Reaching across big rings

Those of us who care about cyclic peptides eventually come to grips with the idea that, despite their relative strength, amide bonds can be fragile when placed within constrained environments. This is the reason why cyclic tripeptides are inherently unstable. The proximity of amide bonds accounts for the transannular reactivity shown below (left). While this sort of reactivity is certainly undesired if one wants to have access to a 9-membered ring composed of amide bonds, it also provides enabling opportunities in synthesis. I can name a couple of examples right here. The first one comes courtesy of Phil Baran (http://pubs.acs.org/doi/abs/10.1021/ja2047232), and showcases how a 9-membered ring collapses in the course of palau’amine synthesis. The second one is a nice example from Dirk Trauner’s lab (http://www.nature.com/nchem/journal/v3/n7/abs/nchem.1072.html). In this case, loline synthesis was shown to proceed through nitrogen attack at the intermediate bromonium ion. These examples prove that powerful reactions can be designed with  transannular reactivity in mind. Unfortunately, these cases further underscore the notion that the majority of medium ring amides are not to be associated with stability…

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