Control of Cyclodecyl Cations Delivers Decalins

Science

Remote Proton Elimination: C–H Activation Enabled by Distal Acidification

P. S. Grant^† , M. Vavrík^† , V. Porte^‡, R. Meyrelles^‡ & N. Maulide*

Science 2024, 384, 815–820 (DOI: 10.1126/science.adi8997)

Generally, the acidity of carbon-hydrogen bonds is most sensitive to functionality just one or two bonds away. Here, the authors present an approach to the formation of carbon-carbon σ bonds by remote proton elimination, a distinct mode of carbon-hydrogen activation enabled by distal acidification through five carbon-carbon bonds. Application of remote proton elimination to cyclodecyl cations unveiled an appealing method for the synthesis of decalins. The transformation is regioconvergent, proceeds without the need for a directing group or precious metal, and demonstrates exquisite site selectivity. An in-depth computational study illuminated the reaction mechanism. Additionally, the authors describe the complete stereoisomeric enrichment of the decalin products through epimerization mediated by hydrogen atom transfer.

Enantioselective Remote Methylene C−H (hetero)Arylation of Cycloalkane Carboxylic Acids

T. Zhang^† , Z.-Y. Zhang^† , G. Kang, T. Sheng, J.-L. Yan, Y.-B. Yang, Y. Ouyang & J.-Q. Yu*

Science 2024, 384, 793–798 (DOI: 10.1126/science.ado1246)

Stereoselective construction of γ- and δ-stereocenters in carbonyl compounds is a pivotal objective in asymmetric synthesis. Here, the authors report chiral bifunctional oxazoline-pyridone ligands that enable enantioselective palladium-catalyzed remote γ-C−H (hetero)arylations of free cycloalkane carboxylic acids, which are essential carbocyclic building blocks in organic synthesis. The reaction establishes γ-tertiary and α-quaternary stereocenters simultaneously in up to >99% enantiomeric excess, providing access to a wide range of cyclic chiral synthons and bioactive molecules. The sequential enantioselective editing of two methylene C–H bonds can be achieved by using chiral ligands with opposite configuration to construct carbocycles containing three chiral centers. Enantioselective remote δ-C−H (hetero)arylation is also realized to establish δ-stereocenters that are particularly challenging to access using classical methodologies.

Nature Communications

Introduction of the Difluoromethyl Group at the meta- or para-Position of Pyridines through Regioselectivity Switch

P. Xu,^† Z. Wang,^† S.-M. Guo & A. Studer*

Nat. Commun. 2024, 15, 4121 (DOI: 10.1038/s41467-024-48383-1) 🔓

Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C−H-difluoromethylation of pyridines represents a highly efficient economic way to access these azines. However, the direct meta-difluoromethylation of pyridines has remained elusive and methods for site-switchable regioselective meta- and para-difluoromethylation are unknown. Here, the authors demonstrate the meta-C−H-difluoromethylation of pyridines through a radical process by using oxazino pyridine intermediates, which are easily accessed from pyridines. The selectivity can be readily switched to para by in situ transformation of the oxazino pyridines to pyridinium salts upon acid treatment. The mild conditions used also allow for the late-stage meta- or para-difluoromethylation of pyridine containing drugs.

Journal of the American Chemical Society

Copper–Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization

C. M. Hanneman, J. Twilton, M. N. Hall, N. C. Goodwin, J. M. Elward, T. Lynch-Colameta & S. S. Stahl*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04359)

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, the authors report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Visible-Light Photocatalytic C–H Amination of Arenes Utilizing Acridine–Lewis Acid Complexes

M. R. Lasky, E.-C. Liu, M. S. Remy & M. S. Sanford*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02991)

This report describes the development of a visible-light photocatalytic system for C(sp² )–H amination that leverages in situ-generated photocatalysts. The authors demonstrate that the combination of acridine derivatives and Lewis acids forms potent photooxidants that promote the C–H amination of electronically diverse arenes upon irradiation with visible-light (440 nm). A first-generation photocatalyst composed of Sc(OTf)₃ and acridine effects the C–H amination of substrates with oxidation potentials ≤ +2.5 V vs. SCE with pyrazole, triazole, and pyridine nucleophiles. Furthermore, the simplicity and modularity of this system enable variation of both Lewis acid and acridine to tune reactivity. This enabled the rapid identification of two second-generation photocatalysts (derived from (i) Al(OTf)₃ and acridine or (ii) Sc(OTf)₃ and a pyridinium-substituted acridine) that catalyze a particularly challenging transformation: C(sp² )–H amination with benzene as the limiting reagent.

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids

N. G.-Simonian,^† P. Spieß,^† M. Riomet, B. Maryasin, I. Klose, A. B. Garcia, L. Pollesböck, D. Kaldre, U. Todorovic, J. M. Liu, D. Kaiser, L. González & N. Maulide*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01755) 🔓

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

Enantioselective Access to β-Amino Carbonyls via Ni-Catalyzed Formal Olefin Hydroamidation

X. Lyu, H. Jung, D. Kim & S. Chang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02497)

The authors describe a Ni-catalyzed formal hydroamidation of readily available α,β-unsaturated carbonyl compounds to afford valuable chiral β-amino acid derivatives (up to >99:1 e.r.) using dioxazolones as a robust amino source. A wide range of alkyl-substituted olefins conjugated to esters, amides, thioesters, and ketones were successfully amidated at the β-position with excellent enantioselectivity for the first time. Combined experimental and computational mechanistic studies supported the working hypothesis that this unconventional β-amidation of unsaturated carbonyl substrates can be attributed to the polar-matched migratory olefin insertion of an (amido)(Cl)Ni^II intermediate, in situ generated from the dioxazolone precursor.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5+3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes

J.-L. Zhou, Y. Xiao, L. He, X.-Y. Gao, X.-C. Yang, W.-B. Wu, G. Wang, J. Zhang* & J.-J. Feng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01851)

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, the authors report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94–99% e.e. has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings.

ACS Central Science

Selective 1,4-syn-Addition to Cyclic 1,3-Dienes via Hybrid Palladium Catalysis

Y. Liang, T. Bian, K. Yadav, Q. Zhou, L. Zhou, R. Sun & Z. Zhang*

ACS Cent. Sci. 2024, ASAP (DOI: 10.1021/acscentsci.4c00094) 🔓

1,4-cis-Disubstituted cyclic compounds play a pivotal role in pharmaceutical development, offering enhanced potency and bioavailability. However, their stereoselective and modular synthesis remains a long-standing challenge. Here, the authors report an innovative strategy for accessing these structures via mild conditions employing cyclic 1,3-dienes/alkyl(aryl)halides and amines. This procedure exhibits a wide substrate scope that tolerates various functional groups. The utility of this method is demonstrated in the efficient synthesis of a TRPV6 inhibitor, CFTR modulator, and other bioactive molecules. Combined experimental and computational studies suggest that the hybrid palladium-catalyzed radical-polar crossover mechanism is crucial for achieving exceptional 1,4-syn-addition selectivity (>20:1 d.r.).

Angewandte Chemie International Edition

Enantioselective Synthesis of Sulfinamidines via Asymmetric Nitrogen Transfer from N-H Oxaziridines to Sulfenamides

M. Fimm & F. Saito*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408380) 🔓

Sulfinamidines are promising aza-S^IV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here, the authors present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N-H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 °C in solution and show remarkable stability against organic acids and bases under non-aqueous conditions. The authors also demonstrate a one-pot, three-component, enantioselective synthesis of sulfinamides using N-H oxaziridine reagents.

A General Iron-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids

L. M. Denkler, M. A. Shekar,^‡ T. S. J. Ngan,^‡ L. Wylie, D. Abdullin, M. Engeser, G. Schnakenburg, T. Hett, F. H. Pilz, B. Kirchner,* Olav Schiemann,* Patrycja Kielb* & Ala Bunescu*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202403292) 🔓

The authors report an iron-catalyzed decarboxylative C(sp³)–O bond-forming reaction under mild, base-free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and TEMPO derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late-stage oxygenation of a series of bio-active molecules. The reaction leverages the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids by photoinduced carboxylate-to-iron charge transfer. Kinetic, electrochemical, EPR, UV-Vis, HRMS and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe-catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C–C and C–heteroatom bond-forming reactions using commercial organo-photocatalysts and nucleophilic reagents

ChemRxiv

Modular, Atroposelective Total Synthesis of Micitide 982

H. Ogawa,^‡ L. Yu,^‡ S. Li, Y. Nagata, T. K. Chan, Y. Matsuda, J. Liu, Y.-X. Li & H. Nakamura*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-cw501) 🔓

A modular, atroposelective total synthesis of micitide 982 is reported. A feature of this report is the gram-scale C-H biarylation of N-phthaloyl-L-alanine followed by atroposelective Larock macrocyclization. This modular approach allowed the construction of a highly strained atrop-Tyr-Trp cross-linkage with unprecedented atropisomerism, as well as the first total synthesis of micitide 982.

Organic Letters

Decarboxylative Nucleophilic Fluorination of Aliphatic Carboxylic Acids

Q. Yu,^† D. Zhou,^† J. Ma* & C. Song*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01185)

The authors present a decarboxylative nucleophilic fluorination of carboxylic acids with a silver catalyst. This strategy enables the synthesis of a myriad of diverse and valuable fluorinated motifs under mild conditions, demonstrating good functional-group tolerance and utility in late-stage functionalization. In contrast to traditional electrophilic fluorination, this nucleophilic method utilizes a more readily available nucleophilic fluorinating reagent, providing substantial advantages in terms of cost efficiency, broad substrate scope, and functional-group compatibility.

N-Oxide-to-Carbon Transmutations of Azaarene N-Oxides

N. A. Falcone,^† S. He,^† J. F. Hoskin, S. Mangat & E. J. Sorensen*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01263)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-2jvms) 🔓

Reactions that change the identity of an atom within a ring system are emerging as valuable tools for the site-selective editing of molecular structures. Herein, the authors describe the expansion of an underdeveloped transformation that directly converts azaarene-derived N-oxides to all-carbon arenes. This ring transmutation exhibits good functional group tolerance and replaces the N-oxide moiety with either unsubstituted, substituted, or isotopically labeled carbon atoms in a single laboratory operation.

A Dual Ni/Photoredox Cross-Coupling Approach toward Mandelic Acids

J. J. Monteith & S. A. L. Rousseaux*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01547)

Mandelic acid derivatives represent a valuable class of compounds due to their wide use in synthetic organic chemistry and the pharmaceutical sector. Herein, the authors report a novel reductive Ni/photoredox cross-coupling of readily accessible, bench stable N-alkoxyphthalimides and aryl halides to prepare unprotected mandelic acid ester derivatives. Mechanistic experiments suggest that this cross-coupling likely proceeds via a pathway that is distinct from previous reports using similar redox-active alkoxy radical precursors.

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