Loughborough University
Leicestershire, UK
LE11 3TU
+44 (0)1509 222222
Loughborough University

Centre for Innovative and Collaborative Construction Engineering

2011

Dr Joannah Towler

Thesis

The application of intramolecular n-acyliminium cyclisation strategies towards biologically active heterocycles

Project Title

The application of intramolecular n-acyliminium cyclisation strategies towards biologically active heterocycles

Company

Charnwood Molecular

Supervisors

Academic:
Dr Steven Allin
Dr Basu Saha

Industrial:
Dr M McKenzie
Prof P Page

Director of Research:
Professor Dino Bouchlaghem

Research Period

2005 - 2009

The application of intramolecular n-acyliminium cyclisation strategies towards biologically active heterocycles

Context/Background

High yielding and novel routes to naturally occurring chemical species and their man-made derivatives continue to attract attention due to the potent pharmacological activities of these compounds and therefore their potential as new drugs. For example the Erythrina natural products are common in tropical and subtropical regions and the alkaloids have been used in tribal medicine. Members of the Erythrina family display a range of potent biological activities. 3-Demethoxyerythratidinone was isolated in 1973 by Barton and co-workers, and despite being structurally one of the simplest of the erythrina class of alkaloid, an efficient route to this compound has only just been reported (by our own research group).

The main disadvantage of common lab. scale chemistries is their poor applicability to large scale manufacture, particularly when the molecules are promising in terms of activity in a biological arena.

Aims and Objectives

The specific aims and objectives of the project include:

(i) to develop a novel approach for the construction of important template systems;

(ii) to demonstrate our new and highly efficient chemistry by making targets of biological significance;

(iii) through an awareness of the reactions planned, to investigate process chemistry routes that allow the large scale preparation of these targets and intermediates, e.g. 20 litre scale.

We will investigate and develop high yielding and new synthetic routes to a wide range of important building blocks, intermediates, and final targets.

Routes will be chosen and investigated for the first time on large scale.

By completion of the programme, we anticipate, through collaboration with the sponsor, access to multi-kilo quantities of intermediates and final products of biological significance.

Method and Current Status

We have developed an efficient lab. scale (<1g) route to advanced heterocyclic targets, and have promising biological data on some compounds as potential anti-cancer agents. We now wish to pursue advanced studies in this arena, particularly addressing the question of production of larger amounts of new materials.

Benefits/Expected Outcomes

A significant benefit will be the development of new and high yielding synthetic routes to a wide range of important building blocks, intermediates, and final active targets.

On completion of the programme, we anticipate, through collaboration with the sponsor, access to multi-kilo quantities of intermediates and final products of biological significance.

Industry will benefit since the programme would provide new routes of access to targets of significance to the pharmaceutical and biotechnology industries.

Academia will benefit due to the availability of new methodology to apply to other challenging target systems.

Towler, J.M.R. ... et al. (2012). N-acyliminium cyclization as an approach for an asymmetric synthesis of the pyrrolo[2,1-a]benzazepine ring system. Synthetic Communications, 2010.
http://www.tandfonline.com/doi/abs/10.1080/00397911.2010.532900

Towler, J.M.R. ... et al. (2010). Enolate amination and derivatization of a pyrroloisoquinoline template: towards novel peptidomimetics. 66, 9538-9544.
doi:10.1016/j.tet.2010.10.012

Towler, J.M.R. ... et al. (2009). Facile asymmetric construction of a functionalized dodecahydrobenz[a]indolo[3,2-h]quinolizine template. 2009, 65 (49), 10230-10234.
https://dspace.lboro.ac.uk/2134/9052

Towler, J.M.R. ... et al. (2007). A new asymmetric synthesis of the anti-tumor alkaloid (R)-(+)-crispine, Journal of Organic Chemistry, 2007, 72 (23) 8972-897.
https://dspace.lboro.ac.uk/2134/3118

 

 

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+44 (0)1509 222623

The Centre Administrator
CICE
Loughborough University
Leicestershire
LE11 3TU

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