Rearrangement-driven synthesis of nitrogen heterocycles, cyclobutanes and spirocycles

Abstract

Pyridines, dihydropyridines and piperidines are important components in bioactive compounds. Cyclobutanes and spirocycles are also attractive motifs in contemporary drug design due to their rigidity and well-defined shape. This thesis outlines investigations into novel methods of achieving sp2-sp3 cross-coupling to pyridines and achieving the synthesis of cyclobutyl boronic esters and dihydropyridine spirocycles.

First, investigations into novel methods of achieving stereospecific sp2-sp3 cross-couplings to pyridines are discussed. A stereoinvertive cross-coupling at the C4-position of the pyridine ring was achieved by addition of a chiral boron-ate nucleophile to an N-acylpyridinium electrophile followed by rearomatisation of the dihydropyridine intermediate to the parent pyridine. A stereoretentive C2 cross-coupling of alpha-magnesiated pyridine N-oxides with boronic esters was also attempted, with the anticipation that electrophilic activation of the N-oxide moiety of the boron-ate intermediate would trigger a 1,2-metallate rearrangement and subsequent elimination/rearomatisation to give the cross-coupled pyridine.

Secondly, contributions towards exploring the scope of a diastereoselective synthesis of cyclobutyl boronic esters are described. This was achieved by an electrophile-triggered ring expansion and 1,2-metallate rearrangement of vinylcyclopropyl boron-ate complexes generated from novel vinylcyclopropyl boronic esters. Electrophilic activation of the alkene double bond forms a carbocation beta- to the boron-ate moiety, triggering concomitant expansion of the cyclopropane ring to a cyclobutane and 1,2-metallate rearrangement from boron to give the cyclobutyl boronic ester product with a high degree of diasteroselectivity. Attempts to extend this methodology to the synthesis of dihydropyridine spirocycles are also briefly discussed.

Finally, the synthesis of dihydropyridine spirocycles was achieved by an electrophile-induced dearomative semi-pinacol rearrangement of hydroxycyclobutylpyridines. This reaction was successfully applied to a variety of acylating agents and substituted hydroxycycloalkylpyridine species.

Date of Award	27 Sept 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Varinder K Aggarwal (Supervisor)