Deaminative Cross-Coupling

Welcome to this week’s Organic Synthesis Newsletter.

Monday 13^th January – Sunday 19^th January 2025 | Volume 2, Issue 2

HIGHLIGHT OF THE WEEK
Radical Sorting as a General Framework for Deaminative C(sp³)–C(sp²) Cross-Coupling

D. Chattapadhyay, E.-C. Liu,^‡ M. J. Diaz,^‡ A. Maity, B. A. Bratten & Q. Michaudel*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-j3lq0) 🔓

While carboxylic acids are routinely used as radical precursors, an equally abundant class of building blocks—aliphatic primary amines—are not typically considered a starting point for radical coupling. Here, the authors present a general method for deaminative cross-coupling relying on a dual-catalytic system that generates geminate pairs of non-identical alkyl radicals via photosensitization of unsymmetrical 1,2-dialkyldiazenes, then selectively engages the desired radical species in C(sp³)–C(sp²) bond formation. This Ni-mediated “radical sorting” of geminate radical pairs is key in obtaining high yields and avoiding side products.

NATURE
Engineered Enzymes for Enantioselective Nucleophilic Aromatic Substitutions

T. M. Lister, G. W. Roberts, E. J. Hossack, F. Zhao, A. J. Burke, L. O. Johannissen, F. J. Hardy, A. A. V. Millman, D. Leys, I. Larrosa* & A. P. Green*

Nature 2025 (DOI: 10.1038/s41586-025-08611-0)

Nucleophilic aromatic substitution (S_NAr) reactions are typically carried out using forcing conditions involving polar aprotic solvents, stoichiometric bases and elevated temperatures, which do not allow for control over reaction selectivity. Despite the importance of S_NAr chemistry, there are only a handful of selective catalytic methods reported. Here, the authors establish a biocatalytic approach to stereoselective S_NAr chemistry by uncovering promiscuous S_NAr activity in a designed enzyme featuring an activated arginine. This activity was optimized over successive rounds of directed evolution to afford an engineered biocatalyst, S_NAr1.3, that is 160-fold more efficient than the parent and promotes the coupling of electron-deficient arenes with carbon nucleophiles with near-perfect stereocontrol (>99% e.e.).

NATURE SYNTHESIS
Nickel-Mediated Aerobic C(sp²)–Nucleophile Coupling Reactions for Late-Stage Diversification of Aryl Electrophiles

D. Das,^† L. P. Dinh,^† R. E. Smith, D. Kalyani* & C. S. Sevov*

Nat. Synth. 2025 (DOI: 10.1038/s44160-024-00721-3)

The authors report a general strategy for carbon–heteroatom bond formation through reactions between a wide range of nucleophiles and nickel-based oxidative addition complexes of drug-like aryl and heteroaryl electrophiles. These organonickel complexes are easily synthesized by oxidative addition of the corresponding electrophiles under electroreductive conditions using an inexpensive nickel precursor. Exposure of these complexes to ambient air forms a high-valent (peroxo)Ni^IIIAr complex intermediate that can undergo substitution with a variety of nitrogen-, oxygen-, sulfur-, carbon-, phosphorus- or halide-based nucleophiles. The breadth of this methodology was demonstrated by reactions with unreactive electrophiles, such as aryl chlorides, drug-like (hetero)aryl electrophiles and small peptides.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and Decarbonylative Cross-Coupling Reactions

Á. D. Hernández-Mejías, A. M. Shimozono, A. Hazra, S. Richter, Z. Tong, N. F. Langille, K. Quasdorf, A. T. Parsons, M. S. Sigman* & S. E. Reisman*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14767) 🔓

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, the authors describe the development of a bis(oxazoline) ligand that enables the desymmetrization of meso-anhydrides. When secondary benzylic electrophiles are employed, doubly stereoselective acyl cross-coupling proceeds to give ketone products with catalyst control over three newly formed stereogenic centers. Alternatively, the use of primary alkyl halides in the presence of an additional halogen atom transfer catalyst results in decarbonylative alkylation to give enantioenriched β-alkyl acids.

Concise Synthesis of (−)-Veratramine and (−)-20-iso-Veratramine via Aromative Diels–Alder Reaction

M. D. Zott, D. W. Zuschlag & D. H. Trauner*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16495)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-ccrr6-v2) 🔓

A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20-iso-veratramine has been accomplished. A Horner–Wadsworth–Emmons olefination joins two chiral building blocks of approximately equal complexity and a transition-metal catalyzed intramolecular Diels–Alder cycloaddition-aromatization cascade constructs the tetrasubstituted arene. This work shows that 20-iso-veratramine is not identical with a natural product proposed to have that structure.

Facile Access to Quaternary Carbon Centers via Ni-Catalyzed Arylation of Alkenes with Organoborons

Z.-C. Wang, L. Gao, S.-Y. Liu, P. Wang* & S.-L. Shi*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17313)

The authors report an efficient nickel-catalyzed intermolecular, Markovnikov-selective arylation of minimally functionalized alkenes with organoboron reagents, affording a broad range of cyclic or acyclic quaternary carbon centers under mild conditions. The utilization of a bulky chiral diimine as the ligand is critical for high reactivity, chemoselectivity and allows for the preparation of quaternary carbon stereocenters with high levels of enantiocontrol.

Secondary Alkylation of Arenes via the Borono–Catellani Strategy

H. Peng, D. Wang, J. Ye, Z.-S. Liu, Z. Zhu, X. Fu, C. Liu, H. Cong, H.-G. Cheng & Q. Zhou*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15956)

A modular platform technology for the synthesis of α-aryl carbonyl derivatives via Borono–Catellani-type secondary alkylation of arenes is presented. This method features a broad substrate scope and diversified terminating reagents, e.g. olefins, alkynes, and Zn(CN)₂. Importantly, the asymmetric version based on a dynamic kinetic asymmetric transformation (DyKAT) has been realized by introducing a 1:1 diastereomeric mixture of α-bromo carboxamides bearing an Evans chiral auxiliary, obtaining excellent diastereoselectivities (>20:1 d.r.). These chiral products can be transformed into diversified enantioenriched α-aryl propionic acid derivatives, laying the foundation for the discovery of new NSAIDs.

Cu-Catalyzed Diastereo- and Enantioselective Synthesis of Borylated Cyclopropanes with Three Contiguous Stereocenters

C. Gao,^† K. Tang,^† X. Yang, S. Gao, Q. Zheng, X. Chen* & J. Liu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14158)

The authors describe a highly diastereo- and enantioselective Cu-catalyzed alkylboration of cyclopropenes for the efficient synthesis of tetra-substituted, borylated cyclopropanes bearing three contiguous stereocenters. This protocol features mild conditions, a broad substrate scope and good functional group tolerance, affording an array of chiral borylated cyclopropanes.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Saturated F₂-rings from Alkenes

Y. Li, X.-B. Liu, V. Sham, I. Logvinenko, J.-H. Xue, J.-Y. Wu, J.-L. Fu, S. Lin, Y. Liu, Q. Li*, P. K. Mykhailiuk* & H. Wang*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202422899)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-0wf3l-v2) 🔓

A general method to convert simple exocyclic alkenes (no Ar-substituents) into saturated F₂-rings has been developed. The reaction involves the I^III-reagent C₆F₅I(OAc)₂ (F₅-PIDA). The reaction efficiently works on the mg-, g-, and even multigram scale.

CHEMRXIV
Isayama–Mukaiyama Peroxidation Eschews Ozonolysis in Hydrodealkenylation

J. H. Dworkin, Z. M. Chen, K. C. Cheasty, A. V. Rubio & O. Kwon*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-vz1c5) 🔓

Advancements in radical capture strategies have expanded the range of products accessible from alkenes through dealkenylative synthesis. However, these methods are limited as they rely on ozonolysis to generate key peroxide intermediates from alkenes. In this paper, using Isayama–Mukaiyama peroxidation (IMP), the authors address the limitations of ozonolysis to rescue previously inaccessible alkene substrates and broaden the applicability of dealkenylative functionalization. A novel reductive hydrogenation was also demonstrated to resolve β-scission issues associated with IMP-generated alkyl silylperoxides.

Bench-Stable Boryl Dication Enables Aziridinyl Boronate Synthesis via Metal-Free Late-Stage Aziridination with Diverse Nitrogen Nucleophiles

V. R. Vulupala, D. Gunasekera, R. Yousef, N. R. Mallampudi, Y. Gyasi, R. G. Reddy & S. Xu*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-gmfsv) 🔓

This study describes the first synthesis of a bench-stable boryl dicationic compound via thianthrenation of vinyl MIDA boronate. The unique boryl dication enables a transition-metal-free, chemo- and diastereoselective synthesis of aziridinyl boronates, utilizing a broad range of nitrogen nucleophiles. The method demonstrates remarkable generality and functional group tolerance, as evidenced by its application to diverse substrates, including the late-stage modification of several drug molecules. The utility of the protocol is further highlighted through an electrochemical one-pot procedure and multiple downstream transformations of the obtained aziridinyl boronates.

Photocatalyst-Dependent Enantioselectivity in the Light-Driven Deracemization of Cyclic α-Aryl Ketones

J. Y. Wang, E. Villalona & R. R. Knowles*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-9qsq1) 🔓

The authors report a photoredox-enabled deracemization of cyclic α-aryl ketones that occurs with high stereoselectivity and yield, and proceeds by mechanistically distinct proton transfer reactions. This reaction is jointly mediated by a visible-light photocatalyst and a chiral phosphate base co-catalyst under blue light irradiation. Notably, the extent of deracemization for this reaction exhibits an unexpected dependence on the identity of the photocatalyst and the concentration of a chiral base co-catalyst, wherein the extent of deracemization can be increased by employing photocatalysts with more positive ground-state reduction potentials, raising the concentration of the chiral base co-catalyst, or by a combination of these factors.

The Radical-Radical Cross-Coupling of Alkyl Carboxylic Acids and Organoborons

J. Zhong,^† M. Boudjelel,^† J. M. Evans, I. Vanswearingen & C. A. Malapit*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-bw2xl) 🔓

Despite over a century of research on radicals from both carboxylic and boronic acids, efficient cross-coupling between these species has not been achieved. Here, the authors revisit radical-radical cross-coupling to enable the first direct coupling of carboxylic and boronic acids to form alkyl-alkyl C–C bonds using abundant precursors. This breakthrough is enabled by integrating redox-matched alternating polarity electrolysis with controlled activation of redox-active species, ensuring high reactivity, selectivity, and broad scope.

Directed Evolution and Unusual Protonation Mechanism of Pyridoxal Radical C–C Coupling Enzymes for the Enantiodivergent Photobiocatalytic Synthesis of Non-Canonical Amino Acids

L. Cheng, Z. Bo, B. Krohn-Hansen & Y. Yang*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-32vjk) 🔓

Using high-throughput photobiocatalysis, a set of stereochemically complementary PLP radical enzymes was evolved, enabling the synthesis of both ʟ- and ᴅ-amino acids with enhanced enantiocontrol across a broad pH window. The newly engineered ʟ- and ᴅ-amino acid synthases permitted the use of a broad range of organoboron substrates with excellent efficiency. Mechanistic investigations suggest a switch of proton donor to account for the stereoinvertive formation of ᴅ-amino acids, highlighting an unusual stereoinversion mechanism that is rare in conventional two-electron PLP enzymology.

Diastereo- and Enantioselective Chemoenzymatic Synthesis of Chiral Tricyclic Intermediate of Anti-HIV Drug Lenacapavir

W. Fu,^† A. Liu^† & Y. Yang*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-w7q5k) 🔓

The authors developed a chemoenzymatic synthesis of the recently developed anti-HIV drug lenacapavir’s 5/5/3 fused tricyclic fragment featuring an unusual chiral cyclopropane moiety. Key to this was the development of a biocatalyst-controlled, diastereo- and enantiodivergent cyclopropanation of a highly functionalized vinylpyrazole substrate, granting access to all four possible stereoisomers of lenacapavir cyclopropane (in up to 99:1 d.r. and 99:1 e.r.). Further developed downstream chemical cyclization afforded the desired lenacapavir 5/5/3 fused tricycle.

A Voltage-Controlled Redox Mediator Strategy Enables Electrocatalytic Z-Selective Semi-Hydrogenation

B. Parnitzke, E. Gerhardt,^‡ R. Lalisse,^‡ T. Maity,^‡ Z. Xuan, Y. Liu, O. Gutierrez* & J. Derosa*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-4wv5d) 🔓

The authors demonstrate a tandem redox-mediated electrocatalytic approach to selectively hydrogenate a variety of alkynes to cis-alkenes via a cobaltocene redox mediator and bisphosphine cobalt co-catalyst under voltage control. Controlled potential electrolysis (CPE) at the potential of the mediator (E_app = −1.45 V vs Fc^+/0) successfully generates a variety of terminal and internal alkenes in moderate to good yields. Notably, substrates with tethered Lewis bases further drive selectivity almost exclusively for the Z-isomer. This developed methodology can be applied toward the synthesis of cis-stilbenoid natural products, as demonstrated through the synthesis of combretastatin A-4.

Photocatalysis Enables Chemodivergent Radical Polar Crossover: Ritter-Type Amidation vs. Heck-Type Olefin Carbofunctionalizations

M. Lepori, C. Pratley,^‡ I. Dey,^‡ V. Roider & J. P. Barham*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-cjjxv) 🔓

The authors report a photoredox catalyzed Ritter-type carboamidation of electronically diverse styrenes harnessing non-stabilized, nucleophilic primary radicals generated from readily accessible redox active esters. Additionally, it was found that Heck-type products were chemoselectively obtained by simply switching aryl olefin acceptors with 1,1-diarylolefins, producing various tri-substituted alkenes. Both Ritter-Type and Heck-type olefin carbofunctionalizations were scalable up to 4 mmol scale in batch and continuous flow.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Air Pollution Linked to Brain Disorders

😷 Air pollution linked to brain disorders. The World Health Organisation (WHO) estimates that almost the entire global population (99%) is exposed to pollution higher than the recommended levels with low- to middle-income countries suffering the most. In the modern world, our use of motor vehicles, burning of fossil fuels and even the tragic California wildfires will all contribute to the release of nitrogen oxides (NO_x), fine particular matter (PM_2.5) and other noxious agents into our atmosphere.

Beyond environmental damage, air pollution is a significant public health concern with its effects on the respiratory system well documented (e.g. in asthma, lung cancer, heart disease). Now, recent studies have established a link between high levels of air pollution and brain disorders, including an increased risk of dementia with a Lancet Commission recognising PM_2.5 as a risk factor for the condition.

Further studies, including an analysis of nearly 400,000 participants in the UK Biobank found that long-term exposure to air pollutants led to higher incidences of anxiety and depression, alongside others noting correlations with neurodevelopmental conditions, such as autism and cognitive deficits. While studies are ongoing to probe the underlying mechanisms and which pollutants cause the most harm, the myriad of toxins present complicate efforts. However, if successful, the information could be used to guide public health strategies and reduce our exposure to specific harmful pollutants.