An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks.

Sushil K Maurya,Rohit Rana

doi:10.3762/bjoc.13.110

Abstract

An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide–alkene building blocks coupled through copper catalyzed azide–alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.

Highlights

Macrocycles offer very complex molecular architectures with a diverse range of ring sizes decorated with many functional groups found application in pharmaceuticals, agrochemicals, cosmetics and materials science [1,2,3,4]
Ring-closing alkyne metathesis (RCAM) [20,21] and ring closing metathesis (RCM) [22,23,24,25,26,27,28,29,30,31] have emerged as very powerful tools for macrocyclization including for the preparation of peptidomimetic [17,18,32] glycosides and macrocyclic glycolipids [11]
Simple and economical polyfunctional substrates available in abundance from the natural resources are ideal starting materials in diversity-oriented synthesis (DOS), which aims at providing quick access to libraries of diverse molecules

Summary

Introduction

Macrocycles offer very complex molecular architectures with a diverse range of ring sizes decorated with many functional groups found application in pharmaceuticals, agrochemicals, cosmetics and materials science [1,2,3,4]. CuAAC adducts were cyclized using a Ru-catalyzed metathesis reaction utilizing Grubbs second generation catalysts under greener reaction conditions (Figure 1). For developing greener conditions for the cycloaddition reaction, a control experiment with alkyne (1a) and azide (2a) in water at room temperature reacted up to 24 hours but in the absence of copper catalyst and base, only 6% conversion was observed (measured by 1H NMR; formation of two products were observed in the ratio of 77:23).

Results

Conclusion