Metal-Free Arylation of Benzothiophenes at C4 by Activation as their Benzothiophene S-Oxides.

Benzothiophenes, activated by oxidation to the corresponding S-oxides, undergo C-H/C-H-type coupling with phenols to give C4 arylation products. While an electron-withdrawing group at C3 of the benzothiophene is important, the process operates without a directing group and a metal catalyst, thus rendering it compatible with sensitive functionalities-e.g. halides and formyl groups. Quantum chemical calculations suggest a formal stepwise mechanism involving heterolytic cleavage of an aryloxysulfur species to give a π-complex of the corresponding benzothiophene and a phenoxonium cation. Subsequent addition of the phenoxonium cation to the C4 position of the benzothiophene is favored over the addition to C3; Fukui functions predict that the major regioisomer is formed at the more electron-rich position between C3 and C4. Varied selective manipulation of the benzothiophene products showcase the synthetic utility of the metal-free arylation process.

Asymmetric Total Synthesis of (-)-Phaeocaulisin A.

The therapeutic properties of Curcuma (ginger and turmeric's family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI2), the lactone intermediate was submitted to two sequential SmI2-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from C. phaeocaulis─as well as their synthetic derivatives─for medicinal chemistry and drug design.

Diastereoselective Radical 1,4-Ester Migration: Radical Cyclizations of Acyclic Esters with SmI2.

Reductive cyclizations of carbonyl compounds, mediated by samarium(II) diiodide (SmI2, Kagan's reagent), represent an invaluable platform to generate molecular complexity in a stereocontrolled manner. In addition to classical ketone and aldehyde substrates, recent advances in radical chemistry allow the cyclization of lactone and lactam-type substrates using SmI2. In contrast, acyclic esters are considered to be unreactive to SmI2 and their participation in reductive cyclizations is unprecedented. Here, we report a diastereoselective radical 1,4-ester migration process, mediated by SmI2, that delivers stereodefined alkene hydrocarboxylation products via radical cyclization of acyclic ester groups in α-carbomethoxy δ-lactones. Isotopic labeling experiments and computational studies have been used to probe the mechanism of the migration. We propose that a switch in conformation redirects single electron transfer from SmI2 to the acyclic ester group, rather than the "more reactive" lactone carbonyl. Our study paves the way for the use of elusive ketyl radicals, derived from acyclic esters, in SmI2-mediated reductive cyclizations.

A Vitamin B2 -Photocatalysed Approach to Methionine Analogues.

Access to new non-canonical amino acid residues is crucial for medicinal chemistry and chemical biology. Analogues of the amino acid methionine have been far less explored-despite their use in biochemistry, pharmacology and peptide bioconjugation. This is largely due to limited synthetic access. Herein, we exploit a new disconnection to access non-natural methionines through the development of a photochemical method for the radical α-C-H functionalization of sulfides with alkenes, in water, using inexpensive and commercially-available riboflavin (vitamin B2 ) as a photocatalyst. Our photochemical conditions allow the two-step synthesis of novel methionine analogues-by radical addition to unsaturated amino acid derivatives-and the chemoselective modification of peptide side-chains to yield non-natural methionine residues within small peptides. The mechanism of the bio-inspired flavin photocatalysis has been probed by experimental, DFT and TDDFT studies.

Enantioselective Copper-Catalyzed Borylative Cyclization for the Synthesis of Quinazolinones.

Quinazolinones are common substructures in molecules of medicinal importance. We report an enantioselective copper-catalyzed borylative cyclization for the assembly of privileged pyrroloquinazolinone motifs. The reaction proceeds with high enantio- and diastereocontrol, and can deliver products containing quaternary stereocenters. The utility of the products is demonstrated through further manipulations.

Synthetic Methods Driven by the Photoactivity of Electron Donor-Acceptor Complexes.

The association of an electron-rich substrate with an electron-accepting molecule can generate a new molecular aggregate in the ground state, called an electron donor-acceptor (EDA) complex. Even when the two precursors do not absorb visible light, the resulting EDA complex often does. In 1952, Mulliken proposed a quantum-mechanical theory to rationalize the formation of such colored EDA complexes. However, and besides a few pioneering studies in the 20th century, it is only in the past few years that the EDA complex photochemistry has been recognized as a powerful strategy for expanding the potential of visible-light-driven radical synthetic chemistry. Here, we explain why this photochemical synthetic approach was overlooked for so long. We critically discuss the historical context, scientific reasons, serendipitous observations, and landmark discoveries that were essential for progress in the field. We also outline future directions and identify the key advances that are needed to fully exploit the potential of the EDA complex photochemistry.

Mechanistic Studies in Photocatalysis.

The fast-moving fields of photoredox and photocatalysis have recently provided fresh opportunities to expand the potential of synthetic organic chemistry. Advances in light-mediated processes have mainly been guided so far by empirical findings and the quest for reaction invention. The general perception, however, is that photocatalysis is entering a more mature phase where the combination of experimental and mechanistic studies will play a dominant role in sustaining further innovation. This Review outlines the key mechanistic studies to consider when developing a photochemical process, and the best techniques available for acquiring relevant information. The discussion will use selected case studies to highlight how mechanistic investigations can be instrumental in guiding the invention and development of synthetically useful photocatalytic transformations.

Asymmetric Photocatalytic C-H Functionalization of Toluene and Derivatives.

Reported herein is a visible-light-mediated organocatalytic direct C-H functionalization of toluene derivatives to afford enantioenriched ß-benzylated aldehydes from the corresponding enals. The process combines the oxidative power of a chiral excited-state iminium ion and the basic nature of its counteranion to trigger the generation of benzylic radicals by means of a sequential multisite proton-coupled electron transfer mechanism. This study shows that feedstock chemicals generally used as solvents, such as toluene and xylene derivatives, can be used as substrates for making chiral molecules with high enantioselectivity.

Iridium-Catalyzed α-Selective Arylation of Styrenes by Dual C-H Functionalization.

An IrI -system modified with a ferrocene derived bisphosphine ligand promotes α-selective arylation of styrenes by dual C-H functionalization. These studies offer a regioisomeric alternative to the Pd-catalyzed Fujiwara-Moritani reaction.

C2-Alkenylation of N-heteroaromatic compounds via Brønsted acid catalysis.

Substituted heteroaromatic compounds, especially those based on pyridine, hold a privileged position within drug discovery and medicinal chemistry. However, functionalisation of the C2 position of 6-membered heteroarenes is challenging because of (a) the difficulties of installing a halogen at this site and (b) the instability of C2 heteroaryl-metal reagents. Here we show that C2-alkenylated heteroaromatics can be accessed by simple Brønsted acid catalysed union of diverse heteroarene N-oxides with alkenes. The approach is notable because (a) it is operationally simple, (b) the Brønsted acid catalyst is cheap, non-toxic and sustainable, (c) the N-oxide activator disappears during the reaction, and (d) water is the sole stoichiometric byproduct of the process. The new protocol offers orthogonal functional group tolerance to metal-catalysed methods and can be integrated easily into synthetic sequences to provide polyfunctionalised targets. In broader terms, this study demonstrates how classical organic reactivity can still be used to provide solutions to contemporary synthetic challenges that might otherwise be approached using transition metal catalysis.

Branch-Selective Alkene Hydroarylation by Cooperative Destabilization: Iridium-Catalyzed ortho-Alkylation of Acetanilides.

An iridium(I) catalyst system, modified with the wide-bite-angle and electron-deficient bisphosphine d(F) ppb (1,4-bis(di(pentafluorophenyl)phosphino)butane) promotes highly branch-selective hydroarylation reactions between diverse acetanilides and aryl- or alkyl-substituted alkenes. This provides direct and ortho-selective access to synthetically challenging anilines, and addresses long-standing issues associated with related Friedel-Crafts alkylations.

Branch-selective, iridium-catalyzed hydroarylation of monosubstituted alkenes via a cooperative destabilization strategy.

Highly branch-selective, carbonyl-directed hydroarylations of monosubstituted alkenes are described. The chemistry relies upon a cationic Ir(I) catalyst modified with an electron deficient, wide bite angle bisphosphine ligand. This work provides a regioisomeric alternative to the Murai hydroarylation protocol.

A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres.

C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes, play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2-catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI2 loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.

A general arene C-H functionalization strategy via electron donor-acceptor complex photoactivation.

The photoactivation of electron donor-acceptor complexes has emerged as a sustainable, selective and versatile strategy for the generation of radical species. However, when it comes to aryl radical formation, this strategy remains hamstrung by the electronic properties of the aromatic radical precursors, and electron-deficient aryl halide acceptors are required. This has prevented the implementation of a general synthetic platform for aryl radical formation. Our study introduces triarylsulfonium salts as acceptors in photoactive electron donor-acceptor complexes, used in combination with catalytic amounts of newly designed amine donors. The sulfonium salt label renders inconsequential the electronic features of the aryl radical precursor and, more importantly, it is installed regioselectively in native aromatic compounds by C-H sulfenylation. Using this general, site-selective aromatic C-H functionalization approach, we developed metal-free protocols for the alkylation and cyanation of arenes, and showcased their application in both the synthesis and the late-stage modification of pharmaceuticals and agrochemicals.

A Vitamin B2-Photocatalysed Approach to Methionine Analogues.

Access to new non-canonical amino acid residues is crucial for medicinal chemistry and chemical biology. Analogues of the amino acid methionine have been far less explored-despite their use in biochemistry, pharmacology and peptide bioconjugation. This is largely due to limited synthetic access. Herein, we exploit a new disconnection to access non-natural methionines through the development of a photochemical method for the radical α-C-H functionalization of sulfides with alkenes, in water, using inexpensive and commercially-available riboflavin (vitamin B2) as a photocatalyst. Our photochemical conditions allow the two-step synthesis of novel methionine analogues-by radical addition to unsaturated amino acid derivatives-and the chemoselective modification of peptide side-chains to yield non-natural methionine residues within small peptides. The mechanism of the bio-inspired flavin photocatalysis has been probed by experimental, DFT and TDDFT studies.

Catalytic asymmetric C-C cross-couplings enabled by photoexcitation.

Enantioselective catalytic processes are promoted by chiral catalysts that can execute a specific mode of catalytic reactivity, channeling the chemical reaction through a certain mechanistic pathway. Here, we show how by simply using visible light we can divert the established ionic reactivity of a chiral allyl-iridium(III) complex to switch on completely new catalytic functions, enabling mechanistically unrelated radical-based enantioselective pathways. Photoexcitation provides the chiral organometallic intermediate with the ability to activate substrates via an electron-transfer manifold. This redox event unlocks an otherwise inaccessible cross-coupling mechanism, since the resulting iridium(II) centre can intercept the generated radicals and undergo a reductive elimination to forge a stereogenic centre with high stereoselectivity. This photochemical strategy enables difficult-to-realize enantioselective alkyl-alkyl cross-coupling reactions between allylic alcohols and readily available radical precursors, which are not achievable under thermal activation.

Stereoselective Glycosylation of 2-Nitrogalactals Catalyzed by a Bifunctional Organocatalyst.

The use of a bifunctional cinchona/thiourea organocatalyst for the direct and α-stereoselective glycosylation of 2-nitrogalactals is demonstrated for the first time. The conditions are mild, practical, and applicable to a wide range of glycoside acceptors with products being isolated in good to excellent yields. The method is exemplified in the synthesis of mucin type Core 6 and 7 glycopeptides.