Macrocyclic library synthesis

It is clear that the ideas of combinatorial chemistry could potentially be applied to identifying excellent matches of "hosts" and "guests", and that to achieve this requires the synthesis of libraries of macrocycles. As noted above, when cyclic oligomers are prepared under thermodynamic conditions the family of oligomers formed can equilibrate, Reactions 3 in Scheme 1, i.e. dimers can interconvert with trimers and tetramers etc. Use can be made of this to establish equilibria between cyclic oligomers of different families, i.e. to "mix" the different families, and in this way a soluble macrocyclic library may be prepared. 

Terrett, N.K. (2010) Methods for the synthesis of macrocycle libraries for drug discovery. Drug Discovery Today Technologies, 7, e97-el04. 

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

In the following sections, examples of hydrogen-bonding templates for the synthesis of macrocycles, cages, interlocked species, helicates and for the photochemical reaction of olefins will be discussed. The use of hydrogen-bonding templates in dynamic combinatorial libraries will also be presented. 

The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

Nicolaou, K. C. Pastor, J. Winssinger, N. Murphy, F. Solid Phase Synthesis of Macrocycles by an Intramolecular Ketophosphonate Reaction. Synthesis of a (7//)-Muscone Library, J. Am. Chem. Soc. 1998,120, 5132. 

SYNTHESIS OF SOLUBLE LIBRARIES OF MACROCYCLES FROM POLYMERS INVESTIGATIONS OF SOME POSSIBLE SCREENING METHODS USING POLYMERS... 

Synthesis of Soluble Libraries of Macrocycles from Polymers... 

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

Fig. 27 Examples of thermodynamically controlled reactions employed in the near-quantitative synthesis of MIMs. (a) Disulfide-exchange reaction permits equilibration between a bis(ammo-nium) disulfide dumbbell and a crown ether macrocycle to yield a mixture of [2]- and [3]rotaxanes quantitatively [194], (b) Olefin metathesis at high concentration on a benzylic amide macrocycle greatly favors the catenated species [196]. (c) Self-correcting imine bonds allow for nearly quantitative selection of a [2]rotaxane from an appropriate dynamic combinatorial library [76], (d) A weak nucleophile (E) equilibrates the components of a donor-acceptor [2]catenane in a dynamic Sn2 reaction [205]...

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