Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay

Antonio Feula,Ferenc Müller,Louise Male,Mariwan A Hama Salih,John S Fossey,Mandeep Sangha,Ronald Ebanks,Rama Byravan,Sundeep S Dhillon,Wei-Ping Deng,Istvan Magyary,Neil Spencer

doi:10.1039/c3ob41007b

Abstract

Room temperature iodocyclisation of homoallylamines stereoselectively delivers functionalised 2-(iodomethyl)azetidine derivatives in high yield. Increasing reaction temperature from 20 °C to 50 °C switches the reaction outcome to realise the stereoselective formation of functionalised 3-iodopyrrolidine derivatives. It was shown that these pyrrolidines are formed via thermal isomerisation of the aforementioned azetidines. Primary and secondary amines could be reacted with iodomethyl azetidine derivatives to deliver stable methylamino azetidine derivatives. With subtle changes to the reaction sequences homoallyl amines could be stereoselectively converted to either cis- or trans-substituted 3-amino pyrrolidine derivatives at will. The stereochemical divergent synthesis of cis and trans substituted pyrrolidines supports an ion part, aziridinium, isomerisation pathway for azetidine to pyrrolidine isomerisation. Six azetidine derivatives were probed in a zebrafish embryo developmental assay to detect potential biological effects through the analysis of morphology and motility behaviour phenotypes. The range of effects across the probed molecules demonstrates the suitability of this assay for screening azetidine derivatives. One of the probed molecules, rac-(((cis)-1-benzyl-4-phenylazetidin-2-yl)methyl)piperidine, exhibited particularly interesting effects in the developmental assay presenting with hypopigmentation and reduced circulation amongst others. This shows that the zebrafish embryo provides a fast, sensitive and effective way to screen new compounds and in the future in combination with existing in vivo and in vitro assays it will become an integral part in drug discovery and development.

Highlights

Four and five membered saturated nitrogen containing heterocycles, azetidines and pyrrolidines respectively, are important
A synthetically versatile protocol for the stereospecific cyclisation of homoallyl amine derivatives delivered cisazetidine and cis or trans pyrrolidine derivatives. It was the subtle change of temperature and reaction sequence in this iodine and base mediated cyclisation and subsequent halide displacement that gave selective access to these three groups of compound
A zebrafish embryo developmental morphology assay was demonstrated as a useful tool in assessing the biological activity of a sample of azetidine derivatives and a compound bearing an azetidine and a piperidine to elicit morphological responses across the panel of indicators of potential activity in a variety of settings

Summary

Introduction

Four and five membered saturated nitrogen containing heterocycles, azetidines and pyrrolidines respectively, are important. Having established the general synthetic protocol for the synthesis of 2,4-cis-azetidines from homoallyl amines, i.e. treatment with iodine and sodium hydrogen carbonate in acetonitrile at room temperature,[11] the effect of varying the base was probed.

Results

Conclusion