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Buchwald-Hartwig (BH) aminations are crucial for synthesizing arylamine motifs in numerous bioactive molecules and fine chemicals. While homogeneous palladium complexes can be effective catalysts, their high costs and environmental impact motivate the search for alternative approaches. Heterogeneous palladium single-atom catalysts (SAC) offer promising recoverable alternatives in C-C cross-couplings. Yet their use in C-N couplings remains unexplored, and mechanistic insights into amine coupling with aryl halides over solid surfaces that could guide catalyst design are lacking. Here, we demonstrate that palladium atoms coordinated to well-defined heptazinic cavities of graphitic carbon nitride (Pd 1 @C 3 N 4 ) deliver practically relevant yields for BH couplings across various aryl halides and amines, exhibiting persistent activity and negligible leaching over several cycles. Notably, Pd 1 @C 3 N 4 shows comparable or superior activity with certain aryl chlorides to bromides, alongside high chemoselectivity for amines over amides. In situ X-ray absorption spectroscopy analyses supported by density functional theory simulations identify the concerted role of the ligand and the C 3 N 4 host in determining the performance, with a Pd(II) nominal oxidation state observed under all coupling conditions. Complementary structural and kinetic studies highlight a distinct reaction mechanism than that typically reported for homogeneous catalysts. These findings offer key insights for designing recyclable SAC for BH coupling, setting the basis for extending the scope toward more complex industrial targets., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Chemical modification of DNA is a common strategy to improve the properties of oligonucleotides, particularly for therapeutics and nanotechnology. Existing synthetic methods essentially rely on phosphoramidite chemistry or the polymerization of nucleoside triphosphates but are limited in terms of size, scalability, and sustainability. Herein, we report a robust alternative method for the de novo synthesis of modified oligonucleotides using template-dependent DNA ligation of shortmer fragments. Our approach is based on the fast and scaled accessibility of chemically modified shortmer monophosphates as substrates for the T3 DNA ligase. This method has shown high tolerance to chemical modifications, flexibility, and overall efficiency, thereby granting access to a broad range of modified oligonucleotides of different lengths (20 → 120 nucleotides). We have applied this method to the synthesis of clinically relevant antisense drugs and ultramers containing diverse modifications. Furthermore, the designed chemoenzymatic approach has great potential for diverse applications in therapeutics and biotechnology., (© 2024. The Author(s).)

Herein, we report the high-yielding solid-phase synthesis of unmodified and chemically modified trinucleotide triphosphates (dN 3 TPs). These synthetic codons can be used for enzymatic DNA synthesis provided their scaffold is stabilized with phosphorothioate units. Enzymatic synthesis with three rather than one letter nucleotides will be useful to produce xenonucleic acids (XNAs) and for in vitro selection of modified functional nucleic acids.

The expeditious synthesis of an API building block, 2-cyanothiazole, from cyanogen gas and a readily available dithiane is reported. A previously undisclosed partially saturated intermediate is formed, which can be further functionalized and isolated by the acylation of the hydroxy group. Dehydration using trimethylsilyl chloride furnished 2-cyanothiazole, which could be further converted to the corresponding amidine. The sequence provided a 55% yield over 4 steps. We envision that this work will spark further interest in cyanogen gas as a reactive and cost-effective synthetic reagent.

Enzymatic, de novo XNA synthesis represents an alternative method for the production of long oligonucleotides containing chemical modifications at distinct locations. While such an approach is currently developed for DNA, controlled enzymatic synthesis of XNA remains at a relative state of infancy. In order to protect the masking groups of 3'- O -modified LNA and DNA nucleotides against removal caused by phosphatase and esterase activities of polymerases, we report the synthesis and biochemical characterization of nucleotides equipped with ether and robust ester moieties. While the resulting ester-modified nucleotides appear to be poor substrates for polymerases, ether-blocked LNA and DNA nucleotides are readily incorporated into DNA. However, removal of the protecting groups and modest incorporation yields represent obstacles for LNA synthesis via this route. On the other hand, we have also shown that the template-independent RNA polymerase PUP represents a valid alternative to the TdT and we have also explored the possibility of using engineered DNA polymerases to increase substrate tolerance for such heavily modified nucleotide analogs., Competing Interests: Authors AS, SH, SB, KP, and FS were employed by F Hoffmann-La Roche Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor NLG declared a past co-authorship with the author NS., (Copyright © 2023 Sabat, Katkevica, Pajuste, Flamme, Stämpfli, Katkevics, Hanlon, Bisagni, Püntener, Sladojevich and Hollenstein.)

Industrial representatives from the Swiss chemistry ecosystem met to formulate unmet needs in the field of sustainability and share the content of the exchange. The aim is to spark inspiration and trigger ambitious and pre-competitive projects collectively at the interface of the academic and industrial worlds, with the hope to profoundly change the current practices and provide an answer to some of the most urgent environmental challenges., (Copyright 2023 F. Gallou, E. Godineau, O. Enger, F. Ewald, C. Herber, S. Hildbrand, N. Künzle, M. Marty, Thomas Netscher, Kurt Püntener, M. Reiter, C. Taeschler, C. Karate. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Optimization of the catalyst structure to simultaneously improve multiple reaction objectives (e.g., yield, enantioselectivity, and regioselectivity) remains a formidable challenge. Herein, we describe a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands. This was demonstrated through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient. To accomplish this, a density functional theory-derived database of >550 bisphosphine ligands was constructed, and a designer chemical space mapping technique was established. The protocol used classification methods to identify active catalysts, followed by linear regression to model reaction selectivity. This led to the prediction and validation of significantly improved ligands for all reaction outputs, suggesting a general strategy that can be readily implemented for reaction optimizations where performance is controlled by bisphosphine ligands.

Chemically modified oligonucleotides have advanced as important therapeutic tools as reflected by the recent advent of mRNA vaccines and the FDA-approval of various siRNA and antisense oligonucleotides. These sequences are typically accessed by solid-phase synthesis which despite numerous advantages is restricted to short sequences and displays a limited tolerance to functional groups. Controlled enzymatic synthesis is an emerging alternative synthetic methodology that circumvents the limitations of traditional solid-phase synthesis. So far, most approaches strived to improve controlled enzymatic synthesis of canonical DNA and no potential routes to access xenonucleic acids (XNAs) have been reported. In this context, we have investigated the possibility of using phosphate as a transient protecting group for controlled enzymatic synthesis of DNA and locked nucleic acid (LNA) oligonucleotides. Phosphate is ubiquitously employed in natural systems and we demonstrate that this group displays most characteristics required for controlled enzymatic synthesis. We have devised robust synthetic pathways leading to these challenging compounds and we have discovered a hitherto unknown phosphatase activity of various DNA polymerases. These findings open up directions for the design of protected DNA and XNA nucleoside triphosphates for controlled enzymatic synthesis of chemically modified nucleic acids., (© 2022. The Author(s).)

The synthesis of drug substances (DS) requires the continuous effort of the pharma industry to ensure high sustainability standards. The Suzuki-Miyaura cross coupling is a fundamental C-C bond-forming reaction to produce complex DS intermediates. The present contribution points out the way in which the synthesis of DS intermediates by C-C cross coupling can be economically competitive, while minimizing waste by selecting the appropriate heterogeneous catalyst. By comparing homogeneous, immobilized heterogeneous catalysts on silica and metal-organic framework (MOF) catalysts, while considering the perspectives of academia and industry, the critical parameters for a successful industrial application of heterogeneous catalytic Suzuki-Miyaura cross coupling reactions were identified. Heterogeneous catalysts, such as MOFs, may provide a complementary platform for reducing waste and the costs of production related to such transformations.

A highly efficient Pd-catalyzed P-C coupling reaction of easily accessible atropisomeric bisphosphane is described in the presence of various electron-poor aromatic iodides. The reactions are conducted in the presence of a Pd(II)/dppf catalyst in acetonitrile at 80 °C. The reaction conditions are compatible with several electron-withdrawing groups such as esters, cyano, chloro, and trifluoromethyl groups and lead to atropisomeric MeOBIPHEP derivatives in good to excellent yields and high enantiomeric purities., (© 2011 American Chemical Society)

The first enantio- and diastereoselective approach to alpha-alkoxy-substituted syn-beta-hydroxyesters through highly efficient catalytic asymmetric transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic beta-ketoesters is described. In this atom-economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.

An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.

Design, synthesis, and SAR of novel alpha-alkoxy-beta-arylpropionic acids as potent and balanced PPARalphagamma coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.