Enabling Etherification

Science

Palladium-Catalyzed Cross-Coupling of Alcohols with Olefins by Positional Tuning of a Counteranion

S. H. M. Kaster, L. Zhu, W. L. Lyon, R. Ma, S. E. Ammann & M. C. White*

Science 2024, 385, 1067–1076 (DOI: 10.1126/science.ado8027)

Transition metal–catalyzed cross-couplings have great potential to furnish complex ethers; however, challenges in the C(sp³ )–O functionalization step have precluded general methods. Here, the authors describe computationally guided transition metal–ligand design that positions a hydrogen-bond acceptor anion at the reactive site to promote functionalization. A general cross-coupling of primary, secondary, and tertiary aliphatic alcohols with terminal olefins to furnish >130 ethers is achieved. The mild conditions tolerate functionality that is prone to substitution, elimination, and epimerization and achieve site selectivity in polyol settings. Mechanistic studies support the hypothesis that the ligand’s geometry and electronics direct positioning of the phosphate anion at the π-allyl-palladium terminus, facilitating the phosphate’s hydrogen-bond acceptor role toward the alcohol.

Nature Chemistry

Zinc and Manganese Redox Potentials in Organic Solvents and their Influence on Nickel-Catalysed Cross-Electrophile Coupling

Z.-M. Su, R. Deng & S. S. Stahl*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01627-5)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-pcdp4) 🔓

Zinc and manganese are widely used as reductants in synthetic methods, such as nickel-catalysed cross-electrophile coupling (XEC) reactions, but their redox potentials are unknown in organic solvents. Here, the authors show how open-circuit potential measurements may be used to determine the thermodynamic potentials of Zn and Mn in different organic solvents and in the presence of common reaction additives. The impact of these Zn and Mn potentials is analysed for a pair of Ni-catalysed reactions, each showing a preference for one of the two reductants. Ni-catalysed coupling of N-alkyl-2,4,6-triphenylpyridinium reagents (Katritzky salts) with aryl halides are then compared under chemical reaction conditions, using Zn or Mn reductants, and under electrochemical conditions performed at applied potentials corresponding to the Zn and Mn reduction potentials and at potentials optimized to achieve the maximum yield.

Nature Synthesis

Light-enabled Scalable Synthesis of Bicyclo[1.1.1]pentane Halides and their Functionalizations

V. Ripenko, V. Sham, V. Levchenko, S. Holovchuk, D. Vysochyn, I. Klymov, D. Kyslyi, S. Veselovych, S. Zhersh, Y. Dmytriv, A. Tolmachev, I. Sadkova, I. Pishel, K. Horbatok, V. Kosach, Y. Nikandrova & P. K. Mykhailiuk*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00637-y) 🔓

In 2012, bicyclo[1.1.1]pentanes were demonstrated to be bioisosteres of the benzene ring. Here, the authors report a general scalable reaction between alkyl iodides and propellane that provides bicyclo[1.1.1]pentane iodides in milligram, gram and even kilogram quantities. The reaction is performed in flow and requires just light; no catalysts, initiators or additives are needed. The reaction is clean enough that, in many cases, evaporation of the reaction mixture provides products in around 90% purity that can be directly used in further transformations without any purification. Combined with the subsequent functionalization, >300 bicyclo[1.1.1]pentanes for medicinal chemistry have been prepared.

Stereospecific C–O Sulfation via Persulfate-Induced 1,4-Metallate Migration

Z. Zhao, Q. Yu, Z. Xia, Z. Ye, X. Huang, C. Song & J. Li*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00636-z)

Sulfation, a ubiquitous post-translational modification in biomolecules, primarily targets substrates containing OH groups through O-sulfonation (O–SO₃). A method for sulfation via the formation of C–O bonds has the potential to access organic sulfates from a broad substrate scope and in a stereoselective manner. However, stereospecific C–O bond formation via 1,2-metallate migration in peroxide oxidation has not been deployed to create any other valuable C–O bonds apart from C–OH. Here, the authors describe a fundamentally unique reactivity of persulfate salts for stereospecific C–O sulfation via 1,4-metallate migration. With the aid of readily accessible, stereodefined organic boron compounds derived from native functionalities and a tandem borylation–sulfation approach, this study includes hydrosulfation of alkenes, C–H sulfation, decarboxylative sulfation, dehalogenative sulfation and deaminative sulfation, which are not otherwise readily accessible.

Journal of the American Chemical Society

Total Synthesis of the Hexacyclic Sesterterpenoid Niduterpenoid B via Structural Reorganization Strategy

Y. Xue, S.-H. Hou,* X. Zhang, F.-M. Zhang, X.-M. Zhang & Y.-Q. Tu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09555)

To date, it remains challenging to precisely and efficiently construct structurally intriguing polycarbocycles with densely packed stereocenters in organic synthesis. Niduterpenoid B, a naturally occurring ERα inhibitor, exemplifies this complexity with its intricate polycyclic network comprising 5 cyclopentane and 1 cyclopropane rings, featuring 13 contiguous stereocenters, including 4 all-carbon quaternary centers. In this work, the authors describe the first total synthesis of niduterpenoid B using a structural reorganization strategy. Key features include an efficient methoxy-controlled cascade reaction that precisely forges a highly functionalized tetraquinane (A–D rings) bearing sterically hindered contiguous quaternary stereocenters, and a rhodium-catalyzed [1+2] cycloaddition that facilitates the construction of a strained 3/5 bicycle (E–F rings) angularly fused with ring D.

A Unified Method for Oxidative and Reductive Decarboxylative Arylation with Orange Light-Driven Ir/Ni Metallaphotoredox Catalysis

K. A. Xie, E. Bednarova, C. L. Joe, T. C. Sherwood, E. R. Welin & T. Rovis*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08375)

Carboxylic acids and their derivatives are powerful building blocks in dual Ir/Ni metallaphotoredox methods of decarboxylative arylation due to their abundance as feedstock compounds. However, the library of accessible carboxylic acids is limited by trends in radical stability, often necessitating the development of specific systems for challenging substrates. Herein, the authors disclose the application of a new Ir(III) photocatalyst and low-energy orange light Ir/Ni metallaphotoredox system with broad applicability in activating both native carboxylic acids and redox-active esters (RAEs). This method represents the first known example of complementary oxidative and reductive decarboxylative paradigms with broadly similar reaction conditions, unlocking the reactivity for challenging substrates. A wide scope of aryl halide and acid coupling partners in both regimes has been shown, with added advantages over blue-light-catalyzed aryl alkylation for photosensitive substrates.

Chiral Brønsted Acid-Catalyzed Intramolecular Asymmetric Dearomatization Reaction of Indoles with Cyclobutanones via Cascade Friedel–Crafts/Semipinacol Rearrangement

X. Yu, C. Zheng* & S.-L. You*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09814)

The highly efficient synthesis of chiral indolines fused with an azabicyclo[2.2.1]heptanone moiety is achieved by an asymmetric dearomatization reaction of indoles with cyclobutanones. A new chiral imidodiphosphorimidate (IDPi) catalyst is synthesized and exhibits extraordinary activity in promoting a cascade Friedel–Crafts/semipinacol rearrangement. Target molecules are prepared in good yields (up to 95%) with excellent enantioselectivity (up to 98% e.e.) with operational convenience.

Catalyst Control over S(IV)-stereogenicity via Carbene-derived Sulfinyl Azolium Intermediates

B. Li,^† J. Hu,^† M. Liao, Q. Xiong, Y. Zhang, Y. R. Chi, X. Zhang* & X. Wu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10486)

Stereoselective synthesis utilizing small-molecule catalysts, particularly N-heterocyclic carbenes (NHCs), has facilitated swift access to enantioenriched molecules through diverse activation modes and NHC-bound reactive intermediates. While carbonyl derivatives, imines, and “activated” alkenes have been extensively investigated, the exploration of heteroatom-centered analogues of NHC-bound intermediates has long been neglected. Herein, the authors disclose a carbene-catalyzed new activation mode by generating unique sulfinyl azolium intermediates from carbene nucleophilic addition to in situ-generated mixed sulfinic anhydride intermediates. Mechanistic investigations pinpoint the chiral NHC-catalyzed formation of sulfinyl azolium intermediate as the enantiodetermining step. The novel “S”-based carbene reactive intermediate imparts high efficiency for the catalytic construction of sulfur-stereogenic compounds, giving rise to sulfinate esters with high yields and enantioselectivities under mild conditions.

Dual Ligand Enabled Pd-Catalyzed Ortho-Alkylation of Iodoarenes

X.-X. Wang & L. Jiao*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06544)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-rfq9d) 🔓

The synthesis of complex polysubstituted aromatic molecules from simple precursors is a central goal in organic chemistry. In this study, the authors developed an approach for the ortho-alkylation of iodoarenes utilizing a dual ligand catalytic system. By combining Pd/olefin ligand cooperative catalysis with bulky trialkylphosphine ligand-promoted C(sp² )–I reductive elimination, an ortho-alkylative Catellani-type reaction with the aryl-iodine bond reconstruction as the final step has been established, which opens new synthetic opportunities within the Catellani-type reactions. Through in-depth mechanistic investigations, key organopalladium intermediates have been isolated and characterized, revealing the synergistic interaction of the dual ligands in merging the Catellani-type process with C(sp² )–I reductive elimination.

Nickel-Catalyzed Enantioselective C(sp³)–C(sp³) Cross-Electrophile Coupling of N-Sulfonyl Styrenyl Aziridines with Alkyl Bromides

Y. Lan,^† Q. Han,^† P. Liao,^† R. Chen, F. Fan, X. Zhao & W. Liu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08435)

The authors report the first example of a highly enantioselective alkylative aziridine ring opening. Under the catalysis of a chiral nickel/pyridine-imidazoline complex, asymmetric C(sp³ )–C(sp³ ) cross-electrophile coupling between racemic N-sulfonyl styrenyl aziridines and readily available primary alkyl bromides furnishes a variety of highly enantioenriched phenethylamine derivatives with complete regiocontrol and good functional group tolerance. Preliminary mechanistic studies support a reaction pathway consisting of regioselective iodolysis of aziridines in situ and subsequent enantioconvergent coupling of the generated β-amino benzyl iodides with alkyl bromides.

Photodriven Sm(III)-to-Sm(II) Reduction for Catalytic Applications

C. M. Johansen,^† E. A. Boyd,^† D. E. Tarnopol & J. C. Peters*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10053) 🔓

The selectivity of SmI₂ as a one electron-reductant motivates the development of methods for reductive Sm-catalysis. Photochemical methods for SmI₂ regeneration are desired for catalytic transformations. In particular, returning Sm^III -alkoxides to Sm^II is a crucial step for Sm-turnover in many potential applications. To this end, photochemical conditions for reduction of both SmI₃ and a model Sm^III -alkoxide to SmI₂(THF)_n are described here. The Hantzsch ester can serve either as a direct photoreductant or as the reductive quencher for an Ir-based photoredox catalyst. In contrast to previous Sm^III reduction methodologies, no Lewis acidic additives or byproducts are involved, facilitating selective ligand coordination to Sm. Accordingly, Sm^II species can be generated photochemically from SmI₃ in the presence of protic, chiral, and/or Lewis basic additives. Both the photoreductant and photoredox methods for SmI₂ generation translate to intermolecular ketone-acrylate coupling as a proof-of-concept demonstration of a photodriven, Sm-catalyzed reductive cross-coupling reaction.

For a recent, related publication from the same authors using a thermal and electrochemical approach in collaboration with the Reisman group, see: Science 2024, 385, 847–853 (DOI: 10.1126/science.adp5777).

Ru-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated γ-Lactams

Z. Ding, Y. Luo, Q. Yuan, G. Wang, Z. Yu, M. Zhao, D. Liu & W. Zhang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09794)

A highly efficient Ru-catalyzed asymmetric hydrogenation of α,β-unsaturated γ-lactams has been developed by using a C2-symmetric ruthenocenyl phosphine-oxazoline as the chiral ligand. This method achieves the enantioselective synthesis of chiral β-substituted γ-lactams in high yields and with excellent enantioselectivities (up to 99% yield with 99% e.e.). Mechanistic studies revealed that the cationic Ru-complex acts as the active catalytic species; the protonation process of the oxa-π-allyl-Ru complex, which is formed by the migratory insertion of the C=C double bond to the Ru–H bond (the stereocontrolling step) followed by an isomerization process, is the rate-determining step, and the existence of PPh₃ is crucial for the highly efficient catalytic behavior. The protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs and bioactive compounds, particularly for the 150 kg-scale industrial production of Brivaracetam, an antiepileptic drug.

Angewandte Chemie International Edition

A Strategy for the Formal C-N Cross-Coupling of Tertiary Amines

P. R. Ledwith, M. L. Cooney, K. A. Bahou, J. García-Cárceles, J. Thomson & J. Bower*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202411555) 🔓

The authors report a strategy for the C-N cross-coupling of tertiary amines via the in situ generation and displacement of N-acyl ammonium species. Specifically, treatment of diverse tertiary amines with TFAA or choroformates in the presence of NaI leads to the efficient generation of alkyl iodides, which can be engaged directly in Ni-catalyzed cross-couplings. The protocol is applicable to acyclic and cyclic systems, including highly hindered variants. Applications to the late-stage modification of complex heterocycles are presented.

Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis

P. Wu, G. Goujon, S. Pan, B. Tuccio, B. Pégot, G. Dagousset, E. Anselmi,* E. Magnier* & C. Bolm*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202412418) 🔓

Benzo[1,3,2]dithiazole-1,1,3-trioxides are bench-stable and easy-to-use reagents, which under photoredox catalysis can generate methyl or perdeuteromethyl radicals that can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N-Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale-up further underscoring the synthetic usefulness of these methylation reagents.

ChemRxiv

Pyrolytic Carbon: An Inexpensive, Robust, and Versatile Electrode for Synthetic Organic Electrochemistry

T. E.-H. Ewing,^† N. Kurig,^† Y. R. Yamaki, J. Sun, T. R. Knowles, A. Gollapudi, Y. Kawamata* & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-4jw94) 🔓

Synthetic organic electrochemistry is recognized as one of the most sustainable forms of redox chemistry that can enable a wide variety of useful transformations. In this study, readily prepared pyrolytic carbon electrodes are explored in several powerful rAP transformations as well as C–C and C–N bond forming reactions. Pyrolytic carbon provides an alternative to classic amorphous carbon-based materials that are either expensive or ill-suited to large-scale flow reactions.

That’s all for this issue! Have a great week and we’ll see you next Monday.