Heteroatom-substituted bicyclo[1.1.1]pentanes

Thesis

The theme of this thesis is to explore novel methodologies to access useful heteroatom-substituted bicyclo[1.1.1]pentane (BCP) scaffolds. BCPs are utilised as non-classical bioisosteres and as a metabolically stable spacer unit in their own right within pharmaceutical and agrochemical industries, they have also found application in materials chemistry.

Firstly, we investigated the addition of nitrogen-centred radicals across the strained central bond of [1.1.1]propellane as an efficient entry to iodo-bicyclo[1.1.1]pentylamines (BCPAs). In an atom-transfer radical addition (ATRA) process, we demonstrated fragmentation of α-iodoaziridines for the formal addition of N,I across [1.1.1]propellane to give BCPAs. The developed methodology demonstrates good functional group tolerance and applicability to pharmaceutical analogues.

Having discovered that BCPA iodides were significantly more challenging to functionalise than carbon-substituted BCPs, due to expulsion of the amine component from anionic BCPA intermediates, the development of a novel C–C bond formation tolerant of heteroatom-substituted BCP halides was required. Through investigation into the use of photocatalysis as a means to generate BCPA radical intermediates, we demonstrated that the resident iodide of BCP(A) iodide compounds could be functionalised through a photocatalysed silyl-mediated Giese reaction. This transformation enables access to challenging and desirable N,C-disubstituted BCPAs, for example α-amino acid analogues. In combination, these two methodologies contribute a significant advancement to the field and provide access to aniline and N-t-butyl bioisosteres.

Following a serendipitous result from the synthesis of BCPA iodides, we discovered that sulfonyl halides, generated in situ from readily accessible sulfinate salts, add rapidly to [1.1.1]propellane under mild conditions and in exceptional yields. This methodology represents the first synthesis of sulfonyl BCP iodides and bromides.

Authors: Pickford, H

• DOI: 10.5287/ora-gjr7rdbz9
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Bioisosteres; Atom transfer radical addition; [1.1.1]propellane; Photochemistry; Sulfonyl halide; Bicyclo[1.1.1]pentane; Giese reaction; Nitrogen Radical
• Subjects: Photochemistry; Organic photochemistry; Chemistry, Organic; Synthesis; Free radicals (Chemistry); Catalysis; Pharmaceutical chemistry