ASYMMETRIC SYNTHESIS AND NATURAL PRODUCTS

Novel Terpenoid-Derived Chiral Ligands

This research has been developing methodology to generate novel chiral ligand libraries from inexpensive chiral natural products sources.

 

Parallel synthesis has generated various families of novel ligands, and initial catalyst activity screening has identified novel ligands which can catalyze an asymmetric C-C bond forming reaction in up to 95% enantiomeric selectivity.

Research workers contributing to this project: Jameel Chughtai and Philip Crewe.

New Synthons from Hindered Substrate KR

 

Several kinetic resolutions of varying effectiveness have been reported using Sharpless' asymemtric dihydroxylation chemistry. We have found that kinetic resolution of the alkenes 1 provides a route to novel chiral diols (3 or 4) in high optical purity. AD using (DHQ)2PHAL provides a single enantiomeric diol (ee>97%) at up to 40% conversion - only one of the eight possible enantiomers shown that could arise from this reaction is obtained! AD using (DHQD)2PHAL is also effective and using a double resolution strategy, this diol is also obtained optically pure.

This provides the most efficient kinetic resolution yet reported using the AD ligand series. NMR experiments on derivatives of these diols have allowed assignment of the diastereomeric structure of the diol, and an X-ray structure has been solved for the diol itself, confirming these stereochemical assignments.

Mycalamides

 

The Mycalamides  - isolated from rare marine sponges - show promising in vivo antiviral activity, and these structurally challenging natural products also show interesting anti-tumour properties, and potent inhibitors of both protein and DNA biosynthesis at nanomolar concentrations. They are also powerful immunosuppressive agents, with comparable efficacy to the clinical agent, cyclosporin A, rapamycin and FK506! This ranks the mycalamides amongst the most potent immunosuppressives discovered.

The powerful immunosuppressive activity of these agents and their novel mechanism of action makes them extremely exciting, both as potential biochemical tools and as potential therapeutic agents for post-transplant surgery therapy and for treatment of a variety of autoimmune conditions. To date, we have prepared a precursor to the right hand side ring system which allows quick entry to the relevant stereochemistry, and access to several types of novel analogues, and we have also made progress on a route to the left-hand side which promises to be significantly shorter than previous syntheses.

  Pumiliotoxins

The venomous skin secretions of Dendrobatid frogs from the Amazonian rain forests have proven a rich source of structurally complex bioactive alkaloids with a wide variety of potent biological activities, including potent neurotoxins such as histrionicotoxin and gephrotoxin. Alkaloids of the Pumiliotoxin family were first isolated more than twenty years ago from this source. Pumiliotoxin A and B are strong potentiators of cardiac activity, while some related natural products, differing only in side chain functionality or hydroxyl group protection, are mild cardiodepressants. These activities make these agents promising potential agents for therapy of heart dysfunction. The cardiac activities displayed by different Pumiliotoxins, indicates the importance of the side chain to the mechanism of action of different congeners. The nature of the binding sites of these agents on the voltage dependent ion channels with which they interact with is as yet uncertain.

 Approaches towards novel ring and side chain modifications, and the development of new methodology for the efficient construction of highly functionalized indolizidines are the objectives of this programme. We developed new methodology relevant to construction of side chain functionality (and novel side chain analogues), as well as preparing various precursors to the ring systems and ring analogues. Ultimately, novel analogues could be valuable tools for evaluating the mechanism of action of these agents and offer potential as heart dysfunction therapeutics.

© 2017-19 John Gardiner

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