Claisen/Retro-Claisen Cascade Transforms Aromatic Ketones into Electrophiles

Science

Scalable Decarboxylative Trifluoromethylation by Ion-Shielding Heterogeneous Photoelectrocatalysis

Y. Chen,^‡ Y. He,^‡ Y. Gao,^‡ J. Xue, W. Qu, J. Xuan* & Y. Mo*

Science 2024 (DOI: 10.1126/science.adm8902)

Electrochemistry offers a sustainable synthesis route to value-added fine chemicals but is often constrained by competing electron transfer between the electrode and redox-sensitive functionalities distinct from the target site. Here, the authors describe an ion-shielding heterogeneous photoelectrocatalysis strategy to impose mass-transfer limitations that invert the thermodynamically determined order of electron transfer. This strategy is showcased to enable decarboxylative trifluoromethylation of sensitive (hetero)arenes by using trifluoroacetate, an inexpensive yet relatively inert trifluoromethyl group (CF₃) source. An ion-shielding layer, formed by trifluoroacetate anions electrostatically adsorbed on a positive molybdenum-doped tungsten trioxide (WO₃) photoanode, prevents undesired electron transfer between substrates and photogenerated holes.

Nature Chemistry

Modular Chemoenzymatic Synthesis of Ten Fusicoccane Diterpenoids

Y. Jiang & H. Renata*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01533-w)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-gfh8l) 🔓

Fusicoccane diterpenoids display intriguing biological activities, including the ability to act as modulators of 14-3-3 protein–protein interactions. However, their innate structural complexity and diverse oxygenation patterns present enormous synthetic challenges. Here, the authors develop a modular chemoenzymatic approach that combines de novo skeletal construction and late-stage hybrid C–H oxidations to achieve the synthesis of ten complex fusicoccanes in 8–13 steps each. A convergent fragment coupling strategy allowed rapid access to a key tricyclic intermediate, which was subjected to chemical and enzymatic C–H oxidations to modularly prepare five oxidized family members. The authors also conceived a complementary biomimetic skeletal remodelling strategy to synthetically access five rearranged fusicoccanes with unusual bridgehead double bonds.

Enantioselective Construction of Stereogenic-at-Sulfur(IV) Centres via Catalytic Acyl Transfer Sulfinylation

T. Wei, H.-L. Wang, Y. Tian,* M.-S. Xie* & H.-M. Guo*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01522-z)

Chiral sulfur pharmacophores are crucial for drug discovery in bioscience and medicinal chemistry. While the catalytic asymmetric synthesis of sulfoxides and sulfinate esters with stereogenic-at-sulfur(IV) centres is well developed, the synthesis of chiral sulfinamides remains challenging, which has primarily been attributed to the high nucleophilicity and competing reactions of amines. In this study, the authors have developed an efficient methodology for the catalytic asymmetric synthesis of chiral sulfinamides and sulfinate esters by the sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using bifunctional chiral 4-arylpyridine N-oxides as catalysts.

Nature Catalysis

C–Heteroatom Coupling with Electron-Rich Aryls Enabled by Nickel Catalysis and Light

S. Ni, R. Halder, D. Ahmadli, E. J. Reijerse, J. Cornella* & T. Ritter*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01160-1) 🔓

Nickel photoredox catalysis has resulted in a rich development of transition-metal-catalysed transformations for carbon–heteroatom bond formation. By harnessing light energy, the transition metal can attain oxidation states that are difficult to achieve through thermal chemistry in a catalytic manifold. For example, nickel photoredox reactions have been reported for both the synthesis of anilines and aryl ethers from aryl(pseudo)halides. However, oxidative addition to simple nickel systems is often sluggish in the absence of special, electron-rich ligands, leading to catalyst decomposition. Electron-rich aryl electrophiles therefore currently fall outside the scope of many transformations in the field. Here, the authors provide a conceptual solution to this problem and demonstrate nickel-catalysed C–heteroatom bond-forming reactions of arylthianthrenium salts, including amination, oxygenation, sulfuration and halogenation. Because the redox properties of arylthianthrenium salts are primarily dictated by the thianthrenium, oxidative addition of highly electron-rich aryl donors can be unlocked using simple NiCl₂ under light irradiation to form the desired C‒heteroatom bonds.

Journal of the American Chemical Society

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade

C. Peng,^‡ Q. Guo,^‡ G.-X. Xu,^‡ L. Huo, W. Wu, T.-Y. Chen, X. Hong* & P. Hu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03995)

The authors report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C–C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6–5–5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Concise Total Synthesis of (−)-Bipolarolide D

S. Sun,^‡ Q. Wei,^‡ Y. Liu & Z. Lu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04059)

The authors report the first total synthesis of a complex ophiobolin-derived sesterterpene, bipolarolide D, which hinges on two strategic applications of pentafulvene: (1) enantioselective pentafulvene-involved [6+2] cycloaddition; (2) regioselective and diastereoselective pentafulvene-involved Heck cyclization. Late-stage selective allylic addition to the ketone moiety facilitates the successful installation of the side chain. This strategy enabled the accomplishment of its first enantioselective total synthesis through a modular approach.

Simultaneous Stereoinvertive and Stereoselective C(sp³)–C(sp³) Cross-Coupling of Boronic Esters and Allylic Carbonates

H.-C. Shen,^‡ Z.-S. Wang,^‡ A. Noble & V. K. Aggarwal*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03686) 🔓

With increasing interest in constructing more three-dimensional entities, there has been growing interest in cross-coupling reactions that forge C(sp³ )–C(sp³ ) bonds, which leads to additional challenges as it is not just a more difficult bond to construct but issues of stereocontrol also arise. Herein, the authors report the stereocontrolled cross-coupling of enantioenriched boronic esters with racemic allylic carbonates enabled by iridium catalysis, leading to the formation of C(sp³ )–C(sp³ ) bonds with single or vicinal stereogenic centers. The method shows broad substrate scope, enabling primary, secondary, and even tertiary boronic esters to be employed, and can be used to prepare any of the four possible stereoisomers of a coupled product with vicinal chiral centers.

Asymmetric Three-Component Radical Alkene Carboazidation by Direct Activation of Aliphatic C–H Bonds

L. Ge, H. Wang, Y. Liu* & X. Feng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02012)

Azide compounds are widely present in natural products and drug molecules, and their easy-to-transform characteristics make them widely used in the field of organic synthesis. The merging of transition-metal catalysis with radical chemistry offers a versatile platform for radical carboazidation of alkenes, allowing the rapid assembly of highly functionalized organic azides. However, the direct use of readily available hydrocarbon feedstocks as sp³ -hybridized carbon radical precursors to participate in catalytic enantioselective carboazidation of alkenes remains a significant challenge that has yet to be addressed. Herein, the authors describe an iron-catalyzed asymmetric three-component radical carboazidation of electron-deficient alkenes by direct activation of aliphatic C–H bonds. This approach involves intermolecular hydrogen atom transfer between a hydrocarbon and an alkoxy/aryl carboxyl radical, leading to the formation of a carbon-centered radical. The resulting radical then reacts with electron-deficient alkenes to generate a new radical species that undergoes chiral iron-complex-mediated C–N₃ bond coupling.

CuH-Catalyzed Regio- and Enantioselective Formal Hydroformylation of Vinyl Arenes

S. Garhwal, Y. Dong, B. K. Mai, P. Liu* & S. L. Buchwald*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04287)

A highly enantioselective formal hydroformylation of vinyl arenes enabled by copper hydride (CuH) catalysis is reported. Key to the success of the method was the use of the mild Lewis acid zinc triflate to promote the formation of oxocarbenium electrophiles through the activation of diethoxymethyl acetate. Using the newly developed protocol, a broad range of vinyl arene substrates underwent efficient hydroacetalization reactions to provide access to highly enantioenriched α-aryl acetal products in good yields with exclusively branched regioselectivity. The acetal products could be converted to the corresponding aldehydes, alcohols, and amines with full preservation of the enantiomeric purity.

Angewandte Chemie International Edition

Site-Selective Ortho/Ipso C-H Difunctionalizations of Arenes using Thianthrene as a Leaving Group

D. Dupommier, M. Vuagnat, J. Rzayev, S. Roy, P. Jubault & T. Besset*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202403950) 🔓

Site-selective ortho/ipso C-H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4-tetrasubstituted ones (62 examples, up to 97% yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a “C-H thianthenation/Catellani-type reaction” sequence was developed starting from simple arenes. Non-prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium-catalyzed, norbornene (NBE)-mediated process allowed the synthesis of ipso-olefinated/ortho-alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). The protocol was robust (gram-scale reaction) and was widely applied to the two-fold functionalization of various arenes including bio-active compounds. The “thianthrenium” strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process.

ChemRxiv

Cine-Substitution of Enolates: Enolate Dance/Coupling of Cycloalkenyl Pivalates by Nickel Catalysis

E. Moriya, K. Muto & J. Yamaguchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-37kvr) 🔓

The authors report the development of Ni/dcype-catalyzed enolate dance/coupling reaction of alkenyl pivalates with nucleophiles, resulting in cine-substitution. Pivalates derived 1-tetralone undergo this reaction, to produce C2-functionalized dihydronaphthalenes. The direct utilization of 1-tetralone is also feasible, employing Piv₂O to generate the corresponding enol pivalate in situ. Mechanistic investigations including stoichiometric experiments, suggest that the reaction proceeds via C–O oxidative addition, nickel 1,2-translocation, and subsequent coupling with a nucleophile.

Reimagining Enantioselective Aminoalcohol Synthesis via Chemoselective Electrocatalytic Radical Cross Couplings

J. Sun,^‡ S. Wang,^‡ K. C. Harper, Y. Kawamata* & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-hq8r8) 🔓

Aminoalcohols are expressed in natural products, blockbuster pharmaceuticals, agrochemicals, and key building blocks for innumerable society-benefitting applications. Historically their synthesis relies on polar-bond retrosynthetic analysis and often suffers from extensive protecting/functional group manipulation chemistry that hinders their direct access. Here, the authors show how a simple serine-derived chemical cassette can be leveraged in a series of electrocatalytic transformations to dramatically simplify the way such structures can be made enantio- and chemoselectively in a modular fashion. This chemistry can be used to rapidly create libraries of useful building blocks and the radical retrosynthetic logic employed can be applied to truncate the synthesis of known structures. This methodology can be used on large scale as well as demonstrated with a unique flow reactor setup.

Streamlining the Synthesis of Pyridones through Oxidative Amination

B. B. Botlik, M. Weber, F. Ruepp, K. Kawanaka, P. Finkelstein & B. Morandi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-xrtr3) 🔓

The authors report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of ¹⁵ N-labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way.

Synergistic Photoenzymatic Catalysis Enables Synthesis of α-Tertiary Amino Acids Using Threonine Aldolases

Y. Ouyang,^‡ C. G. Page,^‡ C. Bilodeau,^‡ T. K. Hyster*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-ww79v) 🔓

α-Tertiary amino acids are essential components of drugs and agrochemicals, yet traditional syntheses are step-intensive and provide access to a limited range of structures with varying levels of enantioselectivity. Here, the authors report the α-alkylation of unprotected alanine and glycine by pyridinium salts using pyridoxal (PLP)-dependent threonine aldolases with a Rose Bengal photoredox catalyst. The strategy efficiently prepares various α-tertiary amino acids in a single chemical step as a single enantiomer. UV-vis spectroscopy studies reveal a ternary interaction between the pyridinium salt, protein, and photocatalyst, which they hypothesize is responsible for localizing radical formation to the protein active site.

Versatile Deacylative Cross-Coupling of Aromatic Ketones

H. Nakahara,^‡ R. Isshiki,^‡ M. Kubo, K. Iizumi, K. Muto & J. Yamaguchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-hd62q) 🔓

Transition metal-catalyzed cross-couplings represent the most dependable techniques for linking aryl electrophiles with nucleophiles to synthesize a diverse array of valuable aromatic compounds. While aromatic ketones are crucial intermediates in the synthesis of aromatic compounds with numerous known methods for carbonyl transformations and aromatic ring modifications, few consider them as aryl electrophiles suitable for cross-coupling. This is primarily because forming new bonds with nucleophiles requires the cleavage of a strong C–C bond. Herein, the authors introduce a cross-coupling method that effectively utilizes aromatic ketones as versatile aryl electrophiles. The cornerstone of their strategy is the transformation of aromatic ketones into aromatic esters via sequential Claisen and regioselective retro-Claisen condensations. The resulting esters are then capable of undergoing reactions with various nucleophiles in a one-pot process.

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

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

ChemRxiv 2024 (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.

Related publication from J. A. Porco, Jr. and co-workers: J. Am. Chem. Soc. 2022, 144, 12970–12978 (DOI: 10.1021/jacs.2c05366).

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