Benzenesulphonyl cyclic ethers are converted in good yield at roomtemperature to the 2-aryl-, 2-alkenyl- or 2-alkynyl product by treatment with the corresponding organozinc species.

Palladium catalysed cyclisation- intermolecular cyclopropanation versus cyclisation Friedel- Crafts alkylation with olefin insertion

Abstract Palladium catalysed cascade processes involving formation of two new rings and three new bonds with incorporation of norbornene are described. Factors influencing 3- versus 5- membered rings are identified.

Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis.