The development of chemoselective processes is of utmost importance for the future of synthetic organic chemistry, and has been described as 'the single greatest obstacle to complex molecule synthesis'. Chemoselectivity is required to exploit the full potential of synthetic developments in organic chemistry, allowing for more efficient procedures and better route design. This thesis will describe the development of chemoselective processes across two cornerstone reactions in organic chemistry. Chapter one will describe the development of dual nucleophile/electrophile chemoselectivity in the Suzuki-Miyaura reaction. Chemoselectivity in this key crosscoupling reaction has previously only been achieved at either the nucleophile or the electrophile independently. Electrophile chemoselectivity is generally well defined and has been used extensively in both academic and industrial settings. Chemoselectivity of the nucleophilic component has been less well explored, and has only been achieved through three distinct approaches; protecting group chemistries, vicinal/geminal activation, and aryl/benzyl selectivity that is based upon activating Ag additives. Herein, we describe the use of media controlled boron speciation between aryl/vinyl BPins and BMIDAs to realize the first example of dual nucleophile/electrophile chemoselectivity. The method was exemplified through the synthesis of a range of diverse substrates and a BET bromodomain inhibitor. Chapter two will describe an investigation into the source of rate independent chemoselectivity in the CuAAC reaction. Chemoselectivity in the CuAAC reaction has chiefly been demonstrated through the use of either activated or deactivated azides, whereas alkyne chemoselectivity is less well developed. Recent work from the Watson and Burley groups described the use of aromatic ynamines to afford exquisite chemoselectivity over alkyl alkynes, allowing for sequential functionalization of multifunctional bisalkynes. Herein, we describe the development of a reactivity scale for alkynes in the CuAAC reaction and a kinetic investigation into the origin of selectivity when using ynamine substrates. A chelation-assisted change in the rate-determining step from Cu-acetylide formation to azide ligation/insertion allows for chemoselectivity over more reactive alkynes despite a slower overall rate. This was harnessed to develop an orthogonal ligation strategy from protected ynamine substrates.
|Date of Award||27 Oct 2017|
- University Of Strathclyde
|Supervisor||Allan Watson (Supervisor) & Craig Jamieson (Supervisor)|