Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction

Abstract

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin b-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Figure 1

The iterative assembly of bifunctional building blocks is a versatile strategy for the preparation of small molecules. a. Nature biosynthesizes macromolecules, including polypeptides, oligonucleotides, and oligosaccharides via the iterative coupling of building blocks. b. Nature similarly prepares small molecules derived from a range of biosynthetic pathways via the iterative assembly of bifunctional building blocks. c. A collection of polyene natural products from a variety of biosynthetic pathways.

Figure 2

Three examples of applying the standardized 3-step retrosynthetic algorithm to previously not synthesized polyene natural products. a. asnipyrone B. b. physarigin A. c. neurosporaxanthin β-D-glucopyranoside.

Figure 3

A general platform for making polyene motifs via iterative cross-coupling. a. A collection of 12 bifunctional MIDA boronate building blocks BB1-BB12 can be used to synthesize the polyene motifs found in >75% of all polyene natural products. b. An iterative cross-coupling strategy involving the coupling of a pinacol boronic ester to a bifunctional halo MIDA boronate building block followed by a deprotection of the resulting MIDA boronate to generate a new pinacol boronic ester suitable for the next round of coupling.

Figure 4

A collection of polyene motifs collectively found in >75% of all polyene natural products.

Figure 5

The synthesis of polyene motifs present in >75% of all known polyene containing natural products using just 12 bifunctional MIDA boronate building blocks and one coupling reaction.

Figure 6

The total synthesis of three polyene natural products using bifunctional MIDA boronate building blocks and one set of reaction conditions in an iterative fashion. a. The total synthesis of asnipyrone B. b. The total synthesis of physarigin A. c. The total synthesis of neurosporaxanthin β-D-glucopyranoside.