The title amide 1 behaves more like a ketone-up to a point! The crystal structure of this (90°) twisted amide shows a pyramidal nitrogen atom next to a planar carbonyl group.

Details are reported of the synthesis, properties and reactions of 3,5,7-trimethyl-1-azatricyclo[3.3.1.1 3,7 ]decan-2-one, 7 (the "most twisted amide"). Its spectroscopic properties show clearly that 7 is a ketone rather than an amide, albeit a ketone with a tertiary amino group directly attached to the carbonyl carbon. The amino group is basic (pK a ∼ 5.2) and nucleophilic, while the C᎐ ᎐ O group reacts normally as a ketone, giving the corresponding twisted enamine with the methylene Wittig reagent and acetals under standard conditions. As expected, 7 is rapidly hydrolysed to the bicyclic amino acid 15, but, remarkably, hydrolysis is readily reversible under mild acidic conditions, and in methanol the amino acid is converted to the twisted amide in 80% yield. This cyclisation of the amino acid is an extraordinarily efficient intramolecular reaction: the effective molarity of the amine nucleophile is estimated at 10 12 M: the carboxylate anion thus acting as an efficient acylating agent for both secondary and tertiary amine groups. The hydrate of the conjugate acid, typically a high-energy intermediate in amide hydrolysis, is stable in dilute aqueous acid and as the crystalline hydrochloride.

Photobiological processes in nature are usually triggered by nonpeptidic chromophores or by modified side chains. A system is presented in which the polypeptide backbone itself can be conformationally switched by light. An amino acid analogue was designed and synthesized based on a reversibly photoisomerizable diarylethene scaffold. This analogue was incorporated into the cyclic backbone of the antimicrobial peptide gramicidin S at several sites. The biological activity of the resulting peptidomimetics could then be effectively controlled by ultraviolet/visible light within strictly defined spatial and temporal limits.

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