Programmable Polysubstitution

Welcome to this week’s Organic Synthesis Newsletter.

Monday 21^st October – Sunday 27^th October 2024 | Volume 1, Issue 31

HIGHLIGHT OF THE WEEK
Multisite Modifications of Arenes using Ketones as Removable Handles Enabled by Pd and Norbornene Cooperative Catalysis

K.-L. Tao, X. Wang, H. Liu, W.-Q. Chen, Y. Sun, Y.-Q. Zhang, Y.-X. Li, Z.-Y. Wang, Y. Ye, H. Xu,* L. Lan* & H.-X. Dai*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00673-8)

Natural products serve as crucial sources for new drugs and play an indispensable role in drug discovery. Late-stage functionalization of natural products is an efficient method for diversifying their structures, fine-tuning their biological properties and rapidly constructing molecular libraries. Polysubstituted arenes serve as structural cores in pharmaceuticals derived from natural products. However, programmable multisite arene modification remains a largely unmet challenge. Here, using commercially available and easy-to-synthesize aryl ketones as substrates, the authors present the programmable multifunctionalization of natural products via a palladium- and norbornene-catalysed Catellani-type reaction. Given the ease of installing an acyl group and using it as a relay, this protocol enables the incorporation of a variety of bioactive molecules into natural products via successive acylation and deacylation processes.

NATURE CATALYSIS
Photoredox-Catalysed Amidyl Radical Insertion to Bicyclo[1.1.0]butanes

C. C. Chintawar,^† R. Laskar,^† D. Rana, F. Schäfer, N. Van Wyngaerden, S. Dutta, C. G. Daniliuc & F. Glorius*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01239-9) 🔓

Replacing planar aromatic rings in drug molecules with C(sp³)-rich isosteric mimetics, such as bicyclo[n.1.1]alkanes, can significantly alter their physicochemical and pharmacokinetic properties. However, unlike a benzene ring, structurally rigid C(sp³)-rich isosteric mimetics of heteroaromatic rings are rare. Heterobicyclo[n.1.1]alkanes are promising in this regard, but the lack of modular synthetic methods has currently hindered their exploration. Herein, the authors report a photoredox-catalysed highly regioselective and chemoselective insertion of amidyl radicals to bicyclo[1.1.0]butanes, providing direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. The exit vector analysis shows a geometric resemblance of these C(sp³)-rich heterobicyclic motifs with pyridine and pyrimidine derivatives, suggesting their potential as isosteric mimetics of such medicinally important heterocycles. Additionally, various downstream transformations demonstrate their utility as versatile building blocks in synthetic chemistry.

Photocatalytic Generation of Alkyl Carbanions from Aryl Alkenes

M. L. Czyz, T. H. Horngren, A. J. Kondopoulos, L. J. Franov, J. A. Forni, L. N. Pham, M. L. Coote & A. Polyzos*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01237-x) 🔓

Organometallic reagents are routinely used as fundamental building blocks in organic chemistry to rapidly diversify molecular fragments via carbanion intermediates. However, the catalytic generation of carbanion equivalents, particularly from sp³-hybridized alkyl scaffolds, remains an underdeveloped goal in chemical synthesis. Here, the authors disclose an approach for the generation of alkyl carbanions via single-electron reduction of aryl alkenes, enabled by multi-photon photoredox catalysis, and demonstrate that these photocatalytically induced alkyl carbanions can engage in intermolecular C–C bond-forming reactions with carbonyl electrophiles. The versatility of this protocol was illustrated by the development of four distinct intermolecular C–C bond-forming reactions with aromatic alkenes (hydroalkoxylation, hydroamidation, aminoalkylation and carboxyaminoalkylation) to generate a range of valuable and complex scaffolds.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Selective C–N Bond Cleavage in Unstrained Pyrrolidines Enabled by Lewis Acid and Photoredox Catalysis

K. Aida, M. Hirao, T. Saitoh, T. Yamamoto, Y. Einaga, E. Ota* & J. Yamaguchi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13210) 🔓

Cleavage of inert C–N bonds in unstrained azacycles such as pyrrolidine remains a formidable challenge in synthetic chemistry. To address this, the authors introduce an effective strategy for the reductive cleavage of the C–N bond in N-benzoyl pyrrolidine, leveraging a combination of Lewis acid and photoredox catalysis. This method involves single-electron transfer to the amide, followed by site-selective cleavage at the C2–N bond. This protocol is widely applicable to various pyrrolidine-containing molecules and enables inert C–N bond cleavage including C–C bond formation via intermolecular radical addition. Furthermore, the current protocol successfully converts pyrrolidines to aziridines, γ-lactones, and tetrahydrofurans, showcasing its potential of the inert C–N bond cleavage for expanding synthetic strategies.

Supramolecular Catalyzed Cascade Reduction of Azaarenes Interrogated via Data Science

S. M. Treacy,^† A. L. Smith,^† Robert G. Bergman, Kenneth N. Raymond & F. Dean Toste*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11482) 🔓

Catalysis of multicomponent transformations requires controlled assembly of reactants within the active site. Supramolecular scaffolds possess synthetic microenvironments that enable precise modulation over noncovalent interactions (NCIs) engaged by reactive, encapsulated species. While molecular properties that describe the behavior of single guests in host cavities have been studied extensively, multicomponent transformations remain challenging to design and deploy. Here, simple univariate regression and threshold analyses are employed to model reactivity in a cascade reduction of azaarenes catalyzed by water-soluble metal organic cages. Yield and stereoselectivity models help deduce unknown mechanisms of reactivity by the multicomponent, host–guest complexes. Furthermore, a comprehensive model is established for NCIs driving stereoselectivity in the reported host–guest adducts.

Ancestral Sequence Reconstruction to Enable Biocatalytic Synthesis of Azaphilones

C.-H. Chiang, Y. Wang, A. Hussain, C. L. Brooks III* & A. R. H. Narayan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08761)

Biocatalysis can be powerful in organic synthesis but is often limited by enzymes’ substrate scope and selectivity. Developing a biocatalytic step involves identifying an initial enzyme for the target reaction followed by optimization through rational design, directed evolution, or both. Thus, an effective strategy for streamlining the process from enzyme identification to implementation is essential to expanding biocatalysis. Here, the authors present a strategy combining bioinformatics-guided enzyme mining and ancestral sequence reconstruction (ASR) to resurrect enzymes for biocatalytic synthesis. Specifically, an enantioselective synthesis of azaphilone natural products was achieved using two ancestral enzymes: a flavin-dependent monooxygenase (FDMO) for stereodivergent oxidative dearomatization and a substrate-selective acyltransferase (AT) for the acylation of the enzymatically installed hydroxyl group. This cascade, stereocomplementary to established chemoenzymatic routes, expands access to enantiomeric linear tricyclic azaphilones.

Regio- and Enantioselective Nickel-Catalyzed Ipso- and Remote Hydroamination Utilizing Organic Azides as Amino Sources for the Synthesis of Primary Amines

S.-C. Wang, L. Liu, M. Duan, W. Xie, J. Han, Y. Xue, Y. Wang, X. Wang* & S. Zhu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12324)

Primary amines serve as key synthetic precursors to most other N-containing compounds, which are important in organic and medicinal chemistry. Herein, the authors present a NiH-catalyzed mild ipso- and remote hydroamination technique that utilizes organic azides as deprotectable primary amine sources. This strategy offers a highly flexible platform for the efficient construction of α-chiral branched primary amines, as well as linear primary amines.

Chemoselective Pd-Based Dyotropic Rearrangement: Fluorocyclization and Regioselective Wacker Reaction of Homoallylic Amides

C.-X. Liu, Q. Wang & J. Zhu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13359)

Fluorocyclization of alkenes tethered with a pronucleophile is an efficient transformation that converts easily accessible starting materials to fluorinated heterocycles in a single step. Herein, the authors report an unprecedented Pd(II)-catalyzed oxidative domino process that transforms homoallylic amides to 5,6-dihydro-4H-1,3-oxazines through a domino oxypalladation/Pd^II–oxidation/dyotropic rearrangement/reductive elimination sequence. Three chemical bonds are created under these operationally simple conditions. Taking advantage of the facile hydrolysis of the α-fluoro tertiary alkyl ether under acidic conditions, a one-pot conversion of homoallylic amides to homologated ketones is subsequently developed, which represents a rare example of regioselective Wacker oxidation reaction of 1,1-disubstituted alkenes.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Activation and C‒C Coupling of Aryl Iodides via Bismuth Photocatalysis

M. Mato, A. Stamoulis, P. C. Bruzzese & J. Cornella*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418367) 🔓

Within the emerging field of bismuth redox catalysis, the catalytic formation of C‒C bonds using aryl halides would be highly desirable; yet such a process remains a synthetic challenge. Herein, the authors present a chemoselective bismuth-photocatalyzed activation and subsequent coupling of (hetero)aryl iodides with pyrrole derivatives to access C(sp²)‒C(sp²) linkages through C‒H functionalization. This unique reactivity is the result of the bismuth complex featuring two redox state-dependent interactions with light, which 1) activates the Bi(I) complex for oxidative addition via MLCT, and 2) promotes the homolytic cleavage of aryl Bi(III) intermediates through a LLCT process.

Enantioselective Electrocatalysis for the Cross-Dehydrogenative Heteroarylation of Indoles, Pyrroles, and Furans

K. Liang, N. Li, M. Liu, J. Song & C. Guo*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202415723)

Oxidative cross-dehydrogenative C-H/C-H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α-heteroarylation. Here, the authors present the development of a direct anodic oxidative coupling process between 2-acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene-assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero-compounds. The consequential α-heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (−)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

Asymmetric Synthesis of β-Ketoamides by Sulfonium Rearrangement

V. Porte, V. R. Nascimento, A. Sirvent, I. Tiefenbrunner, M. Feng, D. Kaiser & N. Maulide*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418070) 🔓

The synthesis of enantioenriched α-substituted 1,3‑dicarbonyls remains a contemporary challenge in synthesis due to their tendency to undergo racemization via keto-enol tautomerization. Herein, the authors report a method to access enantioenriched β-ketoamides by a chiral sulfinimine-mediated [3,3]-sigmatropic sulfonium rearrangement. The transformation displays good chirality transfer, as well as excellent chemoselectivity and functional group tolerance. Diastereoselective reduction of the ketone moiety, also achievable in one-pot fashion, affords enantioenriched β‑hydroxyamides.

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*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202417122)

Previously: ChemRxiv (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.

CHEMRXIV
Regenerative Photocatalysis

C. Rosso,^† G. Barison,^† F. Droghetti, N. Michelazzo, A. Sartorel, G. Pelosi, M. Bortolus, P. Costa, M. Natali & L. Dell’Amico*

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

Aiming to expand the reactivity domain of photocatalysis, the authors discovered the peculiar behaviour of a purely organic catalyst. Upon light irradiation, it undergoes controlled disruption, substrate activation, and regeneration in an unconventional regenerative catalytic cycle. Upon visible-light irradiation (400 nm), the molecule cleaves, generating three different species capable of simultaneously unlocking opposed yet productive oxidative and reductive manifolds under irradiation. These subunits recombine at the end of each catalytic cycle, generating the original scaffold. The authors demonstrate the power of regenerative photocatalysis for activating a variety of structurally diverse inert substrates via both a reduction process and an oxidation process, accessing a redox window as large as 5.7 V.

Overcoming Photocatalytic Hydrogen Atom Transfer (HAT) Limitations via Formyl-Group Directed C‒H Cleavage

E. Cassera,^† V. Martini,^† S. Abrami, N. Della Ca’, D. Ravelli, M. Fagnoni* & L. Capaldo*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-q3k99) 🔓

Photocatalyzed Hydrogen-Atom Transfer (HAT) is now an established methodology in the synthesis of pharmaceuticals and agrochemicals. Yet, the full potential of this methodology is held back by challenges that demand exploration and resolution, such as the lack of regioselectivity and inefficiency. Herein, the authors propose the HAcTive strategy to address these longstanding challenges. The fast HAT from aldehydes and ensuing α-fragmentation of the photogenerated acyl radical (decarbonylation) is exploited to boost efficiency, steer regioselectivity and enable reactivity in HAT-based methodologies. This concept was validated in several decarbonylative C‒C bond formation protocols.

On-Demand Access to Palladium Oxidative Addition Complexes (OACs) from a Stable Organopalladate Salt

A. P. Looby, L. Venigalla, W. Hou, M. Xiao, Y. Yang, H. Chen & B. P. Carrow*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-rxkf4) 🔓

Palladium oxidative addition complexes (OACs) are state-of-the-art catalysts for many C–C and C–heteroatom cross-coupling reactions, but altering the OAC ancillary ligand identity (i.e., phosphine, N-heterocyclic carbene) often requires a bespoke synthesis. This has limited the modularity and accessibility of these ideal catalysts. The authors report a simple admixture approach combining a bench-stable organopalladate salt with a mono- or bidentate ligand to generate OACs within minutes at room temperature. High yields across a suite of canonical cross-coupling reactions demonstrates the “on-demand” Pd OAC strategy can function as a drop-in replacement for isolated OACs as well as several other contemporary Pd precatalysts.

Accessing Azetidines via Magnesium-Mediated Nitrogen Atom Transfer from Iminoiodinane to Donor-Acceptor Cyclopropanes

A. H. Bansode, L. Yin, N. Deng, M. Afrasi, Y. Zhu & M. Parasram*

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

The authors report a Lewis acid-mediated ring expansion of donor-acceptor cyclopropanes (DACs) to substituted azetidines via nucleophilic nitrogen atom transfer from readily accessible iminoiodinane. This protocol operates under mild, transition-metal-free conditions, and showcases excellent chemoselectivity, along with broad functional group tolerance. Mechanistically, the coordination of a Magnesium (Mg)-Lewis acid to the DAC promotes nucleophilic ring opening with a putative Mg-amide species generated from the iminoiodinane under the reaction conditions to furnish the azetidine products.

CHEMICAL SCIENCE
Boryl Radical-Mediated Halogen-Atom Transfer (XAT) Enables the Sonogashira-Like Alkynylation of Alkyl Halides

J. Corpas, M. Alonso & D. Leonori*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC06516F) 🔓

Alkynes are a crucial class of materials with applications across a wide range of chemical disciplines. The alkynylation of alkyl halides presents an ideal strategy for assembling these materials. Current methods rely on the intrinsic electrophilic nature of alkyl halides to couple with nucleophilic acetylenic systems, but these methods faces limitations in terms of applicability and generality. Herein, the authors introduce a different approach to alkynylation of alkyl halides that proceeds via radical intermediates and uses alkynyl sulfones as coupling partners. This strategy exploits the ability of amine-ligated boryl radicals to activate alkyl iodides and bromides through halogen-atom transfer (XAT). The resulting radicals then undergo a cascade of α-addition and β-fragmentation with the sulfone reagent, leading to the construction of C(sp³)–C(sp) bonds. The generality of the methodology has been demonstrated by its successful application in the alkynylation of complex and high-value molecules.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
A Watchful Giant

👀 A watchful giant. Scitility, a technology company specialising in the creation of digital tools to improve the scientific research ecosystem have recently launched “Argos”, a research-integrity tool and retraction service that assigns publications a risk score based on the authors’ publication records and the citation of previously retracted research. Argos, presumably named after the watchful hundred-eyed giant in Greek mythology* and not the British retail giant, has already flagged up over 40,000 high-risk publications and catalogued over 50,000 retracted ones.

*For those interested in the mythic tale, it was said that after Argos’ death at the hands of Hermes, the goddess Hera had his eyes preserved forever in the peacock's tail, giving the animal its distinctive markings.