Amino Acids as Carbene Precursors

Nature

Unlocking Carbene Reactivity by Metallaphotoredox α-Elimination

B. T. Boyle,^† N. W. Dow,^† C. B. Kelly, M. C. Bryan & D. W. C. MacMillan*

Nature 2024 (DOI: 10.1038/s41586-024-07628-1)

The ability to tame high-energy intermediates is critical for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often elusive, high-energy intermediates. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the critical carbon–metal bond. However, these methods are often prohibitive due to reagent safety concerns, limiting their broad implementation in synthesis. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to a metal to forge the initial carbon–metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Herein, this strategy is realized through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N–H, S–H, and P–H bonds from abundant and bench-stable carboxylic acids, amino acids, and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

Nature Chemistry

Repurposing of Halogenated Organic Pollutants via Alkyl Bromide-Catalysed Transfer Chlorination

H. Liu, D.-W. Ji, Y.-K. Mei, Y. Liu, C.-H. Liu, X.-Y. Wang & Q.-A. Chen*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01551-8)

Halogenated organic pollutants (HOPs) are causing a significant environmental and human health crisis due to their high levels of toxicity, persistence and bioaccumulation. Urgent action is required to develop effective approaches for the reduction and reuse of HOPs. Whereas current strategies focus primarily on the degradation of HOPs, repurposing them is an alternative approach, albeit a challenging task. Here, the authors discover that alkyl bromide can act as a catalyst for the transfer of chlorine using alkyl chloride as the chlorine source. They demonstrate that this approach has a wide substrate scope, and successfully apply it to reuse HOPs that include dichlorodiphenyltrichloroethane, hexabromocyclododecane, chlorinated paraffins, chloromethyl polystyrene and poly(vinyl chloride) (PVC). Moreover, the authors show that the synthesis of essential non-steroidal anti-inflammatory drugs can be achieved using PVC and hexabromocyclododecane, and demonstrate that PVC waste can be used directly as a chlorinating agent.

Nature Synthesis

Intermolecular Asymmetric Functionalization of Unstrained C(sp³)–C(sp³) Bonds in Allylic Substitution Reactions

Y.-W. Chen, Y. Qiu, Y. Liu, G.-Q. Lin, J. F. Hartwig* & Z.-T. He*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00555-z)

Catalytic asymmetric functionalization of unstrained C(sp³ )–C(sp³ ) bonds is a promising strategy to edit the structure of a molecule stereoselectively, but such reactions are rare. Existing methods for the catalytic functionalization of C–C bonds typically involve C–C bonds in strained structures. Here, the authors report a strategy to achieve unexplored enantioselective functionalizations of allylic C(sp³ )–C(sp³ ) bonds. Protocols for both kinetic resolution and dynamic kinetic asymmetric transformation are established to construct new C–C bonds at the position of a C(sp³ )–C(sp³ ) bond in the reactant. This study shows that enantioselective functionalizations can be achieved even at unstrained C–C bonds, and an alkyl C–C bond can also work as a leaving group instead of a stable product in enantioselective allylic substitution reactions.

Nature Communications

Enantioselective Synthesis of Chiral Amides by Carbene Insertion into Amide N–H Bond

X.-G. Zhang, Z.-C. Yang, J.-B. Pan, X.-H. Liu & Q.-L. Zhou*

Nat. Commun. 2024, 15, 4793 (DOI: 10.1038/s41467-024-48266-5) 🔓

Chiral amides are important structures in many natural products and pharmaceuticals, yet their efficient synthesis from simple amide feedstocks remains challenging due to their weak Lewis basicity. Herein, the authors describe the enantioselective synthesis of chiral amides by N-alkylation of primary amides taking advantage of an achiral rhodium and chiral squaramide co-catalyzed carbene N–H insertion reaction. This method features mild conditions, rapid reaction rate (in all cases 1 min) and a wide substrate scope with high yield and excellent enantioselectivity.

Journal of the American Chemical Society

C–H Functionalization-Enabled 11-Step Semisynthesis of (−)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment

D. Ma, P. Duran, R. Al-Ahmad, S. Hestehave, M. Joa, O. Alsbiei, E. J. Rodríguez-Palma, Y. Li, S. Wang, R. Khanna* & M. Dai*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04025) 🔓

The authors report an efficient semisynthesis of the cholestane steroidal alkaloid (−)-veragranine A with a 6/6/6/5/6/6 hexacyclic ring system, eight stereocenters, and a unique C12–C23 linkage. The synthesis features a Schönecker–Baran C–H oxidation at C12, a Suzuki–Miyaura cross-coupling to form the C12–C23 bond, and a hydrogen atom transfer (HAT)-initiated Minisci C–H cyclization to forge the C20–C22 bond with desired stereochemistry at C20. These enabling transformations significantly enhanced the overall synthetic efficiency and delivered (−)-veragranine A in 11 steps and over 200 mg from cheap and readily available dehydroepiandrosterone. In addition, this approach allowed flexible syntheses of novel synthetic analogs for biological evaluations in sensory neurons in vitro and in an in vivo model of arthritic pain, from which two novel lead compounds were identified for further development.

Alkoxy Radical Generation Mediated by Sulfoxide Cation Radicals for Alcohol-Directed Aliphatic C–H Functionalization

D. S. Finis & D. A. Nicewicz*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05052)

The C–H functionalization of remote, unactivated C–H bonds offers a unique method of garnering structural complexity in a synthesis. The use of directing groups has provided a means of enacting C–H functionalization on these difficult-to-access bonds; however, the installation and removal of directing groups on a substrate require additional synthetic manipulations, detracting from both the efficiency and economic feasibility of a transformation. The use of alkoxy radicals as transient directing groups for the functionalization of remote C–H bonds allows access to the synthesis of complex molecules without the need for additional functionality. Herein, the authors report a method for alkoxy radical formation from unactivated alcohols and reactivity mediated by photoredox-generated sulfoxide cation radicals. This protocol leverages the unique reactivity of alkoxy radicals to implement different reaction manifolds: 1,5-hydrogen atom transfer (HAT), cyclization, and β-scission. Furthermore, it was discovered that this methodology could be utilized to impose radical group transfer reactions via the β-scission pathway.

Silver-Catalyzed (Z)-β-Fluoro-vinyl Iodonium Salts from Alkynes: Efficient and Selective Syntheses of Z-Monofluoroalkenes

A. T. Sedikides & A. J. J. Lennox*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03826) 🔓

Monofluoroalkenes are stable and lipophilic amide bioisosteres used in medicinal chemistry. However, efficient and stereoselective methods for synthesizing Z-monofluoroalkenes are underdeveloped. The authors envisaged (Z)-β-fluoro-vinyl iodonium salts (Z-FVIs) as coupling partners for the diverse and stereoselective synthesis of Z-monofluoroalkenes. Disclosed herein is the development and application of a silver(I)-catalyzed process for accessing a broad scope of (Z)-FVIs with exclusive Z-stereoselectivity and regioselectivity from alkynes in a single step.

Rhodium-Catalyzed Highly Enantioselective Hydroboration of Acyclic Tetrasubstituted Alkenes Directed by an Amide

H.-X. Lu,^† C. Wang,^† T.-T. Gao, E.-Z. Lin, S.-L. Lu, X. Hong* & B.-J. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04108) 🔓

Although progress has been made in enantioselective hydroboration of di- and trisubstituted alkenes over the past decades, enantioselective hydroboration of tetrasubstituted alkenes with high diastereo- and enantioselectivities continues as an unmet challenge since the 1950s due to its extremely low reactivity and the difficulties to simultaneously control the regio- and stereoselectivity of a tetrasubstituted alkene. Here, the authors report highly regio-, diastereo-, and enantioselective catalytic hydroboration of diverse acyclic tetrasubstituted alkenes. The delicate interplay of an electron-rich rhodium complex and coordination-assistance forms a highly adaptive catalyst that effectively overcomes the low reactivity and controls the stereoselectivity. The generality of the catalyst system is exemplified by its efficacy across various tetrasubstituted alkenes with diverse steric and electronic properties.

Angewandte Chemie International Edition

Chromium Catalyzed Asymmetric Reformatsky Reaction

Y.-F. Lv,^† G. Liu,^† Z. Shi & Z. Wang*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202406109)

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral β-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, the authors achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism.

Radical Fluorosulfonamidation: A Facile Access to Sulfamoyl Fluorides

P. Wang, L. Lin, Y. Huang, H. Zhang & S. Liao*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202405944)

Recently, the introduction of fluorosulfonyl (-SO₂F) groups have attracted considerable research interests, as this moiety can often afford enhanced activities and new functions in the context of chemical biology and drug discovery. Herein, the authors report the design and synthesis of 1-fluorosulfamoyl-pyridinium (FSAP) salts, which can serve as an effective photoredox-active precursors to fluorosulfamoyl radicals and enable the direct radical C−H fluorosulfonamidation of a variety of (hetero)arenes.

Cobalt-Catalyzed Photo-Semipinacol Rearrangement of Unactivated Allylic Alcohols

H. Lindner & E. M. Carreira*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202407827)

The authors report a photochemical method for the semipinacol rearrangement of unactivated allylic alcohols. Aliphatic as well as aromatic groups participate as migrating groups, yielding a variety of α,α-disubstituted ketones. The reaction proceeds under mild conditions and is compatible with ethers, esters, halides, nitriles, carbamates, and substituted arenes. The operationally simple and fully catalytic conditions prescribe 1 mol% benzothiazinoquinoxaline as organophotocatalyst, 0.5 mol% Co-salen, and 10 mol% lutidinium triflate and, importantly, display reactivity complementary to procedures employing Brønsted acid.

ChemRxiv

Total Synthesis of Twenty-Five Picrotoxanes by Virtual Library Selection

C. Li & R. A. Shenvi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-g8j1r) 🔓

Strong-bond activation refers to the conversion of typically inert functional groups (FG) into reactive ones: e.g. C–H or C–C into C–X. Its application in retrosynthetic analysis requires evaluation of strategy (is it simplifying?) and feasibility (will it work?). However, the feasibility of strong bond cleavage can be difficult to predict due to competing low barrier pathways (e.g. 5–8 kcal/mol) in complex molecular environments. If strong bond activation can be strategically evaluated, accurately calculated and experimentally validated, it can simplify the synthesis of complex molecules. Here, the authors build a virtual library of strategic late-stage intermediates en route to diverse picrotoxanes, calculate C–H vs. C–C oxidation preference and experimentally interrogate the predictions. Costly transition state calculations are then simplified to faster parameterizations to explain remote effects on strong bond activation and to devise concise routes to the picrotoxanes.

Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides

B. K. Chi,^† S. J. Gavin,^† B. N. Ahern, N. Peperni, S. Monfette* & D. J. Weix*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2023-rpbs4-v2) 🔓

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules in recent years due to the enhanced biological properties of fluorinated molecules compared to their non-fluorinated analogues. Despite the potential advantages conferred by incorporating a difluoromethyl group in organic compounds, industrial adoption of difluoromethylation methods lags behind fluorination and trifluoromethylation. This is due in part to challenges in applying common difluoromethyl sources towards industrial applications. Here, the authors report the nickel-catalyzed cross-electrophile coupling of (hetero)aryl bromides with difluoromethyl 2-pyridyl sulfone, a sustainably sourced, crystalline difluoromethylation reagent. The scope of this reaction is demonstrated with 24 examples including a diverse array of heteroaryl bromides and precursors to difluoromethyl-containing preclinical pharmaceuticals. This reaction can be applied to small-scale parallel synthesis and benchtop scale-up under mild conditions.

Catalyst-Free Direct Olefin Halo-Hydroxylamination: Rapid Synthesis of Multifunctional Hydroxylamines (MFHAs) for Structurally Complex Amines and N-Heterocycles

Y.-D. Kwon, D. Joaquin, M. Carpio, M. Yousufuddin & L. Kürti*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-l1k7m) 🔓

The authors introduce a novel and powerful alkene difunctionalization process where anomeric amides (e.g., N-halogenated O-activated hydroxylamines) react directly with olefins, without the use of catalysts or additives, to yield the corresponding N-haloalkyl O-activated hydroxylamines. These multifunctional hydroxylamines (MFHAs), containing both alkyl halide and O-activated hydroxylamine moieties, are convenient building blocks/electrophilic aminating reagents for the synthesis of structurally complex N-unprotected secondary amines and N-heterocycles. Both activated and unactivated alkenes (including cyclic and acyclic olefins, dienes, and enynes) are effectively converted to the corresponding difunctionalized hydroxylamine derivatives with excellent atom economy.

A Voltage-Controlled Strategy for Modular Shono-Type Amination

S. Su, Y. Guo,^‡ B. Parnitzke^‡ & J. Derosa*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-m4l1j) 🔓

Shono-type oxidation to generate functionalized heterocycles is a powerful method for late-stage diversification of relevant pharmacophores; however, development beyond oxygen-based nucleophiles remains underdeveloped. The limited scope can often be ascribed to constant current electrolysis resulting in potential drifts that oxidize a desired nucleophilic partner. Herein, the authors report a voltage-controlled strategy to selectively oxidize a broad scope of substrates, enabling modular C–N bond formation from protected amine nucleophiles. They implement an electroanalytically-guided workflow using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) to identify oxidation potentials across a range of heterocyclic substrates. Controlled potential electrolysis (CPE) selectively generates functionalized C–N products in moderate to good yields using carbamate-, sulfonamide-, and benzamide-derived nucleophiles. Lastly, sequential voltage-controlled C–N and C–O functionalization of a model substrate generates difunctionalized pyrrolidines further broadening the utility of this reaction.

Chemical Science

Divergent Functionalization of Alkenes Enabled by Photoredox Activation of CDFA and α-Halo Carboxylic Acids

R. R. Giri, E. Zhilin & D. Katayev*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC01084A) 🔓

The authors present their studies on the solvent-controlled difunctionalization of alkenes utilizing chlorodifluoroacetic acid (CDFA) and α-halo carboxylic acids for synthesis of γ-lactones, γ-lactams and α,α-difluoroesters. Mechanistic insights revealed that photocatalytic reductive mesolytic cleavage of C−X bond delivers elusive α-carboxyl alkyl radicals. In the presence of an olefin molecule, this species act as unique bifunctional intermediate allowing for stipulated formation of C‒O, C‒N and C‒H bonds on Giese-type adducts via single electron transfer (SET) or hydrogen atom transfer (HAT) events. These protocols exhibit great efficiency across a broad spectrum of readily available α-halo carboxylic acids and are amenable to scalability in both batch and flow. To demonstrate the versatility of this concept, the synthesis of (±) boivinianin A, its fluorinated analog and eupomatilones-6 natural products, was successfully accomplished.

α-Amino Bicycloalkylation through Organophotoredox Catalysis

J. Nugent,^† A. López-Francés,^† A. J. Sterling,^† M. Y. Tay, N. Frank, J. J. Mousseau, F. Duarte* & E. A. Anderson*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC01368A) 🔓

Bridged bicycloalkanes such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.1.1]heptanes (BCHeps) are important motifs in contemporary drug design due to their potential to act as bioisosteres of disubstituted benzene rings, often resulting in compounds with improved physicochemical and pharmacokinetic properties. Access to such motifs with proximal nitrogen atoms (i.e. α-amino/amido bicycloalkanes) is highly desirable for drug discovery applications, but their synthesis is challenging. Here, the authors report an approach to α-amino BCPs and BCHeps through the visible-light enabled addition of α-amino radicals to the interbridgehead C-C bonds of [1.1.1] and [3.1.1]propellane respectively. The reaction proceeds under exceptionally mild conditions and displays broad substrate scope, providing access to an array of medicinally-relevant BCP and BCHep products.

Organic Letters

Synthesis of Secondary Amines via Self-Limiting Alkylation

P. Roychowdhury, S. Waheed, U. Sengupta, R. G. Herrera & D. C. Powers*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01430) 🔓

N-centered nucleophilicity increases upon alkylation, and thus selective partial alkylation of ammonia and primary amines can be challenging: Poor selectivity and overalkylation are often observed. Here, the authors introduce N-aminopyridinium salts as ammonia surrogates for the synthesis of secondary amines via self-limiting alkylation chemistry. Readily available N-aryl-N-aminopyridinium salts engage in N-alkylation and in situ depyridylation to afford secondary aryl-alkyl amines without any overalkylation products. The method overcomes classical challenges in selective amine alkylation by accomplishing alkylation via transient, highly nucleophilic pyridinium ylide intermediates and can be applied in the context of complex molecular scaffolds.

Journal of Organic Chemistry

Development of a Divergent Synthesis of Pleurotinoid Natural Products

J. F. Hoskin, M. Jeong, D. A. Siler, D. C. Ebner & E. J. Sorensen*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00468)

The authors describe the evolution of their syntheses of the pleurotinoid natural products pleurotin, pleurogrisein and 4-hydroxypleurogrisein.

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