Room 105

Room 105 | 8:45 a.m.

Energy-Activated and Diversifiable Aryne Precursors

Presented by: Felicia Yu

Felicia Yu; Chris M. Seong; Sallu S. Kargbo Courtney C. Roberts.

yu015478@umn.edu; ccrob@umn.edu

Decorated aromatic rings are ubiquitous in pharmaceuticals and agrochemicals which contribute significantly to human health and wellbeing. Arynes–a triple bond in a benzene ring–are a promising platform of generating decorated arenes due to their reactive ring strain, enabling functionalization at both termini of the triple bond. State-of-the-art aryne precursors are plagued by two challenges: i) the additives required for activation are incompatible with many functional groups intrinsic to the aryne itself as well as the coupling partners which limits the scope, and ii) derivatization of the precursors requires multistep synthesis often using harsh conditions rendering them impractical. Here, we show the design of an o-iodoniobenzoate aryne precursor made in a single step from a commercially available carboxylic acid and then derivatized in a single nucleophilic aromatic substitution (SNAr) step. Unprecedented aryne activation proceeds using blue light or mild heat, avoiding the use of additives. This represents the first example of visible light being used to activate aryne reagents. In this work, we also identified two substituent-dependent design elements governing these energy-activated precursors. Next, we turned to expand the substitution restriction by redesigning the ancillary ligand on hypervalent iodine. The proof- of-concept studies demonstrate the novel chromogenic precursors potentially overcome the limitation associated with ortho-substituent pattern, supporting the feasibility of our hypothesis for further investigation.

Room 105 | 9:10 a.m.

Asymmetric Inert Bond Activation and Functionalization Using Chiral 2-Aminopyridine Transient Directing Groups (cTDGs)

Presented by: Nitha Puthalath

Nitha Puthalath, Christopher J Douglas* 

putha007@umn.edu, cdouglas@umn.edu 

Transient directing groups (TDGs) allow catalytic installation and removal of a ligand, enabling transition metal catalysts to accomplish otherwise challenging transformations. Embedding chirality within the TDG itself (cTDG) enables asymmetric induction without additional chiral ligands. Early in my PhD work, I used 2-aminopyridine-based cTDG to access chiral benzosuberones by asymmetric intramolecular hydroacylation of alkenes with aldehydes. Next, we aim to develop a cTDG strategy to accomplish asymmetric skeletal rearrangements of cyclobutanones. 

Skeletal reorganization of 3-phenylcyclobutanones to indanones can construct an all-carbon quaternary stereocenter. Prior work used 2-amino-3-picoline as a stoichiometric TDG for rhodium, operated at high temperature (150 °C), and delivered up to only 65% yield of racemic indanone after 15 hours. Inspired by this chemistry, we sought to develop a catalytic TDG variant. We introduced an electron-donating N-pyrrolidinyl group to the 2-amino-3-picoline structure, aiming to improve the TDG’s nucleophilicity. This change dramatically improved the reaction efficiency, enabling full conversion to indanone (>99% yield), now using the TDG as a catalyst (30 mol%) at 100 °C within 2 hours. Our current focus is to achieve useful levels of enantioselectivity using a cTDG. My studies revealed that both yield and enantioselectivity depend on four key variables: cTDG structure, solvent, proton source, and phosphine ligand. Studies with the aid of high-throughput experimentation (HTE) aim to identify the optimal combination of these variables and construct a multivariable linear regression model for enantioselectivity. I will present my progress on an enantioselective total synthesis of (–)-taiwaniaquinol B, to demonstrate our work’s synthetic applications. 

Room 105 | 9:35 a.m.

Structure-Property Relationships of Polymers with Main-Chain Polar Heterocycles

Presented by: Stephanie A. Castillo

Stephanie A. Castillo, Allison R. Wong, Jessica R. Lamb* 

casti334@umn.edu, jrlamb@umn.edu

Polyoxazolidinones (POxa) are an emerging subclass of polyurethanes with the urethane linkage embedded in a 5-membered ring known as an oxazolidinone (Oxa). The Oxa ring has a strong dipole (~ 5 D) and offers a unique opportunity to study strong, main-chain dipole-dipole interactions when incorporated into the polymer backbone. Current systematic studies of structure-property relationships on POxa and polar main-chain heterocycles are limited. Previous work in our group has studied the effects of dipole strength and orientation of main-chain dipoles on material properties and improved the synthesis of POxa to access soluble materials. In this talk, we expand on the previous work by systematically tuning polymer properties and leveraging post-polymerization modification via main-chain editing to diversify the polar main-chain heterocycles in polymers. We utilize step-growth polymerization followed by decarboxylative allylic substitution with a heteroallene coupling partner to access a variety of novel materials containing polar heterocycles. We will probe the extent and control of main-chain modification via variations in the heteroallene loading, and we will characterize the effects of main-chain editing on material properties via molecular weight and thermal properties. This study will allow us to further investigate the material properties of this interesting class of molecules and better understand the effect of main-chain dipoles, thus enhancing our insight into how structure influences material properties. 

Room 105 | 10:00 a.m.

EMPLOYING DECARBOXYLATION TO STUDY FIELD EFFECTS

Presented by: Nandha Karthikeyan

Nandha Karthikeyan, Jessica M. Hoover*

karth075@umn.edu, jmhoover@umn.edu

Field effects have been demonstrated to influence organic reactivity, enzymatic interactions, and molecular catalysis, but they have not been efficiently extended to a wider scope of chemical reactions and remain underutilized due to our limited understanding of the phenomenon. In particular, literature reports are often contradictory regarding the nature and manifestation of field effects, such as the through-bond vs through-space nature of the field effect. Recently, silver-mediated decarboxylation of substituted benzoates has been demonstrated to depend strongly on the field effects, with negligible influence from resonance and steric effects. 

Leveraging this result, our work aims to experimentally probe the through-space vs through-bond nature of field effects through the protodecarboxylation of silver(I)-carboxylate complexes. This goal will be achieved through the systematic synthesis and investigation of nitro-substituted carboxylic acids with varying scaffolds (benzoic, naphthoic, phenanthrene, aliphatic acids etc.). The measured rates of thermal protodecarboxylation of the series of Ag-carboxylate complexes will be correlated with structural features such as distance and dihedral angles between the substituent and carboxylic acid, directionality of the substituents, and aromaticity of the scaffold to gain insights into how field effects are influenced by these parameters. 

This talk will describe a brief background, experimental approach and our recent findings that correlate the rate of decarboxylation with the substituent position and aromaticity of the backbone rings. This work will provide an experimental framework into field effects to help establish structure-kinetic relationships and the ability to predict reactivity in reactions dependent on field effects.

Room 105 | 10:40 a.m.

CHALLENGES IN 5-MEMBERED HETEROARYNES: OVERCOMING BORATE COMPLEX FORMATION THROUGH COMPUTATIONALLY GUIDED LIGAND DESIGN

Presented by: Ali Younis

Ali Younis, Sanu Pullurat, Matt Fitzsimmons, Courtney Roberts

Youni017@umn.edu, ccrob@umn.edu

Arynes -- an aromatic ring with a triple bond -- are primed for one-pot difunctionalization, multicomponent, and pericyclic reactions and have been deployed in the synthesis of over 75 natural products. Yet for over a century, this chemistry has been essentially confined to six-membered rings. Five-membered N- and O-heterocyclic arynes carry too much strain to form by classical elimination, a verdict made formal by the Garg–Houk–Paton accessibility model and corroborated by Gribble's decades of unsuccessful attempts at 2,3-indolyne. Our group recently broke this barrier by binding the aryne to a low-valent nickel center, which lengthens the C≡C bond through π-back-donation thereby deeming 5-membered N-Heter- ocycles accessible. That strategy delivered Nickel-bound 7-azaindol-2,3-yne and several related 5-mem- bered N-heteroaryne motifs. Interestingly, structures lacking subtle steric interactions were found to form a borate complex instead of the desired aryne during the key transmetallation step. In this talk, the ligand design for overcoming this borate problem as well as isolation of three new N-heterocycles is demon- strated: 4-azaindol-2,3-yne and pyrrolo-2,3-yne pyrazine, and the first O-heterocycle, Benzofur-2,3-yne. With three new heteroarynes in hand, a previously unexplored class of reactivity for metal-bound 5- membered arynes is also presented.

Room 105 | 11:05 a.m.

MILD EXTERNAL BASE FREE SYNTHESIS OF α-ARYL-α-HETEROARYLMALONONITRILES VIA PROTON-TRANSFER DUAL-IONIZATION NUCLEOPHILIC AROMATIC SUBSTITUTION

Presented by: Avneesh Kumar

Avneesh Kumar, Aakash Gogate, Alexander Grenning*

Kumar960@umn.edu grenning@umn.edu 

Heteroarenes like quinolines and pyridines are ubiquitous in bioactive molecules. While Nucleophilic aromatic substitution (SNAr) reactions are a powerful transition metal- free approach for directly functionalizing arenes and heteroarenes, they typically require electron-withdrawing groups on the ring systems, strong bases, and/or elevated temperature conditions. which significantly limits the substrate scope of these transformations. To overcome these limitations, we report a fundamentally unique proton-transfer dual-ionization SNAr reaction between aryl malononitriles and haloheteroarenes. We hypothesized that the high acidity of aryl malononitriles (pKa = 4.2 in DMSO) would facilitate a proton transfer with haloheteroarenes, simultaneously activating both the electrophilic and nucleophilic components. This allows the reaction to proceed via a neutral Meisenheimer-like intermediate under significantly milder conditions. The versatile functional-group interconversions of malononitrile allow for divergent functionalization into pharmaceutically relevant compounds. Notably, this PTDI-SNAr reaction occurs rapidly at room temperature and faster in water and phosphate-buffered saline (PBS, pH 7.4) a clear contrast to classical anionic SNAr pathways and could be a new biorthogonal reaction. This presentation will detail the development of the reaction, including optimization, substrate scope, and mechanistic studies that address the inherent reactivity challenges of stabilized carbanions. Furthermore, we demonstrate the synthetic utility of this method through the divergent functionalization of the malononitrile group interconversions and its applications in the synthesis of quinolone antibiotics.

Room 105 | 11:30 a.m.

CHAIN-STRAIGHTENING, NON-ALTERNATING COPOLYMERIZATION OF a-OLEFINS AND CARBON MONOXIDE TOWARDS PHOTODEGRADABLE KETO-POLYETHYLENE

Presented by: Alison K. Duckworth

Alison K. Duckworth, Shao-Yu Lo, Ian A. Tonks*

duckw024@umn.edu, itonks@umn.edu

Polyethylene (PE) accounts for nearly one third of plastic produced globally, owing to its broad applicability in products such as packaging, containers, bottles, and bags. Without proper disposal, PE waste persists in the environment for centuries. An alternative “keto-PE” that has comparable physical properties to commercial high-density PE has been synthesized via non-alternating ethylene/carbon monoxide (ECO) copolymerizations; isolated ketone units in the polymer backbone serve as chain scission points via photodegradation. To date, more unique PE microstructures such as linear-low density PE (LLDPE) do not have photodegradable alternatives. Leveraging simple cationic (α-diimine)Pd catalysts that are well-established to polymerize long α-olefins with high linearity is a popular approach to access LLDPE-like polyolefins. Inspired by this system, this work copolymerizes α-olefins with CO to generate keto-PE with an LLDPE-like microstructure. Both chain-straightening and non-alternating character is achieved with highly tunable (α-diimine)Pd catalysts and CO/N₂ gas blends, enabling control of ketone incorporation and degree of polymer branching to generate a myriad of LLDPE-like keto-PE.

Room 105 | 11:55 a.m.

Regioselective Synthesis of Carbazoles: When Mechanistic Investigations Unveil Unexpected Reactivity

Presented by: Douglas M. Kavaguti

Douglas M. Kavaguti, Brylon N. Denman, Courtney C. Roberts*

kavag001@umn.edu, ccrob@umn.edu

The field of aryne chemistry has seen a surge in popularity over the past few decades. The value of arynes as reactive intermediates is owed to their ability to form multiple bonds in a short number of steps, increasing reaction efficiency and reducing overall waste. However, when unsymmetrical arynes are utilized, the regioselectivity of such transformations is often subpar. ortho-Borylaryl (pseudo)halides have more recently emerged as aryne precursors in organic chemistry. They can reliably generate metal-bound arynes, enabling a more consistent study of metal-catalyzed aryne reactions, thus unlocking the use of organometallic chemistry methodology to address current drawbacks in the reactivity of aryne intermediates. Previous work from our group has shown the effect of phosphine ligands in controlling the binding orientation of palladium-aryne intermediates, leading to improved regioselectivity in the synthesis of phenanthridinone products. Here, we employ phosphine ligands to enable an unprecedented palladium-catalyzed cross-coupling reactive pathway for ortho-borylaryl triflates, yielding substituted carbazoles with full regioselectivity. Mechanistic studies highlight the role of phosphine ligands in overriding the otherwise expected aryne-mediated reactive pathway and enabling cross-coupling reactivity. In addition, we make use of Hammett parameters to establish a predictive approach to optimize both substrate choice and overall reaction yields.

Room 105 | 1:35 p.m.

EXPANDING ACCESS TO PREVIOUSLY INACCESSIBLE HETEROARYNES

Presented by: Sanu S. Pullarat

Sanu S. Pullarat, Ali Younis, Matt Fitzsimmons, Courtney C. Roberts*

pulla024@umn.edu, ccrob@umn.edu

N and O-heterocycles are the most prevalent scaffolds in pharmaceutical and agrochemical industries. However, there is a lack of universal method to derivatize different heterocyclic cores. One potential method to achieve this derivatization is by using aryne chemistry. In 2023, the Robert’s group used organometallic techniques to report the first ever access to 5-membered N-heteroarynes. These functional groups were predicted to be energetically “inaccessible” due to high ring strain associated with the aryne “triple” bond within an aromatic ring, explaining why they have eluded synthetic chemists since their postulation in 1902. Nevertheless, the high ring strain in these five-membered ring systems can be alleviated by nickel backbonding and ligand donation. This work demonstrates access to new heteroaryne scaffolds from indoles, azaindoles, benzofuran, pyrrolopyrimidine, pyrrolopyrazine etc, by overcoming challenges with aryne formation. To the best of our knowledge 2,3-benzofuranyne is the first example of accessing a 5-membered oxygen containing heteroaryne which was characterized by SCXRD and NMR spectroscopy. Each of these substrates required various ligand/electronic modifications to enable access to the desired aryne product. The interesting ambiphilic character of these heteroarynes enable access to a variety of diversified heteroaromatic products. Additionally, we were also able to demonstrate with reactivity of newly accessed arynes in inverse electron demand Diels Alder reactions using tetrazines as the coupling partner. Current research is being focused on developing the first ever catalytic reactions with 5-membered arynes. These studies will provide the synthetic community a new platform for decorated heterocycle synthesis since arynes can undergo difunctionalization in a single step.

Room 105 | 2:00 p.m. 

N-HETEROCYCLIC CARBENE-CARBODIIMIDE (NHC-CDI) ADDUCTS AS TUNABLE PLATFORMS FOR STUDYING ORGANIC INTERMEDIATES

Presented by: Rolando Calderón-Oliver

Rolando Calderón-Oliver, Le Dung Pham, William Ramos, Anthony W. Schlimgen, Jessica R. Lamb* 

calde263@umn.edu, jrlamb@umn.edu 

N-Heterocyclic carbenes-carbodiimide (NHC-CDI) adducts are a versatile class of organic molecules. These zwitterions have been used as amidinate-type ligands, polymer linkages, (pre)catalysts, and mechanophores. Although their applications have been explored, not much has been done to understand their electrochemical behavior. In recent years, NHC-CDI adducts, with extended conjugated moieties in the CDI, were shown to undergo reversible single-electron oxidations. This electrochemical behavior makes them a promising platform for the stabilization and study of highly reactive organic intermediates, particularly radical cations and dications. These intermediates possess unique structural and electronic properties significant for the advancement of fundamental chemistry and materials. However, current redox-active NHC-CDIs suffer from limited solubility, tunability, and synthetic accessibility. We designed a simpler NHC-CDI platform, with substituted phenyls on the CDI, that can undergo single-electron oxidations. These adducts possess improved solubility and can be prepared from more accessible starting materials. Furthermore, the system can be structurally modulated to tune the observed redox properties. Electrochemical methods, like cyclic voltammetry, were used to better understand how minor structural changes can affect the redox behavior of this system. Parameters, such as half-wave potential and peak-to-peak separation, will be discussed to assess the stability and (electro)chemical properties of these adducts. This work provides fundamental understanding behind the redox-behavior of NHC-CDIs, enabling the development of tunable platforms for the study of reactive intermediates.

Room 105 | 2:25 p.m.

IDENTIFICATION OF APOBEC3A INHIBITORS FROM A COMPLEX-TO-DIVERSE NATURAL PRODUCT SCREEN

Presented by: Kate J. Dallmier

Kate J. Dallmier¹, Paul J. Hergenrother², Daniel A. Harki*¹ ³

1. Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States

2. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States

3. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States

dallm112@umn.edu, danharki@umn.edu

The APOBEC3A (A3A) enzyme is an endogenous source of DNA mutations that promote cancer metastasis and the evolution of treatment-resistant cancers. A3A is a cytosine deaminase enzyme that converts cytosine to uracil in single-stranded (ss) DNA utilizing zinc-coordinated hydrolysis. DNA repair enzymes immortalize the uracil as thymine producing DNA mutations. These mutations can promote resistance to cancer therapies, such as tyrosine kinase inhibitors in ALK⁺ lung cancer, and CDK4/6 inhibitors in HR⁺ HER2⁻ breast cancer. We hypothesize that the development of selective A3A inhibitors will improve the durability of current therapies by reducing tumor escape. Natural products are a rich class of molecules for drug development due to their complex structure and evolutionary optimization for biological functions. Consequently, we screened a complex-to-diverse (CtD) natural product library to identify A3A inhibitors. The CtD library was produced via ring distortion strategies of natural products and contains 982 stereochemically complex molecules with a high degree of sp³ carbons. Initial library screening utilized an in vitro plate-based deaminase activity assay and generated twelve potential hit molecules. An orthogonal gel-based deaminase activity assay assessed dose-response, which yielded three hits with sustained A3A activity. These hits were further tested for enzyme binding using surface plasmon resonance (SPR), and a single hit showed measurable binding (KD ~60 μM). Ongoing validation includes the resynthesis, retesting, and ultimately, medicinal chemistry optimization to improve potency for A3A-binding and inhibition of deaminase activity. This work represents the first instance of using a diversified natural product library to identify new APOBEC3A inhibitors.