Abstract: “The building block-based approach is increasingly being recognized as a highly flexible and efficient method for the automated construction of molecules. For biomolecules such as polypeptides, oligosaccharides, and oligonucleotides the common linkages between building blocks is easy to recognize. This has led to the development of automated platforms which have broadly enabled both experts and non-experts to explore biomolecule chemistry. If a similar strategy could be applied to small organic molecules, the societal impact would be tremendous as it would address a key bottleneck in the development and discovery of new drugs, fragrances, fertilizers, and materials. Toward the objective of creating a building block-based platform for small molecule synthesis, we have developed a novel method of forming carbon-carbon bonds in near perfect selectivity using carbenoid-boronate building blocks. We are now demonstrating how the saturated and unsaturated portions of small molecules can be installed using this platform, thereby paving the way to the automated construction of small molecules. To further demonstrate the utility of our new method, we plan to complete the synthesis of a natural product, sch 725674, an antifungal macrolide.”

ECI 2020 Talk Transcript

Abstract: “This project describes a site-selective functionalization of an alkenyl C-H bond using a modified Catellani reaction. The Catellani reaction, catalyzed by palladium and norbornene, traditionally results in both ortho and ipso functionalization of an aromatic ring. However, the corresponding alkenyl C-H functionalization via Pd/norbornene dual catalysis remains rare. On the other hand, Pd(II)-catalyzed directed C-H activation is well established through the formation of a palladacycle intermediate. This strategy relies heavily on substrate design and typically only activates the proximal C-H bond. In order to mediate these limitations, we report a catalyst-controlled distal alkenyl C-H functionalization. The reaction conditions are fairly mild and the time span of the reaction is only twelve hours. A variety of functional groups were shown to be compatible with the reaction conditions. In addition, both cyclic and linear alkenes reacted to form the desired product in a high yield. Mechanistic studies demonstrated that the reaction mechanism is consistent with that of the proposed Catellani reaction. Ultimately, the reported reaction is one of the first reactions in which the Catellani reaction can be applied to an alkenyl C-H bond to result in a distal C-H bond functionalization, providing a new and elegant synthetic tool.”

Text Transcript_Fatuzzo

Abstract: “Suzuki-Miyaura (SM) coupling is a metal-catalyzed carbon-carbon bond reaction between organoboron and organohalide under basic conditions. Cross-coupling reactions are typically catalyzed by the expensive palladium (Pd) catalyst. This reaction is commonly used in the synthesis of pharmaceuticals, polymers, and agrochemicals. Our objectives include using the WebMO software in understanding the chemical and physical properties, and the energetics of the reaction between 5-bromopyrimidine and furan-3-boronic acid (Scheme 1) and the reaction between 5-bromopyrimidine and 2-methoxypyridine-3-boronic acid (Scheme 2), along with their products. Our calculations indicated that Schemes 1 and 2 are endothermic reactions, conforming to the well-known fact that connecting two sp2-hybridized carbons is a challenging task. The BDE data reveal that the strength of the C-X bond in the series of halobenzenes decreases with increasing size of the halogen. The C-X bond distances mirror this trend, with the longest bond (C-Br) also being the weakest. In the context of the oxidative addition step of a typical catalytic cycle for a Pd-catalyzed coupling reaction, It can be concluded that the C-Br bond is the most susceptible to oxidative addition. In the broader sense, the BDE data illustrate why aryl bromides are common starting materials for Pd-catalyzed couplings rather than the less expensive and environmentally more favorable aryl chlorides.”

TextTranscript_Paskach

Paskach_Slides.pptx

Abstract: “Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease characterized by muscle wasting, myotonia, cardiac defects, and more. DM1 symptoms are caused by expanded RNAs, r(CUG)exp, that exist as imperfect hairpin structures and sequester alternative splicing regulators, such as muscleblind-like protein 1 (MBNL1). Our therapeutic approach is to rationally design small molecules that target r(CUG)exp and release MBNL1. One of the most accessible methods to assess probable ligand-RNA interactions is computational modeling. Molecular dynamics simulations allow for visualization of the possible binding modes of ligands and computations to assess their relative stabilities; coupled with experimental data, these simulations can provide useful insights to explain the relative binding strengths of different ligands. Molecular dynamics systems are neutralized with counterions to prevent electrostatic repulsions within nucleic acid molecules from skewing the results of the simulation. Generally, simulations are neutralized with a single counterion, such as sodium or magnesium. With the goal of better approximating cellular conditions in silico, we have developed a new neutralization scheme using cellular concentrations of magnesium, sodium, and potassium. We are currently validating the method via comparison to previously reported simulations.”

Text_Transcript_Kocheril