Strategic Uses of Cyclic Sulfonamides in the Synthesis of N-Heterocycles

This thesis is divided into four main parts with the main focus being the synthesis and reductive cleavage of cyclic sulfonamides towards the construction of N-heterocycles. Chapter 1 begins with an introduction, covering the aforementioned topics and later the synthesis and reductive cleavage of cyclic sulfonamide 10, is described. Firstly, we found that the synthetic strategy for the generation of 10 was efficient and robust, giving near identical results to previous reports by our group (Scheme I). However, the low-valent titanium-mediated (LVT) sulfonyl group excision was unpredictable, and the yields obtained for the ultimate compound 11 were not comparable to literature values, 20% yield over two steps. Secondly, one of the main goals of this project was to investigate a novel cyclic sulfonamide-based route towards (±)-crinane 149 and (–)-aphanorphine 150. The key steps in the total synthesis 149 (Scheme II) were a regio- and diastereoselective intramolecular Heck reaction (IHR) which constructed the quaternary all-carbon centre in compound 192, an LVT-mediated sulfonyl group extrusion and finally, a Pictet-Spengler reaction generated the masked hexahydrobenzazepine ring. Details of this work are described in Chapter 2. During this proposed synthesis of (–)-aphanorphine 150 we strategically designed a dihydropyrrole substrate, from L-methionine, that would also undergo a regio- and diastereoselective IHR to afford a key cyclic sulfonamide intermediate of type 308 (Scheme III), following hydrogenation of the resultant olefin. The LVT-mediated sulfonyl group removal of 308 largely resulted in a complex mixture and alcohol 317 was isolated in low yield after N-protection. Details of this synthetic route and strategies towards the total synthesis of 150 are outlined in Chapter 3. Lastly, in Chapter 4, we describe the Mg/MeOH-mediated reductive cleavage of a range of pyrrolidine-, pyrrole- and indole-based benzo-fused cyclic sulfonamides. In some cases, this protocol is a complementary way to reductively cleave the N-S and C-S bonds, providing an efficient, convenient and safer alternative to Birch-type reaction conditions that have been used by our group. Additionally, the use of CD3OD allowed for the regioselective incorporation of deuterium in place of the C-S bond, following reductive cleavage (Scheme IV).