Development of An Asymmetric Radical Cyclisation and Application in the Synthesis of Nakadomarin A

Lead Research Organisation: University of Nottingham
Department Name: Sch of Chemistry

Abstract

The manzamine-related natural product Nakadomarin A was isolated from an Amphimedon sponge sp. (SS-264), and its extraordinary structure was determined by extensive NMR and mass spectral studies and published in 1997. The structure has a remarkable and unprecedented 8/5/5/5/15/6 hexacyclic framework with three contiguous stereogenic centres including one quaternary centre, and, unusually for a natural product, and uniquely for one of the manzamine alkaloids, a furan. It was found to exhibit cytotoxicity against murine lymphoma L1210 cells (IC50 1.3 ug/mL), inhibitory activity against cyclin dependent kinase 4 (IC50 9.9 ug/mL), and antimicrobial activity against a fungus and a Gram-positive bacterium. Furthermore, there is limited availability of this fascinating compound from Nature - just 6 mg were isolated from 1 Kg of sponge. In this project we will develop a highly innovative strategy for the formation of this molecule by developing a highly stereoselective radical cyclisation methodology and using the versatile and highly effective stereodirecting nature of the sulfinyl amine group to direct conjugate addition, alkylation and radical cyclisation. This bespoke methodology will also be fully generalised such that an outstanding and simple method for the formation of chiral cyclic amines will be available to the wider synthetic community.

Publications

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Magnus P (2010) A Versatile Chiral Pyrrolidine Aldehyde Building-Block for Synthesis and Formal Synthesis of ent-Nakadomarin A in Synlett

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Procopiou G (2013) Cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane. in Organic letters

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Rochette EM (2013) Highly diastereoselective radical cyclisations of chiral sulfinimines. in Chemical communications (Cambridge, England)

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Souto JA (2014) Isolation of stable non cyclic 1,2-disulfoxides. Revisiting the thermolysis of S-aryl sulfinimines. in Chemical communications (Cambridge, England)

 
Description The project developed a novel asymmetric radical cyclisation, using the chiral sulfinimine group to direct stereo control in radical cyclisation processes. Furthermore a number of potential synthetic routes for the synthesis of nakadomarin were investigated, which whilst this ultimately did not lead to a total synthesis of this natural product, a formal synthesis was achieved, and a range of novel transformations were developed, leading to potential new avenues for research into the chemistry of sulfinimines, and some highly interesting routes to novel chemical scaffolds for early-stage drug discovery.
Exploitation Route The radical cyclisation and a range of other methods developed in the project will find use in the pharmaceutical sector for making chemical scaffolds for screening collections The novel chemical scaffolds generated in the project will be exploited in the IMI European Lead Factory project for early stage drug discovery.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology