The D. A. Watson Group is focused on the invention of new chemical reactions and their applications in organic synthesis. Organic synthesis is central to modern scientific endeavor, including in such critical areas as the treatment of human disease (providing the tools to synthesize new medicines), understanding of biological processes (providing probes and methods to interrogate biochemical pathways), and the development of advanced materials (providing the building blocks from which they are derived). Advancements in these areas, as well as many others, require new, complex organic molecules and the ability to prepare them. Our group works to invent new, more efficient methods to prepare compounds, which help drive advancements across the spectrum of modern science. Transition-metal catalysis plays a central role in our work, and lies at the heart of many of the methods that we have invented. Our approach combines expertise in catalyst development and organometallic chemistry with insight deep insight into the needs of organic synthesis and complex molecule construction. In this context, we have been particularly focused on the invention of new methods to introduce heteroatoms into non-aromatic organic molecules. The products of these reactions are important intermediates in chemical synthesis, as well as critical structural elements in biologically active molecules.
Cross-Coupling with Heteroaromatic Electrophiles
A major focus of our group’s work is investigating the use of heteroatomic electrophiles in transition metal-catalyzed cross-coupling reactions. These reactions allow for facile incorporation of heteroatoms while building complex molecular structures. Current work in the group focuses on the use of nitrogen, silicon, and boron electrophiles.
Nitrogen Electrophiles
Using palladium catalysis, we have developed intramolecular aza-Heck cyclizations to form a variety of N-heterocycles. These reactions utilize N–O bond activation of O-arylhydroxymates, hydroxamic ethers, and carbamates to form these pharmaceutically relevant compounds in high yields with wide functional group tolerance. We have pursued mechanistic study into these reactions to better understand the fundamental workings of this chemistry, so that future synthetic development comes with a deep understanding of how these methods proceed. Additionally, we have used this chemistry towards the total synthesis of Impatien A—a biologically active natural product. We are continuing to explore this area of chemistry in new total synthesis applications and asymmetric catalysis.
Highlighted Publications
- Org. Lett. 2021, 23, 7285–7289
- Chem. Sci. 2021, 12, 8859-8864
- Angew. Chem. Int. Ed. 2019, 58, 13448-13451
- Chem. Rev. 2019, 119, 8192–8228
Silicon Electrophiles
Over the past several years, our group has developed a wide range of transformations with organosilanes. In the silyl-Heck reaction, both palladium and nickel catalysts can effectively convert simple alkenes into unsaturated organosilanes using electrophilic silicon reagents, such as silyl halides and triflates. We were also able to couple these silyl electrophiles with Grignard or organozinc nucleophiles in a silyl-Kumada and silyl-Negishi reaction to access aryl- and alkylsilanes. Our group developed a multicomponent carbosilylation of alkynes with silyl iodides and organozinc nucleophiles to access highly substituted vinylsilanes with excellent stereoselectivity. We further demonstrated the utility of these products via a Hiyama-Denmark cross-coupling to access a variety of tri- and tetrasubstituted alkenes.
Highlighted Publications
- ACS Catal. 2022, 12, 13108–13115
- J. Am. Chem. Soc. 2020, 142, 28, 12051–12055
- Organometallics, 2019, 38, 19, 3796-3803
Boron Electrophiles
We have also recently begun to explore the use of electrophilic boron reagents in Heck-type reactions. We have shown that palladium catalysis efficiently converts terminal alkenes into trans-vinyl boronic esters. Like with the silyl-Heck chemistry, this allows for simple alkenes to be converted into high-value intermediates that are broadly useful in organic synthesis. We are continuing to explore and develop this transformation.
Highlighted Publications
- Org. Lett. 2021, 23, 4838–4842
- J. Am. Chem. Soc. 2020, 142, 28, 11988–11992
Atroposelective Synthesis of Biaryls
Axially chiral biaryls are a unique class of compounds found in natural products, biologically active compounds, and ligands used in developing new asymmetric reactions to access complicated chemical structures. These types of moieties can be difficult or timely to access using traditional synthetic strategies. Recently, our lab has published efficient nickel-catalyzed reductive couplings to construct atroposiomers. In 2021, our lab disclosed one of the first asymmetric reductive homocouplings of aryl halides to provide highly enantioenriched chiral biarenes. In 2024, we published the first example of an atroposelective reductive cross-coupling of two aryl halides to access monophosphines. We are currently combining mechanistic insight with novel synthetic ideas to expand the scope and understanding of asymmetric reductive couplings. Ultimately, our work will allow us to synthesize a greater variety of axially chiral biarenes, giving rise to facile and efficient synthesis of drug targets and ligands for catalysis.
Highlighted Publications
- J. Am. Chem. Soc, 2024, 146, 26, 17606-17612
- J. Am. Chem. Soc. 2021, 143, 3, 1328-1333
Use of Nitroalkanes in Synthesis
Nitroalkanes are widely used in organic synthesis both for the construction of carbon-carbon bonds and for the introduction of heteroatoms. Our aim is to develop novel transformations of nitroalkanes, both for their preparation, as well as explore new reactivity of these compounds. Reactions such as the alkylation of nitroalkanes with simple alkyl electrophiles has been a long standing challenge in organic synthesis. This seemingly simple transformation is of potential significance because it would allow simple nitroalkanes to be converted into much more complex structures. However, the desired reactivity has been traditionally dominated by alkylation at oxygen. Using a simple copper catalyst, we have shown that C-alkylation of nitroalkanes can be achieved using a broad-range of alkyl halide electrophiles. On-going studies are aimed at further expanding the scope of this transformation, rendering it asymmetric, and furthering our understanding of the mechanism.
Highlighted Publications
- J. Am. Chem. Soc, 2023, 145, 8, 4707-4715
- Org. Lett. 2020, 22, 20, 8106–8110
- J. Am. Chem. Soc. 2019, 141, 8436–8440
