Here, we present a novel continuous flow approach for the Wadsworth–Emmons cyclopropanation of alkyl-substituted chiral epoxides into chiral cyclopropane carboxylic acids. The developed flow process circumvents the risks associated with the harsh conditions (high T/P) required, considering the highly volatile nature of the epoxide-SM. Additionally, the flow reactors offer increased efficiency, as their reduced headspace contributes to keeping a higher concentration of the low-boiling-point reactants in the liquid phase and thus enhanced reactivity, contrary to the use of sealed vessels in batch. The cyclopropane formation process is coupled with in-line workup and hydrolysis transformations to yield the desired enantiomerically pure cyclopropane carboxylic acids in good yields up to the 100 g scale.

InfoMetricsFiguresRef. Organic Process Research & DevelopmentASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse Highlights from the LiteratureSeptember 3, 2024Some Items of Interest to Process R&D Chemists and EngineersClick to copy article linkArticle link copied!Alan StevenAlan StevenEuroapi, 12 Rookwood Way, Haverhill, Suffolk CB9 8PB, U.K.More by Alan Stevenhttps://orcid.org/0000-0002-0134-0918Carlos MateosCarlos MateosDiscovery Chemistry Research and Technologies, Eli Lilly and Co., Avenida de la Industria 30, 28108 Alcobendas, SpainMore by Carlos Mateoshttps://orcid.org/0000-0002-0189-4136Andrei A. ZlotaAndrei A. ZlotaThe Zlota Company, 97 Brooksmont Drive, Holliston, Massachusetts 01746-1770, United StatesMore by Andrei A. Zlotahttps://orcid.org/0000-0002-2048-9187Paul F. RichardsonPaul F. RichardsonPfizer, Chemistry, 10578 Science Center Drive, San Diego, California 09121, United StatesMore by Paul F. Richardsonhttps://orcid.org/0000-0002-3700-8749Robert B. KargboRobert B. KargboUsona Institute, 2881 Woods Hollow Road, Fitchburg, Wisconsin 53711, United StatesMore by Robert B. Kargbohttps://orcid.org/0000-0002-5539-6343Thomas VerheyenThomas VerheyenAPI Small Molecule Process R&D, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumMore by Thomas Verheyenhttps://orcid.org/0000-0003-0831-3901Christopher C. NawratChristopher C. NawratMerck & Co. Inc., Rahway, New Jersey 07065, United StatesMore by Christopher C. Nawrathttps://orcid.org/0000-0003-4550-9954David S. B. DanielsDavid S. B. DanielsIsomorphic Labs, 280 Bishopsgate, London EC2M 4RB, U.K.More by David S. B. Danielshttps://orcid.org/0000-0002-9092-1377John Knight*John KnightJKonsult Ltd, Meadow View, Cross Keys, Hereford HR1 3NT, U.K.*Email: [email protected]More by John KnightOpen PDFOrganic Process Research & DevelopmentCite this: Org. Process Res. Dev. 2024, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acs.oprd.4c00352https://doi.org/10.1021/acs.oprd.4c00352Published September 3, 2024 Publication History Received 22 August 2024Published online 3 September 2024editorialPublished 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS PublicationsPublished 2024 by American Chemical SocietySubjectswhat are subjectsArticle subjects are automatically applied from the ACS Subject Taxonomy and describe the scientific concepts and themes of the article.AlkylsAmidesAminesAnionsCatalystsPharmaceutical Digital Design: From Chemical Structure through Crystal Polymorph to Conceptual Crystallization ProcessClick to copy section linkSection link copied!Even though we are far from being able to completely design a crystallization process a priori, significant progress was made against the "Maddox challenge" which encouraged scientists to develop a methodology to predict crystal structure from molecular structure, an ongoing effort decades later. Scientists from Lilly and several universities in the U.S. and U.K. report the state-of-the-art digital crystallization process design, demonstrating success with two real examples (olanzapine and succinic acid) while also highlighting persistent challenges (Burcham, C. L.; et al. Cryst. Growth. Des., DOI: 10.1021/acs.cgd.3c01390). Among the complex challenges are the predictions of nucleation rates (primary and secondary), of solubility and polymorph landscape. Often predictions can be developed only for a specific compound. The authors clarify that imperfect as they may be, modeling results can focus crystallization process development work and reduce the number of experiments executed. Similarly, if all the polymorphs predicted exhibit equant crystal morphologies, it is very likely that the related bulk powder is free-flowing. On the other hand, if all the predicted polymorphs exhibit needlelike morphology, likely leading to poor flowing powders, then significant experimental effort should be planned to improve powder manufacturability through particle engineering and/or advanced formulation methods. This article has 313 references.Spherical Agglomeration Kinetics: A Mechanistic ApproachClick to copy section linkSection link copied!An emerging particle engineering procedure aimed at improving bulk powder manufacturability is spherical agglomeration by in-suspension particle enlargement. This unit operation can be executed either simultaneously with or after a precipitation or a crystallization process. A team from several UK universities and from AstraZeneca, Pfizer, and Takeda reported insights into the mechanism of spherical agglomeration (Pitt, K.; et al. Powder Technol., DOI: 10.1016/j.powtec.2024.120082). The process requires the addition of an immiscible bridging liquid to a mother suspension of the compound of interest. The authors used a paracetamol suspension in heptane as a model system and water saturated with paracetamol as a bridging liquid. To identify optimal processing conditions, a careful mechanistic investigation was conducted, observing the agglomerates formed under various true bridging liquid to solid ratios, solid loadings, and mixing conditions. Based on the observations made, a model was proposed for the kinetics of agglomerate consolidation and growth. Preliminary recommendations for process design and scale-up are made.Solute Recovery and Productivity in Chiral Resolution through Solid-State Deracemization by Temperature CyclingClick to copy section linkSection link copied!Because of its easy implementation, deracemization of a racemic suspension using temperature cycling has been researched extensively during the past two decades. Mechanistic investigations showed that for deracemization to occur dissolution must be faster than crystal growth; furthermore, to increase the yield, the process is executed in the presence of a racemization catalyst. In continuation of their past work, Prof. Mazzotti's group at ETH reported the development of a high-yield and high-productivity deracemization process by temperature cycling (Hosseinalipour, M. S.; et al. Cryst. Growth. Des., DOI: 10.1021/acs.cgd.4c00233). The model compound was chiral N-(2-methylbenzilidene)-phenylglycine amide (NMPA) in isopropanol/acetonitrile, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a racemization catalyst. Of the two process alternatives evaluated, temperature cycling followed by linear cooling was found to be faster and easier to implement than the option of having the temperature cycling integrated into the cooling protocol. The cooling rate was found to be critical in the process, with slower cooling being the preferred approach. Certain reproducibility challenges were noted, possibly as a result of heterogeneity present in the initial crystals and/or sampling challenges.Evaluating Molecular Complexity with Open-Source Machine Learning Approaches to Predict Process Mass IntensityClick to copy section linkSection link copied!What constitutes a meaningful target process mass intensity (PMI) that can guide the development of an API, irrespective of any synthetic route or process in actual use, is an unresolved issue. Gilead scientists have now contributed to the debate by building on a proprietary assessment of molecular complexity (Tin, N.; Osan, R.; et al. ACS Omega, DOI: 10.1021/acsomega.4c02427). After examining various models, a view of structural complexity crowdsourced from scientists is reproduced using a calculation based on the heteroatom count, stereocenter count, the unique topological torsion, and a so-called "connectivity index". To drive wider community adoption, the team has shared the model and created an open source webapp for anyone to calculate a target value for the PMI of their molecule.Quantitative 31P NMR Spectroscopy Platform Method for the Assay of Oligonucleotides as Pure Drug Substances and in Drug Product Formulations Using the Internal Standard MethodClick to copy section linkSection link copied!The assaying of oligonucleotides by UV–vis spectroscopy is hindered when a high-quality reference for the same or similar material is not available or where there is otherwise uncertainty in the analyte extinction coefficient. Scientists at Novo Nordisk have established that quantitative 31P NMR using an internal standard can be used instead, both for solid samples and when determining the concentration in solution (Bjorøstorp, J.; Malmstrøm, J. Anal. Chem., DOI: 10.1021/acs.analchem.4c00419). The work describes the development of the method, robustness studies, and its qualification with respect to repeatability. The approach is shown to be more accurate than UV–vis when accounting for the attenuating influence of water content and sodium ions on the assay, but there is no mention of the impact of accidental isochronicity when substances structurally related to the analyte are present. Different NMR shifts for phosphorothioate and phosphate 31P centers means the ratio of the signals in both regions allows the method to provide insight into the structure, along with the assay value. The work focuses on small interfering ribonucleic acids; other oligonucleotide-based therapeutics are not mentioned.AJICAP-M: Traceless Affinity Peptide Mediated Conjugation Technology for Site-Selective Antibody–Drug Conjugate SynthesisClick to copy section linkSection link copied!The use of reagents containing so-called affinity peptides to tune which part of an antibody's Fc region is derivatized has attracted a lot of interest as a means of manufacturing site-specific antibody–drug conjugates (ADCs), without the need for antibody engineering. Ajinomoto scientists have refined their method for selectively functionalizing certain lysine residues located in the Fc region (Matsuda, Y.; Fujii, T.; et al. Org. Lett., DOI: 10.1021/acs.orglett.4c00878). An example of the reagent prepared in the latest iteration of the technology is shown. It is prepared in a one-pot telescope and is stable to multiple freeze–thaw cycles when stored in DMF. Addressing the risk of structural damage to antibodies and aggregation when mechanically agitated, the work also demonstrates that the derivatization and ensuing reaction with a payload-linker can sequentially be performed in a plug flow reactor. This allowed the scale of synthesis to be increased 20-fold with retention of the drug:antibody ratio, level of aggregation and overall yield.Phase-Transfer Catalysts Shift the Pathway to Transmetalation in Biphasic Suzuki–Miyaura Cross-CouplingsClick to copy section linkSection link copied!Intimate understanding of the rate-limiting step of a metal-catalyzed cross-coupling is required to drive down the metal loading to a level suitable for use long-term. The Hein group studied the rate-limiting transmetalation step of the biphasic coupling of boronic esters with benzylic electrophiles (Derasp, J. S.; Hein, J. E.; et al. Nat. Commun., DOI: 10.1038/s41467-024-49681-4). A significant driver of the rate was found to be lowering the amount of the water-immiscible solvent relative to the amount of water. The use of a phase-transfer additive switched the predominant transmetalation pathway from oxopalladium-based to boronate-based, giving an up to 12-fold increase in the rate, and allowing the use of a homeopathic level of catalyst for a gram-scale demonstration. The validity of the conclusions was underpinned by high-quality data generated by an automated sampling platform coupled to online HPLC analysis.Sandmeyer Chlorosulfonylation of (Hetero)aromatic Amines Using DABSO as an SO2 SurrogateClick to copy section linkSection link copied!When an arylsulfonyl chloride cannot be bought in bulk, a flexible alternative to thiol or disulfide oxidation is to diazotize an aniline feedstock ahead of reaction with a sulfur dioxide equivalent. Scientists at Idorsia modified literature conditions for this reaction to make it more scale-friendly (Schäfer, G.; Willis, M. C.; et al. Org. Lett., DOI: 10.1021/acs.orglett.4c01908). By performing an in situ Sandmeyer-like reaction with 1,4-diazabicyclo[2.2.2]octanebis(sulfur dioxide) (DABSO), the aryldiazonium salt intermediate formed on dosing in tert-butyl nitrite only accumulates where it is electron-rich. The authors demonstrate the procedure to form a range of electron-poor and electron-rich arylsulfonyl chlorides, and react it in situ with an excess of morpholine. One example is described where the Sandmeyer-like reaction is worked up to allow the isolation of the arylsulfonyl chloride itself.Highly Enantiomerically Enriched Secondary Alcohols via Epoxide HydrogenolysisClick to copy section linkSection link copied!While the transition-metal-mediated hydrogenolysis of terminal epoxides is well-established to provide selectively either the linear- or branched-alcohol isomers depending on the catalyst selected, when the reaction is applied to enantiopure epoxides, rapid racemization is observed thus preventing access to enantiomerically enriched alcohols through this approach. Chianese, Keith, and co-workers described the development of a ruthenium-catalyzed hydrogenolysis of enantiopure epoxides at room temperature using Milstein's PNN-pincer-ruthenium complex to provide secondary alcohols without racemization while also providing a detailed mechanistic study of the stereoselectivity of the transformation ( Organometallics, DOI: 10.1021/acs.organomet.4c00214). The hypothesis behind previous systems leading to racemization was the presence of a pendant NH group facilitating reversible dehydrogenation of the secondary alcohol through a Noyori-type bifunctional mechanism. Given this observation, initial catalyst screening on the hydrogenolysis of (R)-styrene oxide focused on preformed Ru-based pincer complexes lacking this functionality. Milstein's hydrido precatalyst RuCl was shown to be optimal in providing the highest branched:linear selectivity while judicious selection of both the solvent/basic additive enabled the reaction to proceed in high yields without racemization. A range of chiral, monosubstituted epoxides were shown to be effective substrates with good functional tolerance observed, and mechanistic studies suggested that the reaction proceeds through an SN2-like attack of the ruthenium hydride on the less hindered epoxide carbon.Enantioselective Paternò–Büchi Reactions: Strategic Application of Triplet Rebound Mechanism for Asymmetric PhotocatalysisClick to copy section linkSection link copied!While the Paternò–Büchi [2 + 2] photocycloaddition reaction between alkenes and carbonyls is a well-established method for the synthesis of oxetanes, there have been no examples of asymmetric versions of this transformation with methods to control absolute stereochemistry being limited to the use of chiral auxiliaries. The key challenge herein appears to be that binding of a carbonyl to an exogenous catalyst to enable stereocontrol can also alter the electronic structure and reactivity of the excited state with the theory herein being that the (n,π*) state has the significant oxyl radical character required for typical photoreactivity is destablilized to the (π,π*) state upon coordination leading to alternative reaction paths. Yoon and co-workers described the first highly enantioselective catalytic Paternò–Buchi reaction between quinolones and benzoylformate esters to give oxetanes mediated by a novel hydrogen-bonding chiral Ir-based photocatalyst that proceeds through a triplet rebound mechanism ( J. Am. Chem. Soc., DOI: 10.1021/jacs.4c02975). Model studies on the reaction led to several key observations specifically that (i) there was a dependence of the ee on the wavelength of irradiation suggesting that careful tuning of this reaction parameter could minimize the impact of any racemic background reaction; (ii) increasing the steric bulk of the α-keto ester enhanced the stereoselectivity of the process, and (iii) consistently higher ee's were obtained under air. Mechanistic and solubility studies led to an optimized protocol involving minimizing the concentration of the quinolone through slow addition with scope studies demonstrating that the sterics/electronics of the α-keto ester had a profound effect on the enantioselectivity of the process supporting the hypothesis that the reaction proceeds through an excited-state keto ester with the observed structural modifications having subtle impacts on the triplet lifetime and degree of cage escape of the activated species.Modular Synthesis of Cyclic β-DifluoroaminesClick to copy section linkSection link copied!The use of fluorination to modulate physicochemical properties is a well-established strategy in medicinal chemistry with the lowering of amine basicity through this approach commonly encountered. While saturated heterocyclic amines are prevalent motifs in biologically active molecules, the corresponding functionalized cyclic fluorinated systems can be challenging to access requiring either lengthy synthetic sequences or deoxyfluorination reactions, which use hazardous reagents and have limitations regarding functional group tolerance. Denton and co-workers described a two-step synthesis of cyclic β-fluoroalkyl amines featuring a photoredox-catalyzed cyclization/hydrogen atom transfer reaction of bromodifluoroethylamines as the key step ( Chem. Commun., DOI: 10.1039/d4cc00640b). The key substrates to evaluate the cyclization are readily available from a three-component coupling in which bromodifluoroacetic acid is used as the source of the bromodifluoromethyl group. Model studies on the cyclization of the alkynyl amine demonstrated that the strongly reducing catalyst Ir(ppy)3 was optimal while a combination of TEA as base and AcOH as the H source provided the best yields. A similar optimization campaign for the corresponding alkenyl amines revealed that a different base and H source were required to successfully mediate the reaction. Good functional group tolerance was exhibited for the cyclization of a range of substrates with a scale-up protocol in flow developed to access multigram quantities in an expeditious manner.Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles Gives Their Fused Derivatives: Total Synthesis of Bruceolline E and HClick to copy section linkSection link copied!N- and C-fused indole and pyrrole derivatives are present in a broad range of bioactive molecules with a variety of synthetic approaches reported to access such compounds. While metal hydride hydrogen atom transfer (MHAT) radical hydrofunctionalization of isolated olefins has been explored extensively for the formation of C–C and C–heteroatom bonds, examples for the synthesis of substituted heterocycles are rare. Gharpure and co-workers described the development of iron-catalyzed HAT 5-exo-trig and 5-endo-trig radical cyclizations to indoles/pyrroles to access N- and C-fused indoles and pyrroles, with the methodology applied on gram scale and highlighted as a key step in the synthesis of several natural products ( Org. Lett., DOI: 10.1021/acs.orglett.4c00032). Model studies demonstrated that high-loadings of Fe(acac)3 were optimal with more sterically hindered Fe-based catalysts leading to a deterioration in observed yield. Several solvents were shown to be effective for the reaction with a mixed solvent system of EtOH/ethylene glycol being best while a range of silanes could also be utilized. A broad range of N-fused indoles and pyrroles were successfully synthesized through this 5-exo-trig radical cyclization with a variety of substituents tolerated on the heteroaromatic core. Utilizing N-Boc-protected C-3 alkenylated indoles as the substrate for the synthesis of the more challenging C-fused indole derivatives demonstrated that the reaction proceeded through the Baldwin-disfavored 5-endo-trig radical cyclization to provide the tetrahydrocyclopenta[b]indolone derivative as a single diastereomer in good yield.Regioselective Pyridine to Benzene Edit Inspired by Water DisplacementClick to copy section linkSection link copied!Single atom changes within a biologically active compound can have a profound impact on the binding affinity with a protein specifically if the change leads to a more favorable interaction through displacing a water-molecule to enable direct hydrogen-bonding of the ligand. Methodologies to achieve this through single-atom skeletal-editing of a molecular core provide an efficient approach to evaluate matched pairs without the need for de novo syntheses. Boswell and co-workers described a facile method for the conversion of pyridines to substituted benzene derivatives with the overall transformation featuring the transmutation of the pyridine nitrogen to a carbon attached to an ester group ( J. Am. Chem. Soc., DOI: 10.1021/jacs.4c05999). Key to the success of the proposed strategy is selective 1,2-addition to form the intermediate 1,2-dihydropyridine, which then undergoes a [4 + 2] cycloaddition with an alkyne to generate strained aza-dihydrobarrelene intermediate that under thermal conditions will undergo a retro-[4 + 2] cycloaddition to furnish the desired substituted benzene derivative. Ester substituents on the alkyne both facilitate the cycloaddition and provide a functional handle in the products for further elaboration. The preferred method for the dearomatization of the pyridine utilized an alkynyl Grignard to allow isolation of the intermediate while the electronic bias of the cycloaddition led to the formation of pure regioisomers from 3-substituted pyridines despite the formation of mixtures in the 1,2-addition. The protocol was exemplified on gram scale and effectively applied to a range of pyridine-containing drugs and natural products.Molecular Editing of Pyrroles to Benzenes/Naphthalenes by N2O DeletionClick to copy section linkSection link copied!Previously disclosed skeletal-editing methods for the elaboration of widely available pyrroles/indoles typically exploit reactive carbene or nitrene species to achieve atom insertion. While several nitrogen deletion reactions have been reported, examples involving single nitrogen-deletion in heteroaromatic systems are rare. Zhang and co-workers exploited the enhanced diene reactivity of pyrroles substituted with an electron-withdrawing group (EWG) (Boc) on the nitrogen atom to undergo Diels–Alder reactions with alkyne/benzyne derivatives to furnish a strained N-bridged intermediate that after deprotection/nitrosylation extrudes N2O to afford benzene/naphthalene-based products, respectively, featuring the deletion of a single nitrogen atom ( Angew. Chem., Int. Ed., DOI: 10.1002/anie.202411166). Model studies on the Diels–Alder reaction of N-Boc-pyrrole highlighted the need to match the electronic properties with the dienophile through installation of at least one EWG on the alkyne. While a one-pot skeletal editing sequence was low-yielding, separating the Diels–Alder and the deprotection/nitrosylation/N2O extrusion reactions allowed a range of benzene derivatives to be successfully synthesized. Extending the methodology for the synthesis of naphthalene derivatives entailed the identification of a suitable benzyne-precursor with thianthrenium salts selected owing to their formation in a highly site-selective manner from arenes. Treatment with base enabled in situ formation of the benzyne to react with the N-Boc-pyrrole to form the strained N-bridged intermediate, which again could be transformed to a series of differentially substituted naphthalenes. The reactions were applied to several drug-like compounds while control and spectroscopic studies indicate that the nitrogen atom deleted from the pyrrole ring as N2O.Strain-Release-Driven Modular Synthesis of Oxetane-Based Amide Bioisosteres: Concise, Robust, and Scalable ApproachClick to copy section linkSection link copied!While amides are found to be prevalent in the vast majority of both naturally occurring and synthetic biologically active molecules, the use of amide bioisosteres to replace this linkage has become a popular medicinal chemistry strategy to modulate both the physicochemical and pharmacokinetics of drug candidates as well as break into novel intellectual property space. Amino-oxetanes have been effectively employed for this purpose, though there are limited methods to access this motif in a modular fashion. Soós and co-workers developed a new approach to synthesize amino-oxetanes exploiting the intermediacy of benzotriazoyl-based Mannich adducts formed under mild conditions starting from oxetan-3-one ( Angew. Chem., Int. Ed., DOI: 10.1002/anie.202410554). Model studies highlighted that reaction of 4-phenylpiperidine and benzotriazole with oxetan-3-one enabled strain-relief of the exocyclic double bond to furnish the desired, stable Mannich adduct at room temperature without the need for concomitant water removal. The adducts were shown to react smoothly with a broad range of magnesium-based either (hetero)aryl or alkyl organometallic reagents to provide the amino-oxetane products with a high degree of functional group tolerance observed. Only secondary amines could be utilized as the amine component with increased sterics leading to a decrease in yield while in some cases the intermediates were shown to be thermally unstable, and as such used directly without isolation.New Opportunities for Organic Synthesis with Superheated Flow ChemistryClick to copy section linkSection link copied!Flow chemistry offers promising advancements for chemical manufacturing but faces challenges, particularly the need for quick reactions at production scales, which are rare. Superheated (SH) flow technology, operating above solvent boiling points, significantly enhances reaction rates and aligns with sustainability goals by improving productivity, offering solvent flexibility, and enhancing safety. However, it can be complex and resource-intensive, especially for newcomers. Expanding the temperature/pressure process window increases optimization space but can be wasteful using conventional methods. Flow chemists have developed tools to address these issues, including statistical models, AI, and theoretical knowledge. Despite these tools, the rationale for SH conditions has been slow to emerge. In this Account, Monbaliu and Bianchi from the University of Liège provide a comprehensive overview of SH flow chemistry, illustrated with examples from the authors' research and literature. They address advantages, costs, and methodologies, including Design of Experiments, microwave test chemistry, kinetics data, and quantum mechanics ( Acc. Chem. Res., DOI: 10.1021/acs.accounts.4c00340). Notably, the authors rationalize chemistries suitable for SH conditions and guides strategic adoption in order to reduce optimization resources.Expressed Protein Ligation in FlowClick to copy section linkSection link copied!A flow chemistry platform for generating modified protein targets via expressed protein ligation (EPL) has been developed, offering efficient ligation reactions with high recoveries and superior reaction rates compared to batch processes. The technology was demonstrated by Payne and co-workers from the University of Sydney and University of New South Wales, who semisynthesized the tick-derived chemokine-binding protein ACA-01 with two tyrosine sulfate modifications and generated both unmodified and phosphorylated forms of human β-synuclein ( J. Am. Chem. Soc., DOI: 10.1021/jacs.4c07462). The flow EPL process significantly enhanced reaction productivities, producing high-purity proteins in just 90 min. The platform's versatility was showcased by efficiently assembling full-length sulfated ACA-01 through the ligation of a recombinantly expressed C-terminal protein fragment and a synthetic sulfopeptide thioester in flow. Additionally, a one-pot in-line EPL–photodesulfurization strategy for β-synuclein was developed, requiring a demulsifying ligation buffer to manage the aggregation-prone nature of the protein fragment. This approach provided tens of milligrams of high-purity material, enabling functional studies on serine phosphorylation's role in inhibiting α-synuclein aggregation by β-synuclein. This flow EPL platform promises robust and efficient production of modified proteins, with applications in academia and the pharmaceutical and biotechnology industries.Organocatalyzed Carbonylation of Alkyl Halides Driven by Visible LightClick to copy section linkSection link copied!Esters and amides are themselves found in numerous drugs, as well as being versatile intermediates for the synthesis of pharmaceuticals. A popular method for their preparation involves the use of carbon monoxide as a C1 building block in combination with an alkyl or aryl halide and a transition metal catalyst. Although the scope and efficiency of such carbonylation reactions have been greatly improved in recent years through the use of photoredox catalysis, a transition metal catalyst is typically still required, and the photocatalysts reported to work best are often iridium-based. A new protocol for the completely metal-free carbonylation of a range of alkyl halides was recently reported (Miyake, G.; et al. Angew. Chem., Int. Ed., DOI: 10.1002/anie.202410928). Here, the organic photocatalyst 4-DPAIPN is used to facilitate radical generation, which is proposed to be followed by carbocation formation an

Organic halides play a key role as building blocks in synthesis because of their low cost and wide availability. In recent years, halogen-atom transfer (XAT) has emerged as a reliable approach to exploit these substrates in radical processes. Herein, we report a hydroalkylation of electron-poor olefins using alkyl bromides based on a UVA-induced silane-mediated XAT reaction. Our protocol is operationally simple, displays a broad scope and does not require a photocatalyst. Flow technology was used to reduce the reaction times and scale the process. Notably, a two-step protocol, combining the XAT protocol with a subsequent Horner-Wadsworth-Emmons reaction, has been developed to enable the allylation of C(sp3)–Br bonds.

The use of supercritical CO2 (scCO2) as an enabling technology paves the way for an efficient in-line integration of the synthesis and purification of organic molecules. The scCO2 platform presented here provides a streamlined process to produce a diverse family of triazoles, common drug precursors, by 1,3-dipolar copper-catalyzed azide-alkyne cycloaddition (CuAAC, Huisgen reaction), also decreasing the environmental impact by significantly reducing the use of traditional solvents. To further exemplify the potential of this scCO2 platform, the synthesis and purification of rufinamide, a drug used to treat seizures associated with Lennox–Gastaut syndrome, is also reported.

Metal-catalysed asymmetric allylic alkylation reactions have played a pivotal role in the construction of chiral compounds. When applied to the synthesis of butenolides, a common moiety present in many biologically active compounds, this reaction has always provided the C3-allylated products and only traces of the C5-allylated analogues. Here we report a Pd-catalysed C5-selective method that provides direct and highly enantioselective (up to >99% e.e.) access to a wide range of substituted butenolides using 2-substituted allyl acetates as the allylic partner. Mechanistic studies supported by density functional theory calculations have shown that the C5-selectivity observed is the result of a steric constraint induced by the substituent on the central carbon of the π–allyl complex forcing the reactive dienolate intermediate to expose its C5-reactive centre. The practicality, scalability and synthetic utility of the process was demonstrated through the total synthesis of three O-terpenoidal natural products: excavacoumarin B, D and E. The construction of C–C bonds with regio- and stereoselectivity is paramount in natural product synthesis and metal-catalysed asymmetric allylic alkylation reactions have played a key role, with high C3 selectivity demonstrated in butenolide synthesis. Now, a palladium-catalysed C5-selective method is reported, providing direct and highly enantioselective access to a range of diversely substituted butenolides.

Research-scale fully automated flow platform for reaction self-optimization with solids handling facilitates identification of optimal conditions for continuous manufacturing of pharmaceuticals while reducing amounts of raw materials consumed.

A continuous-flow electrochemical synthesis platform has been developed to enable self-optimization of reaction conditions of organic electrochemical reactions using attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) and gas chromatography (GC) as online real-time monitoring techniques. We have overcome the challenges in using ATR FT-IR as the downstream analytical methods imposed when a large amount of hydrogen gas is produced from the counter electrode by designing two types of gas-liquid separators (GLS) for analysis of the product mixture flowing from the electrochemical reactor. In particular, we report an integrated GLS with an ATR FT-IR probe at the reactor outlet to give a facile and low-cost solution to determining the concentrations of products in gas-liquid two-phase flow. This approach provides a reliable method for quantifying low-volatile analytes, which can be problematic to be monitored by GC. Two electrochemical reactions the methoxylation of 1-formylpyrrolidine and the oxidation of 3-bromobenzyl alcohol were investigated to demonstrate that the optimal conditions can be located within the pre-defined multi-dimensional reaction parameter spaces without intervention of the operator by using the stable noisy optimization by branch and FIT (SNOBFIT) algorithm.

Carbon–nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C–H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While this approach has been thoroughly investigated for C(sp2)–H bonds, only few examples have been reported for the direct amination of aliphatic C(sp3)–H bonds. Herein, we report the use of a newly developed flow photoreactor equipped with high intensity chip-on-board LED technology (144 W optical power) to trigger the regioselective and scalable C(sp3)–H amination via decatungstate photocatalysis. This high-intensity reactor platform enables simultaneously fast results gathering and scalability in a single device, thus bridging the gap between academic discovery (mmol scale) and industrial production (>2 kg/day productivity). The photocatalytic transformation is amenable to the conversion of both activated and nonactivated hydrocarbons, leading to protected hydrazine products by reaction with azodicarboxylates. We further validated the robustness of our manifold by designing telescoped flow approaches for the synthesis of pyrazoles, phthalazinones and free amines.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive. Herein, we report the development of a new approach that uses a microscale high-throughput experimentation (HTE) platform to identify optimal reaction conditions that can be directly translated to flow systems. A key design point is to simulate the flow-vessel pathway within a microscale reaction plate, which enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to photocatalysis will allow rapid identification of numerous flow protocols for scale.

Photochemical ATRA reactions of N-chloroamines represent an efficient and green method of alkene functionalization. N-Chloroamine generation, purification and reaction in flow enables an efficient process, with a variety of irradiation wavelengths.

4-Cyano-3-oxotetrahydrothiophene (c-THT) has much more to offer than just a platform to various heterocyclic scaffolds. This solid, bench-stable and commercially available reagent can be readily transformed into thioglycolic acid and acrylonitrile upon simple addition of a hydroxide anion. This interesting feature enables its use as a particularly versatile acrylonitrile anion surrogate.

We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.

Abstract Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp3)–H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical–polar crossover concept to access the direct net‐oxidative C(sp3)–H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous‐flow reactor technology. The developed protocol is also amenable to the late‐stage functionalization of biologically relevant molecules such as stanozolol, (−)‐ambroxide, podophyllotoxin, and dideoxyribose.

Using a Br2 generator in flow process intensified conditions has been developed for photochemical benzylic bromination on a kg scale.

Herein we report a summary of the synthetic development of LY3202626 from the initial discovery route to a final route that was scaled to make 150 kg. Key developments include the use of a [3 + 2] cyclization to set the cis ring junction of the formed isoxazoline, a one-pot thiazine formation, and three different ways to install the aniline: (1) Cu-catalyzed azide coupling and reduction, (2) nitration and reduction, and (3) Buchwald coupling with acetamide.

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported.

This article highlights recent progress in continuous flow self-optimizing platforms.

With ever-evolving light-emitting diode (LED) technology, classical photochemical transformations are becoming accessible with more efficient and industrially viable light sources. In combination with a triplet sensitizer, we report the detailed exploration of [2 + 2] cycloadditions, in flow, of various maleic anhydride derivatives with gaseous ethylene. By the use of a flow reactor capable of gas handling and LED wavelength/power screening, an in-depth optimization of these reactions was carried out. In particular, we highlight the importance of matching the substrate and sensitizer triplet energies alongside the light source emission wavelength and power. Initial triplet-sensitized reactions of maleic anhydride were hampered by benzophenone's poor absorbance at 375 nm. However, density functional theory (DFT) calculations predicted that derivatives such as citraconic anhydride have low enough triplet energies to undergo triplet transfer from thioxanthone, whose absorbance matches the LED emission at 375 nm. This observation held true experimentally, allowing optimization and further exemplification in a larger-scale reactor, whereby >100 g of material was processed in 10 h. These straightforward DFT calculations were also applied to a number of other substrates and showed a good correlation with experimental data, implying that their use can be a powerful strategy in targeted reaction optimization for future substrates.