Strategies for the Diversity-Oriented Synthesis of Macrocycles

Abstract

Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential.

Macrocycle synthesis strategy based on step-wise “adding and reacting” three components enables screening of large combinatorial libraries

“…We next assessed which of the two substitutions, L-b-homoproline (10) to D-b-homoproline (11), or hydroxymethyl-benzylamine (35) to furfurylamine (25) contributed more to the activity improvement, and how much ( Fig. 4b and S8 †).…”

“…8,9 Strategies based on diversity-oriented synthesis allow for generating macrocycles of high structural diversity, but making libraries comprising very large numbers of compounds with such techniques remains work intensive. 10,11 Solid phase-based strategies were used to synthesize larger macrocycle libraries with smaller effort. [12][13][14][15][16] Techniques for encoding macrocycles by DNA-templated chemistry 17,18 or split-and-mix DNA-encoding principles 19,20 are promising but their application to macrocycles is not trivial as side products can accumulate in the sequential build-up of macrocycles.…”

Enthalpic and entropic contributions to the basicity of cycloalkylamines

“…Cycloalkanes C n H 2n and their derivatives are abundant in natural products 1 and fuels, 2 they are precursors to cyclic products, 3 and they and their derivatives are frequent targets of synthesis, where macrocycles are a particular challenge, [4][5][6] oen to serve as receptors for small molecules and ions. [7][8][9] They have been a holy grail for many physical-organic chemists to study their structure and reactivity.…”

Marine Furanocembranoids-Inspired Macrocycles Enabled by Pd-catalyzed Unactivated C(sp3)-H Insertion Reaction of Donor/Donor Carbenes

“…Therefore, the development of new strategies and methods to expeditiously access and enrich diverse natural furanocembranoids-like chemical space is highly desirable. [8][9][10][11][12][13][14] Inspired by natural products or privileged scaffold 15 and our interest in developing new coupling reactions, [16][17][18][19] we set out to create polysubstituted alkene furanembedded macrolactams via a short and modular biomimetic strategy, which simply utilizes either the fundamental building blocks from living organism's endogenous ligands or mimics, such as amino acids or unnatural amino acids. [20][21] A retrosynthetic analysis indicated that a successive and concise Csp 3 -H carbene coupling, and amidation could assemble these readily available building blocks, such as aryl bromides, natural or unnatural amino acids and enynones, faithfully into the target molecules ( Fig.…”