Ring‐Expansion Reactions in the Synthesis of Macrocycles and Medium‐Sized Rings

Abstract

Functionalised macrocycles and medium-sized rings have applications in a number of scientific fields, ranging from medicinal chemistry and supramolecular chemistry, to catalysis and nanotechnology. However, their value in these areas can be undermined by a simple, but important limitation: large ring systems are very often difficult to make. Traditional end-to-end cyclisation reactions of long linear precursors are typically unpredictable and impractical processes, mainly due to unfavourable enthalpic and entropic factors. Most published methods to make large rings focus on minimising the damage inflicted by performing the difficult cyclisation step; in contrast, ring-expansion reactions enable it to be avoided altogether. In this Review article, it is highlighted how "growing" rings from existing cyclic systems via ring expansion can expedite the efficient, practical and scalable synthesis of macrocycles and medium-sized rings.

Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams

“…One approach is to assemble macrocycles via ring expansion ( 5 → 2 , Scheme A) . “Growing” macrocycles in this way has a distinct advantage over most other approaches, in that rather than seeking to make the difficult macrocyclisation step easier, ring expansion enables it to be avoided altogether.…”

“…Importantly, the method works consistently well across a range of ring sizes, with 6–12‐membered lactams all undergoing ring expansion in high yield (78–90 %) by using acid chloride 10 a (Scheme B). In view of the known problems associated with making medium‐sized rings, the formation of 11 e and 11 f using the standard method is particularly pleasing.…”

Ring Expansion, Photoisomerization, and Retrocyclization of 1,4,2‐Diazaboroles

“…distances are significantly shorter than those of 2 (1.617 (14) and 1.573(13) ,r espectively). Furthermore,l engthening of the C1ÀN2 (1.421 (8) )a nd C2ÀN1 bonds (1.376(8) )a nd shortening of the C2 À N2 bond (1.337(8) )w ere observed with respect to those of 2.T hese metric parameters suggest the delocalization of p electrons over the BC 2 N 2 five-membered ring (see Figure S40 in the Supporting Information).…”

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

“…[3,5,54,55] From the calculation side, the anilinic-nitrogen (the nucleophile for the 7-membered ring) has al ow electrostatic potential and is planar comparedt ot he sulfonamide nitrogen. Formation of larger rings via ar ing expansion have been reported.…”