Protein arginine methyltransferase 5 (PRMT5), a SAM-dependent type II methyltransferase implicated in chromatin regulation and cancer, is a highly sought-after target for small-molecule inhibitors. We report an (R,S)-selective vinylogous Mukaiyama aldol reaction enabled by a squaramide organocatalyst identified through HTE, delivering the product with good diastereoselectivity and excellent enantioselectivity. The reaction was translated to multigram scale and integrated into a convergent synthesis of a potent PRMT5 inhibitor, streamlining access to the active isomer and supporting biological and medicinal-chemistry studies.

Peptides may revolutionize the treatment of disease by combining the pharmacological benefits found in both large and small molecules into once-daily oral formulations. For decades, batch-mode solid-phase peptide synthesis (SPPS) has been employed throughout peptide drug discovery and development; however, numerous drawbacks have persisted despite advancements in the technology. Herein, we describe a continuous-flow (CF) SPPS workflow to optimize and deliver multigram quantities of peptide fragments, which are easily transformed to macrocyclic or linear peptide APIs. To develop this workflow, we leveraged a 10-amino acid peptide based on a recently disclosed macrocyclic peptide inhibitor of PCSK9. Compared with batch-mode SPPS, CF-SPPS enables rapid, data-rich optimization of peptide sequences with drastic reductions in development efforts, process execution timelines, and waste generation. To meet project demands and deliver multigram quantities, a hydraulically controlled CF-SPPS prototype was developed, which leverages small-scale optimization data to facilitate a seamless transition to larger deliveries of peptides.

ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTShould You Start a Chemistry Podcast?Louis-Charles CampeauLouis-Charles CampeauDepartment of Process Research & Development, Merck & Co., Inc., Rahway, New Jersey 07065, United StatesMore by Louis-Charles Campeau, Matthew A. Horwitz*Matthew A. HorwitzScale-up Laboratory and Business Subunit, Eurofins Villapharma Research, S.L.U., Fuente Álamo de Murcia 30320, Spain*Email: [email protected]More by Matthew A. Horwitz, and Danielle M. Schultz*Danielle M. SchultzDepartment of Process Research & Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States*Email: [email protected]More by Danielle M. SchultzCite this: Org. Lett. 2024, 26, 14, 2672–2676Publication Date (Web):January 3, 2024Publication History Received13 December 2023Published online3 January 2024Published inissue 12 April 2024https://pubs.acs.org/doi/10.1021/acs.orglett.3c04181https://doi.org/10.1021/acs.orglett.3c04181editorialACS PublicationsCopyright © Published 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views4193Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (2 MB) Get e-Alertsclose Get e-Alerts

MK-7845 was designed as a 3C-like protease inhibitor for the treatment of COVID-19. To enable a rapid kilo-scale delivery of MK-7845 to accelerate its First-in-Human studies, we developed a fit-for-purpose process to produce two key building blocks in less than two months. The key discoveries were a highly diastereoselective Ellman addition route for β-aminoamide 6 and crystallization isolation methods to produce 6 and acid 9 with good quality control.

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

Life is constructed primarily using a toolbox of 20 canonical amino acids-relying upon these building blocks for the assembly of proteins and peptides that regulate nearly every cellular task, including cell structure, function, and maintenance. While Nature continues to be a source of inspiration for drug discovery, medicinal chemists are not beholden to only 20 canonical amino acids and have begun to explore non-canonical amino acids (ncAAs) for the construction of designer peptides with improved drug-like properties. However, as our toolbox of ncAAs expands, drug hunters are encountering new challenges in approaching the iterative peptide design-make-test-analyze cycle with a seemingly boundless set of building blocks. This Microperspective focuses on new technologies that are accelerating ncAA interrogation in peptide drug discovery (including HELM notation, late-stage functionalization, and biocatalysis) while shedding light on areas where further investment could not only accelerate the discovery of new medicines but also improve downstream development.

The collaborative total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from D-Garner's aldehyde and L-serine. Scalable routes toward three non-canonical amino acids were developed to enable the synthesis. The closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where the proper order of cyclizations proved crucial for the formation of the desired atropisomer of the natural product.

dding a promoter to a catalytic reaction can dramatically alter the performance and reactivity of a chemical transformation. By incorporating a Brønsted acid promoter to a photocatalysed reaction, previously unreactive C–H bonds can be functionalized, enabling the discovery of drug molecules.

Aryl and heteroaryl fluorides are growing to be dominant motifs in pharmaceuticals and agrochemicals, yet they are rare in both nature and commodity chemicals. As a consequence, there is an increasingly urgent need to develop mild, cost-effective, and scalable methods for fluorination. The most straightforward route to synthesize aryl fluorides is through the halide exchange "halex" reaction, but conditions, cost, and atom economy preclude most available methods from large-scale manufacturing processes. We report a new approach that leverages the cooperative action of 18-crown-6 ether and tetramethylammonium chloride to catalytically access the reactivity of tetramethylammonium fluoride and achieve halex fluorinations under mild conditions with operational ease. The described methodology readily converts both heteroaryl chlorides and aryl triflates to their corresponding (hetero)aryl fluorides in high yields and purities.

High-throughput experimentation (HTE) can be a powerful tool in chemical research, and the large datasets it generates could play a role in applying machine-learning methods to chemical predictions. But high-throughput experimentation can sometimes be viewed as inaccessible to the academic chemist. This Voices, in conjunction with our recent panel (https://www.brighttalk.com/webcast/16651/499811), asks: what are the myths associated with high-throughput experimentation? What is the role of automation in chemistry moving forward?

We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorporated into MK-8591 via a biocatalytic aldol-glycosylation cascade, which imposes stringent requirements for its synthesis and isolation. Presented herein is the development work leading to a practical, scalable route from guanine, featuring a dual fluorination approach to a novel 9-THP-2,6-difluoropurine intermediate that enables a mild, highly selective, direct amination. This one-pot fluorination/amination sequence utilizes a direct isolation to deliver high purity 9-THP-2-fluoroadenine, which features ideal properties with respect to reactivity, solubility, and crystallinity. An acid-catalyzed liberation of 2-fluoroadenine in aqueous buffer delivers the appropriate purity profile to facilitate the enzymatic cascade to access MK-8591.

The addition of a methyl group to a drug molecule can greatly alter the drug’s pharmacological properties. A catalyst has been developed that enables this ‘magic methyl effect’ to be rapidly explored for drug discovery.

The addition of a methyl group to a drug molecule can greatly alter the drug's pharmacological properties. A catalyst has been developed that enables this 'magic methyl effect' to be rapidly explored for drug discovery.Late-stage functionalization of complex organic molecules.

The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound's biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C-H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)-H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C-H bonds into the corresponding C(sp3)-CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a 'Cu-CF3' species is formed during this process and the critical C(sp3)-CF3 bond-forming step involves the copper catalyst.

The ent-kaurenes represent a class of naturally occurring diterpenes of biological importance. Several members of the ent-kaurenes contain a common, tricyclic spirolactone core as a key structural motif. This study details a concise approach toward the development of a Mizoroki-Heck reaction to access this spirolactone core. The strategy described herein was enabled in microscale high-throughput experiments to allow for the rapid identification and optimization of superior reaction conditions.

Direct analyses of crude reaction mixtures have been carried out using molecular rotational resonance (MRR) spectroscopy. Two examples are presented, a demonstration application in photocatalytic CH-arylation as well as generation of an intermediate in a natural product synthesis. In both cases, the reaction can proceed at more than one site, leading to a mixture of regioisomers that can be challenging to distinguish. MRR structural parameters were calculated for the low lying conformers for the desired compounds, and then compared to the experimental spectra of the crude mixtures to confirm the presence of these species. Next, quantitation was performed by comparing experimentally measured line intensities with simulations based on computed values for the magnitude and direction of the molecular dipole moment of each species. This identification and quantification was performed without sample purification and without isolated standards of the compounds of interest. The values obtained for MRR quantitation were in good agreement with the chromatographic values. Finally, previously unknown impurities were discovered within the photocatalytic CH-arylation work. This paper demonstrates the utility of MRR as a reaction characterization tool to simplify analytical workflows.

A Rh-catalyzed enantioselective hydroamination of allylamines using a chiral BIPHEP-type ligand is reported. Enantioenriched 1,2-diamines are formed in good yields and with excellent enantioselectivities. A diverse array of nucleophiles and amine directing groups are demonstrated, including deprotectable motifs. Finally, the methodology was demonstrated toward the rapid synthesis of 2-methyl-moclobemide.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3-5, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)-heteroatom bonds from strong C-H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp3)-H bonds via substrate-directed transition-metal C-H insertion8, undirected C-H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)-C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.

An operationally simple protocol for a palladium-catalyzed 13CO and 14CO exchange with activated aliphatic and benzoic carbonyls is presented. Several 13C and 14C building blocks, natural product derivatives, and pharmaceuticals have been prepared to showcase the method for late-stage carbon isotope incorporation and its functional group compatibility.