Research Description

Development of New Gas-Releasing Molecules

A variety of gaseous molecules are commonly used as reagents in chemical synthesis and binding studies.  While pressurized cylinders are the most obvious form of delivery of gaseous reagents, there are significant drawbacks when the gas has safety, stability, or other practical handling concerns. Small molecule gas-releasing molecules (GRMs) offer a powerful alternative for delivery of small quantities of gas for practical laboratory uses. These GRMs release gas when triggered by appropriate reaction conditions, and they can be designed for ex situ delivery (the gas-releasing reaction is physically separated from the gas-consuming reaction) and/or in situ delivery (the gas is being produced in the same vessel as the gas-consuming reaction) as shown in the figure above. The most common class of GRMs are the CO-releasing molecules (CORMs), since carbon monoxide (CO) is both a highly versatile one-carbon building block and is toxic due to its ability to bind to the hemoglobin in red blood cells.

In the Tasker Lab, while studying the reactivity S-aryl thioformates (see below), we serendipitously discovered that these molecules release CO rapidly at room temperature upon treatment with an amine base.  These molecules, which we dubbed (punnily!) thioCORMates, have some advantages compared to existing CORMs with respect to cost, ease-of-use, and atom economy. In addition, the rate of CO release is tunable by placing electron-donating or electron-withdrawing groups on the aryl ring (see video demonstration here).  We have demonstrated the thioCORMates in a range of applications, from organic carbon–carbon bond-building reactions to protein binding to synthesis of iridium complexes.

F&M students on this project work to develop new gas-releasing molecules. This process involves a variety of skills including synthesis of the molecules themselves, mechanistic studies and optimization of gas-releasing conditions, and developing new applications for the gases produced.  

Further Reading: 

Photochemistry of S-Aryl Thioformates and Acetates

Using photons of light to provide the energy for a chemical reaction to occur (rather than thermal energy in the form of heating reaction mixtures) can promote unique and interesting reactivity.  Photochemistry has undergone a renaissance in the 21st century, particularly with the wide adoption of photoredox catalysts which can modulate light energy to accomplish electron transfer (redox) reactions.  Molecules in their excited state can undergo concerted pericyclic reactions involving orbital overlap (HOMO/LUMO), or can enter radical pathways. Developing new photochemical reactions can facilitate synthesis of molecules of interest, including pharmaceuticals, organic materials, and complex natural products.

In the Tasker Lab, we are interested in the photochemistry of thioesters like the S-aryl thioformates and acetates shown below.  Upon excitation by direct ultraviolet irradiation or mediated visible light catalysis, thioesters can access an excited state which is primed for [2+2] cycloaddition—the Paternò–Büchi reaction—to form oxetanes.  Alternatively, Norrish-Type I fragmentation can give rise to thiyl and acyl radicals, which can be harnessed in further synthetic transformations.

F&M students working on this project are able to work in novel reaction development (the same process which originated all the reactions learned in Organic Chemistry classes!).  They investigate a variety of reaction conditions through screening, learning how to analyze reaction results by gas chromatography.  Reaction development also involves diving deeper into reaction mechanisms to understand how molecules produce the products observed.

Further Reading: 

Antibiotic Natural Product Synthesis and Development

The spread of antibiotic resistance is a serious threat to human health that is exacerbated by the lack of new antibiotics under development. Traditionally, natural products (small organic molecules produced by living organisms) have served as a rich source of antibiotics, due to evolutionary pressures for organisms to kill competing or pathogenic bacteria in their environment. In fact, between 1981 and 2019, 72% of the 132 novel FDA-approved antibacterial drugs were derived in some way from natural products. While unaltered natural product molecules are sometime used in the clinic, significant structural modifications of active natural products are often necessary to increase potency, avoid resistance mechanisms, or improve drug-like properties. 

In the Tasker lab, we are interested in synthesizing natural products in the lab with reported antibacterial activity, and then making a variety of different unnatural derivatives and testing their ability to kill bacteria.  Investigating the effect of structural modification on a molecular target of interest to optimize its biological activity is a core practice in medicinal chemistry, and is referred to as determining Structure–Activity Relationships (SAR).  Our aim is to understand the scope of modification possible, as well as potentially finding more active derivatives. 

F&M students working on this project are able to develop their organic synthesis skills (running a variety of reactions using modern techniques such as cross-coupling and air-free synthesis) while at the same time evaluating their compounds in bacteria (growing and working with bacterial strains, performing Minimum Inhibitory Concentration assays).  

Further Reading: 

Research Support