The D. A. Watson Group is focused on the invention of new chemical reactions and their applications in organic synthesis. We choose to work in this area as organic chemistry 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.
A major focus of the Watson lab is the development of heteroatomic electrophiles in cross-coupling reactions. We have been particularly focused on novel Heck-like reactions.
Over the past several years, we have shown that both palladium and nickel catalysts can effectively convert simple alkenes into unsaturated organosilanes using electrophilic silicon reagents, such as silyl halides and triflates. Both vinyl and allyl silanes can be produced using these silyl-Heck reactions. Using mechanistic studies and rational catalyst design, we continue to design more effective and more convenient ligands and catalysts for these transformations.
Angew. Chem. Int. Ed. 2012, 51, 3663–3667.
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.
Using palladium catalysis, we have developed an intramolecular aza-Heck cyclization to form unsaturated lactams via activation of the N-O bond of O-aryl hydroxamates. These reactions proceed with excellent yields and exhibit exquisite functional group compatibility. Preliminary investigations have shown promising results towards an asymmetric aza-Heck reaction. Because of the interesting nature of the products, we expect this method will find use in the total synthesis of alkaloids and other biologically active compounds.
New Reactions of Nitroalkanes
Another broad theme in the Watson lab is the development of new reactions of nitroalkanes. These intermediates are widely used in organic synthesis both for the construction of carbon-carbon bonds, and for the introductions heteroatoms. Our aim is to develop novel transformations of nitroalkanes, both for their preparation, as well as explore new reactivity of these compounds.
The C-alkylation of nitroalkanes using 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.
Catalytic Construction of C-N Bonds at Alkyl Centers
Although catalytic construction of C-N bonds at aromatic carbons has received much attention over the last two decades, fewer studies have focused on such reactions at C-sp3 centers. In part this stems not only from the difficulty associated with oxidative additions at sp3 centers, but also the propensity of alkyl groups to undergo beta-hydride elimination. As nitrogen atoms are of prime importance in biologically-active compounds, we are exploring new reactions that allow C-N construction at alkyl centers.
Alkyl Lam-Chan Reactions
Over the past few years, we have discovered reaction conditions that allow the cross-coupling of primary amides with alkyl boronic esters. These reactions result in the construction of new C-N bonds at alkyl centers with minimal levels of beta-hydride elimination. Highly functionalized amides and boronic esters are both tolerated, as are secondary alkyl centers. Current efforts are directed at expanding the scope of these transformations, as well as exploring possible asymmetric variants.