Applications of Hypervalent Iodine Reagents in Organic Synthesis

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


Previous work in the Donohoe group has led to the stereospecific homo- and hetero-dimerisation of styrenes to yield all-trans cyclobutanes in a formal "[2+2]" reaction.1 The ability to synthesise tri- and tetra-substituted cyclobutanes by both homo- and heterodimerisation under mild reaction conditions demonstrates the advantages of our methodology over those previously reported in the literature. This project aims to broaden the scope of the methodology to facilitate addition of a broader range of alkene partners, diazo compounds and cyclopropanes. These methodologies, once optimised, will lead to the synthesis of biologically active natural products.
This project falls within the EPSRC Physical Sciences research area, specifically within the theme of Synthetic Organic Chemistry.
A novel hypervalent iodine-promoted approach to cyclobutanes has recently been reported by the Donohoe group.1 Use of 5 mol% (diacetoxyiodo)benzene (PIDA) in hexafluoroisopropanol (HFIP) facilitates the dimerisation of electron rich styrenes e.g. 1 in good to excellent yields as a single (all-trans) diastereoisomer 3 (Scheme 1). Furthermore, hetero-dimerisation reactions with both electron rich and electron deficient styrenes have also been achieved setting an exciting precedent for a versatile route towards cyclobutane based compounds. This work will focus on expanding
the scope of this formal "[2+2]" cycloaddition reaction and lead to the development of new related synthetic methodologies. Currently, compounds featuring a cyclobutane moiety make up a tiny fraction of pharmaceutical libraries. As a consequence of this GlaxoSmithKline is part funding this project through a CASE Award. This project will also be conducted in collaboration with specialists in both electrochemical4 and computational5 techniques to form a holistic approach towards understanding this novel mode of chemical reactivity.
By exploring the use of alkenes featuring both an electron donating and an electron withdrawing substituent, we hope to expand the scope of partner alkenes beyond the class of styrenes currently used. Variation of the heteroatom X to nitrogen would facilitate access to unnatural cyclobutane amino acids, with potentially interesting biological activities.
This project will investigate diazo compounds as potential partners in this formal "[2+2]" cycloaddition reaction (Scheme 3). The
diazocyclobutanes produced will have important applications in drug discovery programmes, and we aim to cleave the ring e.g. using Zn/H+ to yield the syn-diamine 9. Overall this represents a metal free deamination and is likely to be of great utility in organic synthesis.
It has been postulated that the radical cation produced from the one electron oxidation of an electron rich styrene may react with
cyclopropanes to yield substituted cyclopentanes. Alternatively, it may be possible to perform a one electron oxidation of an electron
rich cyclopropane and react it with alkene partners.6,7 This project will investigate a broad range of cyclopropane and styrene
substrates with varying electron density and steric hindrance. The development of successful conditions would lead to a mode of
reactivity without precedent in the literature.
There are in excess of 1,500 natural products containing a cyclobutane core and many others containing related structures. Following further development of this methodology we will look towards the synthesis of biologically active natural products.


10 25 50
publication icon
Colomer I (2017) Hexafluoroisopropanol as a highly versatile solvent in Nature Reviews Chemistry

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509711/1 01/10/2016 30/09/2021
1809808 Studentship EP/N509711/1 01/10/2016 31/03/2020 Maxwell Haughey
Description New methods have been developed for the synthesis of a complex family of natural products through model studies. The total synthesis of these natural products will provide confirmation of their structure and offer an exciting opportunity to investigate their biological activity.
Exploitation Route The total synthesis of these natural products offer an exciting opportunity to investigate their biological activity.
Sectors Chemicals,Education,Healthcare,Pharmaceuticals and Medical Biotechnology,Other