Atroposelective Arene-Forming Wittig Reaction by Phosphorus PIII/PV=O Redox Catalysis.

The Wittig reaction is renowned as exceptionally versatile method for converting a diversity of aldehydes and ketones into alkenes. Recently, strategies for chiral phosphine catalysis under PIII/PV=O redox cycling emerged to render this venerable transformation stereoselective. Herein, we describe that phosphine redox catalysis enables the enantioselective synthesis of pertinent biaryl atropisomers by means of a stereocontrolled arene-forming Wittig reaction. Key to the process is the release of an endogenous base from readily accessible tert-butyloxycarbonylated Morita-Baylis-Hillman adducts triggered by catalyst intramolecularization, permitting mild phosphine redox catalysis for atroposelective Wittig reactions. By this strategy, a broad diversity of biaryl atropisomers is obtained with up to 94:6 enantioselectivity.

Atroposelective catalysis.

Atropisomeric compounds-stereoisomers that arise from the restricted rotation about a single bond-have attracted widespread attention in recent years due to their immense potential for applications in a variety of fields, including medicinal chemistry, catalysis and molecular nanoscience. This increased interest led to the invention of new molecular motors, the incorporation of atropisomers into drug discovery programmes and a wide range of novel atroposelective reactions, including those that simultaneously control multiple stereogenic axes. A diverse set of synthetic methodologies, which can be grouped into desymmetrizations, (dynamic) kinetic resolutions, cross-coupling reactions and de novo ring formations, is available for the catalyst-controlled stereoselective synthesis of various atropisomer classes. In this Review, we generalize the concepts for the catalyst-controlled stereoselective synthesis of atropisomers within these categories with an emphasis on recent advancements and underdeveloped atropisomeric scaffolds beyond stereogenic C(sp2)-C(sp2) axes. We also discuss more complex systems with multiple stereogenic axes or higher-order stereogenicity.

Decarboxylative Nickel- and Photoredox-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides.

An efficient methodology for the photoredox- and nickel-catalyzed aminocarbonylation of (hetero)aryl bromides was developed. The utilization of readily available oxamic acids, the application of a broadly used organic photoredox catalyst (4CzIPN), and mild reaction conditions make this transformation an appealing alternative to classical amidation procedures. The generation of carbamoyl radicals was supported by trapping reactions with a hydrogen atom transfer catalyst in the presence of D2O, yielding the deuterated formamide. The generality of this deuteration protocol was confirmed for various oxamic acids.

Catalyst control over pentavalent stereocentres.

A monumental diversity of catalytic methods imparts the ability to select one of two configurations of tetravalent stereocentres. Conversely, catalyst control over pentavalent stereocentres, where a fifth moiety bound to the central atom encodes an expanded stereochemical space, remained a challenge to be accomplished. Herein, we report the feasibility of the catalytic tractability of pentavalent stereocentres. A bifunctional iminophosphorane thiourea catalyst enables enantio- and diastereocontrol over pentavalent phosphoranes to differentiate configurationally stable enantiomers and ensembles of diastereomers which emerge together from a single stereocentre. The desired dioxophosphorane stereoisomers are obtained with excellent yield and selectivity (up to 99% yield, 96:4 e.r. and 99:1 d.r.), while stereodivergent catalysis reroutes the reaction for selective access to each of the viable stereoisomeric states of pentavalent phosphoranes. Considering the diversity of high-valent main group species, it is expected that catalyst control over pentavalent stereocentres significantly increases the synthetically addressable stereochemical space.

Isoacridone dyes with parallel reactivity from both singlet and triplet excited states for biphotonic catalysis and upconversion.

Metal-based photosensitizers commonly undergo quantitative intersystem crossing into photoactive triplet excited states. In contrast, organic photosensitizers often feature weak spin-orbit coupling and low intersystem crossing efficiencies, leading to photoactive singlet excited states. By modifying the well-known acridinium dyes, we obtained a new family of organic photocatalysts, the isoacridones, in which both singlet- and triplet-excited states are simultaneously photoactive. These new isoacridone dyes are synthetically readily accessible and show intersystem crossing efficiencies of up to 52%, forming microsecond-lived triplet excited states (T1), storing approximately 1.9 eV of energy. Their photoactive singlet excited states (S1) populated in parallel have only nanosecond lifetimes, but store ∼0.4 eV more energy and act as strong oxidants. Consequently, the new isoacridone dyes are well suited for applications requiring parallel triplet-triplet energy transfer and photoinduced electron transfer elementary steps, which have become increasingly important in modern photocatalysis. In proof-of-principle experiments, the isoacridone dyes were employed for Birch-type arene reductions and C-C couplings via sensitization-initiated electron transfer, substituting the commonly used iridium or ruthenium based photocatalysts. Further, in combination with a pyrene-based annihilator, sensitized triplet-triplet annihilation upconversion was achieved in an all-organic system, where the upconversion quantum yield correlated with the intersystem crossing quantum yield of the photosensitizer. This work seems relevant in the greater contexts of developing new applications that utilize biphotonic photophysical and photochemical behavior within metal-free systems.

Diastereodivergent Catalysis.

Alongside enantioselective catalysis, synthetic chemists are often confronted by the challenge of achieving catalyst control over the relative configuration to stereodivergently access desired diastereomers. Typically, these approaches iteratively or simultaneously control multiple stereogenic units for which dual catalytic methods comprising sequential, relay, and synergistic catalysis emerged as particularly efficient strategies. In this Perspective, the benefits and challenges of catalyst-controlled diastereodivergence in the construction of carbon stereocenters are discussed on the basis of illustrative examples. The concepts are then transferred to diastereodivergent catalysis for atropisomeric systems with twofold and higher-order stereogenicity as well as diastereodivergent catalyst control over E- and Z-configured alkenes.

Atroposelective PIII /PV =O Redox Catalysis for the Isoquinoline-Forming Staudinger-aza-Wittig Reaction.

Herein, we describe the feasibility of atroposelective PIII /PV =O redox organocatalysis by the Staudinger-aza-Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co-catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N-oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration.

Catalyst Control over Threefold Stereogenicity: Selective Synthesis of Atropisomeric Sulfones with Stereogenic C-S Axes.

Catalyst control over higher-order stereogenicity addresses significantly extended stereochemical space, but selective methods to govern threefold stereogenic units remained elusive. Herein, we report the stereoselective synthesis of threefold stereogenic triptycyl sulfones with atropisomerism arising from a C(sp3 )-S bond. An oxidation of a stereodynamic thioether controlled by a chiral phosphoric acid catalyst allowed selective access to enantioenriched triptycyl sulfoxides. The ensuing enantiospecific and diastereoselective catalytic oxidation to a threefold stereogenic sulfone provided overall control over the stereogenic C-S axis. All three stereoisomers were addressable with enantio- and diastereodivergence and a stereoselectivity of up to (-sc): (+sc) : (ap)=94 : 6 :<1.

o-Quinodimethane Atropisomers: Enantioselective Synthesis and Stereospecific Transformation.

o-Quinodimethanes have remarkable utility as reactive intermediates in Diels-Alder reactions, enabling significantly accelerated routes to complex polycyclic compounds. The discovery of different discrete precursors to thermally generate o-quinodimethanes thereby greatly augmented their availability and versatility. However, due to the required high temperatures and the immense reactivity of o-quinodimethanes, stereoselectivity to afford isomerically defined products still constitutes a critical challenge. Herein, we describe the accessibility of atropisomeric o-quinodimethanes, the enantioselective synthesis of their precursors, their remarkable configurational stability and the stereospecific transformation by the benzannulation of dienophiles. A catalyst-stereocontrolled [2+2+2] cycloaddition, the generation of o-quinodimethane atropisomers and ensuing stereospecific Diels-Alder reactions enabled enantioselectivities through these transient intermediates with of up to 96 : 4 e.r.

Atroposelective Arene-Forming Alkene Metathesis.

Alkene metathesis catalyzed by enantiopure metal alkylidene complexes enables exceptionally versatile strategies to products with configurationally-defined stereocenters. Desymmetrization processes thereby provide reliable stereoselective routes to aliphatic structures, while the differentiation of aromatic stereogenic units remained an outstanding challenge. Herein, we describe the feasibility of alkene metathesis to catalytically control stereogenic axes by traceless arene formation. Stereodynamic trienes are selectively converted into corresponding binaphthalene atropisomers upon exposure to a chiral molybdenum catalyst. Remarkably, stereoselective arene-forming metathesis allows enantioselectivities of up to 98 : 2 e.r. and excellent yields. As the disconnection of each bond of an aromatic target is retrosynthetically conceivable, it is anticipated that forging arenes by means of stereoselective metathesis will enable versatile approaches for the synthesis of a broad range of molecular topologies with precisely defined configuration.

Photocatalytic deracemisation of cobalt(III) complexes with fourfold stereogenicity.

The deracemisation of fourfold stereogenic cobalt(III) diketonates with a chiral photocatalyst is described. With only 0.5 mol% menthyl Ru(bpy)32+ photocatalyst, an enantiomeric enrichment of up to 88 : 12 e.r. was obtained for the major meridional diastereomers. Moreover, a distribution of configurationally stable diastereomers distinct from the thermodynamic ratio was observed upon reaching the photostationary state.

Synthesis of Atropisomeric Two-Axis Systems by the Catalyst-Controlled syn- and anti-Selective Arene-Forming Aldol Condensation.

Simultaneous control over the configuration of multiple stereocenters is accomplished by numerous catalytic methods, providing a reliable basis for the synthesis of stereochemically complex targets in isomerically defined form. In contrast, addressing the configurations of multiple stereogenic axes with diastereodivergent catalyst control is thus far only possible by stepwise approaches. Herein we now describe that all four stereoisomers of atropisomeric two-axis systems are directly tractable by assembling a central aromatic unit of teraryls through an arene-forming aldol condensation. By using cinchona alkaloid-based ion-pairing catalysts, the four feasible reaction pathways are differentiated from identical substrates under defined basic conditions without preactivation, thus enabling complete stereodivergence with enantioselectivities of up to 99 : 1 e.r.

Stereoselective Synthesis of Atropisomeric Acridinium Salts by the Catalyst-Controlled Cyclization of ortho-Quinone Methide Iminiums.

Quinone methides are fundamental intermediates for a wide range of reactions in which catalyst stereocontrol is often achieved by hydrogen bonding. Herein, we describe the feasibility of an intramolecular Friedel-Crafts 6π electrocyclization through ortho-quinone methide iminiums stereocontrolled by a contact ion pair. A disulfonimide catalyst activates racemic trichloroacetimidate substrates and imparts stereocontrol in the cyclization step, providing a new avenue for selective ortho-quinone methide iminium functionalization. A highly stereospecific oxidation readily transforms the enantioenriched acridanes into rotationally restricted acridiniums. Upon ion exchange, the method selectively affords atropisomeric acridinium tetrafluoroborate salts in high yields and an enantioenrichment of up to 93 : 7 e.r. We envision that ion-pairing catalysis over ortho-quinone methide iminiums enables the selective synthesis of a diversity of heterocycles and aniline derivatives with distinct stereogenic units.

Catalyst-Controlled Stereoselective Barton-Kellogg Olefination.

Overcrowded alkenes are expeditiously prepared by the versatile Barton-Kellogg olefination and have remarkable applications as functional molecules owing to their unique stereochemical features. The induced stereodynamics thereby enable the controlled motion of molecular switches and motors, while the high configurational stability prevents undesired isomeric scrambling. Bistricyclic aromatic enes are prototypical overcrowded alkenes with outstanding stereochemical properties, but their stereocontrolled preparation was thus far only feasible in stereospecific reactions and with chiral auxiliaries. Herein we report that direct catalyst control is achieved by a stereoselective Barton-Kellogg olefination with enantio- and diastereocontrol for various bistricyclic aromatic enes. Using Rh2 (S-PTAD)4 as catalyst, several diazo compounds were selectively coupled with a thioketone to give one of the four anti-folded overcrowded alkene stereoisomers upon reduction. Complete stereodivergence was reached by catalyst control in combination with distinct thiirane reductions to provide all four stereoisomers with e.r. values of up to 99:1. We envision that this strategy will enable the synthesis of topologically unique overcrowded alkenes for functional materials, catalysis, energy- and electron transfer, and bioactive compounds.

Aldehyde-catalyzed epoxidation of unactivated alkenes with aqueous hydrogen peroxide.

The organocatalytic epoxidation of unactivated alkenes using aqueous hydrogen peroxide provides various indispensable products and intermediates in a sustainable manner. While formyl functionalities typically undergo irreversible oxidations when activating an oxidant, an atropisomeric two-axis aldehyde capable of catalytic turnover was identified for high-yielding epoxidations of cyclic and acyclic alkenes. The relative configuration of the stereogenic axes of the catalyst and the resulting proximity of the aldehyde and backbone residues resulted in high catalytic efficiencies. Mechanistic studies support a non-radical alkene oxidation by an aldehyde-derived dioxirane intermediate generated from hydrogen peroxide through the Payne and Criegee intermediates.

Ad Hoc Adjustment of Photoredox Properties by the Late-Stage Diversification of Acridinium Photocatalysts.

The steadily growing interest in substituting precious-metal photoredox catalysts with organic surrogates is vibrantly sustained by emerging methodologies to vary their photochemical behavior. Herein, we report an ad hoc approach for the preparation of acridinium salts with a particularly broad range of photoredox properties. The method involves an aryne-imine-aryne coupling to a linchpin tetrafluoro acridinium salt for a late-stage diversification by nucleophilic aromatic substitution reactions to form diaminoacridinium and undescribed aza-rhodol photocatalysts. The different functionalities and redox properties of the organic acridinium photocatalysts render them suitable for bifunctional photoredox catalysis and organocatalytic photochemical C-N cross-couplings.

Catalyst Control over Twofold and Higher-Order Stereogenicity by Atroposelective Arene Formation.

Contradictory to the first intuitive impression that forging putatively flat aromatic rings evades stereoisomerism, a striking variety of atropisomeric compounds are conceivable by the formation of arenes, offering captivating avenues for catalyst-controlled stereoselective strategies. Since the assembled atropisomeric products that contain one or several rotationally restricted single bonds are characterized by especially well defined molecular architectures, they are distinctly suitable for numerous pertinent applications. In view of the fascinating arene-forming aldol condensation pathways taking place in polyketide biosynthesis (cyclases/aromatases (CYC/ARO)), the versatile small-molecule-catalyzed aldol reaction appeared as an exceptionally appealing synthetic means to prepare various unexplored atropisomeric compounds in our efforts presented herein. In our initial studies, the use of secondary amine organocatalysts provided excellent selectivities in stereoselective arene-forming aldol condensations for a broad range of atropisomeric products, such as biaryls and rotationally restricted aromatic amides. In further analogy to polyketide biosynthesis, it was also conceivable that several aromatic rings are formed in catalytic cascade reactions. The use of small-molecule catalysts thereby enabled us to transfer this concept to the conversion of unnatural and noncanonical polyketide substrates, thus giving access to atropisomers with particular value for synthetic applications. The versatility of the stereoselective aldol reactions with numerous catalytic activation modes further provided a strategy to individually control several stereogenic axes, similar to the various methodologies developed for controlling stereocenter configurations. By the use of iterative building block additions combined with catalyst-controlled aldol reactions to form the aromatic rings, stereodivergent pathways for catalyst-substrate-matched and -mismatched products were obtained. Besides secondary amines, cinchona-alkaloid-based quaternary ammonium salts also proved to be highly efficient in overcoming severe substrate bias. The obtained atropisomeric multiaxis systems, with all of the biaryl bonds suitably restricted in rotation even at high temperatures, are spatially distinctly defined. The helical secondary structure is therefore excellently suited for several captivating applications.While previous catalyst-controlled stereoselective methods distinguish two stereoisomers for each stereogenic unit, catalyst control beyond the realms of this dualistic stereoisomerism remained unexplored. By the selective preparation of O̅ki atropisomers characterized by their sixfold stereogenicity in Rh-catalyzed [2 + 2 + 2] cyclotrimerizations, one out of the six possible stereoisomers resulting from the restricted rotation of a single bond was shown to be catalytically addressable. Catalyst control over higher-order stereogenicity therefore further interconnects conformational analysis and stereoselective catalysis and offers captivating avenues to explore uncharted stereochemical space for creating a broad range of unprecedented molecular motifs.

Monitoring Solid-Phase Reactions in Self-Assembled Monolayers by Surface-Enhanced Raman Spectroscopy.

Nanopatterned surfaces enhance incident electromagnetic radiation and thereby enable the detection and characterization of self-assembled monolayers (SAMs), for instance in surface-enhanced Raman spectroscopy (SERS). Herein, Au nanohole arrays, developed and characterized as SERS substrates, are exemplarily used for monitoring a solid-phase deprotection and a subsequent copper(I)-catalyzed azide-alkyne cycloaddition "click" reaction, performed directly on the corresponding SAMs. The SERS substrate was found to be highly reliable in terms of signal reproducibility and chemical stability. Furthermore, the intermediates and the product of the solid-phase synthesis were identified by SERS. The spectra of the immobilized compounds showed minor differences compared to spectra of the microcrystalline solids. With its uniform SERS signals and the high chemical stability, the platform paves the way for monitoring molecular manipulations in surface functionalization applications.

Organophotocatalytic Aerobic Oxygenation of Phenols in a Visible-Light Continuous-Flow Photoreactor.

A mild photocatalytic phenol oxygenation enabled by a continuous-flow photoreactor using visible light and pressurized air is described herein. Products for wide-ranging applications, including the synthesis of vitamins, were obtained in high yields by precisely controlling principal process parameters. The reactor design permits low organophotocatalyst loadings to generate singlet oxygen. It is anticipated that the efficient aerobic phenol oxygenation to benzoquinones and p-quinols contributes to sustainable synthesis.

Catalytic Cascade Reactions Inspired by Polyketide Biosynthesis.

Aldol reactions belong to the most important methods for carbon-carbon bond formation and are also involved in one of the most astonishing biosynthetic processes: the biosynthesis of polyketides governed by an extraordinarily sophisticated enzymatic machinery. In contrast to the typical linear or convergent strategies followed in chemical synthesis, this late-stage catalysis concept allows Nature to assemble intermediates that are diversified into a broad range of scaffolds, which assume various crucial biological functions. To transfer this concept to small-molecule catalysis to access products beyond the natural systems, a stepwise approach to differentiate increasingly complex substrates was followed by investigating arene-forming polyketide cyclizations. An outline of our efforts to develop and apply these concepts are presented herein.