Projects in the Beeler Group are focused on synthesis and medicinal chemistry of biologically active small molecules. We focus on developing efficient and scalable processes to synthesize scaffolds of interest. We select molecules that we believe may be optimized as powerful tools to better understand biological processes important to human health. Ultimately, these tools can serve to identify new therapeutic targets or even be lead molecules for future therapeutics.

Photochemistry & Flow Chemistry

This area focuses on photochemical transformations toward the synthesis of natural products, natural product scaffolds, and other complex chemotypes of interest to medicinal chemistry and chemical biology. Flow chemistry has emerged as a powerful tool with many advantages over batch chemistry; its advantages are proved most dramatically in photochemistry, where steady state conditions can be scaled indefinitely. In our Group, we use photochemistry and flow chemistry in a complementary manner to develop robust, useful methods of accessing molecular scaffolds which would be otherwise evasive.

Organic Photoredox Catalysis - Synthesis of Classical Lignan Scaffolds

Classical lignan natural products (CLs) constitute a large, diverse family of phenylpropanoid dimers which exhibit interesting biological activity (e.g. podophyllotoxin). By employing improved organic photoredox catalysts - MD(p-Tol)PT and DTAC - we have gained coordinated access to all CL subtypes using 3+2 cycloadditions of carbonyl ylides and dipolarophiles. The postulated intermediate (bis para-quinone methide) mimics Nature's construction of the CL family and gives access to key entrypoints. Further manipulation of oxidation state grants access to the remaining CLs and several natural products with high efficiency - including the aryltetralin subfamily [link].

2+2 Photocycloadditions

Truxinates are head-to-head cinnamic acid photodimers expressed broadly in Plantae and are found in a number of bioactive natural products. The robust and diastereoselective synthesis of truxinates has remained a major challenge since their isolation. Using filtered UV-light (>305 nm) and a bis-thiourea H-bonding catalyst in continuous flow, we have improved the yield and diastereoselectivity of the intermolecular [2+2] photocycloaddition of cinnamic esters [link]. With further development, we found that the use of biphasic slug flow dramatically accelerates the homodimerization by improving mixing and efficiency of irradiation. This improved protocol boosted yields, shortened reaction times, and expanded the reaction scope [link].

​More recently we have found that catechol is a highly practical template for synthesizing homo- and heterodimeric beta truxinates in scalable fashion. We applied this strategy firstly to the synthesis of potent anticancer compounds, piperarborenines C, D, and E on multigram scale (currently in ChemRxiv; [doi]). A medicinal chemistry campaign on the beta piperarborenines is currently underway, as well as a full investigation of the scope and applications of the catechol-tethered truxinate synthesis.

Dearomative Ring Expansions

The intermolecular Buchner ring expansion is one of the few methods for generating seven-membered carbocycles from arenes. However historically, it has been burdened by mixtures of regioisomeric products, due in part to its exothermic nature and nitrogen out-gassing. By leveraging the back-pressure and increased heat exchange characteristic of flow reactors, we developed a method for the intermolecular Buchner ring expansion with improved regioselectivity and enantioselectivity. [link]
Azepines are represented broadly in natural products, pharmaceuticals, and investigational molecules. Traditional methods of azepine synthesis involve ring-forming reactions which can have significant limitations or rely on expensive transition metal catalysts (e.g. ring-closing metathesis). In our continued interest in dearomative ring expansion methodology, we developed a mild and efficient protocol wherein azepines are synthesized by a visible-light-mediated ring expansion from aromatic N-ylides, constituting a formal aza-Buchner ring expansion. On deprotonation with base under blue light irradiation, N-aromatic salts undergo a dearomative ring expansion providing monocyclic and polycyclic azepines. There are many established methods to synthesize pyridines, so this approach offers a convenient new route to access azepines by two-step N-alkylation followed by ring expansion. [link]

FLOW CHEMISTRY

One of the core components in our research is development of continuous flow technologies to facilitate the synthesis and medicinal chemistry of target molecules. Flow chemistry has emerged as a powerful tool to enable reactions that have traditionally been challenging to carry our and/or difficult to scale. We are utilizing flow technologies to develop photochemical reactions and reactions utilizing reactive intermediates. The methods we develop are applied to the synthesis of molecules for medicinal chemistry. 

Flow Synthesis on the International Space Station
The ability to synthesize organic chemicals on-demand may be crucial in the future of space travel and colonization. We worked closely with Space Tango to develop a Flow Chemistry Cube Lab for conducting organic chemistry reactions in a self-contained system on the International Space Station National Lab (ISS-NL). A first of its kind, the Cube Lab is equipped with cameras, pumps, flow meters, pressure sensors, and sophisticated valving to ensure safe and efficient operation. On its first mission (SpaceX CRS-20), the Cube Lab carried out three different chemical reactions each with multiple trials. This has served as an important proof of concept for synthesis-on-demand onboard the ISS-NL and its findings will guide future efforts for organic synthesis in spaceflight.

HIGH THROUGHPUT EXPERIMENTATION
High-throughput experimentation (HTE) is a set of technologies that allow for many hundreds or thousands of reaction conditions to be assessed simultaneously. Naturally, HTE has proven itself tremendously useful in organic chemistry, being instrumental in the efficient assembly of large medicinal chemistry libraries and in identifying optimal reaction conditions for process optimization. In the Beeler Lab, we’re using HTE to produce highly-consistent datasets to train machine learning algorithms on chemical reactivity. To do this, we’ve built an automation-friendly platform for the distribution of starting materials, incubation of reactions, and have developed a simple, ultra-rapid sample analysis technology to measure reaction success. Working closely with the Kolaczyk Group, we’re taking a multi-faceted approach toward quantifying our understanding on what intrinsic and extrinsic variables affect conversion to product and how best to train machines on such phenomena.
MEDICINAL CHEMISTRY

The Ubiquitin-Mediated Protein Degradation of Histone Acetyltransferase TIP60 to Suppress Treg Cell Activity
Regulatory T (Treg) cells suppress inflammatory immune responses. Treg cell over-expression has been observed in many cancers, making it a great target for potential cancer therapies. A key Treg transcription factor, Foxp3, is a protein that is acetylated by TIP60 histone acetyltransferase protein in multiple types of cancers. Even though Foxp3 acetylation by TIP60 has been targeted for over a decade, there have been no successful inhibitors with high potency and selectivity. Therefore, we are using the targeted protein degradation technology for faster and more beneficial ubiquitination and degradation of TIP60. Protein degradation is a relatively new strategy where the target protein is being degraded by the proteasomal degradation machinery inside the cells. This approach has more benefits compared to functional inhibition, including a longer lasting suppression of the target protein, higher suppression rate of the protein, and more effective cell proliferation and higher apoptosis induction. We have synthesized a small library of TIP60 inhibitors through a fragment based design, and the most active molecule was tested in a Treg suppression assay by our collaborator- Wayne Hancock at Philadelphia Children’s hospital. Using rational design, we optimized the potency of existing TIP60 inhibitors and generated a library of CRBN-based degraders by conjugating the active molecules CRBN ligands. By varying the linker composition and length, we were able to assess conditions that allow for effective degradation of TIP60 in vitro and in vivo.

Synthesis and Development of Potent Anti-Prion Compounds
​Prion diseases are rare, but fatal neurodegenerative diseases caused by widespread accumulation of misfolded prion protein. These misfolded isoforms accumulate through an unusual autocatalytic self-templating process, which shares some similarities to Alzheimer’s disease progression. This suggests therapy development for prion diseases may inform strategies for addressing more widespread neurodegenerative diseases which progress similarly. For several years, we have been working alongside the Harris Lab to identify potent compounds to rescue cells from toxic prion infection and are excited to learn more about our highly-potent chemotype and promising live-animal studies.