To beat a hydrogen bond

As the peptide community keeps talking about intramolecular hydrogen bonds and their significance in enforcing conformations that are pertinent to passive membrane permeability, it is useful to look at examples in which hydrogen bonds are directly involved in explaining the reactivity of a given compound. The chemistry that comes courtesy of Storz and co-workers (see the graphic below) is a testament to the importance of maintaining the right charged state in order to ensure acceptable chemoselectivity of acylation. One can extrapolate this further and reasonably conclude that pH might play an important role in dictating conformations of complex molecules such as cyclic peptides. It is also feasible to expect that pH-dependent conformations will be observed in many cases, particularly if tertiary amines are present in a macrocycle. One can anticipate that pH-dependent conformations might create a nightmare for this class of compounds during biological investigations. For example, I can bet that there will be reproducibility issues in many assays (we have already seen this behavior with our macrocycles). Oh well. I’d rather not think about it anymore and instead concentrate on the bottle of Bordeaux I am about to open for dinner…

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http://pubs.acs.org/doi/pdf/10.1021/op0601464

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