Lighting the Way to C–F Bond Activation

Welcome to this week’s Organic Synthesis Newsletter. 

Monday 18^th November – Sunday 24^th November 2024 | Volume 1, Issue 35

HIGHLIGHT OF THE WEEK
Photocatalytic C–F Bond Activation in Small Molecules and Polyfluoroalkyl Substances

X. Liu, A. Sau,^‡ A. R. Green,^‡ M. V. Popescu,^‡ N. F. Pompetti, Y. Li, Y. Zhao, R. S. Paton,* N. H. Damrauer* & G. M. Miyake*

Nature 2024 (DOI: 10.1038/s41586-024-08327-7)

Organic halides are highly useful compounds in chemical synthesis, where the halide serves as a versatile functional group for elimination, substitution, and cross-coupling reactions with transition metals or photocatalysis. However, the activation of carbon-fluorine bonds, the most commercially abundant organohalide and found in polyfluoroalkyl substances (PFAS), or “forever chemicals”, are much rarer. Current approaches based on photoredox chemistry for activation of small molecule carbon-fluorine (C–F) bonds are limited by the substrates and transition-metal catalysts needed. Here, the authors report an organic photoredox catalyst system that can efficiently reduce C–F bonds to generate carbon-centered radicals, which can then be intercepted for hydrodefluorination (swapping F for H) and cross-coupling reactions. This method was extended to the defluorination of PFAS and fluorinated polymers, a critical challenge in the breakdown of persistent and environmentally damaging forever chemicals.

For a recent, related publication by Y.-B. Kang and co-workers on the “Photocatalytic Low-Temperature Defluorination of PFASs”, see, DOI: 10.1038/s41586-024-08179-1.

NATURE
Coupling of Unactivated Alkyl Electrophiles using Frustrated Ion Pairs

S. Roediger, E. Le Saux, P. Boehm & B. Morandi*

Nature 2024 (DOI: 10.1038/s41586-024-08195-1) 🔓

Cross-electrophile coupling reactions have evolved into a major strategy for rapidly assembling important organic molecules. Two readily accessible electrophiles are coupled to form new C–C bonds, providing a key advantage over traditional cross-coupling strategies that require the preformation of reactive organometallic species. Yet, the formation of C(sp³)–C(sp³) bonds that form the core of nearly all organic compounds remains highly challenging with current approaches, calling for the design of innovative new strategies. Here, the authors report a distinct, transition-metal-free platform to form such bonds without the need for activating or stabilizing groups on the coupling partners. The reaction is enabled by an unusual single-electron transfer in a frustrated ion pair, and it can couple fragments containing functional groups that would be challenging in related transition-metal-catalysed processes.

Synergistic Photobiocatalysis for Enantioselective Triple Radical Sorting

Z. Xing,^† F. Liu,^† J. Feng,^† L. Yu, Z. Wu, B. Zhao, B. Chen, H. Ping, Y. Xu, A. Liu, Y. Zhao, C.g Wang, B. Wang* & X. Huang*

Nature 2024 (DOI: 10.1038/s41586-024-08399-5)

Multicomponent reactions—those where three or more substrates combine into a single product—are highly useful in rapidly building chemical complexity, but achieving this process enzymatically has remained rare. This limitation arises because an enzyme’s active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates. Recently, radical sorting has emerged as an enabling strategy for a variety of useful reactions; however, making such a process enantioselective is challenging due to the inherent difficulty in the stereochemical control of radicals. Here, the authors repurpose a thiamine-dependent enzyme through directed evolution and combine it with photoredox catalysis to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials (aldehydes, α-bromo-carbonyls and alkenes) to give access to enantioenriched ketone products with 25 out of 33 examples achieving ≥97% enantiomeric excess.

NATURE CHEMISTRY
Diversified Ring Expansion of Saturated Cyclic Amines enabled by Azlactone Insertion

L. Wu,^† H. Xia,^† J. Bai, Y. Xi, X. Wu, L. Gao, J. Qu & Y. Chen*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01668-w)

Saturated N-heterocycles are ubiquitous structures among natural products and biologically active compounds. Therefore, the development of synthetic methods for the construction of N-heterocycles is of great importance to the synthetic community. Altering the ring system of these motifs to analogues with different ring sizes by employing molecular editing techniques would be highly appealing in medicinal chemistry. Here, the authors present the direct insertion of glycine derivatives as two-carbon synthons into unstrained five- or six-membered saturated cyclic amines at predictable sites, enabling the construction of synthetically challenging medium-sized azacycles. The conversion of a single azacycle into up to five others provides a promising toolbox for diversifying existing drug candidates and increasing the prospects for clinical success.

Dynamic Amine Sorting enables Multiselective Construction of Unsymmetrical Chiral Diamines

S. Cai, Z. Zhao, G. Yang & H. Huang*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01673-z)

Precisely differentiating chemical structures with only minor discrepancies is a prerequisite for achieving high selectivity in chemical synthesis. However, efficient strategies to differentiate and sort such compounds are lacking. Here, the authors report a dynamic amine-sorting strategy that incorporates the chemoselective formation of a cyclopalladated aminomethyl complex to achieve efficient differentiation of amine congeners. A series of amines sharing similar three-dimensional structures and properties, as well as possessing strong binding ability to metals, can be efficiently differentiated, enabling the chemo-, regio- and enantioselective multicomponent aminomethylamination of dienes to construct a variety of unsymmetrical chiral diamines.

NATURE COMMUNICATIONS
Halogencarbene-Free Ciamician-Dennstedt Single-Atom Skeletal Editing

S. Liu,^† Y. Yang,^† Q. Song,^† Z. Liu,* P. Sivaguru, Y. Zhang, G. de Ruiter, E. A. Anderson* & X. Bi*

Nat. Commun. 2024, 15, 9998 (DOI: 10.1038/s41467-024-54379-8) 🔓

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than a century of research, the Ciamician-Dennstedt rearrangement remains limited to halocarbene precursors. Herein, the authors report a general methodology for the Ciamician-Dennstedt reaction using α-halogen-free carbenes generated in situ from N-triftosylhydrazones. This one-pot, two-step protocol enables the insertion of various carbenes into indoles/pyrroles scaffolds to access 3-functionalized quinolines/pyridines.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Homologation of Carboxylic Acids Using a Radical-Polar Conjunctive Reagent

J. N. Gruhin,^† R. Kim,^† A. Vasilopoulos, E. A. Voight & E. J. Alexanian*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13687)

Carboxylic acids are present in many bioactive molecules and are widely available building blocks for chemical synthesis, yet their direct homologation is unknown. This valuable transformation currently necessitates implementation of multistep processes and commonly involves highly reactive and toxic reagents. Herein, the authors report the first one-step homologation directly from native carboxylic acids using a novel, bench-stable (1-phosphoryl)vinyl sulfonate reagent under mild conditions. This strategy was applied to a wide range of aliphatic carboxylic acid building blocks and biologically relevant complex molecules to access an array of ester, amide, and carboxylic acid homologues in a single step.

Iron-Catalyzed Cross-Electrophile Coupling for the Formation of All-Carbon Quaternary Centers

A. L. Pace, F. Xu, W. Liu, M. N. Lavagnino & D. W. C. MacMillan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14942)

Quaternary carbon centers are desirable targets for drug discovery and complex molecule synthesis, yet the synthesis of these motifs within traditional cross-coupling paradigms remains a significant challenge due to competing β-hydride elimination pathways. In contrast, the bimolecular homolytic substitution (S_H2) mechanism offers a unique and attractive alternative pathway. Metal porphyrin complexes have emerged as privileged catalysts owing to their ability to selectively form primary metal–alkyl complexes, thereby eliminating the challenges associated with tertiary alkyl complexation with a metal center. Herein, the authors report an iron-catalyzed cross-electrophile coupling of tertiary bromides and primary alkyl electrophiles for the formation of all-carbon quaternary centers through a biomimetic S_H2 mechanism.

Molecular Complexity-Inspired Synthetic Strategies toward the Calyciphylline A-Type Daphniphyllum Alkaloids Himalensine A and Daphenylline

B. A. Wright, T. Okada, A. Regni, G. Luchini, S. Sowndarya S. V., N. Chaisan, S. Kölbl, S. F. Kim, R. S. Paton* & R. Sarpong*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11252)

The authors detail two distinct synthetic approaches to calyciphylline A-type Daphniphyllum alkaloids himalensine A and daphenylline. Using MolComplex, a Python-based web application the authors developed, the structural complexity of all possible precursors resulting from one-bond retrosynthetic disconnections were quantified. This led to the identification of transannular bonds as especially simplifying to the molecular graph, and based on this analysis, the total synthesis of himalensine A was pursued from macrocyclic intermediates with planned late-stage transannular ring formations. Despite initial setbacks in accessing an originally designed macrocycle, targeting a simplified macrocycle ultimately enabled investigation of this intermediate’s unique transannular reactivity. Given the lack of success to access himalensine A based solely on molecular graph analysis, the approach to the related alkaloid, daphenylline, was revised.

Catalytic Asymmetric Cycloaddition of Olefins with in situ Generated N-Boc-Formaldimine

M. Guillén, M. Leutzsch & B. List*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13538) 🔓

Chiral 1,3-amino alcohols are ubiquitous structural motifs in natural products and active pharmaceutical ingredients. The authors present a highly enantioselective, inverse-electron-demand hetero-Diels–Alder reaction of olefins with in situ generated N-Boc-formaldimine catalyzed by strong and confined Brønsted acids. This transformation provides direct access to valuable 1,3-amino alcohols from styrenes and 1,1-disubstituted alkenes.

Enantioselective Synthesis of vic-Aminoalcohol Derivatives by Nickel-Catalyzed Reductive Coupling of Aldehydes with Protected Amino-pentadienoates

T. Bender & A. Fürstner*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12002) 🔓

A VAPOL-derived phosphoramidite ligand is uniquely effective at reverting the regiochemical course of nickel-catalyzed reactions of aldehydes with carbamate-protected 5-amino-2,4-pentadienoates as “push/pull” dienes; the ensuing carbonyl α-amino-homoallylation reaction affords anti-configured vic-aminoalcohol derivatives in good yields with high optical purity. The reductive coupling is conveniently performed with a bench-stable Ni(0) precatalyst and Et₃B as the promoter.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Synthesis and Functionalization of Sulfoximine-Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine-Selective Chiral Warheads

Z. Zhong, B. J. W. Hocking, C. P. Brown, T.-K. Ma, A. J. P. White, D. J. Mann, A. Armstrong & J. A. Bull*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202420028) 🔓

Electrophilic covalent warheads with appropriate reactivity and selectivity are crucial to the investigation of protein function and the discovery of therapeutics. Here, the authors report the synthesis of sulfoximine bicyclo[1.1.0]butanes (BCBs) as novel thiol reactive chiral warheads, achieved in one-pot from methylsulfoximines. Unusually the warhead can then be derivatized, keeping the BCB intact, over 3 vectors: i) sulfoximine N-modification instills a broad range of strain-release reactivity; ii) sp²-cross-coupling reactions on aryl-BCB-sulfoximines allows direct diversification, and iii) functionalization of the BCB motif itself is achieved by metalation and trapping with electrophiles. The BCB sulfoximines are shown to react selectively with cysteine including in a protein model (CDK2) under biocompatible conditions. Preliminary data indicate suitability for chemoproteomic applications, and enantioselective cysteine-labelling. The reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity.

Iodide Anion enables a Reductive Cross-Electrophile Coupling for Preparing Tertiary Amines

M. Lemmerer,^† V. Tona,^† D. Just, M. Vavrík, B. Maryasin, G. Di Mauro, A. B. zur Bonsen, D. Kaiser & N. Maulide*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409688) 🔓

The reducing power of iodide anion is an underexplored property that can be used for the cross-electrophile coupling of organic molecules. Herein, the authors harness this trait for the preparation of tertiary amines through the combination of two simple reagents: an electrophilic-carbon precursor and an iminium iodide in a dual role—both as nitrogen-containing building block and as reducing agent. The underlying mechanism of this new C–C bond-formation paradigm is explored through a combination of experiment and quantum chemical calculations.

meta-Dimethylation of Arenes via Catellani Reaction from Aryl Thianthrenium Salts

M. Mrozowicz, S. Chatterjee, M. A. Mermigki, D. Pantazis & T. Ritter*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202419472) 🔓

The authors report the reaction of aryl thianthrenium salts that allows selective functionalization of the meta-position of arenes. The combination of a site-selective thianthrenation with a Catellani reaction provides access to 3,5-dimethylated arenes. The developed reaction is complementary to the previously discovered reductive ipso-alkylation of aryl thianthrenium salts and extends the possibilities for late-stage methylation of arenes with a single aryl thianthrenium salt.

CHEMRXIV
Cheminformatic Analysis of Core-Atom Transformations in Pharmaceutically Relevant Heteroaromatics

G. L. Bartholomew,^† L. J. Karas,^† R. M. Eason, C. S. Yeung,* M. S. Sigman* & R. Sarpong*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-6j5md) 🔓

Heteroaromatics are the basis for many pharmaceuticals. The ability to modify these structures through selective core-atom transformations, or "skeletal edits", can dramatically expand the landscape for drug discovery and development. However, despite the importance of core-atom modifications, the quantitative impact of such transformations on accessible chemical space remains undefined. Here, the authors report a cheminformatic platform to analyze which skeletal edits would most increase access to novel chemical space. This study underscores the significance of emerging single and multiple core-atom transformations in heteroaromatics in enhancing chemical diversity, for example, at a late-stage of a drug discovery campaign. The findings provide a quantitative framework for prioritizing core-atom modifications in heteroaromatic structural motifs.

Migrative Reductive Amination of Ketones Enabled by Multitasking Reagents

A. Khegay & D. G. Hall*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-ln5f6) 🔓

Skeletal editing and “single-atom logic” are emerging strategies that accelerate compound synthesis and open new chemical space by modifying organic molecules using unconventional bond forming processes. Herein, a practical modification of the classical reductive amination of ketones and aldehydes, a staple reaction in drug discovery research, was developed to provide isomeric amines by way of a migratory reductive amination (MRA). This one-pot method combines three distinct chemical reactions in a single flask, without solvent changes, via the orchestrated addition of two inexpensive and non-toxic multitasking reagents: Zn(II) salts and a hydrosilane. This method demonstrates a wide scope of acyclic and cyclic ketones and aldehydes with aliphatic or aromatic groups, including complex molecules such as drug intermediates and natural products with an exceptionally low E-factor compared to established methods.

CHEM
Excited-State Protonation and Reduction enables the Umpolung Birch Reduction of Naphthalenes

J. Corpas, E. Rivera-Chao, E. M. Arpa, M. Gomez-Mendoza, Y. Katayama, V. A. de la Peña O’Shea, C. Bouchel, C. Jacob, P.-G. Echeverria, A. Ruffoni & D. Leonori*

Chem 2024, Online Now (DOI: 10.1016/j.chempr.2024.10.009) 🔓

The Birch reaction is a classical process used for the partial reduction of aromatics into non-conjugated cyclohexadienes that can be further functionalized. This strategy and its more modern variants are all based on an initial single-electron transfer event converting the arene into the corresponding radical anion for either protonation or hydrogen-atom transfer. Herein, the authors demonstrate an umpolung approach where the aromatic is first protonated to its corresponding carbocation and then reduced using the Lewis acid-base complex Et₃N−BH₃. This strategy requires aromatic photoexcitation so that protonation is favored by charge-transfer and driven by excited-state antiaromaticity relief. The mild conditions and the avoidance of strong reductants have enabled tolerance of functionalities generally not compatible under standard Birch conditions.

THE JOURNAL OF ORGANIC CHEMISTRY
Computational Library Enables Pattern Recognition of Noncovalent Interactions and Application as a Modern Linear Free Energy Relationship

J. A. Read,* T. E. Ball, B. R. Miller, E. N. Jacobsen* & M. S. Sigman*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01790) 🔓

A quantitative and predictive understanding of how attractive noncovalent interactions (NCIs) influence functional outcomes is a long-standing goal in mechanistic chemistry. In that context, better comprehension of how substituent effects influence NCI strengths, and the origin of those effects, is still needed. The authors sought to build a resource capable of elucidating fundamental origins of substituent effects in NCIs and diagnosing NCIs in chemical systems. To accomplish this, a library of 893 NCI energies was calculated encompassing cation−π, anion−π, CH−π, and π–π interactions across 60 different arenes and heteroarenes. The interaction energies (IEs) were calculated using symmetry-adapted perturbation theory (SAPT), which identifies electrostatic, inductive, exchange-repulsive, and dispersive contributions to total IE. This descriptor library provides a comprehensive platform for evaluating substituent effect trends beyond traditional molecular descriptors such as Hammett values, frontier molecular orbital energies, and electrostatic potential, thereby expanding the tools available to analyze modern chemical processes that involve NCIs. To demonstrate the application of this library, three case studies in asymmetric catalysis and supramolecular chemistry are presented. These case studies informed the development of an automated NCI analysis tool, which employs statistical analyses to diagnose a particular NCI in a chemical system of interest.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
A Catalyst for Change

🧪 A Catalyst for Change. Per- and polyfluorinated alkyl substances (PFAS) have a wide-range of uses and can be found in everything from non-stick cookware to mobile phones and even jet engines. There’s about 15,000 unique PFAS compounds out there and let’s face it, they’re not going anywhere anytime soon—even more so because they don’t degrade naturally over time, earning them the title “forever chemicals”. These persistent pollutants have been found everywhere from the heights of Mount Everest to penguins in the Antarctic and its not just the environment that’s in danger, they’ve been detected in blood, organs and breast milk too. Unfortunately, decomposing PFAS isn’t a straight forward process, often requiring high temperatures and pressure. However, new research published in Nature (and highlighted above!) from two separate research groups has found that organic photocatalysts can be used to effect the mild decomposition of PFAS. One approach breaks PFAS compounds all the way down to simple potassium fluoride while the other replaces the fluorines with hydrogens, generating potentially useful feedstock hydrocarbons.