The Synthesis of Macrocycles for Drug Discovery

Abstract

Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

Forward and Reverse (Retro) Iron(III) or Gallium(III) Desferrioxamine E and Ring-Expanded Analogues Prepared Using Metal-Templated Synthesis from endo-Hydroxamic Acid Monomers

“…The macrocyclic siderophore desferrioxamine E (DFOE) coordinates iron­(III) in a 1:1 ratio via three bidentate hydroxamate groups (log K = 32.5) to form ferrioxamine E (FOE). − DFOE is native to many Streptomyces species and other actinomycetes, including marine Salinispora tropica CNB-440. , DFOE is biosynthesized from the condensation and ring closure of three units of the forward endo -hydroxamic acid monomer 4-[(5-aminopentyl)­(hydroxy)­amino]-4-oxobutanoic acid ( for -PBH). − Macrocycles are an important class of clinical agents, with research focused on improved chemical or biosynthetic methods to access new candidates. − …”

Heck Macrocyclization in Forging Non-Natural Large Rings including Macrocyclic Drugs

“…Having unmatched architecture and functional group disposition, macrocycles constitute a cutting edge of modern drug discovery well poised to engage challenging pharmaceutical targets [14][15][16]. To our surprise, though sporadically mentioned [17,18], the title reaction has hitherto not been scrutinized in the context of making non-natural macrocycles. Accordingly, the present review aims to conduct a systematic survey of this reaction forging diverse synthetic macrocycles beyond natural products.…”

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

“…However, current drugs rarely contain nature‐inspired macrocycles, presumably because the chemical synthesis of medium‐sized rings (ring sizes 8–11) and macrocyclic compounds (ring sizes ≥11) is simultaneously an attractive and challenging task for organic chemists. Numerous methods have been devised and used to close the ring from acyclic intermediates, including macrolactamization and macrolactonization, substitution chemistry, ring‐closing metathesis, the Wittig reaction, organometallic methods, cycloaddition, multicomponent reactions, and ring expansion, as detailed in an excellent recent review by Peterson . The recent reports describing multicomponent reaction and successive ring expansion testify to the current interest in the development of synthetic methods for macrocyclization.…”