Natural product synthesis in the age of scalability

Abstract

The ability to procure useful quantities of a molecule by simple, scalable routes is emerging as an important goal in natural product synthesis. Approaches to molecules that yield substantial material enable collaborative investigations (such as SAR studies or eventual commercial production) and inherently spur innovation in chemistry. As such, when evaluating a natural product synthesis, scalability is becoming an increasingly important factor. In this Highlight, we discuss recent examples of natural product synthesis from our laboratory and others, where the preparation of gram-scale quantities of a target compound or a key intermediate allowed for a deeper understanding of biological activities or enabled further investigational collaborations.

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…434 Furthermore, some of the syntheses discussed herein are quite efficient in terms not only of step count, but yield and material throughput as well. 46,49,136,435 Some have overall yields approaching 20%, 64,95 and one has produced gram quantities of the target in a single synthetic pass. 114 However, much work remains to be able to accomplish this on a consistent basis, particularly owing to the highly variable structures of terpenes and the lack of a universal synthetic strategy.…”

Natural Product Synthesis at the Interface of Chemistry and Biology

“…In recent years, the organic chemistry community has been incorporating the fundamental principles behind the remarkable efficiency of biosynthesis into their synthetic approaches to address these drawbacks and to achieve a scalable production of natural product. [24] These novel concepts and strategies include atom, step and redox economy, protecting-group-free synthesis, and biomimetic synthesis. [25] An example that shows these new trends is the synthesis of ingenol by Baran and co-workers (Scheme 3).…”

Harnessing natural product assembly lines: structure, promiscuity, and engineering

“…Notably, approximately 65% of the current drugs on the market are derived or inspired from natural products [98,97]. Consequently, polyketides and non-ribosomal peptides, including their biologically active precursors and derivatives, have proven popular targets for total synthesis [144,76]. Though there has been much success in this area, most synthetic routes to complex polyketides and non-ribosomal peptides require dozens of chemical steps and are generally low yielding [62].…”