For synthetic organic chemistry to reach its full potential as an enabling science, especially in terms of its impact on biomedical research, we must develop the skills not only to prepare any molecule efficiently, on-scale, and in environmentally benign ways, but also to tailor it in any way imaginable so that we can confer upon it whatever new properties we might desire. Meeting this lofty objective requires complete command over chemoselectivity: the ability to differentiate and controllably functionalize any site within a given molecule.
The Snyder research group uses the inspiration of Nature’s chemoselective syntheses of tens of thousands of natural products through highly controlled cyclization and functionalization chemistries both to provide a sense of our ultimate goal and to identify critical challenges worthy of laboratory execution. Efforts to date have focused on oligomeric polyphenols, halogenated natural products, stereochemically-dense terpenes, and polycyclic alkaloids, resulting in several new reagents, strategies, and tactics of broad applicability.
For instance, we have developed a broadly effective class of chemoselective halogenating reagents; Et2SBr•SbCl5Br (BDSB) is the flagship member and is commercially available from Sigma–Aldrich. These reagents are the first that can achieve halonium-induced polyene cyclizations for stereochemically diverse terpenes. They have also allowed the rapid synthesis of 8- and 9-membered bromoethers of the Laurencia class via a unique biogenetic hypothesis as well as accomplished a positionally selective electrophilic aromatic substitution that other halogen sources could not achieve.
We have also developed a number of strategies and methods for rapid polycycle construction, evidenced by a recent total synthesis of the stereochemically rich, but largely non-functionalized terpene known as rippertenol. In work towards compact alkaloids such as scholarisine A, members of the norsecurinines, and gracilamine, we have developed unique C–H functionalization chemistries, N-heterocyclic carbene-induced cascade bond constructions, and pyrone Diels–Alder chemistries which can rapidly form multiple ring systems at once where previous efforts required many steps.
We have also pioneered the first strategy, predicated on the identification of non-obvious starting materials and a number of chemoselective transformations and reaction cascades, for the controlled (and sometimes gram-scale) synthesis of diverse oligomeric natural product families, unlocking their members for further biological exploration through collaborative study. These efforts include dozens of members of the resveratrol, rosmarinic acid, myrmicarin, and coccinellid families of natural products.
