A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions

Abstract

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and mediumsized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5−7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.

Expanding the scope of the successive ring expansion strategy for macrocycle and medium-sized ring synthesis: unreactive and reactive lactams

“…1 New methods to synthesise large rings are therefore of value, especially those that can be performed on scale and avoid the problems typically associated with end-to-end macrocyclisation reactions, 2,3 most notably competing intermolecular coupling. Ring expansion reactions 4,5 are important in this regard, as they allow macrocycles and medium-sized rings to be prepared without the need to perform a discrete end-to-end macrocyclisation step; in well-designed cases, large ring products can be obtained without resorting to high-dilution conditions, via rearrangements that operate solely via ‘normal-sized ring’ (5–7-membered) cyclisation reactions. 4 e…”