Rules that are meant to be broken

Over the past two weeks, I have been out of touch with the blogosphere for several family-related reasons, but now I am back and want to wish all of my readers a Happy New Year. Which science-related wishes do I think about now? To all of you graduate students out there, my wish is unequivocal: be skeptical of any rules that might otherwise bind you. I will illustrate this point using the Erlenmeyer rule, which is one of those obscure dogmas that state that, in an alpha-peptide, one is unlikely to find heteroatom substituents bonded to the C(alpha) atom. However, there have been a number of natural product whose structures clash with this statement. Below I am showing Sch 419559, which is one of those molecules (its relative stereochemistry has not yet been established). This aminal-containing structure is no exception and there are many others like it. I am sure you have seen alpha-hydroxylated amides in many other contexts, for instance as products of asymmetric organocatalysis. I have always been fascinated by the fact that these units not only exist, but are also configurationally stable despite the possibility of iminium ion formation (well, there is microscopic reversibility after all…). So here we have it: while it is possible to form iminium ions from the corresponding heteroatom-substituted amides, these precursor structures are often stable and isolable.