Macrocyclic library synthesis approaches

Library of Congress Cataloging in Publication Data Macrocycle synthesis a practical approach / edited by David Parker. 

The use of imines as the dynamic covalent bond significantly augmented the versatility of the thermodynamic approach toward the formation of interlocked systems. Stoddart et al. reported on the synthesis of [2]rolaxanes by the clipping protocol, in which a dialdehyde was used to clip the macrocycle under thermodynamically controlled conditions (Figure 6). In this system, the driving force for the formation of rotaxane 10 is the stabilizing interaction between ammonium ions and crown ethers, which was widely exploited by Stoddart and coworkers. In the first instance, a library of macrocyclic and linear compounds was prepared on condensation of tetraethylene glycol bis(2-aminophenyl)ether 6 and 2,6-diformylpyridine 7. 

Many drugs and namral products are (or contain) macro-cyclic structures that require the synthesis, and functionalization, of large rings in an asymmetric fashion. At its simplest, this can involve immobilization of a preassembled macrocyclic core on a solid support, and subsequent modification. This approach was used by Sowin and colleagues to prepare a library of macrolide antibiotics. Aldehyde core 262, readily accessible from 6-0-allyl-erythromycin A, was immobilized on support 263 using a... 

In a notable exception, Yudin has described the use of amphoteric aldehydes (178) in an Ugi MCR with isonitriles and linear peptides (179) to prepare a series of modified peptidomimetie macrocycles (180) with ring sizes from 9 to 18 atoms (Scheme 11.24). These compounds, via nucleophilic attack on the aziridine, also can be employed as intermediates for further reactions and, hence, provide access to additional structural diversity suitable for library production. Towards this end, the sequence was successfully transferred to an automated mierofluidies platform. The process did not need to be performed under high dilution eonditions (0.2 M). More recently, this approach was applied sueeessfully to the synthesis of bityclic peptidomimetie derivatives, for example 181, in whieh macrocyclization and then disulfide formation were best eondueted in solution after the solid phase MCR to avoid side reaetions. ... 

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