Amino Acids from Alkenes and a 'Universal' Ruthenium Catalyst?

Science

Carbon Quaternization of Redox Active Esters and Olefins by Decarboxylative Coupling

X.-c. Gan,^‡ B. Zhang,^‡ N. Dao,^‡ C. Bi, M. Pokle, L Kang, M. R. Collins, C. C. Tyrol, P. N. Bolduc, M. Nicastri, Y. Kawamata,* P. S. Baran* & R. Shenvi*

Science 2024 (DOI: 10.1126/science.adn5619)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-7vb8x-v2) 🔓

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, the authors report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (S_H2) reaction.

Nature Chemistry

A Directed Enolization Strategy Enables By-Product-Free Construction of Contiguous Stereocentres en route to Complex Amino Acids

F. Hong, T. P. Aldhous, P. D. Kemmitt & J. F. Bower*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01473-5) 🔓

Homochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing β-stereocentres are much harder to synthesize. Here, the authors demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Their method exploits the native directing ability of a glycine-derived N–H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres.

Asymmetric Photoredox Catalytic Formal de Mayo Reaction Enabled by Sensitization-Initiated Electron Transfer

X. Sun, Y. Liu, Y. Yin, X. Ban, X. Zhao & Z. Jiang*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01502-3)

Visible-light-driven photoredox catalysis is known to be a powerful tool for organic synthesis. Its occurrence critically depends on the twice exothermic single-electron transfer processes of photosensitizers, which are governed by the redox properties of the species involved. Hence, the inherently narrow range of redox potentials of photosensitizers inevitably constrains their further availability. Sensitization-initiated electron transfer has recently been found to effectively overcome this substantial challenge. However, feasible and practical strategies for designing such complicated catalytic systems are rather scarce. Herein, the authors report an elaborate dual-catalyst platform, with dicyanopyrazine as a visible light photosensitizer and a pyrenyl-incorporated chiral phosphoric acid as a co-sensitizer, and they demonstrate the applicability of this sensitization-initiated electron transfer strategy in an asymmetric formal de Mayo-type reaction. The catalysis platform enables otherwise thermodynamically unfavourable electron transfer processes to close the redox cycle and allows for precise access to valuable enantioenriched 1,5-diketones with a wide substrate range.

An Air- and Moisture-Stable Ruthenium Precatalyst for Diverse Reactivity

G. McArthur, J. H. Docherty, M. D. Hareram, M. Simonetti, I. J. Vitorica-Yrezabal, J. J. Douglas & I. Larrosa*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01481-5) 🔓

Versatile, efficient and robust (pre)catalysts are pivotal in accelerating the discovery and optimization of chemical reactions, shaping diverse synthetic fields such as cross-coupling, C–H functionalization and polymer chemistry. Yet, their scarcity in certain domains has hindered the advancement and adoption of new applications. Here, the authors present a highly reactive air- and moisture-stable ruthenium precatalyst [(t-BuCN)₅Ru(H₂O)](BF₄)₂, featuring a key exchangeable water ligand. This versatile precatalyst drives an array of transformations, including late-stage C(sp² )–H arylation, primary/secondary alkylation, methylation, hydrogen/deuterium exchange, C(sp³ )–H oxidation, alkene isomerization and oxidative cleavage, consistently outperforming conventionally used ruthenium (pre)catalysts. The generality and applicability of this precatalyst is exemplified through the potential for rapid screening and optimization of photocatalytic reactions with a suite of in situ generated ruthenium photocatalysts containing hitherto unknown complexes, and through the rapid discovery of reactivities previously unreported for ruthenium.

Journal of the American Chemical Society

(Phenoxyimine)nickel-Catalyzed C(sp²)–C(sp³) Suzuki–Miyaura Cross-Coupling: Evidence for a Recovering Radical Chain Mechanism

L. R. Mills, E. M. Simmons, H. Lee, E. Nester, J. Kim, S. R. Wisniewski, M. V. Pecoraro & P. J. Chirik*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01474)

Phenoxyimine (FI)–nickel(II)(2-tolyl)(DMAP) compounds were synthesized and evaluated as precatalysts for the C(sp² )–C(sp³ ) Suzuki–Miyaura cross-coupling of (hetero)arylboronic acids with alkyl bromides. With 5 mol% of the optimal (Me^OMe FI)Ni(Aryl)(DMAP) precatalyst, the scope of the cross-coupling reaction was established and included a variety of (hetero)arylboronic acids and alkyl bromides (>50 examples, 33–97% yield). A β-hydride elimination–reductive elimination sequence from reaction with potassium iso-propoxide base, yielding a potassium (FI)nickel(0)ate, was identified as a catalyst activation pathway that is responsible for halogen atom abstraction from the alkyl bromide. A combination of NMR and EPR spectroscopies identified (FI)nickel(II)–aryl complexes as the resting state during catalysis with no evidence for long-lived organic radical or odd-electron nickel intermediates. These data establish that the radical chain is short-lived and undergoes facile termination and also support a “recovering radical chain” process whereby the (FI)nickel(II)–aryl compound continually (re)initiates the radical chain. Kinetic studies established that the rate of C(sp² )–C(sp³ ) product formation was proportional to the concentration of the (FI)nickel(II)–aryl resting state that captures the alkyl radical for chain propagation. The proposed mechanism involves two key and concurrently operating catalytic cycles; the first involving a nickel(I/II/III) radical propagation cycle consisting of radical capture at (FI)nickel(II)–aryl, C(sp² )–C(sp³ ) reductive elimination, bromine atom abstraction from C(sp³ )–Br, and transmetalation; and the second involving an off-cycle catalyst recovery process by slow (FI)nickel(II)–aryl → (FI)nickel(0)ate conversion for nickel(I) regeneration.

γ-Amino Alcohols via Energy Transfer Enabled Brook Rearrangement

R. Laskar,^‡ S. Dutta,^‡ J. C. Spies, P. Mukherjee, Á. Rentería-Gómez, R. E. Thielemann, C. G. Daniliuc, O. Gutierrez* & F. Glorius*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01667) 🔓

In the long-standing quest to synthesize fundamental building blocks with key functional group motifs, photochemistry in the recent past has comprehensively established its attractiveness. Amino alcohols are not only functionally diverse but are ubiquitous in the biologically active realm of compounds. The authors developed bench-stable bifunctional reagents that could then access the sparsely reported γ-amino alcohols directly from feedstock alkenes through energy transfer (EnT) photocatalysis. A designed 1,3-linkage across alkenes is made possible by the intervention of a radical Brook rearrangement that takes place downstream to the EnT-mediated homolysis of their reagent(s).

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes

F. Cong, G.-Q. Sun, S.-H. Ye, R. Hu, W. Rao & M. J. Koh*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02284)

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

The construction of C(sp³ )–C(sp³ ) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, the authors report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp³ )–C(sp³ ) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (S_H2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp³ -hybridized carbon scaffolds.

Angewandte Chemie International Edition

Beyond Tertiary Amines: Introducing Secondary Amines via Palladium/Norbornene-Catalyzed Ortho Amination

X. Liu, Q. Zhu & G. Dong*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202404042)

Since the discovery of the palladium/norbornene (Pd/NBE)-catalyzed ortho amination in 2013, escaping the limitation of only yielding tertiary anilines has been a long-standing challenge in the past decade. Here, the authors describe that, by carefully choosing the phosphine ligand and NBE mediator, installation of a N-mono-alkylamino group becomes feasible. The reaction tolerates a wide range of aryl iodide substrates and various N-mono-tertiary alkylamine-derived electrophiles. Both ipso alkenylation and alkynylation can be realized. The synthetic utility of this method is exemplified in the formation of primary amino group via selective deprotection and streamlined access to N-heterocycles.

ChemRxiv

Photoredox-Catalyzed 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*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-4s0f9) 🔓

Heteroaromatic rings play a prominent role in medicinal chemistry, featuring in numerous biologically relevant molecules. However, unlike benzene rings, the saturated and structurally rigid bioisosteric mimetics of heteroaromatic rings are rarely known, mainly due to the inherent challenges associated with the stability and synthesis of heteroatom-substituted C(sp³ )-rich polycyclic hydrocarbons. The authors envisioned that the strategic and highly selective insertion of different heteroatomic units to bicyclo[1.1.0]butanes (BCBs) could offer an ideal platform to access diverse heterobicyclo[n.1.1]alkanes. Herein, by circumventing the intrinsic challenges associated with the reaction of BCBs with heteroatomic radicals, they report a photoredox-catalyzed highly regio- and chemoselective insertion of amidyl radicals to BCBs, which provided direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. Detailed experimental and computational studies have been carried out to underpin the mechanistic paradigm of this reaction. The newly synthesized heterobicyclic motifs are structurally rigid and exhibit well-defined exit vectors, two important molecular properties in medicinal chemistry.

Electrochemically Driven Nickel-Catalyzed Enantioselective Reductive Conjugate (Hetero)Arylation of Enones

Z. Ye, W. Ma, X. Zhang, H. Liu & F. Zhang*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-zb3sh) 🔓

The authors report an electrochemical nickel-catalyzed enantioselective reductive conjugate (hetero)arylation of enones in an undivided cell with low-cost electrodes in the absence of external reductants. Aryl bromides/iodides/triflates or vinyl bromides were employed as electrophilic reagents for the efficient preparation of >50 β-arylated ketones (up to 97% yield, 97% e.e.). With the advantages of electrochemistry, excellent functional group tolerance and late-stage modification of complex natural products and pharmaceuticals made the established protocol greener and more economic. Mechanistic investigations suggest that a Ni^I /Ni^III cycle is involved in this electro-reductive reaction rather than metal reductant driven Ni⁰ /Ni^II cycle. Overall, the efficient electrochemical activation and turnover of the nickel catalyst avoid the drawbacks posed by the employment of stoichiometric amount of sensitive metal powder reductants.

Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Y. Liu, S. Lin, Z. Ding, Y. Li, Y.-J. Tang, J.-H. Xue, Q. Li, P. Li* & H. Wang*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-n3wlw) 🔓

The exploration of C(sp³ )-rich three-dimensional (3D) scaffolds as bioisosteres for planar aromatics has garnered increasing attention. While the bioisosterism of benzenes has been extensively studied, the bioisosterism of pyridines, the second most prevalent aromatic compounds in pharmaceuticals, faces additional challenges and has encountered surprisingly limited success. In this study, the authors propose unprecedented 2-azabicyclo[3.1.1]heptenes as effective bioisosteres of 1,3,5-trisubstituted pyridines in terms of not only 3D conformation but also basicity. They have developed a pyridine-boryl radical-catalyzed [3π + 2σ] cycloaddition reaction of vinyl azides with bicyclo[1.1.0]butanes (BCBs) as an efficient synthetic approach, allowing for the modular synthesis of various pyridine bioisosteres.

“Naked Nickel”-Catalyzed Amination of Heteroaryl Bromides

R. Saeb, B. Boulenger & J. Cornella*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-znfw5) 🔓

In this article, the authors report that the air-stable “naked nickel” [Ni(^4-t-Bu stb)₃] is a competent catalyst in thermal C–N bond formation between (hetero)aryl bromides and N-based nucleophiles. The catalytic system is characterized by a “naked nickel” complex and Zn, the absence of external light sources, photocatalysts, exogeneous ligands, as well as electrical setups. By applying this method, various heteroaryls bearing Lewis-basic heteroatoms can be accommodated and directly aminated with a set of primary and secondary amines.

Facile Access to Bicyclo[2.1.1]hexanes by Formal Cycloaddition between Silyl Enol Ethers and Bicyclo[1.1.0]butanes with Lewis acids

S. Hu, Y. Pan, D. Ni* & L. Deng*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-486kr) 🔓

Saturated three-dimensional carbocycles have gained increasing prominence in synthetic and medicinal chemistry. In particular, bicyclo[2.1.1]hexanes (BCHs) were identified as the molecular replacement for benzenes. Here, the authors present a facile access to a variety of BCHs via a stepwise two-electron formal [2+3] cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes (BCBs) under Lewis acid catalysis. The reaction features wide functional group tolerance for silyl enol ethers, allowing for the efficient construction of two vicinal quaternary carbon centers and a silyl-protected tertiary alcohol unit in a streamlined fashion. Interestingly, the reaction with conjugated silyl dienol ethers could provide access to bicyclo[4.1.1]octanes (BCOs) equipped with silyl enol ethers that facilitate further transformation. The utilities of this methodology were demonstrated by the late-stage modification of natural products, transformations of tertiary alcohol units on BCH frameworks, and derivatization of silyl enol ethers on BCOs.

Redox-Tunable Ring Expansion Enabled By A Single-Component Electrophilic Nitrogen Atom Synthon

P. Q. Kelly, N. Keramati, K. R. Kaplin, T. Lynch-Colameta, J. P. Phelan & M. D. Levin*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-8rq8l) 🔓

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N-atom source. Here, the authors introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β-ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone-dbabh adducts are compared to other nitrogenous precursors.

Csp³-Csp² Coupling of Isonitriles and (Hetero)arenes through a Photoredox-Catalyzed Double Decyanation Process

M. Martín, R. M. Romero, C. Portolani & M. Tortosa*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-70psv) 🔓

The authors demonstrate the ability of isonitriles to be used as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C-N cleavage and Csp³ -Csp² bond formation. This protocol allows for the preparation of functionalized heteroarenes from readily available isonitriles through a decyanation process. The reaction is general for primary, secondary and tertiary substrates, including amino acid derivatives and druglike molecules.

Organic Process Research & Development

Streamlining Catalysis Screenings on a Budget

P. Czember, F. Weber, A. Kokollari, H. Spreitzer & N. Fleck*

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.3c00506)

Striving for efficiency within chemical development, lab automation is unequivocally on the run. With a plethora of technology available off the shelves, holistic platforms that automate full workstreams have been a target of the industry. However, their implementation is conducted hesitatively, as large capital expenditures and customizing/training efforts are frequently required. The present work addresses this issue by introducing a simple software solution to facilitate catalysis screenings and ease the bottleneck of solid dispensing. Working with a fully integrated benchtop dispensing robot, the platform becomes inexpensive and easy to handle. All resources to rebuild the platform are provided along with the Supporting Information, enabling the readership to implement the approach in their facilities.

Organic Letters

Synthetic Efforts toward Lannotinidine G Based on an Aziridinium-Mediated Ring Contraction and Dienyne Metathesis

Z. Peitsinis & D. Trauner*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00791)

Lannotinidine G is a unique Lycopodium alkaloid that features a tricyclic [6/6/6] core with 3 contiguous stereocenters and a 1,3-diene moiety in addition to a 7-membered lactone. Herein, the authors disclose their efforts toward the synthesis of this natural product, which achieved the construction of the aza-tricyclic core with the correct configuration at its three stereocenters. Key features of the strategy include a highly diastereoselective Fráter–Seebach alkylation and Corey–Chaykovsky type epoxide formation, an unusual aziridinium-mediated ring contraction for the formation of the piperidine moiety, and a regioselective dienyne metathesis.

Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors

A. J. Zahara, B. E. Haines* & S. M. Wilkerson-Hill*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00547)

The authors report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2-a]pyridines or 7-alkyl azaindoles in two steps from known compounds. Using halomucononitrile reagents, they can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25–93% yield) through the cyclization of transient aminomucononitrile intermediates. They then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (13 examples, up to 91% yield). Under oxidative conditions, the pyridinimines serve as directing groups for C–H functionalization reactions to afford imidazo[1,2-a]pyridines.

Journal of Organic Chemistry

Catalytic 2-Ethylhexanoic Acid Promotes Mild Miyaura Borylations

B. M. Klootwyk, J. C. Ruble, G. R. Cumming & E. M. Woerly*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00280)

The Miyaura borylation of aryl and heteroaryl chlorides and bromides using a combination of potassium carbonate and 5 mol% 2-ethylhexanoic acid at 25 °C is reported. The in situ generation of a catalytic amount of potassium 2-ethylhexanoate under these conditions avoids the need for special handling of stoichiometric quantities of hygroscopic potassium 2-ethylhexanoate during the reaction setup as well as difficulties in removing the resulting carboxylic acid during product isolation.

Mild Method for Deprotection of the N-Benzyloxycarbonyl (N-Cbz) Group by the Combination of AlCl₃ and HFIP

V. Vinayagam*, S. K. Sadhukhan, D. V. Botla, R. R. Chittem, S. R. Kasu & T. V. H. Kumar

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00177)

The authors report on the ability of AlCl₃ in HFIP to deprotect the N-benzyloxycarbonyl (N-Cbz) group. The methodology would serve as an alternative to the use of hydrogen gas and metal catalysts that pose safety and environmental concerns. The most notable feature of this methodology is the orthogonal deprotection of the N-Cbz group in the presence of O- and N-Bn protecting groups, hence, expanding the scope for designing synthetic routes to target compounds requiring multiple functional group transformations.

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