Stephen J. Shuttleworth

The preparation and first application of a polymer-supported "Evans" oxazolidinone

Abstract The preparation of a polymer-supported “Evans” oxazolidinone is described. and its use as a chiral auxiliary is demonstrated by the synthesis of a chiral α-alkyl carboxylic acid (e.e. 96%).

Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.

A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

Parallel synthesis of isatin-based serine protease inhibitors

The synthesis of N-functionalised isatins using parallel, solution synthesis is described. Functionalised polymers were employed as stoichiometric and catalytic reagents as well as purification media in the exercise, and the derivatives were screened against a panel of serine proteases; high percentage inhibition was observed in several cases.

Chapter 4 Applications of chiral sulfoxides as stereocontrol elements in organic synthesis

Publisher Summary This chapter discusses the applications of chiral sulfoxides as stereocontrol elements in organic synthesis. The chapter highlights the relative ease of introduction of the sulfoxide moiety into the desired substrate, the ability of the sulfoxide group to control—predictably—the stereochemical outcome of a wide range of reaction types and the facile removal of the sulfoxide moiety to yield the desired chiral products without the loss of stereochemical integrity. The applications described outline the effectiveness of the chiral sulfoxide moiety as a stereocontrol element and highlight the ready removal of the sulfoxide group after its contribution to the synthetic scheme. In all cases, the sense of stereochemical induction can be rationalized and predicted on the basis of steric, stereoelectronic, and/or chelation control factors. The sulfoxide group is incorporated into the substrate structure, using established methods. In most cases, the sulfinyl group can be removed after its contribution to the synthetic scheme without loss of enantiomeric purity in the desired product. In most cases, the sense of stereoselection observed can be predicted and rationalized on the basis of steric, stereoelectronic, and/or helation control mechanisms.

Design and synthesis of protein superfamily-targeted chemical libraries for lead identification and optimization.

This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.

Synthesis of aryl ethers from aminoalcohols using polymer-supported triphenylphosphine

Abstract Optimum conditions for the preparation of aryl–alkyl ethers from N-protected aminoalcohols using polymer-supported triphenylphosphine have been developed. In contrast to previous literature reports, it was discovered that the progress of this reaction is greatly improved when a tertiary amine base is employed, along with minor modifications being made to the order of reagent addition.

Convenient preparation of aryl ether derivatives using a sequence of functionalized polymers

A four-step synthesis to aryl ether derivatives, three of which utilize polymer-supported reagents, has been developed. Supported triphenylphosphine was successfully utilized in two distinct synthetic processes in the first step, whilst supported base and ionic and covalent scavengers were employed to complete the synthesis and purification of the target compounds.

Synthesis and purification of 3-N-acylaminopyrazolinones using a sequence of functionalized polymers

A parallel synthesis route to 3-acylaminopyrazolinones using a sequence of functionalized polymers has been developed. The polymers were utilized as both stoichiometric reagents and purification agents to allow for the clean formation of the desired target compounds.

Pictet–Spengler synthesis of tetrahydro-β-carbolines using vinylsulfonylmethyl resin

Abstract A novel, solid phase Pictet–Spengler synthesis has been developed using vinylsulfonylmethyl resin. A library of 800 structurally diverse tetrahydro-β-carbolines was prepared in a four-step sequence starting from tryptamines. The final resin cleavage step enabled the introduction of a basic tertiary amine in the six-membered heterocyclic ring.