A New Reagent for Carbon-Atom Transfer

Science

Ph₃PCN₂: A Stable Reagent for Carbon-Atom Transfer

T. Koike, J.-K. Yu & M. M. Hansmann*

Science 2024, 385, 305–311 (DOI: 10.1126/science.ado4564)

Precise modification of a chemical site in a molecule at the single-atom level is one of the most elegant yet difficult transformations in chemistry. A reagent specifically designed for chemoselective introduction of monoatomic carbon is a particularly formidable challenge. Here, the authors report a straightforward, azide-free synthesis of a crystalline and isolable diazophosphorus ylide, Ph₃PCN₂, a stable compound with a carbon atom bonded to two chemically labile groups, triphenylphosphine (PPh₃) and dinitrogen (N₂). Without any additives, the diazophosphorus ylide serves as a highly selective transfer reagent for fragments, including Ph₃PC, to deliver phosphorus ylide–terminated heterocumulenes and CN₂ to produce multisubstituted pyrazoles. Ultimately, even exclusive carbon-atom transfer is possible. In reactions with aldehydes and acyclic and cyclic ketones (R₂C=O), the carbon-atom substitution forms a vinylidene (R₂C=C:) en route to alkynes or butatrienes.

Nature

Catalysis of an S_N2 Pathway by Geometric Preorganization

G. J. Lovinger,^† M. H. Sak^† & E. N. Jacobsen*

Nature 2024 (DOI: 10.1038/s41586-024-07811-4)

Bimolecular nucleophilic substitution (S_N2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry. Despite the importance of S_N2 pathways in synthesis, catalytic control of ionic S_N2 pathways is rare and notably uncommon even in biocatalysis, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the S_N2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity. Here, the authors show that a small-molecule (646 Da) hydrogen-bond-donor (HBD) catalyst accelerates the S_N2 step of an enantioselective Michaelis–Arbuzov reaction by recapitulating the geometric preorganization principle employed by enzymes. Mechanistic and computational investigations reveal that the HBD diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the S_N2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations.

Nature Chemistry

An Evolved Artificial Radical Cyclase Enables the Construction of Bicyclic Terpenoid Scaffolds via an H-Atom Transfer Pathway

D. Chen,^† X. Zhang,^† A. A. Vorobieva, R. Tachibana, A. Stein, R. P. Jakob, Z. Zou, D. A. Graf, A. Li, T. Maier, B. E. Correia* & T. R. Ward*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01562-5)

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

While natural terpenoid cyclases generate complex terpenoid structures via cationic mechanisms, alternative radical cyclization pathways are underexplored. The metal-catalysed H-atom transfer reaction (M-HAT) offers an attractive means for hydrofunctionalizing olefins, providing access to terpenoid-like structures. Artificial metalloenzymes offer a promising strategy for introducing M-HAT reactivity into a protein scaffold. Here, the authors report their efforts towards engineering an artificial radical cyclase (ARCase), resulting from anchoring a biotinylated [Co(Schiff-base)] cofactor within an engineered chimeric streptavidin. After two rounds of directed evolution, a double mutant catalyses a radical cyclization to afford bicyclic products with a cis-5-6-fused ring structure and up to 97% enantiomeric excess. The involvement of a histidine ligation to the Co cofactor is confirmed by crystallography. A time course experiment reveals a cascade reaction catalysed by the ARCase, combining a radical cyclization with a conjugate reduction. The ARCase exhibits tolerance towards variations in the dienone substrate, highlighting its potential to access terpenoid scaffolds.

Nature Synthesis

Photocatalytic Carbyne Reactivity of Phosphorus Ylides for Three-Component Formal Cycloaddition Reactions

R. Suzuki, T. Ando,^‡ F. Deufel,^‡ K. Ohmatsu* & T. Ooi*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00612-7)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-mx0vg) 🔓

Selective reactions between more than two molecules are governed by appropriate combinations of polar functionalities. This restriction can be ameliorated by photoredox umpolung reactivity, which enables the functionalization of unreactive bonds of chemical reagents while leaving their inherent reactive functional groups intact, paving the way for otherwise difficult multicomponent reactions. Here, the authors report that the photocatalytic single-electron oxidation of phosphorus ylides underpins their sequential assembly with electron-rich olefins and α,β-unsaturated carbonyl compounds to form functionalized six-membered carbocycles. This three-component formal cycloaddition, featuring consecutive C–H functionalization and Wittig reaction of phosphorus ylides, offers a carbyne-like transformation that involves the conversion of inert C–H and C=P bonds into C–C and C=C bonds, respectively, as a powerful tool for the rapid construction of versatile synthetic building blocks from readily available substrates.

Nature Communications

Regioselective Hydroamination of Unactivated Olefins with Diazirines as a Diversifiable Nitrogen Source

Q. Xing, P. P. Chandrachud, K. Tillett & J. M. Lopchuk*

Nat. Commun. 2024, 15, 6049 (DOI: 10.1038/s41467-024-50254-8) 🔓

Nitrogen-containing compounds, such as amines, hydrazines, and heterocycles, play an indispensable role in medicine, agriculture, and materials. Alkylated derivatives of these compounds, especially in sterically congested environments, remain a challenge to prepare. Here, the authors report a versatile method for the regioselective hydroamination of readily available unactivated olefins with diazirines. Over fifty examples are reported, including the protecting group-free amination of fourteen different natural products. A broad functional group tolerance includes alcohols, ketones, aldehydes, and epoxides. The proximate products of these reactions are diaziridines, which, under mild conditions, are converted to primary amines, hydrazines, and heterocycles. Five target- and diversity-oriented syntheses of pharmaceutical compounds are shown, along with the preparation of a bis-¹⁵ N diazirine validated in the late-stage isotopic labeling of an RNA splicing modulator candidate.

Journal of the American Chemical Society

Crafting Unnatural Peptide Macrocycles via Rh(III)-Catalyzed Carboamidation

C. W. Lamartina, C. A. Chartier, J. M. Hirano, N. H. Shah* & T. Rovis*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05248)

Contemporary developments in the field of peptide macrocyclization methodology are imperative for enabling the advance of drug design in medicinal chemistry. This report discloses a Rh(III)-catalyzed macrocyclization via carboamidation, reacting acryloyl-peptide-dioxazolone precursors and arylboronic acids to form complex cyclic peptides with concomitant incorporation of noncanonical α-amino acids. The diverse and modular technology allows for expedient access to a wide variety of cyclic peptides from 4 to 15 amino acids in size and features simultaneous formation of unnatural phenylalanine and tyrosine derivatives with up to >20:1 diastereoselectivity. The reaction showcases an expansive substrate scope with 45 examples and is compatible with the majority of standard protected amino acids used in Fmoc-solid phase peptide synthesis. The methodology is applied to the synthesis of multiple peptidomimetic macrocyclic analogs, including derivatives of cyclosomatostatin and gramicidin S.

Oxidative Nitrogen Insertion into Silyl Enol Ether C═C Bonds

A. Lin, A. Ghosh,^‡ S. Yellen,^‡ Z. T. Ball* & L. Kürti*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07111)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-2k2g0) 🔓

The authors demonstrate a fundamentally new reactivity of the silyl enol ether functionality utilizing an in situ-generated iodonitrene-like species. The present transformation inserts a nitrogen atom between the silyl enol ether olefinic carbons with the concomitant cleavage of the C═C bond. Overall, this facile transformation converts a C-nucleophilic silyl enol ether to the corresponding C-electrophilic N-acyl-N,O-acetal. This unprecedented access to α-amido alkylating agents enables modular derivatization with carbon and heteroatom nucleophiles and the unique late-stage editing of carbon frameworks. The reaction efficiency of this transformation is well correlated with enol ether nucleophilicity as described by the Mayr N scale. Applications presented herein include late-stage nitrogen insertion into carbon skeletons of natural products with previously unattainable regioselectivity as well as modified conditions for ¹⁵ N labeling of amides and lactams.

Accessing Alkoxy Radicals via Frustrated Radical Pairs: Diverse Oxidative Functionalizations of Tertiary Alcohols

M. Ju, S. Lee, H. M. Marvich & S. Lin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07125)

Alkoxy radicals are versatile reactive intermediates in organic synthesis. Here, the authors leverage the principle of frustrated radical pairs to provide convenient access to these highly reactive species directly from tertiary alcohols via oxoammonium-mediated oxidation of the corresponding alkoxides. This approach enabled various synthetically useful transformations including β-scission, radical cyclization, and remote C–H functionalization, giving rise to versatile alkoxyamines that can be further elaborated to various functionalities.

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition

X. Wang, R. Gao & X. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06436)

The direct construction of bioisosteric compounds enriched in Csp³ content represents an attractive and dependable approach to imbuing biologically active molecules with enhanced three-dimensional characteristics, finding wide utility across the synthetic and medicinal chemistry community. Despite recent advancements in the synthesis of (aza)-bicyclo[3.1.1]heptanes (BCHeps and aza-BCHeps), which serve as meta-substituted (aza)-arene bioisosteres, the enantioselective assembly of chiral 3-aza-BCHeps remains a coveted goal yet to be achieved. Here, the authors disclose an unprecedented copper-catalyzed asymmetric formal [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) and azomethine ylides, furnishing a diverse array of enantioenriched 3-aza-BCHeps with exceptional levels of diastereo- and enantioselectivites (51 examples, all >20:1 d.r., mostly 97–99% e.e,). Both mono- and disubstituted BCBs are well compatible with this protocol, offering an enticing route for the efficient synthesis of challenging tetrasubstituted bicyclic products bearing two quaternary centers. The synthetic significance of this methodology is further demonstrated by the successful preparation of several piperidine drug analogues.

Copper-Catalyzed Diastereo-, Enantio-, and (Z)-Selective Aminoallylation of Ketones through Reductive Couplings of Azatrienes for the Synthesis of Allylic 1,2-Amino Tertiary Alcohols

J. Zhu, F. Rahim, P. Zhou, A. Zhang & S. J. Malcolmson*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05637)

The authors introduce a method for the (Z)-selective aminoallylation of a range of ketones to prepare allylic 1,2-amino tertiary alcohols with excellent diastereo- and enantioselectivity. Copper-catalyzed reductive couplings of 2-azatrienes with aryl/alkyl and dialkyl ketones proceed with Ph-BPE as the supporting ligand, generating anti-amino alcohols with >98% (Z)-selectivity under mild conditions. The utility of the products is highlighted through several transformations, including those that leverage the (Z)-allylic amine moiety for diastereoselective reactions of the alkene. Calculations illustrate Curtin–Hammett control in the product formation over other possible isomers and the origin of (Z)-selectivity.

Regio- and Stereoselective Transfer Hydrogenation of Aryloxy Group-Substituted Unsymmetrical 1,2-Diketones: Synthetic Applications and Mechanistic Studies

W. Liu, C. Ren, L. Zhou, H. Luo, X. Meng, P. Luo, Y. Luo, W. Dong, S. Lan, J. Liu, S. Yang, Q. Zhang* & X. Fang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04171)

Developing a general method that leads to the formation of different classes of chiral bioactive compounds and their stereoisomers is an attractive but challenging research topic in organic synthesis. Furthermore, despite the great value of asymmetric transfer hydrogenation (ATH) in both organic synthesis and the pharmaceutical industry, the monohydrogenation of unsymmetrical 1,2-diketones remains underdeveloped. Here, the authors report the aryloxy group-assisted highly regio-, diastereo-, and enantioselective ATH of racemic 1,2-diketones. The work produces a myriad of enantioenriched dihydroxy ketones, and further transformations furnish all eight stereoisomers of diaryl triols, polyphenol, emblirol, and glycerol-type natural products. Mechanistic studies and calculations reveal two working modes of the aryloxy group in switching the regioselectivity from a more reactive carbonyl to a less reactive one, and the potential of ATH on 1,2-diketones in solving challenging synthetic issues has been clearly demonstrated.

ACS Central Science

One-Step Synthesis of [¹⁸F]Aromatic Electrophile Prosthetic Groups via Organic Photoredox Catalysis

M. Li, C. Staton, X. Ma, W. Zhao, L. Pan, B. Giglio, H. S. Berton, Z. Wu, D. A. Nicewicz* & Z. Li*

ACS Cent. Sci. 2024, ASAP (DOI: 10.1021/acscentsci.4c00407) 🔓

To avoid the harsh conditions that are oftentimes adopted in direct radiofluorination reactions, conjugation of bioactive ligands with ¹⁸ F-labeled prosthetic groups has become an important strategy to construct novel PET agents under mild conditions when the ligands are structurally sensitive. Prosthetic groups with [¹⁸ F]fluoroarene motifs are especially appealing because of their stability in physiological environments. However, their preparation can be intricate, often requiring multistep radiosynthesis with functional group conversions to prevent the decomposition of unprotected reactive prosthetic groups during the harsh radiofluorination. Here, the authors report a general and simple method to generate a variety of highly reactive ¹⁸ F-labeled electrophiles via one-step organophotoredox-mediated radiofluorination. The method benefits from high step-economy, reaction efficiency, functional group tolerance, and easily accessible precursors. The obtained prosthetic groups have been successfully applied in PET agent construction and subsequent imaging studies, thereby demonstrating the feasibility of this synthetic method in promoting imaging and biomedical research.

Angewandte Chemie International Edition

Modular, Scalable Total Synthesis of Lapparbin with a Noncanonical Biaryl Linkage

J. Zhang,^† L. Yu,^† H. Ogawa, Y. Nagata & H. Nakamura*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409987) 🔓

This work reports the development of a novel synthetic approach for the highly strained atrop-Tyr C-6-to-Trp N-1' linkage, which can be executed on a decagram scale using a modular strategy involving Pd-catalyzed C-H arylation followed by Larock macrocyclization. Moreover, the first total synthesis of lapparbin was achieved by applying this synthetic strategy. Furthermore, the modular synthesis utilizing C-H arylation and Larock macrocyclization, discovered in the total synthesis of lapparbin, was demonstrated to be applicable to various arbitrary biaryl linkages, including non-natural types.

Photoinduced Cu(II)-Mediated Decarboxylative Thianthrenation of Aryl and Heteroaryl Carboxylic Acids

Z. He & P. Dydio*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202410616) 🔓

Given that (hetero)aryl carboxylic acids are inexpensive materials available in a great variety from commercial and natural resources or synthesis, the strategies enabling their use as starting materials for preparing fine chemicals are highly sought after. Here, the authors report a photoinduced Cu(II)-mediated protocol converting (hetero)aryl carboxylic acids into (hetero)aryl thianthrenium salts, high value-added building blocks that can undergo various subsequent transformations, creating an attractive two-step pathway for the divergent functionalization of these ubiquitous starting materials. The excellent compatibility of the method is shown by preparing a broad range of sterically and electronically varied (hetero)aryl thianthrenium salts, including derivatives of pharmaceuticals, such as ataluren, celecoxib, flavoxate, probenecid, repaglinide, and tamibarotene. The syntheses of ¹³ C-labeled probenecid and bioisosteres of ataluren as well as the unconventional modifications of celecoxib and flavoxate, illustrate the synthetic potential of the strategy.

ChemRxiv

Organocatalytic Asymmetric Allylic Benzylborylation via Fluoride-Assisted Catalytic Generation of α-Boryl Carbanionic Intermediates

J. Duran, P. Rodríguez, W. Vermeer & X. Companyó*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-7ld1j) 🔓

The authors describe the organocatalytic asymmetric allylic benzylborylation of racemic allyl fluorides with racemic α-silyl benzylboronic esters under Lewis-base catalysis. The catalytic protocol leverages the unique features of fluoride to act as unconventional leaving group and to enable the catalytic generation of reactive α-boryl carbanion species through fluoride-assisted desilylative activation. It allows the construction of a wide set of homoallylic benzylated organoboronic esters bearing two contiguous stereocenters in a regio-, diastereo-, and enantioselective fashion. In addition, the chiral boronic ester moiety installed in the final products serves as a synthetic lynchpin for stereospecific derivatizations to construct complex chemical architectures.

The Direct Pd-Catalyzed γ-Lactonization of Aliphatic Carboxylic Acids

T. Xu,^† S. Mal^† & M. van Gemmeren*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-w1qd6) 🔓

A direct palladium-catalyzed γ-lactonization of free carboxylic acids via C–O reductive elimination as a key step is described. Notable aspects of this protocol include the use of convenient and easily available sodium percarbonate as an oxidant and the development of a new beta-alanine derived ligand. The reported method enables the functionalization of a wide range of aliphatic acids including previously inaccessible β-non-quaternary acids. The regioselectivity and consequently substrate scope of this protocol proved complementary to established routes for the direct lactonization of aliphatic carboxylic acids. A modification of this method furthermore enables a direct β-C(sp³ )–H hydroxylation of challenging α-non-quaternary carboxylic acids with considerable functional group tolerance.

Biomimetic Total Synthesis of Lappaceolides A and B

R. R. Pallerla, J. Hakola, L. Härkönen & J. H. Siitonen*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-v338f) 🔓

A two-step total synthesis of lappaceolides A and B is achieved using a biomimetic vinylogous-Michael–oxa-Michael domino reaction. The domino reaction proceeds with Cs₂CO₃ in 1,2-DCE at elevated temperatures and requires careful kinetic control. The total synthesis provides further proof to the biosynthetic hypothesis of lappaceolides as being dimers of the natural product siphonodin.

Deoxytrifluoromethylation/Aromatization of Cyclohexan(en)ones to Access Highly Substituted Trifluoromethyl Arenes

P. Bhattarai,^† M. K. Abd El-Gaber,^† S. Koley & R. A. Altman*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-nggx1) 🔓

Trifluoromethyl arenes (Ar–CF₃) are amongst the commonly encountered fluorinated substructures in pharmaceutical, agrochemical, and material sciences. However, predominant methods to access Ar–CF₃ possess several limitations, including harsh conditions, lack of availability of substrates, and poor regioselectivity, which combined restrict access to desirable highly functionalized Ar–CF₃-containing compounds. To expand the scope of accessible Ar–CF₃-based molecules, the authors present an innovative and orthogonal deoxyfluoroalkylation/aromatization approach that exploits readily accessible and programable cyclohexan(en)one substrates, which undergo a reliable 1,2-addition reaction with the Ruppert-Prakash reagent (TMSCF₃) followed by aromatization to deliver highly functionalized Ar–CF₃ compounds in a one/two-pot sequence. This general strategy enables access to highly substituted Ar–CF₃-containing molecules that are difficult, expensive, and/or impossible to access by current synthetic methods.

Organic Letters

eFluorination for the Rapid Synthesis of Carbamoyl Fluorides from Oxamic Acids

F. Pulikkottil,^† J. S. Burnett,^† J. Saiter, C. A. I. Goodall, B. Claringbold & K. Lam*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01605) 🔓

The authors disclose the anodic oxidation of oxamic acids in the presence of Et₃N·3HF as a practical, scalable, and robust method to rapidly access carbamoyl fluorides from readily available and stable precursors. The simplicity of this method also led us to develop the first flow electrochemical preparation of carbamoyl fluorides, demonstrating scale-up feasibility as a proof of concept.

Room-Temperature Photochemical Copper-Mediated Fluorination of Aryl Iodides

T. E. Spiller,^† K. Donabauer,^† A. F. Brooks, J. A. Witek, G. D. Bowden, P. J. H. Scott & M. S. Sanford*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02227)

This report describes a method for the photochemical Cu-mediated fluorination of aryl iodides with AgF via putative aryl radical (Ar•) intermediates. It involves irradiating an aryl iodide with UVB light (λ_max = 313 nm) in the presence of a mixture of Cu^I and Cu^II salts and AgF. Under these conditions, fluorination proceeds at room temperature for substrates containing diverse substituents, including alkoxy and alkyl groups, ketones, esters, sulfonate esters, sulfonamides, and protected amines. This method has been translated to radiofluorination using a combination of K¹⁸ F, K₃PO₄, and AgOTf.

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