Mechanism • Catalyst Design • Reaction Development • Complex Molecule Synthesis/Modification
OUR GENERAL APPROACH
We are chemists who consider catalysis and synthesis as our core specialty. We view ourselves as molecular designers keen on learning more about catalysis and how it might be used to generate functional molecules of all sizes. Our approach is multidisciplinary and collaborative.
Catalytic transformations that deliver stereochemically defined fragments, necessary to the function of a molecule, regardless of its size, is one central tenet of our research. For instance, we have developed catalysts that can be used to prepare a range of otherwise difficult-to-access E– or Z-trisubstituted alkenes in high stereoisomeric purity. Another example are catalytic strategies for forming C–prenyl bonds. We have taken on the task of designing catalysts that can be used to synthesize readily alterable tetrasubstituted olefins in either stereoisomeric form – processes that are of value to drug discovery and development. We introduce new multicomponent transformations, involving one or perhaps more catalysts, capable of delivering products that are densely functionalized and are easy to modify. Mechanistic understanding is central to our studies, and with each advance we hope to enrich this foundation.
Our search is not only for a practical way of synthesizing natural products, it is also to develop strategies for securing, through networks of shared transformations, precisely re-modelled skeletal analogs. We recently put forward a catalytic multicomponent diastereo- and enantioselective process that generates a multi-functional and chemoselectively modifiable platform that can be used for concise synthesis of a rare polycyclic indole alkaloid. What is more, it facilitates access to several scaffolds that have been expanded, contracted or distorted by one-two methylene units. Together with the Hergenrother group (UIUC) we established that a doubly-expanded skeletal analog of the aforementioned weakly anti-malarial natural product – but not itself or the other exactly altered frameworks – is cytotoxic against the four cancer cell lines screened (3 mM). Molecular dynamics and AI-accelerated docking studies performed by the Liu group (Pittsburgh) and Accutar Biotech (Shanghai) helped us gain insight regarding what differentiates various scaffolds and what might be the origins of their marked proclivity for binding to various biological receptors. On an associated front, we are keen on developing efficient ways of surgically altering scaffolds of complex bioactive molecules; this would facilitate drug discovery by making it possible to explore rarely visited regions in the diversity space.
We favor investigating catalytic approaches that can expedite access to new molecules, small (bioactive) and large (functional polymers). We have had great fun designing a link-and-modify strategy that is orthogonal to CuAAC and SuFEx. By merging these three catalytic processes, one can quickly fabricate site-selectively modifiable and/or cleavable macromolecules. The strategy can be used for concise synthesis of multi-drug conjugates that also have fluorescent linkages.
What we will be searching for in five to ten years we do not know. What we can tell you is that, if you join us, you will have something to say about it.
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.