ABSTRACT
A long-held rationale for natural products synthesis is that, in the course of planning and executing a complex multistep synthesis, incompatibilities between structures, synthetic methodologies, and functionalities arise that reveal the gaps in current synthetic technology. Although decades of natural products research demonstrates the faith that scientists have held in the central dogma of chemical genetics, one can reasonably ask why it should be true. For a given natural product drug lead, the ability to synthesize a derivative library for evaluation would greatly increase the efficiency of drug development compared to conventional medicinal chemistry. The “combinatorialization” of a natural product represents a significant challenge for synthetic chemistry. For the illudinoids, a significant investment in synthesis of the building blocks was required, limiting the size of the library. Future designs of natural product synthesis may incorporate the commercial availability of appropriate building blocks into the retrosynthetic planning.
