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

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydratederived building blocks Sushil K. Maurya*1,2,§ and Rohit Rana1,2 Full Research Paper Open Access Address: 1Natural Product Chemistry and Process Development Division, CSIR- Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, 176 061, India and 2Academy of Scientific and Innovative Research, CSIR- Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, 176 061, India Beilstein J. Org. Chem. 2017, 13, 1106–1118. doi:10.3762/bjoc.13.110 Email: Sushil K. Maurya* - This article is part of the Thematic Series "Chemical biology". Received: 27 December 2016 Accepted: 12 May 2017 Published: 09 June 2017 Guest Editor: H. B. Bode * Corresponding author § Phone: +91-1894-230742 © 2017 Maurya and Rana; licensee Beilstein-Institut. License and terms: see end of document. Keywords: carbohydrate; click chemistry; diversity-oriented synthesis; macrocycles; ring-closing metathesis 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. 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 [1-4]. Carbohydrate-embedded macrocycles represent an important class of macrocyclic com- pounds in which at least two bonds from a monosaccharide residue form a part of the macrocyclic rings and have shown important biological properties [5-12]. For example, macrocyclic aminoglycoside analogues have shown binding with the trans-activating region (TAR) RNA of the human immunodefi- 1106 Beilstein J. Org. Chem. 2017, 13, 1106–1118. ciency virus (HIV); an attractive target for RNA-based drug discovery [13]. Further, macrocyclic glycolipids have shown phosphatase inhibition, cytotoxicity and antiviral activities [12,14]. Generally, the synthesis of these molecules involves a multi-step construction of linear precursors incorporating synthetically compatible functional groups followed by a cyclization in the late stage of the synthesis. The cyclization of the linear precursor is usually achieved by utilizing various ringclosing reactions such as Diels–Alder reactions, [15] aldol reactions, [16] copper-catalyzed azide–alkyne cycloaddition, [17,18] macrolactonization, macrolactamizations, Staudinger ligation or transition-metal-catalyzed coupling reactions [19]. Recently, ring-closing alkyne metathesis (RCAM) [20,21] and ring closing metathesis (RCM) [22-31] have emerged as very powerful tools for macrocyclization including for the preparation of peptidomimetic [17,18,32] glycosides and macrocyclic glycolipids [11]. Similarly, the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction has found wide application in medicinal chemistry [33], biology [34,35], polymer chemistry [36], carbohydrates [37-40], peptides [41-44] and in materials science [45-48]. There are several reports wherein different strategies have been developed and used for the synthesis of glycoconjugates [9,49-51], however, the combination of a CuAAC and a RCM reaction has been used very little and rarely combinations of these reactions have been used for the synthesis of sugar-embedded glycoconjugates [52,53]. Further, the linear syntheses of macrocycles based on multistep protocols are not cost-effective and the development of efficient, sustainable, greener and economical methods is highly desired. Synthetic methods to produce a diverse collection of macrocycles are rare and usually produce only compounds with a similar skeleton [20,33]. However, to achieve a higher hit rate against a broader range of targets libraries of diverse collections of macrocycles are desired [54]. The various diversity elements of a given library should include the molecular size, shape, heteroatoms, functional groups and stereo chemical complexity for selective binding [4]. The diversity-oriented synthesis (DOS), an algorithm in organic chemistry used to generate diverse molecules that include two-directional coupling, ring expansion methods, multidimensional coupling and domain shuffling has been used for the synthesis of small molecules and macrocyclic libraries. Further, several DOS strategies based around build/couple/pair (B/C/P) were developed for the synthesis of compound libraries including macrocycles [18,55]. Carbohydrates as building blocks are inexpensive and easily available commercial products and are well-endowed with functionalities which enable them to establish catalytic sites as well as secondary binding sites [56]. The abundance of various functional groups in the carbohydrate precursor allows for easy access to multiple building blocks by incorporating diversity- oriented synthesis (DOS). These moieties can be easily furnished with alkyne or azide functionality with routine synthetic transformation protocols that allow facile access to monoas well as poly-functionalized derivatives via CuAAC reaction. The approach enables the rapid synthesis of carbohydrate conjugates in which the heterocyclic triazolyl ring serves as a shackle for joining the carbohydrate building blocks. Further, these carbohydrate conjugates decorated with appropriate coupling partner can be paired through ring closing metathesis (RCM) reaction. Carrying out the metathesis processes in green solvents is a major challenge. Unfortunately, halogenated solvents such as dichloromethane (DCM), 1,2-dichloroethane (DCE) or aromatics such as benzene and toluene are the most frequently used solvents for metathesis reactions whereas these solvents possess serious health and environmental hazards [57,58]. Here we report a novel application of the popular build-couplepair (B/C/P) strategy [4,18,54,55,59,60] for the synthesis of sugar embedded macrocycles by iterative use of carbohydrate derived building blocks armed with azide/alkyne–alkene functionalities. The building blocks were coupled via 1,3-dipolar cycloaddition (click reaction) iteratively through the development of a greener (...truncated)