Synthesis of portimines reveals the basis of their anti-cancer activity.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Novel Coronavirus Main Protease Di- and Tripeptide Inhibitors for Treating COVID-19.

COVID-19 is a highly infectious disease caused by SARS-CoV-2. First reported in December 2019, it rapidly escalated into a global pandemic, resulting in over 6.3 million fatalities by July 4, 2022. The first oral coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA in December 2021. It is a tripeptide incorporated with a C-terminal nitrile designed to bind and form a covalent attachment to the SARS-CoV-2 main protease. Shortly after nirmatrelvir's approval, Enanta Pharmaceuticals' peptidomimetic SARS-CoV-2 main protease inhibitor entered clinical trials in February 2022. This patent highlight reports key structures of di- and tripeptide inhibitors described in Enanta Pharmaceuticals' patent WO 2022/020242 A1.

Novel Halomethylketone Azadipeptides for Treating COVID-19.

COVID-19 is a highly infectious disease caused by the SARS-CoV-2 coronavirus. It rapidly escalated into a global pandemic, causing more than 6 million fatalities by March 2022, a little over 2 years since its emergence in December 2019. The first peptidomimetic coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA on Dec 22, 2021. Less than a month after its patent application, Hoffmann La-Roche scientists filed a patent application describing azadipeptide peptidomimetic inhibitors (WO 2022/043374 A1). This patent highlight reveals the structure-activity relationship of key azadipeptide inhibitors described in the patent.

A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors.

The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.

Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination.

Nucleophilic aromatic fluorination (SNAr) is among the most common methods for the formation of C(sp2)-F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me4NF·ROH) as fluoride sources for SNAr fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me4NF·t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for SNAr fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated.

Development of SNAr Nucleophilic Fluorination: A Fruitful Academia-Industry Collaboration.

The identification of reliable, general, and high yielding methods for the formation of C(sp2)-fluorine bonds remains a major challenge for synthetic organic chemists. A very common approach involves nucleophilic aromatic fluorination (SNAr fluorination) reactions of aryl chlorides or nitroarenes. Despite being known for more than a century, traditional SNAr fluorination reactions suffer from significant limitations, particularly on a process scale. These include the high cost of common reagents [e.g., cesium fluoride (CsF)], a requirement for elevated temperatures and long reaction times, poor functional group tolerance, and the need for rigorous exclusion of water. This Account summarizes our collaboration with Corteva Agriscience (previously Dow Agrosciences) to address many of these challenges. This collaboration has provided a platform for fundamental scientific advances involving the development of new methods, reagents, and substrates for mild and high yielding nucleophilic fluorination reactions.Our early studies established that the combination of potassium fluoride (KF) and superstoichiometric tetrabutylammonium chloride (Bu4NCl) serves as a cost-effective alternative to CsF for the SNAr fluorination of chloropicolinate substrates. However, these reactions still require elevated temperatures (>130 °C) and afford moderate yields due to competing decomposition of the substrate and product. The need for high temperature is largely due to slow reaction rates resulting from the low concentration of the active fluorinating reagent [anhydrous tetrabutylammonium fluoride (Bu4NF)] under these conditions. To address this issue, we developed several strategies for generating high concentration solutions of anhydrous tetraalkylammonium fluoride in situ by combining fluorine-containing electrophiles (e.g., hexafluorobenzene, acyl fluorides, sulfonyl fluorides) with tetraalkylammonium nucleophiles (R4NCN or R4NOR). These systems enable SNAr fluorination under unusually mild conditions, affording nearly quantitative yield with chloropicolinate substrates at room temperature. However, the high cost of the electrophiles and the generation of large quantities of byproducts in the R4NF-forming step render this approach unsuitable for process scale applications. As an alternative, we next explored anhydrous tetramethylammonium fluoride (Me4NF) for these transformations. This highly reactive fluoride source can be synthesized directly from inexpensive KF and Me4NCl and then dried by heating under vacuum. Unlike Bu4NF, it is not susceptible to Hofmann elimination. As such, anhydrous Me4NF is stable and isolable, as well as highly effective for the room temperature SNAr fluorination of chloropicolinates and other electron deficient substrates.The studies with anhydrous R4NF drew our attention to another challenge associated with traditional SNAr fluorination reactions: their limitation to substrates bearing resonance electron-withdrawing groups. We hypothesized that this challenge could be addressed by circumventing the Meisenheimer intermediate, a canonical mechanistic feature of SNAr fluorination. By designing reactions that involve an alternative concerted delivery of the fluoride to the ipso C(sp2) center, we developed a deoxyfluorination of arylfluorosulfonates using anhydrous Me4NF. This reaction exhibits a broad scope with respect to the aryl electrophile, with substrates bearing both electron-withdrawing (CN, ester, CF3, Cl) and moderately electron donating (phenyl, alkyl) substituents participating in deoxyfluorination. These deoxyfluorination conditions were also expanded to nonaromatic substrates, including aldehydes and benzylic/aliphatic alcohols.This Account concludes by delineating several ongoing challenges and opportunities in this fast-moving field. For instance, one important future direction will be to address the high moisture sensitivity of these transformations. In addition, the application of these new reagents and methods in the synthesis of pharmaceuticals, agrochemicals, and PET imaging agents will continue to test the versatility and functional group compatibility of these methods.

C-H Amination of Arenes with Hydroxylamine.

This Letter describes the development of a TiIII-mediated reaction for the C-H amination of arenes with hydroxylamine. This reaction is applied to a variety of electron-rich (hetero)arene substrates, including a series of natural products and pharmaceuticals. It offers the advantages of mild conditions (room temperature), fast reaction rates (<30 min), compatibility with ambient moisture and air, scalability, and the use of inexpensive commercial reagents.

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C-H Bonds.

The use of copper in directed C-H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O2 promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu2O2 intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCuII(OOR) intermediate undergoes homolytic O-O cleavage to generate reactive RO• species, which are responsible for key C-H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.

Scalable C-H Oxidation with Copper: Synthesis of Polyoxypregnanes.

Steroids bearing C12 oxidations are widespread in nature, yet only one preparative chemical method addresses this challenge in a low-yielding and not fully understood fashion: Schönecker's Cu-mediated oxidation. This work shines new light onto this powerful C-H oxidation method through mechanistic investigation, optimization, and wider application. Culminating in a scalable, rapid, high-yielding, and operationally simple protocol, this procedure is applied to the first synthesis of several parent polyoxypregnane natural products, representing a gateway to over 100 family members.