Rhodanine-Based Chromophores: Fast Access to Capable Photoswitches and Application in Light-Induced Apoptosis.

Molecular photoswitches are highly desirable in all chemistry-related areas of research. They provide effective outside control over geometric and electronic changes at the nanoscale using an easy to apply, waste-free stimulus. However, simple and effective access to such molecular tools is typically not granted, and elaborate syntheses and substitution schemes are needed in order to obtain efficient photoswitching properties. Here we present a series of rhodanine-based photoswitches that can be prepared in one simple synthetic step without requiring elaborate purification. Photoswitching is induced by UV and visible light in both switching directions, and thermal stabilities of the metastable states as well as quantum yields are very high. An additional benefit is the hydrogen-bonding capacity of the rhodanine fragment, which enables applications in supramolecular or medicinal chemistry. We further show that the known rhodanine-based inhibitor SMI-16a is a photoswitchable apoptosis inducer. The biological activity of SMI-16a can effectively be switched ON or OFF by reversible photoisomerization between the inactive E and the active Z isomer. Rhodanine-based photoswitches therefore represent an easy to access and highly valuable molecular toolbox for implementing light responsiveness to the breadth of functional molecular systems.

Synthesis of Waixenicin A: Exploring Strategies for Nine-Membered Ring Formation.

We present a comprehensive account on our efforts behind the recently published synthesis of waixenicin A. Our approach for constructing the dihydropyran ring relied on an Achmatowicz rearrangement. For the assembly of the nine-membered ring, four distinct strategies were investigated. Our initial attempts using radical-based addition/fragmentation reactions targeting the C7-C11 bond proved unsuitable for accessing the 6/9-bicycle. By employing anionic fragmentation conditions at the furfuryl alcohol stage, we successfully reached a 5/9-bicycle. However, subsequent ring-expansion was unsuccessful. Alternative approaches, such as Nozaki-Hiyama-Kishi or Heck reactions to connect the C6-C7 bond, also encountered difficulties, with no nine-membered ring formation observed. Our first breakthrough came from our attempts to install the C5-C6 bond via an intramolecular alkylation. Surprisingly, subsequent functional group modifications proved unexpectedly challenging, necessitating a redesign of our synthetic route. Drawing from all our investigations, we concluded that construction of the C9-C10 bond would enable efficient nine-membered ring alkylation and would facilitate the installation of the desired substitution pattern along the southern periphery. Exploration of this strategy yielded further surprises but ultimately led to the successful synthesis of waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. For the latter compound, a bioinspired one-step rearrangement to xeniafauranol A was achieved.

Azotriptycenes: Photoswitchable Molecular Brakes.

The control of molecular motions is a central topic of molecular machine research. Molecular brakes are fundamental building blocks towards such goal as they allow deliberately decelerating specific motions after an outside stimulus is applied. Here we present azotriptycenes as structural framework for light-controlled molecular brakes. The intrinsic kinetics and their changes upon azotriptycene isomerization are scrutinized comprehensively by a mixed theoretical and variable temperature NMR approach. With azotriptycenes C-N bond rotation rates can be decelerated or accelerated reversibly by up to five orders of magnitude. Rate change effects are highly localized and are strongest for the C-N bond connecting a triptycene rotor fragment to the central diazo group. The detailed mechanistic insights provide a solid basis for further conscious design and applications in the future.

An Exploration of Substituent Effects on the Photophysical Properties of Monobenzopentalenes.

Monobenzopentalenes have received moderate attention compared to dibenzopentalenes, yet their accessibility as stable, non-symmetric structures with diverse substituents could be interesting for materials applications, including molecular photonics. Recently, monobenzopentalene was considered computationally as a potential chromophore for singlet fission (SF) photovoltaics. To advance this compound class towards photonics applications, the excited state energetics must be characterized, computationally and experimentally. In this report we synthesized a series of stable substituted monobenzopentalenes and provided the first experimental exploration of their photophysical properties. Structural and opto-electronic characterization revealed that all derivatives showed 1H NMR shifts in the olefinic region, bond length alternation in the pentalene unit, low-intensity absorptions reflecting the ground-state antiaromatic character and in turn the symmetry forbidden HOMO-to-LUMO transitions of ~2 eV and redox amphotericity. This was also supported by computed aromaticity indices (NICS, ACID, HOMA). Accordingly, substituents did not affect the fulfilment of the energetic criterion of SF, as the computed excited-state energy levels satisfied the required E(S1)/E(T1)>2 relationship. Further spectroscopic measurements revealed a concentration dependent quenching of the excited state and population of the S2 state on the nanosecond timescale, providing initial evidence for unusual photophysics and an alternative entry point for singlet fission with monobenzopentalenes.

Enantioselective Syntheses of 3,4-Dihydropyrans Employing Isochalcogenourea-Catalyzed Formal (4+2)-Cycloadditions of Allenoates.

We herein successfully demonstrate the use of chiral isochalcogenoureas as Lewis Base catalysts for a variety of (4+2)-cycloaddition reactions of allenoates and different Michael acceptors. In all cases the same structural key-motive, a dihydropyran with a (Z)-configurated exocyclic double bond could be accessed as the major regio- and diastereoisomer in an enantioselective manner. Furthermore, these chiral dihydropyrans were successfully engaged in different follow-up transformations.

Revisiting Hafner's Azapentalenes: The Chemistry of 1,3-Bis(dimethylamino)-2-azapentalene.

Stable azaheterocyclic derivatives of pentalene have been reported by the group of Hafner in the 1970s. However, these structures remained of low interest until recently, when they started to be investigated in the context of organic light-emitting diodes' (OLEDs') development. Herein, we revisit the synthesis of stable azapentalene derivative 1,3-bis(dimethylamino)-2-azapentalene and further explore its properties both computationally and experimentally. Beyond the reproduction and optimization of some previously reported transformations, such as formylation and amine substitution, the available scope of reactions was expanded with azo-coupling, selective halogenations, and cross-coupling reactions.

Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones.

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

Chiral Isochalcogenourea-Catalysed Enantioselective (4+2) Cycloadditions of Allenoates.

Allenoates are versatile building blocks which are primarily activated and controlled using chiral tert. phosphine and tert. amine Lewis bases. We herein report the first example of allenoate activation by using chiral isochalcogenoureas (IChU) for formal (4+2) cycloaddition reactions. Compared to established phosphine and amine catalysis, the use of these easily available Lewis bases enables new stereoselective reaction pathways proceeding with high enantioselectivities, diastereoselectivities, and in good yields. In addition, the factors governing enantioselectivity and the origin of the observed differences compared to other commonly used Lewis bases are explained.

Mechanistic Elucidation of the Hula-Twist Photoreaction in Hemithioindigo.

The Hula-Twist (HT) photoreaction represents a fundamental photochemical pathway for bond isomerizations and is defined by the coupled motion of a double bond and an adjacent single bond. This photoreaction has been suggested as the defining motion for a plethora of light-responsive chromophores such as retinal within opsins, coumaric acid within photoactive yellow protein, or vitamin D precursors, and stilbenes in solution. However, due to the fleeting character of HT photoproducts a direct experimental observation of this coupled molecular motion was severely hampered until recently. To solve this dilemma, the Dube group has designed a molecular framework able to deliver unambiguous experimental evidence of the HT photoreaction. Using sterically crowded atropisomeric hemithioindigo (HTI) the HT photoproducts are rendered thermally stable and can be observed directly after their formation. However, following the ultrafast excited state process of the HT photoreaction itself has not been achieved so far and thus crucial information for an elementary understanding is still missing. In this work, we present the first ultrafast spectroscopy study of the HT photoreaction in HTI and probe the competition between different excited state processes. Together with extensive excited state calculations a detailed mechanistic picture is developed explaining the significant solvent effects on the HT photoreaction and revealing the intricate interplay between productive isomerizations and unproductive twisted intramolecular charge transfer (TICT) processes. With this study essential insights are thus gained into the mechanism of complex multibond rotations in the excited state, which will be of primary importance for further developments in this field.

Hemithioindigo-Based Trioxobicyclononadiene: 3D Multiswitching of Electronic and Geometric Properties.

Molecular photoswitches that offer simultaneous precise control over geometrical and electronic changes are rare yet highly sought tools for the development of responsive nanosystems. Here we present such an advantageous combination of property control within a novel multiphotoswitch architecture. Hemithioindigo-based trioxobicyclononadiene (HTI-TOND) offers a rigid three-dimensional molecular structure that undergoes different exotic rearrangement reactions upon photochemical and thermal signaling. Three to four different states with distinct geometric and electronic properties can be accessed reversibly in high yields within this molecular framework. Thus, a highly promising and unique switching tool has become available to instill the next level of addressability at the smallest scales.

An Eight-State Molecular Sequential Switch Featuring a Dual Single-Bond Rotation Photoreaction.

Typical photoswitches interconvert between two different states by simple isomerization reactions, which represents a fundamental limit for applications. To expand the switching capacity usually different photoswitches have to be linked together leading to strong increase in molecular weight, diminished switching function, and less precision and selectivity of switching events. Herein we present an approach for solving this essential problem with a different photoswitching concept. A basic molecular switch architecture provides precision photoswitching between eight different states via controlled rotations around three adjacent covalent bonds. All eight states can be populated one after another in an eight-step cycle by alternating between photochemical Hula-Twist isomerizations and thermal single-bond rotations. By simply changing solvent and temperature the same switch can also undergo a different cycle instead interconverting just five isomers in a selective sequence. This behavior is enabled through the discovery of an unprecedented photoreaction, a one-photon dual single-bond rotation.

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

Quantification of the Electrophilicities of Diazoalkanes: Kinetics and Mechanism of Azo Couplings with Enamines and Sulfonium Ylides.

Kinetics and mechanism of the reactions of methyl diazoacetate, dimethyl diazomalonate, 4-nitrophenyldiazomethane, and diphenyldiazomethane with sulfonium ylides and enamines were investigated by UV-Vis and NMR spectroscopy. Ordinary alkenes undergo 1,3-dipolar cycloadditions with these diazo compounds. In contrast, sulfonium ylides and enamines attack at the terminal nitrogen of the diazo alkanes to give zwitterions, which undergo various subsequent reactions. As only one new bond is formed in the rate-determining step of these reactions, the correlation lg k2 (20 °C)=sN (N+E) could be used to determine the one-bond electrophilicities E of the diazo compounds from the measured second-order rate constants and the known reactivity indices N and sN of the sulfonium ylides and enamines. The resulting electrophilicity parameters (-21

Photoswitching of Local (Anti)Aromaticity in Biphenylene-Based Diarylethene Molecular Switches.

Photoinduced tuning of (anti)aromaticity and associated molecular properties is currently in the focus of attention for both tailoring photochemical reactivity and designing new materials. Here, we report on the synthesis and spectroscopic characterization of diarylethene-based molecular switches embedded in a biphenylene structure composed of rings with different levels of local (anti)aromaticity. We show that it is possible to modulate and control the (anti)aromatic character of each ring through reversible photoswitching of the aryl units of the system between open and closed forms. Remarkably, it is shown that the irreversible formation of an annulated bis(dihydro-thiopyran) side-product that hampers the photoswitching can be efficiently suppressed when the aryl core formed by thienyl groups in one switch is replaced by thiazolyl groups in another.

Effective chiral pool synthesis of both enantiomers of the TRPML inhibitor trans-ML-SI3.

Two independent chiral pool syntheses of both enantiomers of the TRPML inhibitor, trans-ML-SI3, were developed, starting from commercially available (1S,2R)- and (1R,2S)-configured cis-2-aminocyclohexanols. Both routes lead to the target compounds in excellent enantiomeric purity and good overall yields. For the most attractive (-)-trans-enantiomer, the R,R-configuration was identified by these unambiguous syntheses, and the results were confirmed by single-crystal X-ray structure analysis. These effective synthetic approaches further allow flexible variation of prominent residues in ML-SI3 for future in-depth analysis of structure-activity relationships as both the piperazine and the N-sulfonyl residues are introduced into the molecule at late stages of the synthesis.

An Overlooked Pathway in 1,3-Dipolar Cycloadditions of Diazoalkanes with Enamines.

Methyl diazoacetate reacts with 1-(N-pyrrolidino)cycloalkenes to give products of 1,3-dipolar cycloadditions and azo couplings. The kinetics and mechanisms of these reactions were investigated by NMR spectroscopy and DFT calculations. Orthogonal π-systems in the 1,3-dipoles of the propargyl-allenyl type allow for two separate reaction pathways for the (3+2)-cycloadditions. The commonly considered concerted pathway is rationalized by the interaction of the enamine HOMO with LUMO+1, the lowest unoccupied orbital of the heteropropargyl anion fragment of methyl diazoacetate. We show that HOMO/LUMO(π*N=N ) interactions between enamines and methyl diazoacetate open a previously unrecognized reaction path for stepwise cycloadditions through zwitterionic intermediates with barriers approximately 40 kJ mol-1 lower in energy in CHCl3 (DFT calculations) than for the concerted path.

All-Red-Light Photoswitching of Indirubin Controlled by Supramolecular Interactions.

Red-light responsiveness of photoswitches is a highly desired property for many important application areas such as biology or material sciences. The main approach to elicit this property uses strategic substitution of long-known photoswitch motives such as azobenzenes or diarylethenes. Only very few photoswitches possess inherent red-light absorption of their core chromophore structures. Here, we present a strategy to convert the long-known purple indirubin dye into a prolific red-light-responsive photoswitch. In a supramolecular approach, its photochromism can be changed from a negative to a positive one, while at the same time, significantly higher yields of the metastable E-isomer are obtained upon irradiation. E- to Z-photoisomerization can then also be induced by red light of longer wavelengths. Indirubin therefore represents a unique example of reversible photoswitching using entirely red light for both switching directions.

Steric Effects on the Thermal Processes of Hemithioindigo Based Molecular Motor Rotation.

Tuning the thermal behavior of light driven molecular motors is fundamentally important for their future rational design. In many molecular motors thermal ratcheting steps are comprised of helicity inversions, energetically stabilizing the initial photoproducts. In this work we investigated a series of five hemithioindigo (HTI) based molecular motors to reveal the influence of steric hindrance in close proximity to the rotation axle on this process. Applying a high yielding synthetic procedure, we synthesized constitutional isomeric derivatives to distinguish between substitution effects at the aromatic and aliphatic position on the rotor fragment. The kinetics of thermal helix inversions were elucidated using low temperature 1 H NMR spectroscopy and an in situ irradiation technique. In combination with a detailed theoretical description, a comparative analysis of substituent effects on the thermal helix inversions of the rotation cycle is now possible. Such deeper understanding of the rotational cycle of HTI molecular motors is essential for speed regulation and future applications of visible light triggered nanomachines.

Evolution of a Strategy for the Total Synthesis of (+)-Cornexistin.

Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4-substituted furan and on forming the nine-membered carbocycle in an intramolecular Conia-ene or Nozaki-Hiyama-Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late-stage installation of the Z-alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral-pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z-alkene, a syn-Evans-aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine-membered carbocycle, and a challenging stepwise hydrolysis of a ß-keto nitrile to furnish the maleic anhydride.

Construction and Properties of Donor-Acceptor Stenhouse Adducts on Gold Surfaces.

The construction of a donor-acceptor Stenhouse adduct molecular layer on a gold surface is presented. To avoid the incompatibility of the thiol surface-binding group with the donor-acceptor polyene structure of the switch, an interfacial reaction approach was followed. Poly(dopamine)-supported gold nanoparticles on quartz slides were chosen as substrates, which was expected to facilitate both the interfacial reaction and the switching process by providing favorable steric conditions due to the curved particle surface. The reaction between the surface-bound donor half and the CF3-isoxazolone-based acceptor half was proved to be successful by X-ray photoelectron spectroscopy (XPS). However, UV-vis measurements suggested that a closed, cyclopentenone-containing structure of the switch formed on the surface irreversibly. Analysis of the wetting behavior of the surface revealed spontaneous water spreading that could be associated with conformational changes of the closed isomer.