N-(Sulfonio)Sulfilimine Reagents: Non-Oxidizing Sources of Electrophilic Nitrogen Atom for Skeletal Editing.

The one-pot synthesis of λ4-dibenzothiophen-5-imino-N-dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh2(esp)2 (esp=α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid) generating a Rh-coordinated sulfonitrene species, which is able to transfer the electrophilic nitrene moiety to olefins. When indenes are used as substrates, isoquinolines are obtained in good yields. We assumed that after formation of the corresponding N-sulfonio aziridine, a ring expansion occurs via selective C-C bond cleavage and concomitant elimination of dibenzothiophene. Unexpectedly, a similar protocol transforms 1-arylcyclobutenes into 1-cyano-1-arylcyclopropanes. Our calculations indicate that aziridination is not favored in this case; instead, sulfilimine-substituted cyclobutyl carbocations are initially formed, and these evolve to the isolated cyclopropanes via ring contraction. Both procedures are operationally simple, tolerate a range of functional groups, including oxidation-sensitive alcohols and aldehydes, and enable the convenient preparation of valuable 15N-labelled products. These results demonstrate the potential of 1 to provide alternative pathways for the selective transfer of N-atoms in organic molecules.

Reactivity of α-diazo sulfonium salts: rhodium-catalysed ring expansion of indenes to naphthalenes.

In the presence of catalytic amounts of the paddlewheel dirhodium complex Rh2(esp)2, α-diazo dibenzothiophenium salts generate highly electrophilic Rh-coordinated carbenes, which evolve differently depending on their substitution pattern. Keto-moieties directly attached to the azomethinic carbon promote carbene insertion into one of the adjacent C-S bonds, giving rise to highly electrophilic dibenzothiopyrilium salts. This intramolecular pathway is not operative when the carbene carbon bears ester or trifluoromethyl substituents; in fact, these species react with olefins delivering easy to handle cyclopropyl-substituted sulfonium salts. When indenes are the olefins of choice, the initially formed cyclopropyl rings smoothly open with concomitant departure of dibenzothiophene, enabling access to a series of 2-functionalized naphthalenes.

Synthesis of (±)-Angustatin A: Assembly of the Phenanthrene Moiety Despite Increasing Ring Strain.

The synthesis of (±)-angustatin A, a phenanthrene-containing cyclophane that possesses conformational chirality, is reported. Key steps include a Pd-catalyzed Negishi coupling to assemble the necessary terphenyl intermediate, its closure into a 14-membered macrocycle via a catalytic-in-phosphine Wittig olefination, and finally a Pt-catalyzed alkyne hydroarylation, which is able to assemble the phenanthrene unit despite the thermodynamic cost of significantly bending arene A from the ideal plane.

Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space.

Saturated bridged-bicyclic compounds are currently under intense investigation as building blocks for pharmaceutical drug design. However, the most common methods for their preparation only provide access to bridgehead-substituted structures. The synthesis of bridge-functionalised species is highly challenging but would open up many new opportunities for molecular design. We describe a photocatalytic cycloaddition reaction that provides unified access to bicyclo[2.1.1]hexanes with 11 distinct substitution patterns. Bridge-substituted structures that represent ortho-, meta-, and polysubstituted benzene bioisosteres, as well as those that enable the investigation of chemical space inaccessible to aromatic motifs can all be prepared using this operationally simple protocol. Proof-of-concept examples of the application of the method to the synthesis of saturated analogues of biorelevant trisubstituted benzenes are also presented.

Dimethylsilanediol from silicone elastomers: Analysis, release from biopharmaceutical process equipment, and clearance studies.

Polysiloxanes are considered one of the most important commercial families of synthetic elastomers. They are frequently employed in biopharmaceutical manufacturing equipment as flexible single-use solutions due to superior material properties and compatibility with diverse sterilization methods. Extractables and leachables (E&L) testing is essential in qualifying such equipment, involving extraction studies to assess the potential release of compounds from plastic components for risk assessment. Silicone releases oligomeric siloxanes and small hydrolysis products, with dimethylsilanediol (DMSD) being the main hydrolysis product found in significant concentrations in aqueous process solutions. DMSD presents challenges for analysis, requiring specifically tailored analytical methods to detect it, which are commonly not applied in standard E&L screening tests. In biopharmaceutical manufacturing, it is relevant to consider the potential of DMSD to repolymerize into silicone oil when specific process parameters are altered. This may lead to interactions with drug ingredients, including proteins, resulting in the formation of aggregates. We synthesized and characterized DMSD using X-ray structure analysis and established an HPLC method with a refractive index detector to investigate the release of DMSD from commercially available silicone tubing used in drug manufacturing following autoclaving and irradiation. Subsequently, we assessed typical biopharmaceutical downstream operations for effectively removing this compound from the process stream.

Pentafluorocyclopropanation of (Hetero)arenes Using Sulfonium Salts: Applications in Late-Stage Functionalization.

The evaluation of the pentafluorocyclopropyl group as a chemotype in crop protection and medicinal chemistry has been hampered in the past by the lack of suitable methodologies that enable the practical incorporation of this moiety into advanced synthetic intermediates. Herein, we report the gram-scale synthesis of an unprecedented sulfonium salt, 5-(pentafluorocyclopropyl)dibenzothiophenium triflate, and its use as a versatile reagent for the photoinduced C-H pentafluorocyclopropylation of a broad series of non-previously functionalized (hetero)arenes through a radical mediated mechanism. The scope and potential benefits of the protocol developed are further demonstrated by the late-stage introduction of the pentafluorocyclopropyl unit into biologically relevant molecules and widely used pharmaceuticals.

Replacing the BO in BODIPY: unlocking the path to SBDIPY and BIDIPY chromophores.

Boron-based dipyrrin chromophores (BODIPY) have found widespread application over the last twenty years in fields as diverse as medicine and materials. Thus, several efforts have been placed to exchange boron with other elements, with the aim of developing materials with complementary luminescent properties. However, despite these attempts, the incorporation of other main-group elements in dipyrrin scaffolds remains still rare. We have successfully synthesized and characterized novel chromophores based on antimony and bismuth, SBDIPY and BIDIPY. Solution stabilities have been investigated by VT-UV/vis spectroscopy and the fluorescence emission studied and supported by computational analysis. We were also able to isolate the first direct analogue of BODIPY containing fluoride handles, disclosing preliminary luminescent features.

Enantioselective Au-Catalyzed Synthesis of Thia[5]- and Thia[6]helicenes and Their Transformation into Bowl-shaped Pleiadenes.

A series of helically shaped benzo[b]chryseno[4,3-d]thiophenes, naphtho[1,2-b]phenanthro[4,3-d]thiophenes, and chryseno[3,4-b]naphtho[1,2-d]thiophenes is synthesized via a highly enantioselective Au-catalyzed intramolecular alkyne hydroarylation reaction. The inversion barriers of the structures obtained are determined both theoretically and experimentally, and their chiroptical properties are reported. Preliminary studies on the post-synthetic functionalization of these thiahelicenes and their transformation into azahelicenes are also presented. In addition, a straightforward one-step protocol is developed, which wraps the initially obtained chryseno[3,4-b]naphtho[1,2-d]thiophenes into bowl-shaped pleiadene derivatives without erosion of the enantiopurity. The number of structurally related products that are obtained with high enantioselectivity enables the establishment of comprehensive correlations between the structure and conformational stability or (chir)optical properties.

Organophotocatalytic [2+2] Cycloaddition of Electron-Deficient Styrenes.

A visible-light organophotocatalytic [2+2] cycloaddition of electron-deficient styrenes is described. Photocatalytic [2+2] cycloadditions are typically performed with electron-rich styrene derivatives or α,ß-unsaturated carbonyl compounds, and with transition-metal-based catalysts. We have discovered that an organic cyanoarene photocatalyst is able to deliver high-value cyclobutane products bearing electron-deficient aryl substituents in good yields. A range of electron-deficient substituents are tolerated, and both homodimerisations and intramolecular [2+2] cycloadditions to fused bicyclic systems are available by using this methodology.

5-(Trifluorovinyl)dibenzothiophenium Triflate: Introducing the 1,1,2-Trifluoroethylene Tether in Drug-Like Structures.

This manuscript reports the synthesis and structure of an unprecedented sulfonium salt, 5-(trifluorovinyl)dibenzothiophenium triflate, and its use as a versatile reagent for the introduction of the bioisosteric 1,1,2-trifluoroethylene linker in drug-like structures. The protocol developed consists of the reaction of this compound with alcohols and phenols to deliver a complete set of 1,2,2-trifluoro-2-(alkoxy-/aryloxy)ethyl sulfonium salts, which have been purified by column chromatography and fully characterized. Subsequent single electron reduction under mild photochemical conditions efficiently affords the corresponding fluoroalkyl radicals that are trapped either intra- or intermolecularly through their reaction with (hetero)arenes. Theoretical calculations are used to evaluate the conformational consequences derived from the presence of the CF2 -CHF tether.

Ligand-Enabled Disproportionation of 1,2-Diphenylhydrazine at a PV -Center.

We present herein the synthesis of a nearly square-pyramidal chlorophosphorane supported by the tetradentate bis(amidophenolate) ligand, N,N'-bis(3,5-di-tert-butyl-2-phenoxy)-1,2-phenylenediamide. After chloride abstraction the resulting phosphonium cation efficiently promotes the disproportionation of 1,2-diphenylhydrazine to aniline and azobenzene. Mechanistic studies, spectroscopic analyses and theoretical calculations suggest that this unprecedented reactivity mode for PV -centres is induced by the high electrophilicity at the cationic PV -center, which originates from the geometry constraints imposed by the rigid pincer ligand, combined with the ability of the o-amidophenolate moieties to act as electron reservoir. This study illustrates the promising role of cooperativity between redox-active ligands and phosphorus for the design of organocatalysts able to promote redox processes.

Organic Four-Electron Redox Systems Based on Bipyridine and Phenanthroline Carbene Architectures.

Novel organic redox systems that display multistage redox behaviour are highly sought-after for a series of applications such as organic batteries or electrochromic materials. Here we describe a simple strategy to transfer well-known two-electron redox active bipyridine and phenanthroline architectures into novel strongly reducing four-electron redox systems featuring fully reversible redox events with up to five stable oxidation states. We give spectroscopic and structural insight into the changes involved in the redox-events and present characterization data on all isolated oxidation states. The redox-systems feature strong UV/Vis/NIR polyelectrochromic properties such as distinct strong NIR absorptions in the mixed valence states. Two-electron charge-discharge cycling studies indicate high electrochemical stability at strongly negative potentials, rendering the new redox architectures promising lead structures for multi-electron anolyte materials.

The Pseudo-Natural Product Rhonin Targets RHOGDI.

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented "pseudo-natural products" in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases.

Enantioselective Synthesis of Dithia[5]helicenes and their Postsynthetic Functionalization to Access Dithia[9]helicenes.

A highly enantioselective synthesis of 5,13-disubstituted dibenzo[d,d']benzo[1,2-b:4,3-b']dithiophenes is reported. Key for the successful assembly of these helical architectures is the last two successive Au-catalyzed intramolecular alkyne hydroarylation events. Specifically, the second cyclization is the enantiodetermining step of the whole process and provides the desired helicenes with excellent ee values when a TADDOL-derived 1,2,3-(triazolium)phosphonite moiety (TADDOL: α,α,α',α'-tetraaryl-1,3-dioxolane-4,5-dimethanol) is employed as an ancillary ligand. The absolute stereochemistry of the newly prepared structures has been determined by X-ray crystallography to be P; the optical properties of these heterohelicenes are also reported. A three-step procedure was subsequently developed that allows the transformation of the initially obtained dithia[5]helicenes into dithia[9]helicenes without erosion of the enantiopurity.

Reactivity of 5-(Alkynyl)dibenzothiophenium Salts: Synthesis of Diynes, Vinyl Sulfones, and Phenanthrenes.

The reactivity of 5-(alkynyl)dibenzothiophenium salts 1 is explored in the presence of different nucleophiles, dienes, and under photochemical conditions. Reaction with lithium acetylides affords diynes in moderate yields; while depending on the substitution pattern, the reaction with sulfinates delivers either the alkyne transfer products, alkynyl sulfones, or ß-(sulfonium) vinyl sulfones through addition to the C-C triple bond. Similar behavior is observed when tosylamines are used as nucleophiles. Salts of general formula 1 also react with dienes to render the corresponding Diels-Alder cycloadducts. The vinyl sulfonium salts obtained by these routes further react with nucleophiles through a Michael addition, dibenzothiophene elimination sequence. Alternatively, they also engage in photoinduced radical cyclizations to produce substituted phenanthrenes. Attempts to use this specific addition/radical cyclization sequence for the construction of the 6a,7-dehydroaporphine skeleton present in several families of alkaloids are also described.

In-Fjord Substitution in Expanded Helicenes: Effects of the Insert on the Inversion Barrier and Helical Pitch.

A series of expanded helicenes of different sizes and shapes incorporating phenyl- and biphenyl-substituents at the deepest part of their fjord have been synthesized via sequential Au-catalyzed hydroarylation of appropriately designed diynes, and their racemization barriers have been calculated employing electronic structure methods. These show that the overall profile of the inversions (energies, number of transition states and intermediates, and their relative position) is intensively affected by the interplay of steric and attractive London dispersion interactions. Hence, in-fjord substitution constitutes an additional tool to handle the mechanical properties in helicenes of uncommonly large diameter. The photochemical characterization of the newly prepared helical structures is also reported.

Synthesis of 6H-Benzo[c]chromene Scaffolds from O-Benzylated Phenols through a C-H Sulfenylation/Radical Cyclization Sequence.

S-Aryl dibenzothiophenium salts, obtained through a highly regioselective C-H sulfenylation of o-benzyl-protected phenols, are used as precursors of 6H-benzo[c]chromenes. The reaction starts with a photocatalytically triggered single-electron transfer to the sulfonium salt, which promotes the formation of an aryl radical via selective mesolitic cleavage of the S-Arexo bond. Mechanistic studies reveal that this initial radical species cyclizes following a kinetically favored 5-exo-trig pathway. Subsequent ring expansion, favored by rearomatization, delivers the desired tricyclic systems.

5-(Diarylimino)- and 5-(sulfoximido)dibenzothiophenium triflates: syntheses and applications as electrophilic aminating reagents.

The one-pot synthesis of well-defined 5-(diarylimino) and 5-(sulfoximido)dibenzothiophenium triflates, respectively from diarylimines or sulfoximines, is reported and the structures of a series of these compounds are elucidated by X-ray crystallography. In analogy to their hypervalent I(iii) analogues, the iminoyl and sulfoximidoyl groups of these compounds can be selectively transferred to organic substrates. Specifically, the uncatalyzed imination of thiols or sulfinates proceeds with good yields, while under the mild reaction conditions offered by visible light photoredox catalysis, the radical amination of hydrazones or the sulfoximidation of benzylic, allylic and propargylic C-H bonds takes place satisfactorily.

New Haloterpenes from the Marine Red Alga Laurencia papillosa: Structure Elucidation and Biological Activity.

Analysis of the air-dried marine red alga Laurencia papillosa, collected near Ras-Bakr at the Suez gulf (Red Sea) in Egypt delivered five new halogenated terpene derivatives: aplysiolic acid (1), 7-acetyl-aplysiol (2), aplysiol-7-one (3), 11,14-dihydroaplysia-5,11,14,15-tetrol (5a), and a new maneonene derivative 6, named 5-epi-maneolactone. The chemical structures of these metabolites were characterized employing spectroscopic methods, and the relative and absolute configurations were determined by comparison of experimental and ab initio-calculated NMR, NOE, ECD, and ORD data, and by X-ray diffraction of 2 and 6. The antimicrobial activities of the crude extract and compounds 1-3, 5a and 6 were studied.

α-Diazo Sulfonium Triflates: Synthesis, Structure, and Application to the Synthesis of 1-(Dialkylamino)-1,2,3-triazoles.

The one-pot synthesis of a series of sulfonium salts containing transferable diazomethyl groups is described, and the structure of these compounds is elucidated by X-ray crystallography. Under photochemical conditions, reaction of these salts with N,N-dialkyl hydrazones affords 1-(dialkylamino)-1,2,3-triazoles via diazomethyl radical addition to the azomethine carbon followed by intramolecular ring closure. The straightforward transformation of the structures thus obtained into mesoionic carbene-metal complexes is also reported and the donor properties of these new ligands characterized.