We have used dynamic combinatorial chemistry in close collaboration with the group of Sijbren Otto for the optimization of the anion affinity of covalently linked bis(cyclopeptides). In this context, a cyclopeptide disulfide was equilibrated under suitable conditions with different dithiols. Addition of anionic templates, for example sulfate (as potassium sulfate), caused the amplification of receptors in this dynamic library that possess high affinity for this template.¹

Two of the amplified receptors were synthesized and their affinity toward iodide and sulfate was compared with that of a bis(cyclopeptide) in which the receptor subunits were linked via adipic acid. Both bis(cyclopeptides) bound the two anions ca. one order of magnitude more strongly than the adipic acid containing derivative.

The cooperative action in guest binding of the two cyclopeptide rings is clearly visible in the crystal structure of the sulfate complex of one receptor identified by dynamic combinatorial chemistry.²

[For an interactive version of the crystal structure click here]

Doubly-linked bis(cycopeptides) that are better preorganized for anion binding in comparison to the corresponding singly-linked derivatives were shown to possess anion affinities in aqueous solvent mixtures (acetonitrile/water 2:1) approaching the nanomolar range.³

References

1. S. Otto, S. Kubik J. Am. Chem. Soc. 2003, 125, 7804-7805.
2. Z. Rodriguez-Docampo, S. I. Pascu, S. Kubik, S. Otto J. Am. Chem. Soc. 2006, 128, 11206-11210.
3. Z. Rodriguez-Docampo, E. Eugenieva-Ilieva, C. Reyheller, A. Belenguer, S. Kubik, S. Otto Chem. Commun. 2011, 47, 9798-9800.