Transition metal-free amino-cyclization for the synthesis of saturated azaheterocycles

• Main Author: Kaga, Atsushi
• Other Authors: Chiba Shunsuke
• Format: Theses and Dissertations
• Language: English
• Published: 2018
• Subjects: DRNTU::Science::Chemistry::Organic chemistry::Organic synthesis; DRNTU::Science::Chemistry::Organic chemistry::Heterocyclic compounds
• Online Access: https://hdl.handle.net/10356/89438; http://hdl.handle.net/10220/47114
• Institution: Nanyang Technological University

This thesis focused on the development of transition metal-free amino-cyclization towards the synthesis of saturated azaheterocycles and benzannulated saturated azaheterocycles that are ubiquitous scaffolds in biologically active natural products as well as pharmaceuticals. Part 1 of the thesis described alkali metal-mediated amino-cyclization for the synthesis of saturated azaheterocycles and benzannulated saturated azaheterocycles. In Chapter 2, t-BuOK-mediated hydroamination of alkenyl hydrazones was discussed. Modification of the substituents on the hydrazones enabled diastereo-divergent synthesis of 2,5-disubstituted pyrrolidines whereas a unique 2,6-trans selectivity was observed in piperidine formation, which were rationalized by experiments and DFT computation. Chapter 3 described nucleophilic amination of methoxy arenes by means of sodium hydride in the presence of lithium iodide. This protocol served as an efficient route to benzo-fused saturated azaheterocycles as well as aryl amines via intermolecular amination. Mechanistic studies showed that the reaction proceeded through an unprecedented concerted nucleophilic aromatic substitution. In part 2 of the thesis, the author presented total synthesis of (±)-fasicularin having the DNA alkylation ability. The synthesis was stemmed from NBS-mediated spirocyclizing bromoamination of alkenyl azidoester to construct key azaspirocycle. The resulting azaspirocycle was converted to (±)-fasicularin in 14 steps including stereoselective installation of desired hexyl side chain at C(2). Chapter 6 disclosed the experimental and computational data for Chapter 2, 3, and 5.