Synthesis, properties and applications of all-cis-pentafluorocyclohexane 'Janus' ring building blocks

Abstract

Strategically fluorinated compounds such as the all-cis-pentafluorocyclohexane ‘Janus’ rings, the subject of this research, can have strong molecular dipole moments because the electronegative fluorines polarise the geminal hydrogens rendering them electropositive.
In Chapter 1, a general discussion of the dominant interactions associated with organofluorine compounds is given. This is followed by an examination of the variety of fluorination methods available. The role of fluorine in medicinal chemistry is explored including in positron emission tomography (PET). A summary of previous work from the St Andrews group provides the contextual basis on which the following chapters build.
Chapter 2 explores a recently reported Rh-catalysed hydrogenation reaction of fluoroarenes to access all-cis-fluorocyclohexanes in excellent diastereoselectivity. The scope of this reaction is expanded to generate novel cyclohexane products such as alcohol 2.47 and methyl ester 2.60. Derivatisation of these products has furnished a library of all-cis-pentafluorocyclohexane building blocks for further study. These include alkyl bromide 2.82, organoazide 2.83 and aldehyde 2.87.
In Chapter 3, the elaboration of these building blocks to higher order molecular structures is explored. Ugi 4-component reactions (Ugi-4CR) with aldehyde 2.87 provide combinatorial access to medicinally relevant bis-amides 3.20-3.27. The Ugi-4CR, optimised by microwave assistance, can be completed within 45 mins. Using an HPLC method the Log P of three of these Ugi products (3.23, 3.25 and 3.27) was measured and in each case the Log P value reduced relative to phenyl ring analogues. This finding suggests a potential application of the ‘Janus’ ring as an arene isostere in medicinal chemistry. Other methods of elaboration explored in Chapter 3 include amide coupling, Wittig and CuAAC ‘click’ reactions.
Chapter 4 reports the preparation of ‘Janus’ ring bearing novel amphiphiles, the long chain carboxylic acid 4.1 and alcohol 4.2 as well as analogous hydrocarbon reference compounds 4.4 and 4.5. A Langmuir isotherm study examined the influence of the ring system on phase behaviour at the air-water interface. Evidence is presented of molecular self-assembly for the long chain 4.1 and 4.2, unlike the classical behaviour observed for the hydrocarbon counterparts 4.4 and 4.5. This analysis is supported by a thorough examination of X-ray crystal structures and presents a platform for the further development of the ‘Janus’ ring motif for supramolecular chemistry.
Finally, Chapter 5 summarises the findings of the previous chapters and explores possible avenues for future work such as the development of a ‘pull-down’ assay using biotinylated affinity probes 5.1 and 5.2 to better understand interactions between the ‘Janus’ ring and proteins of interest.

Date of Award	15 Jun 2022
Original language	English
Awarding Institution	University of St Andrews
Supervisor	David O'Hagan (Supervisor)