A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling

Abstract

A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling. In this approach, structural diversity is not only defined by the nature of the building blocks employed, but also by the linking motif installed during the coupling reaction. We applied this step-efficient approach in a DOS of a library that consisted of 73 macrocyclic compounds based around 59 discrete scaffolds. The macrocycles prepared cover a broad range of different molecular shapes, as illustrated by principal moment-of-inertia analysis. This demonstrates the capability of the advanced B/C/P strategy using multidimensional coupling for the preparation of structurally diverse compound collections.

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…234 Macrocycles of a non-peptidic nature are often difficult to prepare and are thus not well represented in compound collections employed for pharmaceutical screening purposes. Azido building blocks, of different geometries and containing a fluorous tag to facilitate purification 235 were constructed and then coupled, not using cycloadditions, but via aza-Wittig-type reactions.…”

De novo branching cascades for structural and functional diversity in small molecules

“…4a) preferred energetically favoured olefinic isomerization to 12 over a sigmatropic rearrangement to azepinone 11 that requires higher temperature. Formation of allyl indoles (13) apparently occurs via isomerization of vinyl indoles (20) formed from 11 under optimized reaction conditions (Fig. 4a).…”

“…Different approaches have been developed to incorporate structural diversity to a compound collection, for instance, in the build-couple-pair strategies 12,13 , folding 14 and branching pathways [15][16][17] , structural variations either in the building blocks or the reacting partners of common substrates derive the formation of new scaffolds. Synthesis of natural product scaffold-based [18][19][20][21] compound libraries either employs accessible complex natural products or their derivatives for generating new and complex scaffold structures or build up compound libraries around privileged scaffolds 1,22 . However, most of the above mentioned synthesis designs require carefully functionalized substrates, as well as their reacting partners and often deliver structural diversity in a compound library at the cost of tedious multistep synthesis protocol.…”

Decorated Macrocycles via Ring-Closing Double-Reductive Amination. Identification of an Apoptosis Inducer of Leukemic Cells That at Least Partially Antagonizes a 5-HT2 Receptor

“…17 The utilization of the amine in the final ring-closing step provides an efficient way to expand the number of macrocyclic compounds for screening, given the wide number of available amines. The strategy used herein could potentially contribute to preparation of more macrocyclic scaffolds 18 and follows the build-couple-pair strategy 19 used in diversity-oriented synthesis. Evaluation of a preliminary set of molecules based on the macrocycle has led to identification of a compound selectively toxic to tumour cells and evidence is provided that the apoptosis induced is at least partially due to binding to either the 5-HT2A and/or 5-HT2B receptor.…”