Nat. Chem. doi:10.1038/nchem.1947

Most natural product syntheses begin with a full retrosynthetic analysis to break the molecule down into convenient starting points, with each new compound class deconstructed in different ways. Woerly et al. now suggest this practice has limited the reach of organic synthesis. To encourage general strategies and accessibility by nonexperts, the authors suggest a modular strategy akin to that employed in peptide and oligonucleotide synthesis. To demonstrate the approach, the authors focused on polyene structures, as these functional groups are both common in natural products and amenable to synthesis via N-methyliminodiacetic acid (MIDA) boronates as stable and commercially available reagents. A query of the Dictionary of Natural Products yielded nearly 3,000 compounds derived from all major biosynthetic classes containing polyenes, a retrosynthetic analysis of which revealed that more than 75% of the polyene motifs within these compounds could be constructed using only 12 MIDA boronate blocks. Preparation of the 12 blocks and preliminary coupling experiments demonstrated that although the MIDA precursors were stable, some of the deprotected intermediates were not. Revision of the reaction conditions to generate stable boronate esters by reacting with pinacol, along with exploration of possible solvents and reagents, led to a general synthetic strategy applicable to all cross-coupling experiments. The authors then used their methodology to synthesize 15 examples of polyene motifs and complete the first total synthesis of 3 natural products.