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Bulged sites in DNA and RNA have become targets for rational drug design due to their suspected involvement in a number of key biomolecular processes. A lead compound, derived from the enediyne natural product NCS-chrom has been used to inform chemical synthesis of a family of designed probes of DNA bulges, one of which shows 80 nM affinity for a two base bulged target. Key contributors to binding of these spirocyclic compounds have been studied in order to correlate affinity and specificity with structural features. Herein, we demonstrate that the glycosyl linkage stereochemistry of the pendant aminofucosyl group plays a pivotal role in binding, and coupled with insight obtained with various bulged targets, will allow rational design of second generation ligands.

A family of highly selective chiral auxiliaries containing arene chromium (0) complexes has been prepared using biogenic precursors from the chiral pool. The systems, derived from isomannide, prolinol, and xylofuranose were applied to the asymmetric Diels–Alder reaction of derived acrylate esters. Factors influencing stereoselectivity with the auxiliaries have been investigated and delineated including the impact of mixed ligands on the chromium (0) complex. Under optimal conditions, the auxiliaries give >95% e.e. and 98:2 exo:endo ratio in cycloaddition with cyclopentadiene.