An efficient intermolecular conjugate addition of alcohols to activated alkenes catalyzed by N-heterocyclic carbenes has been developed. With 5 mol % of the free carbene derived from IMes•HCl, unsaturated ketones and esters are competent substrates and a variety of primary and secondary alcohols can be employed as the nucleophile. No oligomerization is observed under these mild conditions for effective hydroalkoxylation. In addition to reactions with activated alkenes, IMes catalyzes the formation of vinyl ethers through the 1,4-addition of alcohols to ynones and promotes tandem conjugate addition/Michael cascade reactions. Preliminary data supports a Brønsted base mechanism with the free carbene.

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Quinolones are antibacterial drugs that are thought to bind preferentially to disturbed regions of DNA. They do not fall into the classical categories of intercalators, groove binders or electrostatic binders to the backbone. We solved the 3D structure of the DNA duplex (ACGCGU-NA)2, where NA denotes a nalidixic acid residue covalently linked to the 2′-position of 2′-amino-2′-deoxyuridine, by NMR and restrained torsion angle molecular dynamics (MD). In the complex, the quinolones stack on G:C base pairs of the core tetramer and disrupt the terminal A:U base pair. The displaced dA residues can stack on the quinolones, while the uracil rings bind in the minor groove. The duplex-bridging interactions of the drugs and the contacts of the displaced nucleotides explain the high UV-melting temperature for d(ACGCGU-NA)2 of up to 53°C. Further, non-covalently linked complexes between quinolones and DNA of the sequence ACGCGT can be generated via MD using constraints obtained for d(ACGCGU-NA)2. This is demonstrated for unconjugated nalidixic acid and its 6-fluoro derivative. The well-ordered and tightly packed structures thus obtained are compatible with a published model for the quinolone–DNA complex in the active site of gyrases.

Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3-hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity.