Beeler Group Publications
Publications:
50. "High-Throughput Infrared Spectroscopy for Quantification of Peptides in Drug Discovery" Nathaniel Hendrick, Douglas Fraser, Raffeal Bennett, Kaitlyn Corazzata, Donovon A. Adpressa, Alexey A. Makarov, Aaron Beeler. Journal of Pharmaceutical and Biomedical Analysis. 2023, 115350. [link]
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Peptides have gained an increasing importance in drug discovery as potential therapeutics. Discovery efforts toward finding new, efficacious peptide-based therapeutics have increased the throughput of peptide development, allowing the rapid generation of unique and pure peptide samples. However, high-throughput analysis of peptides may be still challenging and can encumber a high-throughput drug discovery campaign. We report herein a fit-for-purpose method to quantify peptide concentrations using high-throughput infrared spectroscopy (HT-IR). Through the development of this method, multiple critical method parameters were optimized including solvent composition, droplet deposition size, plate drying procedures, sample concentration, and internal standard. The relative absorbance of the amide region (1600-1750 cm-1) to the internal standard, K3Fe(CN)6 (2140 cm-1), was determined to be most effective at providing lowest interference for measuring peptide concentration. The best sample deposition was achieved by dissolving samples in a 50:50 v/v allyl alcohol/water mixture. The developed method was used on 96-well plates and analyzed at a rate of 22 minutes per plate. Calibration curves to measure sample concentration versus response relationship displayed sufficient linearity (R2 > 0.95). The repeatability and scope of detection was demonstrated with eighteen peptide samples that were measured with most values below 20% relative standard deviation. The linear dynamic range of the method was determined to be between 1 and 5 mg/mL. This developed HT-IR methodology could be a useful tool in peptide drug candidate lead identification and optimization processes.
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49. "Multigram Scale Synthesis of Piperarborenines C-E" Jason M. Lenihan, Matthew J. Mailloux, Aaron B. Beeler. Org. Process Res. Dev. 2022, 26, 1812-1819. [link]
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We report the multigram scale synthesis of heterodimeric β-truxinic imides piperarborenines C-E using a catechol-tethered diastereoselective intramolecular [2+2] photocycloaddition. Key innovations lie in the use of catechol as a practical auxiliary for the synthesis of homo- and heterodimeric β-truxinates, and the use of a UV-LED flow photoreactor in the [2+2] step. This approach is highly scalable, requiring a single column purification, no photocatalysts, and no cryogenic conditions.
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48. "Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis" Sujoy Chatterjee, Shivraj M. Yabaji, Oleksii S. Rukhlenko, Bidisha Bhattacharya, Emily Waligurski, Nandini Vallavoju, Somak Ray, Boris N. Kholodenko, Lauren E. Brown, Aaron B. Beeler, Alexander R. Ivanov, Lester Kobzik, John A. Porco, Igor Kramnik. iScience, 2021, 102845. [Link]
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Macrophages contribute to host immunity and tissue homeostasis via alternative activation programs. M1-like macrophages control intracellular bacterial pathogens and tumor progression. In contrast, M2-like macrophages shape reparative microenvironments that can be conducive for pathogen survival or tumor growth. An imbalance of these macrophages phenotypes may perpetuate sites of chronic unresolved inflammation, such as infectious granulomas and solid tumors.
We have found that plant-derived and synthetic rocaglates sensitize macrophages to low concentrations of the M1-inducing cytokine IFN-gamma and inhibit their responsiveness to IL-4, a prototypical activator of the M2-like phenotype. Treatement of primary macrophages with rocaglates enhanced phagosome - lysosme fusion and control of intracellular mycobacteria. Thus, rocaglates represent a novel class of immunomodulators that can direct macrophage polarization towards the M1-like phenotype in complex microenvironments associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g. chronic bacterial infections, allergies and, possibly, certain tumors. |
47. "Recapitulating the Binding Affinity of Nrf2 for KEAP1 in a Cyclic Heptapeptide, Guided by NMR, X-Ray Crystallography, and Machine Learning" Paula C. Ortet, Samantha N. Muellers, Lauren A. Viarengo-Baker, Kristina Streu, Blair R. Szymczyna, Aaron B. Beeler, Karen N. Allen, and Adrian Whitty. JACS 2021, 143, 3779. [Link]
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Macrocycles, including macrocyclic peptides, have shown promise for targeting challenging protein-protein interactions (PPIs). One PPI of high interest is between Kelch-like ECH-Associated Protein-1 (KEAP1) and Nuclear Factor (Erythroid-derived 2)-like 2 (Nrf2). Guided by X-ray crystallography, NMR, modeling, and machine learning, we show that the full 20 nM binding affinity of Nrf2 for KEAP1 can be recapitulated in a cyclic 7-mer peptide, c[(D)-β-homoAla-DPETGE]. This compound was identified from the Nrf2-derived linear peptide GDEETGE (KD = 4.3 mM) solely by optimizing the conformation of the cyclic compound, without changing any KEAP1 interacting residue. X-ray crystal structures were determined for each linear and cyclic peptide variant bound to KEAP1. Despite large variations in affinity, no obvious differences in the conformation of the peptide binding residues or in the interactions they made with KEAP1 were observed. However, analysis of the X-ray structures by machine learning showed that locations of strain in the bound ligand could be identified through patterns of sub-Ångstrom distortions from the geometry observed for unstrained linear peptides. We show that optimizing the cyclic peptide affinity was driven partly through conformational pre-organization associated with a proline substitution at position 78 and with the geometry of the non-interacting residue Asp77, and partly by decreasing strain in the ETGE motif itself. This approach may have utility in dissecting the trade-off between conformational pre-organization and strain in other ligand-receptor systems. We also identify a pair of conserved hydrophobic residues flanking the core DxETGE motif which play a conformational role in facilitating the high-affinity binding of Nrf2 to KEAP1.
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46. "Unified Synthesis of Azepines by Visible-Light-Mediated Dearomative Ring-Expansion of Aromatic N-Ylides" Matthew J. Mailloux, Gabrielle S. Fleming, Shruti S. Kumta, and Aaron B. Beeler Org. Lett. 2021, 23, 525. [Link]
Featured in: Nöel et al Chem. Rev. 2022, 122, 2752-2906. [doi] ; Sarpong & Levin et al Nature Synthesis 2022 ; [doi]
Featured in: Nöel et al Chem. Rev. 2022, 122, 2752-2906. [doi] ; Sarpong & Levin et al Nature Synthesis 2022 ; [doi]
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Herein we report a unified approach to azepines by dearomative photochemical rearrangement of aromatic N-ylides. Deprotonation of quaternary aromatic salts with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N,N’,N’-tetramethylquanidine (TMG) under visible light irradiation provides mono- and polycyclic azepines in yields up to 98%. This ring-expansion presents a new mode of access to functionalized azepines from N-heteroarenes using two straightforward steps and simple starting materials.
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45. "Reversible PCET and Ambient Catalytic Oxidative Alcohol Dehydrogenation by {V=O} Perfluoropinacolate Complexes" Jessica K. Elinburg, Samantha L. Carter, Joshua J. M. Nelson, Douglas G. Fraser, Michael P. Crockett, Aaron B. Beeler, Ebbe Nordlander, Arnold L. Rheingold, and Linda H. Doerrer. Inorg. Chem. 2020, 59, 22, 16500–16513 [Link]
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A new air-stable catalyst for the oxidative dehydrogenation of benzylic alcohols under ambient conditions has been developed. The synthesis and characterization of this compound and the related monomeric and dimeric V(IV)- and V(V)-pinF (pinF = perfluoropinacolate) complexes are reported herein. Monomeric V(IV) complex (Me4N)2[V(O)(pinF)2] (1) and dimeric (μ-O)2- bridged V(V) complex (Me4N)2[V2(O)2(μ-O)2(pinF)2] (3a) are prepared in water under ambient conditions. Monomeric V(V) complex (Me4N)[V(O)(pinF)2] (2) may be generated via chemical oxidation of 1 under an inert atmosphere, but dimerizes to 3a upon exposure to air. Complexes 1 and 2 display a perfectly reversible VIV/V couple at 20 mV (vs Ag/AgNO3), whereas a quasi-reversible VIV/V couple at −865 mV is found for 3a. Stoichiometric reactions of 3a with both fluorenol and TEMPOH result in the formation of (Me4N)2[V2(O)2(μ-OH)2(pinF)2] (4a), which contains two V(IV) centers that display antiferromagnetic coupling. In order to structurally characterize the dinuclear anion of 4a, {K(18C6)}+ countercations were employed, which formed stabilizing K···O interactions between the counterion and each terminal oxo moiety and H-bonding between the oxygen atoms of the crown ether and μ-OH bridges of the dimer, resulting in {K(18C6)}2[V2(O)2(μ- OH)2(pinF)2] (4b). The formal storage of H2 in 4a is reversible and proton-coupled electron transfer (PCET) from crystals of 4a regenerates 3a upon exposure to air over the course of several days. Furthermore, the reaction of 3a (2%) under ambient conditions with excess fluorenol, cinnamyl alcohol, or benzyl alcohol resulted in the selective formation of fluorenone (82% conversion), cinnamaldehyde (40%), or benzaldehyde (7%), respectively, reproducing oxidative alcohol dehydrogenation (OAD) chemistry known for VOx surfaces and demonstrating, in air, the thermodynamically challenging selective oxidation of alcohols to aldehydes/ketones.
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44. "Photoredox Generated Carbonyl Ylides Enable a Modular Approach to Aryltetralin, Dihydronaphthalene and Arylnaphthalene Lignans" Alfonzo, E.; Millimaci, A. M.; Beeler, A. B. Org. Lett. 2020, 22, 6489. [Link]
Featured in: Overman & Pitre Chem. Rev. 2022, 22, 1717-1751. ; [doi]
Featured in: Overman & Pitre Chem. Rev. 2022, 22, 1717-1751. ; [doi]
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A one-pot synthesis of dihydronaphthalenes and arylnaphthalenes from epoxides and common dipolarophiles is described. The reaction proceeds through photoredox activation of epoxides to carbonyl ylides, which undergo concerted [3 + 2] dipolar cycloaddition with dipolarophiles to provide tetrahydrofurans or 2,5-dihydrofurans. In the same flask, acid promoted rearrangement affords densely functionalized dihydronaphthalenes and arylnaphthalenes, respectively, in an overall redox-neutral sequence of transformations. Succinct total synthesis (4−6 steps) of pycnanthulignene B and C and justicidin E are reported.
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43. "A sterically encumbered photoredox catalyst enables the unified synthesis of the classical lignan family of natural products" Alfonzo, E.; Beeler, A. B. Chem. Sci. 2019, Advance Article. [link]
Featured in: Overman & Pitre Chem. Rev. 2022, 22, 1717-1751. ; [doi]
Featured in: Overman & Pitre Chem. Rev. 2022, 22, 1717-1751. ; [doi]
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Herein, we detail a unified synthetic approach to the classical lignan family of natural products that hinges on divergence from a common intermediate that was strategically identified from nature's biosynthetic blueprints. Efforts toward accessing the common intermediate through a convergent and modular approach resulted in the discovery of a sterically encumbered photoredox catalyst that can selectively generate carbonyl ylides from electron-rich epoxides. These can undergo concerted [3 + 2] dipolar cycloadditions to afford tetrahydrofurans, which were advanced (2–4 steps) to at least one representative natural product or natural product scaffold within all six subtypes in classical lignans. The application of those synthetic blueprints to the synthesis of heterolignans bearing unnatural functionality was demonstrated, which establishes the potential of this strategy to accelerate structure–activityrelationship studies of these natural product frameworks and their rich biological activity.
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42. "One-pot Synthesis of Epoxides from Benzyl Alcohols and Aldehydes" Alfonzo, E.; Mendoza, J. W. L.; Beeler, A. B. Bel. J. Org. Chem. 2018, 14, 2308-2312. [link]
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A one-pot synthesis of epoxides from commercially available benzyl alcohols and aldehydes is described. The reaction proceeds through in situ generation of sulfonium salts from benzyl alcohols and their subsequent deprotonation for use in Corey-Chaykovsky epoxidation of aldehydes. The generality of the method is exemplified by the synthesis of 34 epoxides that were made from an array of electronically and sterically varied alcohols and aldehydes.
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41. "Synthesis of Complex Stereoheptads En Route to Daphnane Diterpene Orthoesters" Nguyen, L. V.; Beeler, A. B. Org. Lett. 2018, 20, 5177-5180. [link]
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Tricyclic cores of the daphnane diterpene orthoesters (DDOs) are synthesized in ten steps from readily available materials. Key to their assembly is the development of a stereocontrolled p-quinol functionalization sequence which enables rapid access to DDO C-ring stereopolyads from simple precursors. Problems encountered in stereo- and regioselectivity are highlighted and solved by exact changes in choreography although it is shown the undesired stereochemical outcomes also proceed with high selectivity.
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40. "Liquid-Liquid Slug Flow Accelerated [2+2] Photocycloaddition of Cinnamates" Telmesani, R.; White, J. A. H.; Beeler, A. B. Chem. Photo. Chem. 2018, 2, 1-6. [link]
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[2+2] photocycloaddition of cinnamates using a previously described cone reactor and a bis-thiourea catalyst is greatly accelerated by employing liquid-liquid slug flow. In most cases, a 4-fold acceleration in reaction time was observed with equivalent or superior yields. This approach has enabled significant improvement in the reaction throughput and expansion of the substrate scope to include challenging substrates. It has also enabled, to our knowledge, the first reported direct photodimerization in solution of electron rich cinnamamide substrates.
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39. "Integrated Drug Discovery in Continuous Flow" Fleming, G. S.; Beeler, A. B. J. Flow Chem. 2017, 7, 124. (Invited Review) [link]
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There are great opportunities for innovation in the drug discovery process, particularly in the lead development phase. The traditional “design–synthesize–screen” cycle has seen little innovation as a whole despite major advances at each stage, including automated purification and synthesis as well as high throughput biological screening. It could be argued that the hit-to-lead and lead optimization processes remain slow and modular with inefficient flow of information, resulting in a loss of time and money. New flow technologies may provide a promising foundation for developing a continuous integrated small molecule optimization platform that would greatly enhance hit-to-lead and lead optimization programs. Herein, we discuss major developments in integrating synthesis, purification, screening, and machine learning into a single continuous-flow platform and provide some insight into future directions of this field.
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38. "Regioselective and Enantioselective Intermolecular Buchner Ring Expansions in Flow" Fleming, G. S.; Beeler, A. B. Org. Lett. 2017, 19, 5268. [link]
Highlighted in Organic Process Research and Development "Highlights from the Literature," December 2017 [link]
Highlighted in Organic Process Research and Development "Highlights from the Literature," December 2017 [link]
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The first example of a regioselective and enantioselective intermolecular Buchner ring expansion is reported using continuous flow. The practicality and scope of the reaction are greatly improved under flow conditions. Reactions of ethyl diazoacetate with symmetric and nonsymmetric arenes afford cycloheptatrienes in good yield and excellent regioselectivity. The first example of an asymmetric intermolecular Buchner reaction is demonstrated with disubstituted diazo esters in good to excellent enantioselectivity. The asymmetric reactions proceed with absolute regioselectivity to afford cycloheptatrienes with an all-carbon quaternary center.
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37. "A Photochemical Flow Reactor for Large Scale Syntheses of Aglain and Rocaglate Natural Product Analogs" Yueh, H.; Gao, Q.; Porco, J. A.; Beeler, A. B. Bioorg. Med. Chem. 2017, 25, 6197. [link]
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Herein, we report the development of continuous flow photoreactors for large scale ESIPT-mediated [3+2]-photocycloaddition of 2-(p-methoxyphenyl)-3-hydroxyflavone and cinnamate- derived dipolarophiles. These reactors can be efficiently numbered up to increase throughput two orders of magnitude greater than the corresponding batch reactions.
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36. "Redesign of a Pyrylium Photoredox Catalyst and Its Application to the Generation of Carbonyl Ylides" Alfonzo, E.; Alfonso, F. S.; Beeler, A. B. Org. Lett. 2017, 19, 2989-2992. [link]
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We report the exploration into photoredox generation of carbonyl ylides from benzylic epoxides using newly designed 4-mesityl-2,6-diphenylpyrylium tetrafluoroborate (MDPT) and 4-mesityl-2,6-di-p-tolylpyrylium tetrafluoroborate (MD(p-tolyl)PT) catalysts. These catalysts are excited at visible wavelengths, are highly robust, and exhibit some of the highest oxidation potentials reported. Their utility was demonstrated in the mild and efficient generation of carbonyl ylides from benzylic epoxides that otherwise could not be carried out by current common photoredox catalysts.
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35. "Identification of Anti-Prion Compounds Using a Novel Cellular Assay" Imberdis, T.; Heeres, J. T.; Yueh, H.; Fang, C. Zhen, J.; Rich, C. B.; Glicksman, M.; Beeler, A.; Harris, D. A. J. Bio. Chem. 2016, 291, 26164-26176. [link]
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Prion diseases are devastating neurodegenerative disorders with no known cure. One strategy for developing therapies for these diseases is to identify compounds that block conversion of the cellular form of the prion protein (PrPC) into the infectious isoform (PrPSc). Most previous efforts to discover such molecules by high-throughput screening methods have utilized, as a read-out, a single kind of cellular assay system: neuroblastoma cells that are persistently infected with scrapie prions. Here, we describe the use of an alternative cellular assay based on suppressing the spontaneous cytotoxicity of a mutant form of PrP (Δ105–125). Using this assay, we screened 75,000 compounds, and identified a group of phenethyl piperidines (exemplified by LD7), which reduces the accumulation of PrPSc in infected neuroblastoma cells by >90% at low micromolar doses, and inhibits PrPSc-induced synaptotoxicity in hippocampal neurons. By analyzing the structure-activity relationships of 35 chemical derivatives, we defined the pharmacophore of LD7, and identified a more potent derivative. Active compounds do not alter total or cell-surface levels of PrPC, and do not bind to recombinant PrP in surface plasmon resonance experiments, although at high concentrations they inhibit PrPSc-seeded conversion of recombinant PrP to a misfolded state in an in vitro reaction (RT-QuIC). This class of small molecules may provide valuable therapeutic leads, as well as chemical biological tools to identify cellular pathways underlying PrPSc metabolism and PrPC function.
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34. "Introduction: Photochemistry in Organic Synthesis" Beeler, A. B. Chem. Rev. 2016, 116, 9629-9630. [link]
33. “Development of a Potent and Selective HDAC8 Inhibitor" Ingham, O. J.; Paranal, R. M.; Smith, W. B.; Escobar, R. A.; Yueh, H.; Snyder, T.; Porco, J. A.; Bradner, J. E.; Beeler, A. B. ACS Med. Chem. Lett. 2016, 7, 929. [link]
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A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.
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32. "Fine-tuning of macrophage activation using synthetic rocaglate derivatives" Bhattacharya, B.; Chatterjee, S.; Devine, W. G.; Kobsik, L.; Beeler, A. B.; Porco, J. A.; Kramnik, I. Scientific Reports 2016, 6, 24409. [link]
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Drug-resistant bacteria represent a significant global threat. Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. As IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using an interferon-inducible nuclear protein Ipr1 as a biomarker of macrophage activation, we performed a high-throughput screen and identified molecules that synergized with low concentration of IFNγ. Several active compounds belonged to the flavagline (rocaglate) family. In primary macrophages a subset of rocaglates 1) synergized with low concentrations of IFNγ in stimulating expression of a subset of IFN-inducible genes, including a key regulator of the IFNγ network, Irf1; 2) suppressed the expression of inducible nitric oxide synthase and type I IFN and 3) induced autophagy. These compounds may represent a basis for macrophage-directed therapies that fine-tune macrophage effector functions to combat intracellular pathogens and reduce inflammatory tissue damage. These therapies would be especially relevant to fighting drug-resistant pathogens, where improving host immunity may prove to be the ultimate resource.
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31. "Photochemistry in Flow" Beeler, A. B.; Corning, S. in Photochemistry: Volume 43; Royal Society of Chemistry: Cambridge, 2016.
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Recently developed photochemical reactions in flow are reviewed. Strategies applied range from simple tubing reactors to complex microfluidic devices. In several cases, more efficient, highly accelerated, or greater throughput are achieved by using flow reactors.
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30. “[2+2]-Photocycloaddition of Cinnamates in Flow and Development of a Thiourea Catalyst” Telmesani, R.; Park, S. H.; Lynch-Colameta, T.; Beeler, A. B. Angew. Chem. Int. Ed. 2015, 54, 11521-11525. [link]
Highlighted in Organic Process Research and Development "Highlights from the Literature," September 2015 [link]
Highlighted in Organic Process Research and Development "Highlights from the Literature," September 2015 [link]
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Cyclobutanes derived from the dimerization of cinnamic acids are the core scaffolds of many molecules with potentially interesting biological activities. By utilizing a powerful flow photochemistry platform developed in our laboratory, we have evaluated the effects of flow on the dimerization of a range of cinnamate substrates. During the course of the study we also identified a bis(thiourea) catalyst that facilitates better reactivity and moderate diastereoselectivity in the reaction. Overall, we show that carrying out the reaction in flow in the presence of the catalyst affords consistent formation of predictable cyclobutane diastereomers.
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29. “Development of a Photolabile Amine Protecting Group Suitable for Multistep Flow Synthesis” Yueh, H.; Voevodin, A.; Beeler, A. B. J. Flow Chem. 2015, 5, 155-159. [link]
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9-Hydroxymethylxanthene derivatives were optimized as a photolabile protecting group for amines in flow chemistry. 9-Methylxanthene and 2-methoxy-9-methylxanthene showed excellent deprotection yields in protic and aprotic solvents, respectively. The protecting group has good stability in acidic, basic, and thermal conditions and was successfully utilized for protection and deprotection of a variety of amines. A multistep continuous-flow synthesis of a piperazinylcarbonyl-piperidine derivative utilized the 2-methoxy-9-methylxanthene as the key protecting group utilized in an orthogonal manner.
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28. “Multidimensional Reaction Screening for Photochemical Transformations as a Tool for Discovering New Chemotypes” Martin, M. I.; Goodell, J. R.; Ingham, O. J.; Porco, J. A.; Beeler. A. B. J. Org. Chem. 2014, 79, 3838-3846. [link]
- Highlighted in Derek Lowe’s blog ‘In the Pipeline’ [link].
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We have developed an automated photochemical microfluidics platform that integrates a 1 kW high-pressure Hg vapor lamp and allows for analytical pulse flow or preparative continuous flow reactions. Herein, we will discuss the use of this platform toward the discovery of new chemotypes through multidimensional reaction screening. We will highlight the ability to discretely control wavelengths with optical filters, allowing for control of reaction outcomes.
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Publications through 2012
27. “Synthesis of azaphilone-based chemical libraries, Achard, M.; Beeler, A.; Porco, J., ACS Comb. Sci. 2012, 14, 236-280. [link]
26. “Synthesis and Reactivity of Bicyclo[3.2.1]Octanoid-Derived Cyclopropanes,” Goodell, J. R.; Poole, J. L.; Beeler, A. B.; Aubé, J.; Porco, J. A. Jr. J. Org. Chem. 2011, 76, 9792. [link]
25. “Development of a Photochemical Microfluidics Platform,” Pimparkar, K.; Yen, B.; Goodell, J. R.; Martin, V. I.; Lee, W-H.; Porco, J. A. Jr.; Beeler, A. B. Jensen, K. F. J. Flow Chem. 2011, 2, 53. [link]
24. “Remodelling of the Natural Product Fumagillol Employing a Reaction Discovery Approach,” Balthaser, B. R.; Maloney, M. C.; Beeler, A. B.; Porco, J. A. Jr.; Snyder, J. K. Nature Chem. 2011, 3, 969. [link]
23. “Truncated Aspidosperma Alkaloid-like Scaffolds: Unique Structures For the Discovery of New, Bioactive Compounds,” Benson, S. C.; Lee, L.; Wei, W.; Ni, F.; David, J.; Olmos, J.; Strom, K. R.; Beeler, A. B.; Cheng, K. C-C.; Inglese, J.; Kota, S.; Takahashi, V.; Strosberg, A. D.; Connor, J. H.; Bushkin, G. G.; Snyder, J. K. Heterocycles, 2011, 84, 135. [link]
22. “Discovery of New Antimalarial Chemotypes Through Chemical Methodology and Library Development,” Brown, L. E.; Cheng, K, C-C; Wei, W-G.; Yuana, P.; Dai, P.; Trilles, R.; Ni, F.; Yuan, J.; MacArthur, R.; Guhab, R.; Johnson, R. L.; Suc, X-Z; Dominguez, M. M.; Snyder, J. K.; Beeler, A. B.; Schaus, S. E.; Inglese, J.; Porco, J. A. Jr. Proc. Nat. Aca. Sci. 2011, 108, 6775. [link]
21. “Catalytic Enantioselective Alkylative Dearomatization−Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K,” Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A. Jr. J. Am. Chem. Soc. 2011, 132, 13642. [link]
20. “Multidimensional Screening and Methodology Development for Condensations Involving Complex 1,2-Diketones,” Goodell, J. R.; Leng, B.; Snyder, T. K.; Beeler, A. B.; Porco, J. A. Jr. Synthesis, 2010, 2254. [link]
19. “Tandem Processes Identified from Reaction Screening: Nucleophilic Addition to Aryl N-Phosphinylimines Employing La(III)-TFAA Activation,” Kinoshita, H.; Ingham, Oscar, J.; Ong, W. W.; Beeler, A. B.; Porco, J. A., Jr. J. Am. Chem. Soc. 2010, 132, 6412. [link]
18. “A Time-Resolved Fluorescence–Resonance Energy Transfer Assay for Identifying Inhibitors of Hepatitis C Virus Core Dimerization,” Kota, S.; Scampavia, L.; Spicer, T.; Beeler, A. B.; Takahashi, V.; Snyder, J. K.; Porco, J. A., Jr.; Hodder, P.; Strosberg, A. D. Assay Drug Dev. 2010, 8, 96. [link]
17. “Development of an Automated Microfluidic Reaction Platform for Multidimensional Screening: Reaction Discovery Employing Bicyclo[3.2.1]octanoid Scaffolds.” Goodell J. R.; McMullen, J. P; Zaborenko, N.; Maloney, J. R.; C-X Ho; Jensen, K. F.; Porco, J. A. Jr.; Beeler, A. B. J. Org. Chem. 2009, 74, 6169. [link]
16. “Reaction Discovery Employing Macrocycles: Transannular Cyclizations of Macrocyclic Bis-lactams,” Han, C.; Rangarajan, S.; Voukides, A. C.; Beeler, A. B.; Johnson, R.; Porco, J. A., Jr. Org. Lett., 2009, 11, 413–416. [link]
15. “Library Synthesis Using 5,6,7,8-Tetrahydro-1,6-naphthyridines as Scaffolds,” Zhou, Y.; Beeler, A. B.; Cho, S.; Wang, Y.; Franzblau, S. G.; Snyder, J. K. J. Comb. Chem. 2008, 10, 534–540. [link]
14. “Identification of novel epoxide inhibitors of hepatitis C virus replication using a high-throughput screen,” Peng, L. F.; Kim, S. S.; Matchacheep, S.; Lei, X.; Su, S.; Lin, W.; Runguphan, W.; Choe, W-H; Sakamoto, N.; Ikeda, M.; Kato, N.; Beeler, A. B.; Porco, J. A. Jr.; Schreiber, S. L.; Chung, R. T. Antimicrobi. Agents Chemo. 2007, 10, 3756. [link]
13. “Nucleophilic addition to N-phosphinylimines by rare-earth-metal triflate/trifluoroacetic anhydride activation,” Winnie W. Ong; Aaron B. Beeler; Sarathy, Kesavan; James S. Panek; John A. Porco Angew. Chem. Int. Ed. 2007, 39, 7470. [link]
12. “1,2,3,4-Tetrahydro-1,5-naphthyridines and related heterocyclic scaffolds: exploration of suitable chemistry for library development,”Grace H. C. Woo; Aaron B. Beeler; John K. Snyder Tetrahedron 2007, 63, 5649. [link]
11. “Generation of Oxamic Acid Libraries: Antimalarials and Inhibitors of Plasmodium falciparum Lactate Dehydrogenase,” Choi, S-R.; Beeler, A. B.; Pradhan, A.; Watkins, E. B.; Rimoldi, J. M.; Tekwani, B.; Avery, M. A. J. Comb. Chem. 2007, 9, 292. [link]
10. “Discovery of Chemical Reactions through Multidimensional Screening,” Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A. Jr. J. Am. Chem. Soc. 2007, 129,1413. [link]
9. “Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by copper-catalyzed cycloaddition-coupling of azides and terminal alkynes,” Gerard, B; Ryan, J.; Beeler, A. B.; Porco, J. A Jr. Tetrahedron, 2006, 62, 6405. [link]
8. “Convergent Synthesis of Complex Diketopiperazines Derived from Pipecolic Acid Scaffolds and Parallel Screening against GPCR Targets,” Dandapani, S.; Lan, P.; Beeler, A. B.; Beischel, S.; Abbas, A.; Roth, B. L.; Porco, J. A. Jr.; Panek, J. S. J. Org. Chem. 2006, 71, 8934.[link]
7. “Synthesis of a Library of Complex Macrodiolides Employing Cyclodimerization of Hydroxy Esters,” Beeler, A. B.; Acquilano, D. E.; Su, Q.; Yan, F.; Roth, B. L.; Panek, J. S.; Porco, J. A. Jr. J. Comb. Chem. 2005, 7, 673. [link]
6. “Chemical Library Synthesis Using Convergent Approaches,” Beeler, A. B.; Schaus, S. E.; Porco, J. A. Jr. Curr. Opin. Chem. Bio. 2005, 9, 277. [link]
5. “Convergent Synthesis of a Complex Oxime Library Using Chemical Domain Shuffling,” Su S.; Eastwood, E. L.; Beeler, A. B.; Yeager, A. R.; Lan, P.; Arumugasamy, J.; Acquilano, D. E.; Min, G. K.; Giguere, J. R.; Lei, X.; Zhou, Y.; Panek, J. S.; Snyder, J. K.; Schaus, S. E.; Porco, J. A. Jr. Org. Lett. 2005, 9, 2751. [link]
4. “Synthesis and In-Vitro Biological Evaluation of Fluorosubstituted-4-Phenyl-1,2,3,6-Tetrahydropyridines as Monoamine Oxidase B Substrates,” Beeler, A. B.; Gadepalli, R. S.; Steyn, S.; Castagnoli, N. Jr.; Rimoldi, J. M. Biorg. Med. Chem. 2003, 11, 5229-5234. [link]
3. “Stereochemical Diversity Through Cyclodimerization: Synthesis of Polyketide-like Macrodiolides,” Su, Q.; Beeler, A. B.; Lobkovsky, E.; Porco, J. Jr.; Panek, J. Org. Lett. 2003, 5, 2149-2152. [link]
2. “Toxicity of Fipronil and Its Degradation Products in Procambarus sp.: Field and Laboratory Studies,” Schlenk, D.; Huggett, D. B.; Allgood, J.; Bennett, E.; Rimoldi, J.; Beeler, A. B.; Block, D.; Holder, A. W.; Hovinga, R.; Bedient, P.Arch. Environ. Contam. Toxicol. 2001, 41, 325-332. [link]
1. “Synthesis of fipronil sulfide, an active metabolite from the parent insecticide fipronil,” Beeler, A. B.; Schlenk, D. K.; Rimoldi, J. M. Tetrahedron Lett. 2001, 42, 5371-5372
26. “Synthesis and Reactivity of Bicyclo[3.2.1]Octanoid-Derived Cyclopropanes,” Goodell, J. R.; Poole, J. L.; Beeler, A. B.; Aubé, J.; Porco, J. A. Jr. J. Org. Chem. 2011, 76, 9792. [link]
25. “Development of a Photochemical Microfluidics Platform,” Pimparkar, K.; Yen, B.; Goodell, J. R.; Martin, V. I.; Lee, W-H.; Porco, J. A. Jr.; Beeler, A. B. Jensen, K. F. J. Flow Chem. 2011, 2, 53. [link]
24. “Remodelling of the Natural Product Fumagillol Employing a Reaction Discovery Approach,” Balthaser, B. R.; Maloney, M. C.; Beeler, A. B.; Porco, J. A. Jr.; Snyder, J. K. Nature Chem. 2011, 3, 969. [link]
23. “Truncated Aspidosperma Alkaloid-like Scaffolds: Unique Structures For the Discovery of New, Bioactive Compounds,” Benson, S. C.; Lee, L.; Wei, W.; Ni, F.; David, J.; Olmos, J.; Strom, K. R.; Beeler, A. B.; Cheng, K. C-C.; Inglese, J.; Kota, S.; Takahashi, V.; Strosberg, A. D.; Connor, J. H.; Bushkin, G. G.; Snyder, J. K. Heterocycles, 2011, 84, 135. [link]
22. “Discovery of New Antimalarial Chemotypes Through Chemical Methodology and Library Development,” Brown, L. E.; Cheng, K, C-C; Wei, W-G.; Yuana, P.; Dai, P.; Trilles, R.; Ni, F.; Yuan, J.; MacArthur, R.; Guhab, R.; Johnson, R. L.; Suc, X-Z; Dominguez, M. M.; Snyder, J. K.; Beeler, A. B.; Schaus, S. E.; Inglese, J.; Porco, J. A. Jr. Proc. Nat. Aca. Sci. 2011, 108, 6775. [link]
21. “Catalytic Enantioselective Alkylative Dearomatization−Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K,” Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A. Jr. J. Am. Chem. Soc. 2011, 132, 13642. [link]
20. “Multidimensional Screening and Methodology Development for Condensations Involving Complex 1,2-Diketones,” Goodell, J. R.; Leng, B.; Snyder, T. K.; Beeler, A. B.; Porco, J. A. Jr. Synthesis, 2010, 2254. [link]
19. “Tandem Processes Identified from Reaction Screening: Nucleophilic Addition to Aryl N-Phosphinylimines Employing La(III)-TFAA Activation,” Kinoshita, H.; Ingham, Oscar, J.; Ong, W. W.; Beeler, A. B.; Porco, J. A., Jr. J. Am. Chem. Soc. 2010, 132, 6412. [link]
18. “A Time-Resolved Fluorescence–Resonance Energy Transfer Assay for Identifying Inhibitors of Hepatitis C Virus Core Dimerization,” Kota, S.; Scampavia, L.; Spicer, T.; Beeler, A. B.; Takahashi, V.; Snyder, J. K.; Porco, J. A., Jr.; Hodder, P.; Strosberg, A. D. Assay Drug Dev. 2010, 8, 96. [link]
17. “Development of an Automated Microfluidic Reaction Platform for Multidimensional Screening: Reaction Discovery Employing Bicyclo[3.2.1]octanoid Scaffolds.” Goodell J. R.; McMullen, J. P; Zaborenko, N.; Maloney, J. R.; C-X Ho; Jensen, K. F.; Porco, J. A. Jr.; Beeler, A. B. J. Org. Chem. 2009, 74, 6169. [link]
16. “Reaction Discovery Employing Macrocycles: Transannular Cyclizations of Macrocyclic Bis-lactams,” Han, C.; Rangarajan, S.; Voukides, A. C.; Beeler, A. B.; Johnson, R.; Porco, J. A., Jr. Org. Lett., 2009, 11, 413–416. [link]
15. “Library Synthesis Using 5,6,7,8-Tetrahydro-1,6-naphthyridines as Scaffolds,” Zhou, Y.; Beeler, A. B.; Cho, S.; Wang, Y.; Franzblau, S. G.; Snyder, J. K. J. Comb. Chem. 2008, 10, 534–540. [link]
14. “Identification of novel epoxide inhibitors of hepatitis C virus replication using a high-throughput screen,” Peng, L. F.; Kim, S. S.; Matchacheep, S.; Lei, X.; Su, S.; Lin, W.; Runguphan, W.; Choe, W-H; Sakamoto, N.; Ikeda, M.; Kato, N.; Beeler, A. B.; Porco, J. A. Jr.; Schreiber, S. L.; Chung, R. T. Antimicrobi. Agents Chemo. 2007, 10, 3756. [link]
13. “Nucleophilic addition to N-phosphinylimines by rare-earth-metal triflate/trifluoroacetic anhydride activation,” Winnie W. Ong; Aaron B. Beeler; Sarathy, Kesavan; James S. Panek; John A. Porco Angew. Chem. Int. Ed. 2007, 39, 7470. [link]
12. “1,2,3,4-Tetrahydro-1,5-naphthyridines and related heterocyclic scaffolds: exploration of suitable chemistry for library development,”Grace H. C. Woo; Aaron B. Beeler; John K. Snyder Tetrahedron 2007, 63, 5649. [link]
11. “Generation of Oxamic Acid Libraries: Antimalarials and Inhibitors of Plasmodium falciparum Lactate Dehydrogenase,” Choi, S-R.; Beeler, A. B.; Pradhan, A.; Watkins, E. B.; Rimoldi, J. M.; Tekwani, B.; Avery, M. A. J. Comb. Chem. 2007, 9, 292. [link]
10. “Discovery of Chemical Reactions through Multidimensional Screening,” Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A. Jr. J. Am. Chem. Soc. 2007, 129,1413. [link]
9. “Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by copper-catalyzed cycloaddition-coupling of azides and terminal alkynes,” Gerard, B; Ryan, J.; Beeler, A. B.; Porco, J. A Jr. Tetrahedron, 2006, 62, 6405. [link]
8. “Convergent Synthesis of Complex Diketopiperazines Derived from Pipecolic Acid Scaffolds and Parallel Screening against GPCR Targets,” Dandapani, S.; Lan, P.; Beeler, A. B.; Beischel, S.; Abbas, A.; Roth, B. L.; Porco, J. A. Jr.; Panek, J. S. J. Org. Chem. 2006, 71, 8934.[link]
7. “Synthesis of a Library of Complex Macrodiolides Employing Cyclodimerization of Hydroxy Esters,” Beeler, A. B.; Acquilano, D. E.; Su, Q.; Yan, F.; Roth, B. L.; Panek, J. S.; Porco, J. A. Jr. J. Comb. Chem. 2005, 7, 673. [link]
6. “Chemical Library Synthesis Using Convergent Approaches,” Beeler, A. B.; Schaus, S. E.; Porco, J. A. Jr. Curr. Opin. Chem. Bio. 2005, 9, 277. [link]
5. “Convergent Synthesis of a Complex Oxime Library Using Chemical Domain Shuffling,” Su S.; Eastwood, E. L.; Beeler, A. B.; Yeager, A. R.; Lan, P.; Arumugasamy, J.; Acquilano, D. E.; Min, G. K.; Giguere, J. R.; Lei, X.; Zhou, Y.; Panek, J. S.; Snyder, J. K.; Schaus, S. E.; Porco, J. A. Jr. Org. Lett. 2005, 9, 2751. [link]
4. “Synthesis and In-Vitro Biological Evaluation of Fluorosubstituted-4-Phenyl-1,2,3,6-Tetrahydropyridines as Monoamine Oxidase B Substrates,” Beeler, A. B.; Gadepalli, R. S.; Steyn, S.; Castagnoli, N. Jr.; Rimoldi, J. M. Biorg. Med. Chem. 2003, 11, 5229-5234. [link]
3. “Stereochemical Diversity Through Cyclodimerization: Synthesis of Polyketide-like Macrodiolides,” Su, Q.; Beeler, A. B.; Lobkovsky, E.; Porco, J. Jr.; Panek, J. Org. Lett. 2003, 5, 2149-2152. [link]
2. “Toxicity of Fipronil and Its Degradation Products in Procambarus sp.: Field and Laboratory Studies,” Schlenk, D.; Huggett, D. B.; Allgood, J.; Bennett, E.; Rimoldi, J.; Beeler, A. B.; Block, D.; Holder, A. W.; Hovinga, R.; Bedient, P.Arch. Environ. Contam. Toxicol. 2001, 41, 325-332. [link]
1. “Synthesis of fipronil sulfide, an active metabolite from the parent insecticide fipronil,” Beeler, A. B.; Schlenk, D. K.; Rimoldi, J. M. Tetrahedron Lett. 2001, 42, 5371-5372
