Ian W. James

Synthesis of Chiral Building Blocks for Use in Drug Discovery

In the past decade there has been a significant growth in the sales of pharmaceutical drugs worldwide, but more importantly there has been a dramatic growth in the sales of single enantiomer drugs. The pharmaceutical industry has a rising demand for chiral intermediates and research reagents because of the continuing imperative to improve drug efficacy. This in turn impacts on researchers involved in preclinical discovery work. Besides traditional chiral pool and resolution of racemates as sources of chiral building blocks, many new synthetic methods including a great variety of catalytic reactions have been developed which facilitate the production of complex chiral drug candidates for clinical trials. The most ambitious technique is to synthesise homochiral compounds from non-chiral starting materials using chiral metal catalysts and related chemistry. Examples of the synthesis of chiral building blocks from achiral materials utilizing asymmetric hydrogenation and asymmetric epoxidation are presented.

Incorporation of 2-hydroxy-4-methoxybenzyl protection during peptide synthesis via reductive alkylation on the solid phase

Abstract A method has been developed for the synthesis of Hmb protected amino acid residues via reductive alkylation of 2-hydroxy-4-methoxybenzaldehyde with resin bound amino acids/peptides. The methodology potentially allows incorporation of Hmb protected amino acids at any point in the synthesis of difficult peptides. Synthesis of ACP (65–74) illustrates the method.

A review of solid-phase organic synthesis on synphase lanterns and synphase crowns

Publisher Summary This chapter reviews the solid-phase organic synthesis of various heterocycles on SynPhase Lanterns and SynPhase Crowns. Some of these heterocycles include benzodiazepines, purines, quinazolines, oxazoles, carbohydrates, and cyclic peptides. The solid-phase synthesis is a well-established tool in the pharmaceutical industry for the generation of large sets of small molecule compounds for lead finding and optimization. Mimotopes has been involved in the development, use, and commercialization of radiation-grafted polymer surfaces for multiple parallel syntheses. The graft polymer devices manufactured and sold by Mimotopes (SynPhase Crowns, SynPhase Lanterns) are the only current commercial products of this type. Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. These compounds were prepared on the Mimotopes pins that were grafted with polyacrylic acid. In the case of quinazolines, polystyrene grafted SynPhase Lanterns were used to synthesize a diverse quinazoline-2 thioxo-4 one library. Lanterns functionalized with long-chain, HMP (hydroxymethylphenoxyvaleric amide) linker were coupled with nitrophenols by the action of DIC/HOAt/DMAP to give nitrobenzenes.

Synthesis of hydroxamic acids using SynPhase™ crowns: Development of the hydroxylamine trityl linker

The synthesis of peptide and small molecule hydroxamic acids utilising SynPhase™ crowns is demonstrated. A hydroxylamine trityl linker is generated from chlorotrityl derivatised Synphase™ crowns by reaction with N-hydroxyphthalimide followed by subsequent deprotection. The loading of hydroxylamine crowns is quantified spectrophotometrically by measuring phthalhydrazide absorbance at 346 nm.

Chiral building blocks: enantioselective syntheses of benzyloxymethyl phenyl propionic acids.

The synthesis of (2S)-2-benzyloxymethyl-3-(2-fluoro-4-methoxyphenyl)- propionic acid, (2S)-2-benzyloxymethyl-3-(2-fluoro-4-methylphenyl)propionic acid and (2S)-2-benzyl-oxymethyl-3-(2,4-dimethylphenyl)propionic acid has been achieved by TiCl4 mediated alkylation of the corresponding (4R)-4-benzyl-3-[3-(2-fluoro-4-methoxyphenyl-, 2-fluoro-4-methylphenyl-, 2,4- dimethylphenyl-)propionyl]-2-oxazolidinones, followed by hydrolysis of the chiral auxiliary. The stereochemistry of the alkylation reaction was confirmed by an X-ray crystal structure of (4R)-4-benzyl-3-[(2S)-2-benzyloxymethyl-3-(2- fluoro-4-methylphenyl)propionyl]-2-oxazolidinone.