A Double-Helix for [6+4] Cycloadditions

Science

A Solid Noncovalent Organic Double-Helix Framework Catalyzes Asymmetric [6+4] Cycloaddition

T. Zheng, N. Nöthling, Z. Wang, B. Mitschke, M. Leutzsch & B. List*

Science 2024, 385, 765–770 (DOI: 10.1126/science.adp1127)

Whereas [4+2] cycloadditions are among the most powerful tools in the chemist’s synthetic arsenal, controlling reactivity and selectivity of [6+4] cycloadditions has proven to be extremely challenging. Such transformations, especially if compatible with simple hydrocarbon-based substrates, could ultimately provide a general approach to highly valuable and otherwise difficult to access 10-membered rings. The authors report here that highly acidic and confined imidodiphosphorimidate catalysts do not catalyze this reaction under homogeneous conditions. Notably, however, they can spontaneously precipitate an insoluble and double helix–shaped noncovalent organic framework, which acts as a distinctively reactive and stereoselective catalyst of [6+4] cycloadditions of simple dienes with tropone.

Nature Synthesis

Synthesis of Chiral Carbocycles via Enantioselective β,γ-Dehydrogenation

T. Sheng,^† T. Zhang,^† Z. Zhuang & J.-Q. Yu*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00628-z)

Dehydrogenation of an alkyl group via C–H activation forms a vinyl unit, which can act as a versatile stepping stone for diverse late-stage structural modifications at two adjacent sp³ carbon centres. However, enantioselective dehydrogenation via C–H metalation remains a challenge. Here, the authors describe the realization of palladium-catalysed enantioselective β,γ-dehydrogenation of cycloalkyl amides enabled by chiral oxazoline–pyridone ligands to afford a wide range of highly elaborated carbocycles with exceptional enantioselectivity (>99% e.e.). Notably, the resulting chiral β,γ-unsaturated carbocycles are difficult to access via an inverse electron demand Diels–Alder reaction. Through ligand control, a tandem dehydrogenation and C–H olefination sequence also led to the formation of chiral β-alkylidene-γ-lactams. Remarkably, this catalyst is also compatible with biologically important natural products, including diterpenes and pentacyclic triterpenes, where each enantiomer of the chiral ligand enables site-selective modification at four distinct sites within the E ring.

Nature Catalysis

Radical Strain-Release Photocatalysis for the Synthesis of Azetidines

R. I. Rodríguez, V. Corti, L. Rizzo, S. Visentini, M. Bortolus, A. Amati, M. Natali, G. Pelosi, P. Costa & L. Dell’Amico*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01206-4) 🔓

The increasing popularity of four-membered rings in drug discovery has prompted the synthetic chemistry community to advance and reinvent old strategies to craft these structures. Recently, the strain-release concept has been used to build complex architectures. However, although there are many strategies for accessing small carbocyclic derivatives, the synthesis of azetidines remains underdeveloped. Here, the authors report a photocatalytic radical strategy for accessing densely functionalized azetidines from azabicyclo[1.1.0]butanes. The protocol operates with an organic photosensitizer, which finely controls the key energy-transfer process with distinct types of sulfonyl imines. The radical intermediates are intercepted by the azabicyclo[1.1.0]butanes via a radical strain-release process, providing access to difunctionalized azetidines in a single step. The power and generality of this method is illustrated with the synthesis of various azetidine targets, including derivatives of celecoxib and naproxen.

Overcoming Limitations in Non-Activated Alkene Cross-Coupling with Nickel Catalysis and Anionic Ligands

D. Wu, W. Kong, Y. Bao, C. Huang, W. Liu, Y. Li* & G. Yin*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01211-7)

Multicomponent cross-coupling reactions involving alkenes represent a compelling strategy for accessing three-dimensional molecules, a key pursuit in contemporary medicinal chemistry. Transition metal-catalysed processes predominantly necessitate the use of conjugated alkenes or non-activated alkenes equipped with specific auxiliary functional groups, for example, 8-aminoquinoline. However, it remains a huge challenge to directly use unmodified native functional groups, such as alcohols and ethers, as directing groups. Here, by utilizing an anionic bidentate ligand such as acac, the authors have successfully addressed the challenge of employing weakly coordinating native functional groups as directing groups in a nickel-catalysed cross-coupling of non-activated alkenes. This reaction enables the simultaneous introduction of an sp² fragment and an sp³ fragment to two carbons of the alkenes with high chemo- and regioselectivity.

Nature Communications

Strain-Release Driven Reactivity of a Chiral SuFEx Reagent Provides Stereocontrolled Access to Sulfinamides, Sulfonimidamides, and Sulfoximines

P. R. Athawale,^† Z. P. Shultz,^† A. Saputo, Y. D. Hall & J. M. Lopchuk*

Nat. Commun. 2024, 15, 7001 (DOI: 10.1038/s41467-024-51224-w) 🔓

Efforts aimed at enriching the chemical and structural diversity of small molecules have invigorated synthetic exploration in the last two decades. Spatially defined molecular functionality serves as the foundation to construct unique chemical space to further advance discovery science. The chiral SuFEx reagent t-BuSF provides a modular platform for the stereocontrolled bifunctionalization of sulfur. Here, the authors report a third functional feature of t-BuSF enabled by carbamoyl torsional strain-release that further expands the S(IV) and S(VI) chemical space accessible as showcased in over seventy examples, multiple applications in medicinal chemistry, organocatalysis, and diversity-oriented synthesis.

Journal of the American Chemical Society

α,β-Desaturation and Formal β-C(sp³)–H Fluorination of N-Substituted Amines: A Late-Stage Functionalization Strategy Enabled by Electrochemistry

L. F. T. Novaes,^† J. S. K. Ho,^† K. Mao, E. Villemure, J. A. Terrett* & S. Lin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02548)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-hcn3j) 🔓

Incorporation of C(sp³ )–F bonds in biologically active compounds is a common strategy employed in medicinal and agricultural chemistry to tune pharmacokinetic and pharmacodynamic properties. Due to the limited number of robust strategies for C(sp³ )–H fluorination of complex molecules, time-consuming de novo syntheses of such fluorinated analogs are typically required, representing a major bottleneck in the drug discovery process. In this work, the authors present a general and operationally simple strategy for site-specific β-C(sp³ )–H fluorination of amine derivatives including carbamates, amides, and sulfonamides, which is compatible with a wide range of functional groups including N-heteroarenes. In this approach, an improved electrochemical Shono oxidation is used to set the site of functionalization via net α,β-desaturation to access enamine derivatives. A series of new transformations of these enamine intermediates was further developed to synthesize a variety of β-fluoro-α-functionalized structures, allowing efficient access to pertinent targets to accelerate drug discovery campaigns.

Synthesis and Suzuki–Miyaura Cross-Coupling of Alkyl Amine-Boranes. A Boryl Radical-Enabled Strategy

C. S. Buettner,^† C. Stavagna,^† M. J. Tilby, B. Górski, J. J. Douglas, N. Yasukawa* & D. Leonori*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07767) 🔓

Alkyl organoborons are powerful materials for the construction of C(sp³ )–C(sp² ) bonds, predominantly via Suzuki–Miyaura cross-coupling. These species are generally assembled using 2-electron processes that harness the ability of boron reagents to act as both electrophiles and nucleophiles. Herein, the authors demonstrate an alternative borylation strategy based on the reactivity of amine-ligated boryl radicals. This process features the use of a carboxylic acid containing amine-ligated borane that acts as boryl radical precursor for photoredox oxidation and decarboxylation. The resulting amine-ligated boryl radical undergoes facile addition to styrenes and imines through radical-polar crossover manifolds. This delivers a new class of sp³ -organoborons that are stable solids and do not undergo protodeboronation. These novel materials include unprotected α-amino derivatives that would typically be unstable. Crucially, these aliphatic organoboron species can be directly engaged in Suzuki–Miyaura cross-couplings with structurally complex aryl halides. Preliminary studies suggest that they enable slow-release of the corresponding and often difficult to handle alkyl boronic acids.

Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n+1] Oligocyclotryptamine Alkaloids

T. Z. Scott & M. Movassaghi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07705)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-qmb1s-v2) 🔓

The authors describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Inspired by their hypothesis for the biogenesis of these alkaloids via an iterative concatenative addition of homochiral cyclotryptamines to a meso-chimonanthine headcap, they leverage the modular, diazene-directed assembly of stereodefined cyclotryptamines to introduce successive C3a–C7’ quaternary stereocenters on a heterodimeric meso-chimonanthine surrogate with full stereochemical control at each quaternary linkage. A new strategy for iterative aryl-alkyl diazene synthesis was developed using increasingly complex oligomeric hydrazide nucleophiles and a bifunctional cyclotryptamine bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of this strategy is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Enabled by the completely stereoselective total syntheses and expanded characterization data sets, the authors provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C, provide evidence that it is identical to the alkaloid known as (+)-isopsychotridine B, and report that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I, resolving longstanding questions about the structures of the highest-order [n+1] oligocyclotryptamine alkaloids.

Ligand Oxidation Activates a Ruthenium(II) Precatalyst for C–H Hydroxylation

P. J. Lauridsen, Y. J. Kim, D. P. Marron, J. S. Zhu, R. M. Waymouth & J. Du Bois*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04117)

A new class of Ru-sulfonamidate precatalysts for sp³ C–H hydroxylation is described along with a versatile process for assembling unique heteroleptic Ru(II) complexes. The latter has enabled structure–performance studies to identify an optimal precatalyst bearing one 4,4′-di-tert-butylbipyridine (dtbpy) and one pyridylsulfonamidate ligand. Single-crystal X-ray analysis confirmed the structure and stereochemistry of this adduct. Catalytic hydroxylation reactions are conveniently performed in an aqueous, biphasic solvent mixture with 1 mol % precatalyst and ceric ammonium nitrate as the terminal oxidant to deliver oxidized products in yields ranging from 37–90%. A comparative mechanistic investigation of the precatalyst against a related homoleptic precatalyst, [Ru(dtbpy)₂(MeCN)₂](OTf)₂, convincingly establishes that the former generates one or more surprisingly long-lived active species under the reaction conditions, thus accounting for the high turnover numbers. Structure–performance, kinetics, mass spectrometric, and electrochemical analyses reveal that ligand oxidation is a prerequisite for catalyst activation. These findings sharply contrast a large body of prior art showing that ligand oxidation is detrimental to catalyst function.

ACS Central Science

Nickel-Catalyzed Enantio- and Diastereoselective Synthesis of Fluorine-Containing Vicinal Stereogenic Centers

U. Dhawa,^† L. Lavrencic^† & X. Hu*

ACS Cent. Sci. 2024, ASAP (DOI: 10.1021/acscentsci.4c00819) 🔓

The construction of fluorinated architectures has been a topic of interest to medicinal chemists due to their unique ability to improve the pharmacokinetic properties of bioactive compounds. However, the stereoselective synthesis of fluoro-organic compounds with vicinal stereogenic centers is a challenge. Herein, the authors present a directing-group free nickel-hydride catalyzed hydroalkylation of fluoroalkenes to afford fluorinated motifs with two adjacent chiral centers in excellent yields and stereoselectivities. The method provides expedient access to biologically relevant, highly enantioenriched organofluorine compounds. Furthermore, the strategy can be used for the diastereo- and enantioselective synthesis of vicinal difluorides, which have recently gained attention in the fields of organocatalysis and peptide mimics.

Substitution, Elimination, and Integration of Methyl Groups in Terpenes Initiated by C–H Bond Functionalization

Y. C. Kang, R. T. Wetterer, R. R. Karimov, M. Kojima, M. Surke, I. Martín-Torres, J. Nicolai, M. Elkin & J. F. Hartwig*

ACS Cent. Sci. 2024, ASAP (DOI: 10.1021/acscentsci.4c01108) 🔓

Methyl groups are ubiquitous in natural products and biologically active compounds, but methods for their selective transformation in such structures are limited. For example, terpenoids contain many methyl groups, due to their biosynthetic pathways, but few reactions of these groups in such structures have been reported. The authors demonstrate that the combination of methyl C–H silylation and oxidation proximal to native hydroxyl or carbonyl groups occurs in a range of terpenoids and show that the installed hydroxyl group serves as a toehold to enable substitution, elimination, or integration of the methyl carbon into the terpenoid skeleton by the cleavage of C–C bonds. In one case, substitution of the entire methyl group occurs by further oxidation and decarboxylative coupling. In a second, substitution of the methyl group with hydrogen occurs by photochemical hydrodecarboxylation or epimerization by retro-Claisen condensation. In a third, photocatalytic decarboxyolefination formally eliminates methane from the starting structure to generate a terminal olefin for further transformations. Finally, a Dowd–Beckwith-type rearrangement cleaves a nearby C–C bond and integrates the methyl group into a ring, forming derivatives with unusual and difficult-to-access expanded rings.

Angewandte Chemie International Edition

Platinum-Catalyzed Regio- and Enantioselective Diboration of Unactivated Alkenes with (pin)B−B(dan)

H. Fang, N. Manoj, M. Popescu, A. Noble, R. Paton* & V. K. Aggarwal*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202413504)

Asymmetric diboration of terminal alkenes is well established, and subsequent selective functionalization of the less hindered primary boronic ester is commonly achieved. Conversely, selective functionalization of the sterically less accessible secondary boronic ester remains challenging. An alternative way to control chemoselective functionalization of bis(boron) compounds is by engendering different Lewis acidity to the two boryl moieties, since reactivity would then be dictated by Lewis acidity instead of sterics. The authors report herein the regio- and enantioselective Pt-catalyzed diboration of unactivated alkenes with (pin)B−B(dan). A broad range of terminal and cyclic alkenes undergo diboration to furnish the differentiable 1,2-bis(boron) compounds with high levels of regio- and enantiocontrol, giving access to a wide variety of novel building blocks from a common intermediate. The reaction places the less Lewis acidic B(dan) group at the less hindered position and the resulting 1,2-bisboryl alkanes undergo selective transformations of the B(pin) group located at the more hindered position. The regioselectivity of diboration has been studied by DFT calculations and is believed to originate from the trans influence, which lowers the activation barrier for formation of the regioisomer that places the weaker electron donor [B(pin) vs. B(dan)] opposite the strong electron donor (alkyl group) in the platinum complex.

Stereodivergency in Copper-Catalyzed Borylative Difunctionalizations: The Impact of Boron Coordination

B. Mirabi, S. Li, J. Ching, M. Lenz, S. M Popovic & M. Lautens*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202411156) 🔓

A reagent-controlled diastereodivergent copper-catalyzed borylative difunctionalization is reported. The formation of Lewis adducts that guide selectivity is commonly invoked in organic reaction mechanisms. Using density functional theory calculations, the authors identified BpinBdan as a sterically similar and less Lewis acidic alternative to B­₂pin₂. Using a newly developed borylative aldol domino reaction as the proof-of-concept, they demonstrate a change in stereochemical outcome by a simple change of borylating reagent – B₂pin₂ affords the diastereomer associated with coordination control while BpinBdan overturns this mode of binding. This strategy can be generalized to other scaffolds and, more importantly, BpinBdan does not alter the diastereomeric outcome of the reaction when coordination is not involved.

Photoinduced Copper-Catalyzed Enantioselective Allylic C(sp³)–H Oxidation of Acyclic 1-Aryl-2-Alkyl Alkenes as Limiting Substrates

X. Chen, H.-H. Li & S. Kramer*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202413190) 🔓

The authors disclose a simple copper-catalyzed method for enantioselective allylic C(sp³ )–H oxidation of unsymmetrical acyclic alkenes, specifically 1-aryl-2-alkyl alkenes. The C–H substrates are used in limiting amounts, and the products are obtained with high enantioselectivity, E/Z-selectivity, and regioselectivity. The method exhibits broad functional group tolerance, and E/Z-alkene mixtures are suitable C–H substrates. The transformation is enabled by light irradiation, which sustains the enantioselective copper catalysis by photoinduced oxidant homolysis.

Nickel Catalyzed Carbonylative Cross-Coupling for Direct Access to Isotopically Labeled Alkyl Aryl Ketones

K. S. Mühlfenzl,^† V. J. Enemærke,^† S. Gahlawat, P. I. Golbækdal, N. Munksgaard-Ottosen, K. T. Neumann, K. H. Hopmann, P.-O. Norrby, C. S. Elmore & T. Skrydstrup*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202412247)

The authors present an effective nickel-catalyzed carbonylative cross-coupling for direct access to alkyl aryl ketones from readily accessible redox-activated tetrachlorophthalimide esters and aryl boronic acids. The methodology, which is run employing only 2.5 equivalents of CO and simple Ni(II) salts as the metal source, exhibits a broad substrate scope under mild conditions. Furthermore, this carbonylation chemistry provides an easy switch between isotopologues for stable (¹³ CO) and radioactive (¹⁴ CO) isotope labeling, allowing its adaptation to the late-stage isotope labeling of pharmaceutically relevant compounds.

ChemRxiv

Catalytic Asymmetric Oxidative Coupling Between C(sp³)–H Bonds and Carboxylic Acids

X.-M. Liu,^† F. Li, T. Wang,^† L. Dai, Y. Yang, N.-Q. Jiang, L.-Y. Xue, J.-Y. Liu, X.-S. Xue,* L.-J. Xiao* & Q.-L. Zhou*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-hqqb0) 🔓

Direct enantioselective functionalization of C(sp³ )–H bonds in organic molecules could fundamentally transform the synthesis of chiral molecules. In particular, the enantioselective oxidation of these bonds would dramatically change the production of chiral alcohols and esters, which are prevalent in natural products, pharmaceuticals, and fine chemicals. Remarkable advances have been made in the enantioselective construction of carbon-carbon and carbon-nitrogen bonds through C(sp³ )–H bond functionalization. However, the direct enantioselective formation of carbon-oxygen bonds from C(sp³ )–H bonds remains a considerable challenge. The authors report a highly enantioselective C(sp³ )–H bonds oxidative coupling with carboxylic acids using molecular copper catalyst activated by blue light. The method applies to allylic and propargyl C–H bonds and more importantly employs various carboxylic acids as oxygenating agents. By this method, they have successfully synthesized a range of chiral esters directly from readily available alkenes and alkynes, greatly simplifying the synthesis of chiral esters and related alcohols.

Regioselectivity of Non-Symmetrical Borylated Dienes via EnT Catalysis: Unveiling the Relationship between Structure and Reactivity

H. Fang, A. García-Eguizábal, C. G. Daniliuc, I. Funes-Ardoiz* & J. J. Molloy*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-3hsm9) 🔓

Energy transfer catalysis (EnT) has had a profound impact on contemporary organic synthesis enabling the construction of higher in energy, complex molecules, via efficient access to the triplet excited state. Despite this, intermolecular reactivity, and the unique possibility to access several reaction pathways via a central triplet diradical has rendered control over reaction outcomes, an intractable challenge. Extended chromophores such as non-symmetrical dienes have the potential to undergo [2+2] cycloaddition, [4+2] cycloaddition or geometric isomerization, which, in combination with other mechanistic considerations (site- and regioselectivity), results in chemical reactions that are challenging to regulate. Leveraging spin density as a predictive tool, in combination with the use of a core functionality that can be adequately tuned to potentially modulate reactivity, would be highly enabling in revealing the intimate links between core structure and EnT induced reactivity. Herein, the authors utilize boron as a tool to explore reactivity of non-symmetrical dienes under EnT catalysis, paying particular attention to the impact of boron hybridization effects on the target reactivity. Through this, a highly site- and regioselective [2+2] cycloaddition was realized with the employed boron motif effecting reaction efficiency. Reaction divergence to enable [4+2] cycloaddition was achieved, while a counterintuitive regiodivergence was observed in geometric isomerization versus [2+2] cycloaddition.

Organic Letters

Formate-Mediated Reductive Cross-Coupling of Vinyl Halides and Aryl Iodides: cine-Substitution via Palladium(I) Catalysis

C. G. Santana, Y. S. Teoh, M. M. Evarts, J. Z. Shezaf & M. J. Krische*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02642)

Formate-mediated reductive cross-couplings of vinyl halides with aryl iodides via palladium(I) catalysis occur with highly uncommon cine-substitution. The active dianionic palladium(I) catalyst, [Pd₂I₄][NBu₄]₂, is generated in situ from Pd(OAc)₂, Bu₄NI, and formate. Oxidative addition of aryl iodide followed by dissociation of the dimer provides the monomeric anionic T-shaped arylpalladium(II) species, [Pd(Ar)(I)₂(NBu₄)], which, upon vinyl halide carbopalladation, forms products of cine-substitution by way of palladium(IV) carbenes, as corroborated by deuterium-labeling experiments.

Journal of Organic Chemistry

Evolution of a Strategy for the Unified, Asymmetric Total Syntheses of DMOA-Derived Spiromeroterpenoids

F. Yang, A. Oladokun & J. A. Porco Jr.*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01116)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-0m8pp) 🔓

DMOA-derived spiromeroterpenoids are a group of natural products with complex structures and varied biological activities. Recently, the authors reported the first enantioselective total synthesis of five spiromeroterpenoids based on a fragment coupling strategy. This full account describes details of a strategy evolution that culminated in successful syntheses of the targeted natural products. To enable scalable access of the natural products, a refined, multigram-scale synthesis of the coupling partners was developed. A series of stereoselective transformations was developed through judicious choice of reagents and conditions. Finally, modular spirocycle construction logic was demonstrated through the synthesis of a small library of spiromeroterpenoid analogues.

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