Chemistry Research Projects 2022

Reece Carew-Lyons

Advisor: Bill Malachowski

Enantioselective Total Synthesis of Cephanolide B via Birch-Heck sequence

The Malachowski group has previously focused on synthesizing phenanthridinone analogs with more chiral centers and sp3 carbons, developing the Birch-Heck reaction sequence as an efficient tool to generate these molecules. Another class of molecules known as cephalotaxus diterpenoids have reported antitumor, antineoplastic, and antiviral bioactivities. The sequence used for generating enantioselective phenanthridinone-like molecules can be applied to the synthesis of cephalotaxus diterpenoids, specifically the one I will be working with known as cephanolide B. Using the Birch-Heck sequence previously studied in the Malachowski lab group, the main goal of my project this summer will be to create a tricyclic core structure via an enantioselective Heck reaction. Multiple different approaches using both palladium (II) and nickel (II) catalysts will be used in order to create this 6-6-6 tricyclic structure. Once this reaction can be achieved, it can be taken through the proposed total synthesis to produce cephanolide B. If successful, this will be the most efficient sequence to cephanolide B (only 12 reactions) while also being enantioselective. This proposed sequence could be useful in drug development as the family of cephalotaxus diterpenoids have potent anti-tumor activity.

Trinity Dillard

Advisor: Yan Kung

Exploration of HsMK and ScMK Structure and Functionality

The mevalonate pathway is an important metabolic pathway that is responsible for the production of isoprenoid building blocks. Isoprenoids are the largest class of natural products and are essential for cell life. This class is especially important as isoprenoids are commonly employed in drug treatments. The fourth step in the mevalonate pathways is catalyzed by the enzyme mevalonate kinase (MK). This is an ATP-dependent phosphorylation of mevalonate and is often the target of feedback inhibition. Focusing on two homologs of MK, Homo sapiens (HsMK) and Saccharomyces cerevisiae (ScMK), I will try to crystalize and determine the structure with both an analog of ATP and the substrate mevalonate bound. In addition, I will research MK inhibition, specifically the structure of a competitive inhibitor, GGPP, bound to each MK homolog to determine orientation. The results of this research will aid in the understanding of MK’s structure and functionality.

Christina Douglas

Advisor: Bill Malachowski

Advancing Cephanolide B Synthesis Using Racemic Material

Cephanolide B is a compound with anticancer activity, and an efficient synthesis for this compound would allow for further research of its properties and medicinal application of the compound. Another member of the Malachowski group has proposed an enantioselective, 12-step synthesis for cephanolide B from relatively simple reagents and will be focusing on successfully conducting the second reaction of the process, the enantioselective step. Thus, my research will explore the subsequent steps of the synthesis with racemic material. The results of these experiments will later be applied to the enantioselective product of the second reaction. By taking the racemic product of the second reaction forward through other steps in the synthesis and working to efficiently generate the product of each step, significant progress can be made toward an efficient synthesis of cephanolide B using the proposed synthesis. Another aspect of my research will be to efficiently conduct the Birch reduction-alkylation and esterification necessary to transform 4-methyl phenylacetic acid into one of the necessary starting reagents for cephanolide synthesis. An efficient synthesis of cephanolide B may also make possible the synthesis of various derivatives that could demonstrate better potency or more advantageous drug properties, such as less susceptibility to metabolic decomposition or improved bioavailability.

Yael Eiben

Advisor: Patrick Melvin

Synthesis of Palladium Precatalysts Supported by Various Bidentate Ligands and Investigations into their Catalytic Abilities

Palladium precatalysts have become central to the improvement of a variety of catalytic transformations, but, in particular, cross-coupling reactions. These precatalysts have simultaneously yielded improved reaction conditions and generated novel reactivity. Therefore, we aim to synthesize and fully characterize a library of palladium precatalyst complexes supported by three different types of bidentate ligand: phosphine (P / P) ligands, analogues of bidentate N-heterocyclic carbene (NHC / NHC) ligands, as well as analogues of bidentate phosphine / N-heterocyclic carbene (P / NHC) ligands.  Following the synthesis of the NHC / NHC and P / NHC ligands, we aim to generate novel indenyl-based palladium precatalysts and to fully characterize these new palladium precatalysts by both NMR and X-ray crystallography. Further, we aim to ascertain the catalytic ability of these palladium complexes through the investigation of their efficiency in cross-coupling reactions

Rubia Fernandes

Advisor: Jonas Goldsmith

Bi-organometallic Complex as a Photosynthesizer and Electron Relay Duo-Compound

Transition metal complexes can serve as catalysts and electron shuttles, for producing hydrogen from water and sunlight so that it can be used as carbon-free source of energy. This catalytic process is based on an electron transfer facilitated by the shuttle between multiple transition metal complexes. The cycle is dependent on the interaction between a photosynthesizers, and an electron relay compounds, by combining them into one complex the catalytic process would become more efficient. Ruthenium and Rhodium will serve as the center of the transition metal complexes and they will be united through a COMU peptide coupling sequence. Ultimately, the goal will be to form [Ru(2,2’-bipyridyl)2(2,2’-bipyridine-5-carboxylic acid)]2+ and [Rh(4-amino-2,2’-bipyridine)2(2,2’-bipyridyl)]2+. Additionally, to reduce the amount of steric hindrance in such a complex structure, the length of the carbon chain in between the bipyridine and the carboxylic acid and amino groups will be explored to see it’s effect on yield and efficiency.

Sarah Gao

Advisor: Yan Kung

The Effect of Different Oligomeric Shapes on the Cofactor Specificity in BpHMGR

The enzyme HMG-CoA reductase (HMGR) in the mevalonate pathway has specific regions dictating the enzyme’s affinity to NADH or NADPH cofactors and is capable of forming polymers. Previous studies show that when the HMGR monomers assemble into a homodimer, the enzyme is specialized for NADPH. However, when an HMGR hexamer (trimer of three HMGR dimers) is formed, the enzyme is affinitive to NADH. My research will focus on whether changing HMGR’s spatial arrangement from a hexamer to three dimers will turn the enzyme’s preference for NADH to NADPH. I will perform mutagenesis studies on BpHMGR, which prefers NADH, by introducing a mutant that breaks the interfaces between the three HMGR dimers, thus switching HMGR from expressing hexamer to expressing homodimers. After expressing and purifying the mutated enzymes, I will determine their oligomeric states using size-exclusion chromatography. Furthermore, I will conduct kinetic experiments to test the enzyme’s activity and identify their NAD(P)H preferences. The potential results of this research will lead to a better understanding of the relationship between HMGR structure and cofactor specificity.

Madelynn Hicks

Advisor: Jonas Goldsmith

The Synthesis and Polymerization of Photosentizers and Electron Relays in Photocatalytic Light Harvesting Systems

The potential of hydrogen as a clean energy source and the pathway to a better, more green future for our planet is well known. Knowledge of water splitting, particularly water splitting which is green, efficient, and less costly, would provide a basis for new ideas concerning the transition to a hydrogen based economy, a cleaner environment, and a brighter future. Transition metal complexes are highly utilized as electron carriers and catalysts in the process of water splitting. More specifically, for this process to occur, transition metal complexes such as photosensitizers (PSs) and electron relays (ERs) must be employed in this electron transfer so hydrogen can be produced. The interaction between these two categories of transition metal complexes is of particular interest as increased efficiency in this portion of the reaction would lend to increased efficiency of the overall reaction, water splitting and hydrogen creation, as a whole. The long-term goal of my research is to use electropolymerization of vinyl groups which can be attached to the PSs and the ERs to create stacked, thin layers of the two such that electron transfer can occur more efficiently. My current goal is to synthesize the vinyl groups which will be attached to these PS and ER complexes.

Yui Kosukegawa

Advisor: Bill Malachowski

The Enantioselective Synthesis of Phenanthidinone Derivatives with Quaternary Carbon Through the Birch-Heck Sequence

The goal of my summer research is to learn the process of developing a new synthetic chemistry tool that would potentially improve current drug candidates. Studies show that currently, there are many drug candidates that have flat, aromatic structures with a high proportion of sp2 carbons. However, in fact, drug candidates with more chiral centers and sp3 carbons are more successful in clinical trials. This is because molecules with more quaternary carbons have higher selectivity and prevent undesirable interactions with other biomolecules. They are also believed to be more soluble and therefore better able to distribute themselves around the human body after administration.

This research focuses on the synthesis of phenanthidinone analogs. Phenanthidinone has a flat, aromatic structure like other drug candidates which can cause unwanted bioactivities in the body. To make phenanthidinone analogs with quaternary carbon, a new enantioselective synthetic tool called the Birch-Heck sequence is used. The sequence includes 1) Birch reduction-alkylation, 2) amid synthesis, 3) MOM protection, and finally 4) Mizoroki-Heck reaction. This summer, I will be focusing on the nickel-catalyzed Mizoroki-Heck reaction and improving the yield, stereoselectivity, and substrate scope of the reaction.

Hannah Kreider

Advisor: Bill Malachowski

Enantioselective synthesis of tricyclic compounds with chiral stereocenters using the Birch-Heck Sequence

Phenanthridinone and carbazole are two molecules that are often found in drug candidates due to their biological interactions. Their bioactivity is partially due to their structure: flat, aromatic molecules. However, these flat structures and their high levels of bioactivity often lead to problems such as adverse side effects. In the Malachowski lab, the goal is to develop a synthetic tool to efficiently create analogs of phenanthridinone and carbazole with chiral centers in order to reduce these side effects. Recent structural studies of drug candidates have shown that molecules with more tetrahedral, sp3 centers, including chiral ones, are more likely to succeed in clinical trials and eventually become successful drugs. The tool that allows the efficient and selective formation of chiral tetrahedral carbons, and that I will study this summer, is called the Birch-Heck sequence and it consists of four or five reactions. The first step in the sequence is the Birch reduction-alkylation reaction and it creates prochiral sp3 carbons with a variety of substituents from inexpensive benzoic acid. The second step is an amide bond formation and the third involves an amide nitrogen protection step. The final and most important step, the Mizoroki-Heck reaction, involves an intramolecular desymmetrizing reaction that enantioselectively creates a tricyclic molecule with two chiral centers. The Heck reaction product is an analog of phenanthridinone, but it contains two chiral sp3 carbon centers. The phenanthridinone analogs created using the Birch-Heck sequence will be tested for bioactivity related to anti-cancer properties.

Jenna Krussman

Advisor: Patrick Melvin

Investigation into the Deoxyflorination of Benzyl Alcohols and Benzaldehydes to Obtain Monofluoro- and Difluoromethyl Products

Recently, pharmaceuticals containing fluorine are becoming more prevalent due to the overwhelmingly positive influence fluorine can have on important metabolic properties.  Therefore, the development of quicker and more effective ways of including fluorine into organic molecules is highly impactful. One key method for installing fluorine into organic molecules is deoxyfluorination, a process that replaces an oxygen-containing functional group with fluorine. This summer, we will synthesize two different sulfonimidoyl fluoride reagents as this class of molecule has been previously shown to execute deoxyfluorination efficiently. Then, we will investigate the use of these reagents for the deoxyfluorination of benzyl alcohols to generate monofluoromethyl groups while also pursuing the transformation of benzaldehydes to difluoromethyl substituents.

Ruofei Li

Advisor: Yan Kung

Studying the role of the individual residues of HMGR cofactor helix in cofactor specificity

The mevalonate pathway includes seven enzymes responsible for synthesizing the precursors to steroids and isoprenoids, many of which are used as drugs, fragrances, and fuels. HMG-CoA reductase (HMGR), the third enzyme in the mevalonate pathway, binds two molecules of the cofactor NAD(P)H to reduce HMG-CoA to mevalonate. The cofactor helix is an alpha helix in the vicinity of NAD(P)H in HMGR, which is suspected of controlling the preference for either NADH or NADPH cofactors. The previous work has switched the entire cofactor helix between NADH-preferring DaHMGR and NADPH-preferring SpHMGR, and it turns out that both enzymes also switched their NAD(P)H preference. My research will focus on the relationship between individual residues of the cofactor helix of HMGR and the HMGR cofactor specificity. To address this, I will use mutagenesis to make mutations to switch single, double, or triple residues between DaHMGR and SpHMGR cofactor helix that were previously implicated in cofactor specificity. After expressing, purifying, and applying kinetics experiments on the modified HMGR protein, I will observe and determine the effect of those individual residues on cofactor specificity. This study is important because it gives us a better understanding of the HMGR structure and mechanism.

Darya Ostapenko

Advisor: Sharon Burgmayer

Increasing the effectiveness of Moco model compounds synthesis and deriving Sulfido- Bis(tetrasulfido)molybdenum(IV) Anions

Molybdenum enzymes are a cornerstone of multiple catalytic reactions involved in oxygen transport that are vital for virtually all living organisms, including humans. A Molybdenum cofactor (Moco) is found at the active site of those enzymes. Burgmayer group focuses on making and analyzing the synthetic model compounds for Moco in order to help the scientific community gain a better sense of mechanisms involved in molybdenum enzymes operations.

Synthesizing Moco-resembling complexes is a multistep process that involves numerous intermediate steps and handling special equipment. During the last SSR program, I learned how to use the Schlenk line, gained proficiency in conducting several inorganic synthesis reactions, and studied the impact of factors such as moisture and oxygen presence on the reaction speed and the yield of the products.

This summer, I plan to further develop my IR and NMR spectroscopy skills to finalize my conclusion on whether heating can negatively affect the purity of synthetic [TEA][Tp*Mo(+4)S(S4)], a precursor for one of our model compounds. Moreover, I intend to study and synthesize other complexes involved in Moco modeling, such as 2-pivaloyl-6-chloropterin and [TEA][Tp*Mo(CO)3], while looking for ways to improve the procedures. Later in the research I will be assigned a project first undertaken by a former lab member, Emma. The project entails synthesis and analysis of bis-dithiolene molybdenum complex found in the cofactors of DMSO reductase family enzymes.

In conclusion, my research goal would be to continue working on the projects the group has started in the past, provide other lab members with necessary compounds by synthesizing them, and deepen my understanding of the Burgmayer research.

Erin Ramsey

Advisor: Yan Kung

Structural Analysis of Mevalonate Kinase

The mevalonate pathway is a metabolic pathway that generates precursors to steroids and isoprenoids, compounds with applications ranging from anticancer drugs to biofuels. Mevalonate kinase (MK) is a key enzyme in this pathway that phosphorylates mevalonate using ATP to generate 5-phosphomevalonate. MK is also a major site of feedback inhibition. Although several crystal structures of MK from various organisms are currently available, the structure of MK while bound by both its ATP and mevalonate substrates remains unknown. The goal of this research is to employ X-ray crystallography to visualize the structure of two mevalonate kinase homologs (ScMK and MjMK) when bound by a non-hydrolyzable ATP analog and mevalonate, which will further our understanding of MK’s reaction mechanism and process of inhibition.

Angelina Rogatch

Advisor: Sharon Burgmayer

Silence in Mo-court: Interrogating the Non-innocent Pterin Ligands in Molybdenum Cofactor

Molybdenum enzymes, implicated as among the earliest bioinorganic catalysts, are vital to nearly all forms of life on Earth. The slightest malfunction in the cohesive mechanism of molybdenum bioinorganic catalysis results in severe neurological damage and death in humans. Therefore, the catalytic site of Mo enzymes known as the molybdenum cofactor (Moco) has become a major focus of the Burgmayer research group. In the Burgmayer research group, synthetic model compounds for Moco are actively being used to study pterin dithiolene ligand functions and their biochemical role.

Model compound synthesis is a multi-step process involving both organic and inorganic branches of synthesis. One of the focuses of my research focus is the synthesis of Tp* ligand, an ancillary ligand that improves solubility and stabilizes the model compound (as recorded in Inorg. Chem. 2001, 40, 7, 1677–1682), and TEA+[Tp*Mo(CO)3-], an inorganic “skeleton” needed for further stages of model compound synthesis. Another potential direction of my research is pterin ligand synthesis. By mastering various synthetic techniques, such as Schlenk line, and developing fluency in different analysis methods, such as FT-NMR, FT-IR, UV-vis, my goal is to optimize the synthetic procedures used by Burgmayer research group.

Eunjeong (Sal) Shin

Advisor: Sharon Burgmayer

Mononuclear molybdenum (Mo) and tungsten (W) enzymes form different groups of enzymes that are essential to the living organisms. These groups of enzymes specifically play an important role in the metabolic and catabolic process of transferring oxygen atoms. They also have structurally complex cofactors, molybdenum cofactor (Moco), which includes molybdopterin (MPT). The role of MPT is still not completely understood and in order to study this cofactor, the team goes through numerous synthesis steps where I will focus on the beginning steps of this synthesis. The cornerstone material, neutralized chlorinated pterin-HCl, is made with four steps, making pterin (using reflux technique), pterin-8-oxide, chlorinated pterin as a form of HCl salt, then obtaining neutralized chlorinated pterin-HCl for later steps. Furthermore, I will be working on finding possible modifications that could make the synthesis faster with higher yield. I will also gain experience on how to work on a Schlenk line under nitrogen which is used for the fifth step, making piv-Cl-pterin, an air-sensitive material.

Catherine Soto

Advisor: Bill Malachowski

Stereoselective synthesis of non-planar phenanthridinone derivatives via Birch-Heck sequence

Tricyclic phenanthridinone derivatives have shown significant bioactivity and may serve as good lead compounds, but their planar architecture can be a liability in drug development programs. For that reason, enantioselective synthetic transformations that produce sp3 carbons and quaternary stereocenters are being explored in Malachowski research group. Quaternary and sp3 carbons have been shown to be more prevalent structures in successful drugs because they had less random or unwanted binding to protein structures. It is also thought to have enhanced solubility, which is essential for drug distribution in the body. However, prior research on phenanthridinone derivatives that have quaternary all-carbon stereocenters has not been reported. The Malachowski group has discovered and recently reported a new synthetic tool called the Birch-Heck sequence that has generated some new phenanthridinone derivatives, but more are needed. 

​​This process is a four-step synthetic sequence where inexpensive benzoic acid is converted into new phenanthridinone structures. My research goal is to develop phenanthridinone derivatives through new synthetic tools that help expand access to complex molecules that have the potential to be better drug candidates. This summer I will be working to further develop this reaction and generate new phenanthridinone derivatives for biological testing for anti-cancer activity

Ebrar Yilmaz

Advisor: Patrick Melvin

Synthesis of Acid Fluorides, Trifluoromethyl Groups and Aryl Fluorides Via Deoxyfluorination Using Sulfonimidoyl Fluorides

Fluorine is one of the more privileged atoms of the periodic table and has been frequently used in the pharmaceutical industry to increase metabolic stability and lipophilicity of potential drug targets. In recent years, a great deal of attention has been given to developing different approaches to incorporate fluorine into organic molecules, with deoxyfluorination being the most prevalent. Our goal is to design reagents that will increase the efficiency of deoxyfluorination reactions. In particular, we aim to synthesize two sulfonimidoyl fluoride reagents that will be utilized 1) to convert benzoic acid substrates into trifluoromethyl substituted compounds; 2) to transform phenols into aryl fluorides and 3) to see how these reagents participate in conjugate addition reactions.

Ruolin Zhang

Advisor: Jonas Goldsmith

Synthesis of a bi-metallic macromolecule and vinyl bipyridine thin films to optimize the photocatalytic water reduction system

The demand for clean and renewable resources has been increasing in the past few decades. Hydrogen, popular clean energy used to slow down global warming in recent decades, was produced in an environmentally-harm way, so it is essential to find a clean production method, the photocatalytic water reduction system. Three molecules included in the system are photosensitizer(PS), electron relay(ER), and Sacrificial Reductant (Sac). Sac will donate the electron to PS, and with the energy from light, the electron in PS will be excited to a higher energy level. ER is the intermediate molecule that can carry the energy from the excited electron to reduce water. The synthesis and attaching between PS and ER are focused on in this research. Two possible applications for PS and ER attaching are the synthesis of bi-metallic macromolecules and vinyl bipyridine thin-film production. The macromolecules are produced when PS is already attached to ER. The period when PS stays at an excited state is short, so it is hard to find an ER in nanoseconds. The pre-connection achieved by peptide bond formation can work out this problem to make electron transfer happen, which can save light energy and increase hydrogen production. The formation of vinyl bipyridine thin films can also increase the efficiency of hydrogen production. The PS and ER now contain the vinyl groups, and their thin films will be put at a pre-position achieved by the electropolymerization process of the group. This summer research aims to successfully synthesize photosensitizers and electron relays that can be used in macromolecules formation and thin films of PS and ER. Additionally, the time and percent yield will be compared to figure out which functional groups on PS and ER are optimal choices for bi-metallic molecule production.