OUR GENERAL APPROACH
We like to learn as much as possible about fundamentals of reactivity and selectivity by designing and developing catalysts that promote high-impact chemical transformations. We usually identify a problem first and then try to solve it. Reaction mechanism is the basis for every project, impacting the way we design and carry out a project.
Achieving high regio-, diastereo-, and/or enantioselectivities is not our only goal. We have a number of requirements for a catalytic process or a synthesis route that we develop. We prefer earth-abundant metals (such as Cu or Mo); we like ligands and catalysts that are derived from renewable resources, such as amino acids. We are partial to catalysts that are easy to prepare and use, are robust and efficient (do not require more than 6-8 hours to deliver complete conversion), and that have as low a molecular weight as possible. Our goal is to develop catalytic protocols that are economical, reliable, and practical. For example, we recently discovered a two-catalyst/four-component process, based on a strategy that we call “delayed catalysis”, to effect sequential additions of different types of nucleophiles to nitriles, an abundant and underexplored class of electrophiles. The reactions generate unprotected and versatile N-H amines with high efficiency, diastereoselectivity and enantioselectivity without any need for oxidation/reduction, or protection/deprotection; the method is stereodivergent too. We were able to use this advance (along with some of our other catalysts) to accomplish a nine-step gram-scale synthesis of a naturally occurring alkaloid (versus 26 steps previously).
Applying our catalysts, methods and strategies to complex molecule synthesis is important to us. Such initiatives show us how effective our catalysts and methods truly are, and what problems we should be focusing on. Our interest in larger molecules extends well beyond natural product synthesis; we are equally keen on introducing catalytic strategies that may be applied to assembling non-natural macromolecules and/or site selectively modifying them.
November 14, 2022
“Diastereo- and Enantioselective Synthesis of Compounds with a Trifluoromethyl- and Fluoro-Substituted Carbon Centre“
Organic molecules that have a trifluoromethyl- and fluoro-substituted carbon have considerable potential in drug development. However, because methods for their diastereo- and/or enantioselective synthesis are scarce, these entities are underdeveloped. We have recently introduced a catalytic regio- and enantioselective strategy for preparation of homoallylic alcohols bearing a stereogenic carbon center bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalyzed by an in situ formed organozinc catalyst, may be used for diastereodivergent synthesis of tetrafluoro-monosaccharides, including ribose core analogues of anti-viral drug, Sovaldi™. Several unique reactivity/selectivity profiles, originating from the trifluoromethyl- and fluoro-substituted carbon site, are presented, foreshadowing additional unusual chemistries that remain to be discovered.
May 16, 2022
“E– and Z-Trisubstituted Macrocyclic Alkenes for Natural Product Synthesis and Skeletal Editing”
Many therapeutic agents are macrocyclic trisubstituted alkenes, and yet, preparation of these structures is typically inefficient and nonselective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors, and are often low yielding and/or non-stereoselective. We recently developed the first ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. One being the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an anti-fungal natural product. The other is a late-stage stereoselective generation of a E-trisubstituted alkene in a 24-membered ring, en route to cytotoxic natural product dolabelide C.