Vinylsulfonium salts as efficient annulation reagents for the synthesis of heterocycles

• Main Author: Matlock, Johnathan Vincent
• Published: University of Bristol 2015
• Subjects: 615.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682179

This thesis is concerned with the use of vinylsulfonium salts as efficent annulation reagents for the synthesis of heterocycles. Firstly, a novel, efficient and versatile route for the formation of cyclopropane-fused hetereocycles from easily available starting materials has been developed, giving access to a range of functionalised 3-azabicyclo[3.1.0]hexanes in good yields and with high levels of diastereoselectivity. Treatment of easily prepared allylic amines, or aza-Morita-Baylis-Hillman adducts, with bromoethylsulfonium triflate, gave access to 3-azabicyclo[3.1.0]hexanes with both α,β-substitution (45 -63%, >20:1 dr) and a,y-substitution patterns (43-76%, up to >20:1 dr), In comparison to previous methods, this protocol enables the synthesis of a more diverse range of substituted and functionalised [3.1.0] scaffolds with very high diastereoselectivity. There is considerable interest in exploring this class of bioactive compounds, which should now be enabled by the methodology described in this work. The synthesis of a new class of vinylsulfonium salts bearing α-substituents, in three steps from commercially available styrenes, has also been achieved. An investigation into the annulation properties of this new class of reagents has revealed similar properties to the original bromoethylsulfonium triflate. Application of these a-substituted vinylsulfonium salts in the epoxyannulation of the easily prepared p-amino ketones, gave a range of 6-oxa-3-azabicyclo[3 .1.0]hexanes in moderate to good yields (41-83%) and with high levels of diastereocontrol (>20: 1 dr). Cyclopropanation of allylic ammes with a-substituted vinylsulfonium salts also gave 3-azabicyclo[3 .1.0]hexanes in moderate to good yields (45 -72%) and with high levels of diastereocontrol (>20: 1 dr). It is envisaged that this new class of reagents will further expand the scope of vinylsulfonium salt methodology, leading to further applications in both pharmaceutical and academic research.