Novel ring expansion methods for the synthesis of functionalized macrocycles

Macrocycles, are a class of interesting compounds with extensive applications; most
notable is the increasing interest in their applications in drug discovery in recent years.
Despite constant efforts made to develop new chemistry to study macrocycles, making
them efficiently is still considered to be a major challenge for synthetic chemistry.

In this work, different synthetic methods for macrocycle synthesis are introduced, with
special emphasis on novel successive ring expansion reactions (SuRE) which has been
recently developed in York. Distinct from other macrocyclization methods, SuRE was
developed as two step ring expansion reactions based on intermolecular acylation,
followed by intramolecular cyclization/rearrangement reactions. Instead of going through
the a challenging macrocyclization steps, SuRE has achieved macrocyclization by
annulation of intramolecularly cyclized 5 or 6 membered rings onto the existing cyclic
compound, and utilizes thermodynamic driving forces to collapse the fused bicyclic
bridge, release ring strain and producing enlarged monocyclic compound. SuRE enables
macrocycles to be ‘grown’ from smaller rings, without ever performing a macrocyclization
step.

In this thesis, three sub-projects connected to the Unsworth’s SuRE research programme
are described. Following a short review of ring expansion reactions and introduction, first
the ring expansion and elaboration of benzosuberone derivatives as part of a successful
collaboration with the European Lead factory is described (Chapter 2). Then, focus shifts
to describing our efforts to prepare and expand novel medium sized ring scaffolds to
expand the scope of SuRE (chapter 3). Finally, we describe progress towards an ambitious
new ring expansion concept based on the pre-organization of long PEG side chains and
our attempts to promote ring expansion via their insertion into lactams.