New directions towards the synthesis of bicyclo[1.1.1]pentane derivatives

Thesis

Bicyclo[1.1.1]pentanes have emerged as bioisosteres, used by medicinal chemists to replace 1,4-disubstituted arenes and improve the physicochemical properties of the drugs they synthesise. The existing methods to synthesise 1,3-disubstituted bicyclo- [1.1.1]pentane involve toxic reagents, hazardous chemistries and lengthy synthetic sequences. We present in this thesis a novel, modular way to access 1,3-disubstituted bicyclo[1.1.1]pentane as well as monosubstituted bicyclo[1.1.1]pentane (Figure 1). The first chapter presents a triethylborane-initiated atom transfer radical addition reaction of organohalides on tricyclo[1.1.1.0^1,3]pentane (1) to access in a rapid and efficient manner brominated and iodinated bicyclo[1.1.1]pentane (2). The reduction of the C–I bond of iodinated bicyclo[1.1.1]pentanes is presented in the second chapter. Tris(trimethylsilyl)silane was used as the reducing agent and triethylborane as the initiator, providing a less toxic alternative to tin hydride reductions and affording monosubstituted bicyclo[1.1.1]pentanes building blocks such as acids, amides, amines and amino acids (3). Nucleotides, peptides and drugs were successfully labelled with a bicyclo[1.1.1]pentane unit. The third chapter focusses on an iron-catalysed Kumada-Tamao-Corriu cross-coupling reaction of iodinated bicyclo[1.1.1]pentane to form arylated bicyclo[1.1.1]pentane (4). The reaction is particularly efficient with electron-rich organomagnesium reagents. A analogue to the drug Flurbiprofen was synthesised in excellent yield in just two steps from ethyl 2-iodopropionate and 1.

Authors: Caputo, D

• DOI: 10.5287/ora-xrx8z942z
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English