Many natural and unnatural complex organic molecules contain terminal guanidine functional groups. Often, the affinity and specificity with which a terminal guanidine binds to the active site of a small molecule's protein target determines biological activity. In the practice of total synthesis, the basicity and nucleophilicity of the guanidine group seemingly prompts synthetic chemists to introduce this group late in their synthesis. Furthermore, the use of latent amine, such as an azide or a carbamate as guanidine progenitor can lengthen a synthetic route by several unnecessary functional group interconversions.Because of their biological activity, intriguing structure, and accessibility by undergraduates, we have pursued the total synthesis of terminal guanidine-containing natural products such as phidianidine A and B, and clavatadine A. Frustrated by extant approaches to late-stage guanidinylation, we sought a more deliberate approach. In summary, early-stage, direct introduction of the guanidine functional group in a protected form led to streamlined total syntheses of these natural products.

Application of a straightforward approach to incorporate terminal guanidines in natural product total synthesis

246th National Meeting (2013)

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