New lithiation methodologies to 2-substituted nitrogen heterocycles

Abstract

This thesis describes the development of methodologies for lithiation-trapping and lithiation-arylation of N-Boc heterocycles in the position α to nitrogen as well as in situ infra-red spectroscopic monitoring of lithiation reactions and the application of lithiation-arylation in total synthesis. Chapter 2 details the use of in situ infra-red spectroscopy to monitor the lithiation of N-Boc pyrrolidine, N-Boc piperidine, N-Boc homopiperidine, an N-Boc acetal piperidine, N-Boc-Nʹ-benzyl piperazine, N-Boc-Nʹ-i-Pr imidazolidine and an O-alkyl carbamate in diethyl ether using s-BuLi and the diamines TMEDA, (–)-sparteine, or the (+)-sparteine surrogate. Chapter 3 describes the expansion of a previously reported two-ligand catalytic lithiation-trapping procedure for N-Boc pyrrolidine, discussing the optimisation of catalytic lithiation conditions, the use of new bispidine-derived diamine ligands and examples of two-ligand catalytic lithiation-arylation of N-Boc pyrrolidine. The application of stoichiometric and catalytic lithiation-arylation of N-Boc pyrrolidine in total synthesis is presented in chapter 4. Lithiation-arylation is used to complete the shortest and most efficient synthesis of (S)-nicotine to date, as well as the shortest synthesis of SIB1508Y and to attempt the first asymmetric synthesis of (R)-dihydroshihunine. Additionally, a protocol for the lithiation-vinylation of N-Boc pyrrolidine is developed and used to carry out the first asymmetric synthesis of (R)-maackiamine. Chapter 5 details the development of a new diamine-free racemic lithiation procedure for the lithiation-trapping and lithiation-arylation of N-Boc pyrrolidine, N-Boc-Nʹ-i-Pr imidazolidine and N-Boc-Nʹ-benzyl piperazine. Additionally, diamine-free lithiations are monitored using in situ infra-red spectroscopy. In chapter 6, benzylic lithiation-trapping of N-Boc-2-phenyl pyrrolidine is described. Lithiation-trapping of rac-N-Boc-2-phenyl pyrrolidine is first discussed, followed by lithiation-trapping of enantioenriched (R)-N-Boc-2-phenyl pyrrolidine, giving access to products bearing enantioenriched quaternary stereocentres. The use of in situ infra-red spectroscopic monitoring was integral to the development of this methodology.