Padlocking dihydrofurannulation for the control of small degree of helicity built on a fused-tetracyclic core.

Enantioselective construction of small molecules displaying a configurationally stable helical shape built on a fused-tetracyclic core is a daunting synthetic challenge even more pronounced when five-membered rings are incorporated in the structure. The resulting higher configurational lability strongly hampers their access, and therefore the development of new efficient methodologies is timely and highly desirable. In this context, we describe a padlocking approach via the enantioselective organocatalytic domino furannulation of appropriately designed achiral fused-tricyclic precursors resulting in the synthesis of configurationally locked helically chiral tetracyclic scaffolds featuring one or two five-membered rings with the simultaneous control of central and helical chiralities.

Correction to "Diving into the Molecular Diversity of Aplysina cavernicola's Exometabolites: Contribution of Bromo-Spiroisoxazoline Alkaloids".

[This corrects the article DOI: 10.1021/acsomega.2c05415.].

Conformational, Structural, and Chiroptical Properties of an Overcrowded Triply Fused Carbo[7]helicene.

Recently, the synthesis of the racemate of an overcrowded triply fused carbo[7]helicene of formula C66H36 with three carbo[7]helicenes fused within a central six-membered ring was described. This molecule was found to embed an extremely contorted central six-membered ring and two negative curvatures. We report herein the resolution of the corresponding enantiomers and their conformational, structural, photophysical, and chiroptical properties. The racemization of the triply fused carbo[7]helicene was determined to proceed at a rate of krac = 8.06 × 10-4 s-1 at 175 °C in ortho-dichlorobenzene, corresponding to a barrier to enantiomerization ΔGenant‡ = 140.4 kJ·mol-1, a value significantly lower than for pristine carbo[7]helicene. Interestingly, the crystalline structures of the racemic and enantiopure materials show some differences regarding the molecular geometry, with an increased negative curvature in the latter cases. This unusual curved delocalized π-conjugated system afforded notably green fluorescence at room temperature and far-red phosphorescence at low temperature. Finally, electronic circular dichroism and circularly polarized luminescence responses of the enantiopure compounds have been measured and showed very close absorption and emission dissymmetry factors, gabs and glum, respectively, of ca. 2.6 × 10-3, indicating a similar chiral rigid geometry for both ground and excited states.

Asymmetric Allenylation of Alkynes mediated by Chiral Organoselenated Reagents under Oxidative Conditions.

The reactivity of novel chiral lactamide-substituted diselenide-based reagents under oxidative conditions was exploited to develop a metal-free method for the preparation of enantioenriched allenylamides from simple alkynes in good yields, and with enantiomeric excesses up to 99 %. The key of the success in this method is attributed to the hydrogen-bonded lactamide appendages that ensure configurational stability of chiral vinyl selenoxide intermediates for an optimal enantiotopic ß-syn-elimination step.

Cytotoxic Metabolites from Calophyllum tacamahaca Willd.: Isolation and Detection through Feature-Based Molecular Networking.

Isocaloteysmannic acid (1), a new chromanone, was isolated from the leaf extract of the medicinal species Calophyllum tacamahaca Willd. along with 13 known metabolites belonging to the families of biflavonoids (2), xanthones (3-5, 10), coumarins (6-8) and triterpenes (9, 11-14). The structure of the new compound was characterized based on nuclear magnetic resonance (NMR), high-resolution electrospray mass spectrometry (HRESIMS), ultraviolet (UV) and infrared (IR) data. Its absolute configuration was assigned through electronic circular dichroism (ECD) measurements. Compound (1) showed a moderate cytotoxicity against HepG2 and HT29 cell lines, with IC50 values of 19.65 and 25.68 µg/mL, respectively, according to the Red Dye method. Compounds 7, 8 and 10-13 exhibited a potent cytotoxic activity, with IC50 values ranging from 2.44 to 15.38 µg/mL, against one or both cell lines. A feature-based molecular networking (FBMN) approach led to the detection of a large amount of xanthones in the leaves extract, and particularly analogues of the cytotoxic isolated xanthone pyranojacareubin (10).

Diving into the Molecular Diversity of Aplysina cavernicola's Exometabolites: Contribution of Bromo-Spiroisoxazoline Alkaloids.

Sponges are prolific producers of specialized metabolites with unique structural scaffolds. Their chemical diversity has always inspired natural product chemists working in drug discovery. As part of their metabolic filter-feeding activities, sponges are known to release molecules, possibly including their specialized metabolites. These released "Exo-Metabolites" (EMs) may be considered as new chemical reservoirs that could be collected from the water column while preserving marine biodiversity. The present work aims to determine the proportion and diversity of specialized EMs released by the sponge Aplysina cavernicola (Vacelet 1959). This Mediterranean sponge produces bromo-spiroisoxazoline alkaloids that are widely distributed in the Aplysinidae family. Aquarium experiments were designed to facilitate a continuous concentration of dissolved and diluted metabolites from the seawater around the sponges. Mass Spectrometry (MS)-based metabolomics combined with a dereplication pipeline were performed to investigate the proportion and identity of brominated alkaloids released as EMs. Chemometric analysis revealed that brominated features represented 12% of the total sponge's EM features. Consequently, a total of 13 bromotyrosine alkaloids were reproducibly detected as EMs. The most abundant ones were aerothionin, purealidin L, aerophobin 1, and a new structural congener, herein named aplysine 1. Their structural identity was confirmed by NMR analyses following their isolation. MS-based quantification indicated that these major brominated EMs represented up to 1.0 ± 0.3% w/w of the concentrated seawater extract. This analytical workflow and collected results will serve as a stepping stone to characterize the composition of A. cavernicola's EMs and those released by other sponges through in situ experiments, leading to further evaluate the biological properties of such EMs.

Catalytic Reversible (De)hydrogenation To Rotate a Chemically Fueled Molecular Switch.

We report here the development of a rotating molecular switch based on metal-catalyzed reversible (de)-hydrogenation. Under an argon atmosphere, acceptorless dehydrogenation induces a switch from an alcohol to a ketone, while reversing to a hydrogen pressure switches back the system to the alcohol. Based on a tolane scaffold, such reversible (de)-hydrogenation enables 180° rotation. The absence of waste accumulation in a switch relying on chemical stimuli is of great significance and could potentially be applied to the design of efficient complex molecular machines.

Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1'-bi-2,2'-naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two-step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9'-bianthracenyl-based atropisomers could be prepared enantiospecifically in high enantiomeric purity. Alternatively, bidirectional reactions with anthracene, 2-bromostyrene, and perylene as the arynophiles afforded very congested bis(benzotriptycene), bis(tetraphene) and bis(anthra[1,2,3,4-ghi]perylene) nanocarbon atropisomers in equally high enantiomeric purity. In complement, cross reactions with two different arynophiles revealed possible. The unusual atropisomer prototypes described in this study open the way to enantiopure nanographene atropisomers designed for functions.

Smart IM-MS and NMR study of natural diastereomers: the study case of the essential oil from Senecio transiens.

Unambiguous identification of the components of a natural mixture remains a challenging and meticulous issue. Usually, different analytical techniques and laborious separation protocols are employed; nevertheless, in some cases, delicate and equivocal problems are hardly addressed by traditional methods. In this context, an original methodology for the analysis of natural samples consisting of recent mass spectrometry methods based on ion mobility (MS-IM) is proposed. As an example, a polar fraction obtained by the essential oil prepared from Senecio transiens, an endemic plant harvested on the Corsica Island, was selected for this study to show how IM-MS-based methods easily provide very useful insights suggesting the presence of two diastereomers. To unambiguously confirm this hypothesis and verify reliability of the IM-MS results, the purified compounds were further analysed by means of nuclear magnetic resonance (NMR) methodologies, allowing the structural elucidation and the identification of two new natural compounds, diastereomers of 4-acetoxy-5,9-dimethyl-3-(2-methylpropenyl)-2-oxabicyclo[4.4.0] dec-9-ene, reported here for the first time.

Dissipative Acid-Fueled Reprogrammable Supramolecular Materials.

Smart materials reversibly changing properties in response to a stimuli are promising for a broad array of applications. In this article, we report the use of trichloroacetic acid (TCA) as fuel to create new types of time-controlled materials switching reversibly from a gel to a solution (gel-sol-gel cycle). Applying various neutral amines as organogelators, TCA addition induces amine protonation, switching the system to a solution, while TCA decarboxylation over time enables a return to the initial gel state. Consequently, the newly obtained materials possess interesting time-dependent properties applied in the generation of remoldable objects, as an erasing ink, as chiroptical switches, or for the generation of new types of electrical systems.

Racemization mechanism of lithium tert-butylphenylphosphido-borane: A kinetic insight.

The racemization mechanism of tert-butylphenylphosphido-borane is investigated experimentally and theoretically. Based on this converging approach, it is shown, first, that several phosphido-borane molecular species coexist at the time of the reaction and, second, that one particular of both initially assumed reactive routes most significantly contribute to the overall racemization process. From our converging modeling and experimental measurement, it comes out that the most probable species to be here encountered is a phosphido-borane-Li (THF)2 neutral solvate, whose P-stereogenic center monomolecular inversion through a Y-shaped transition structure (Δr G°≠ : 81 kJ mol-1 ) brings the largest contribution to the racemization process.

Fast interaction dynamics of G-quadruplex and RGG-rich peptides unveiled in zero-mode waveguides.

G-quadruplexes (GQs), a non-canonical form of DNA, are receiving a huge interest as target sites for potential applications in antiviral and anticancer drug treatments. The biological functions of GQs can be controlled by specifically binding proteins known as GQs binding proteins. Some of the GQs binding proteins contain an arginine and glycine-rich sequence known as RGG peptide. Despite the important role of RGG, the GQs-RGG interaction remains poorly understood. By single molecule measurements, the interaction dynamics can be determined in principle. However, the RGG-GQs interaction occurs at micromolar concentrations, making conventional single-molecule experiments impossible with a diffraction-limited confocal microscope. Here, we use a 120 nm zero-mode waveguide (ZMW) nanoaperture to overcome the diffraction limit. The combination of dual-color fluorescence cross-correlation spectroscopy (FCCS) with FRET is used to unveil the interaction dynamics and measure the association and dissociation rates. Our data show that the RGG-GQs interaction is predominantly driven by electrostatics but that a specific affinity between the RGG sequence and the GQs structure is preserved. The single molecule approach at micromolar concentration is the key to improve our understanding of GQs function and develop its therapeutic applications by screening a large library of GQs-targeting peptides and proteins.

Breaking Symmetry Relaxes Structural and Magnetic Restraints, Suppressing QTM in Enantiopure Butterfly Fe2 Dy2 SMMs*.

The {Fe2 Dy2 } butterfly systems can show single molecule magnet (SMM) behaviour, the nature of which depends on details of the electronic structure, as previously demonstrated for the [Fe2 Dy2 (µ3 -OH)2 (Me-teaH)2 (O2 CPh)6 ] compound, where the [N,N-bis-(2-hydroxyethyl)-amino]-2-propanol (Me-teaH3 ) ligand is usually used in its racemic form. Here, we describe the consequences for the SMM properties by using enantiopure versions of this ligand and present the first homochiral 3d/4 f SMM, which could only be obtained for the S enantiomer of the ligand for [Fe2 Dy2 (µ3 -OH)2 (Me-teaH)2 (O2 CPh)6 ] since the R enantiomer underwent significant racemisation. To investigate this further, we prepared the [Fe2 Dy2 (µ3 -OH)2 (Me-teaH)2 (O2 CPh)4 (NO3 )2 ] version, which could be obtained as the RS-, R- and S-compounds. Remarkably, the enantiopure versions show enhanced slow relaxation of magnetisation. The use of the enantiomerically pure ligand suppresses QTM, leading to the conclusion that use of enantiopure ligands is a "gamechanger" by breaking the cluster symmetry and altering the intimate details of the coordination cluster's molecular structure.

Chemically Fueled Three-State Chiroptical Switching Supramolecular Gel with Temporal Control.

The recent discovery of temporally controlled gels opens broad perspectives to the field of smart functional materials. However, to obtain fully operative systems, the design of simple and robust gels displaying complex functions is desirable. Herein, we fuel dissipative gelating materials through iterative additions of trichloroacetic acid (TCA). This simple fuel enables to switch over time an acid/base-dependent commercially available amino acid gelator/DBU combination between three distinct states (anionic, cationic, and neutral), while liberating volatile CO2 and CHCl3 upon fuel consumption. Of interest, the anionic resting state of the system is obtained through trapping of 1 equiv of CO2 through the formation of a carbamate. The system is tunable, robust, and resilient over time with over 25 consecutive sol-gel-sol cycles possible without significant loss of properties. Most importantly, because of the chiral nature of the amino acid gelator, the system features chiroptical switching properties moving reversibly between three distinct states as observed by ECD. The described system considerably enhances the potential of smart molecular devices for logic gates or data storage by adding a time dimension based on three states to the gelating materials. It is particularly simple in terms of chemical components involved, but it enables sophisticated functions.

Allosteric Guest Binding in Chiral Zirconium(IV) Double Decker Porphyrin Cages.

Chiral zirconium(IV) double cage sandwich complex Zr(1)2 has been synthesized in one step from porphyrin cage H21. Zr(1)2 was obtained as a racemate, which was resolved by HPLC and the enantiomers were isolated in >99.5 % ee. Their absolute configurations were assigned on the basis of X-ray crystallography and circular dichroism spectroscopy. Vibrational circular dichroism (VCD) experiments on the enantiomers of Zr(1)2 revealed that the chirality around the zirconium center is propagated throughout the whole cage structure. The axial conformational chirality of the double cage complex displayed a VCD fingerprint similar to the one observed previously for a related chiral cage compound with planar and point chirality. Zr(1)2 shows fluorescence, which is quenched when viologen guests bind in its cavities. The binding of viologen and dihydroxybenzene derivatives in the two cavities of Zr(1)2 occurs with negative allostery, the cooperativity factors α (=4 K2/K1) being as low as 0.0076 for the binding of N,N'-dimethylviologen. These allosteric effects are attributed to a pinching of the second cavity as a result of guest binding in the first cavity.

Synthesis of Protected 3,4- and 2,3-Dimercaptophenylalanines as Building Blocks for Fmoc-Peptide Synthesis and Incorporation of the 3,4-Analogue in a Decapeptide Using Solid-Phase Synthesis.

3,4-Dimercaptophenylalanines and 2,3-dimercaptophenylalanines have been synthesized for the first time by nucleophilic substitution of a protected aminomalonate on 3,4- and 2,3-dimercaptobenzyl bromide derivatives. The dithiol functions were protected as thioketals, and the key precursors, diphenylthioketal-protected dimercaptobenzyl bromides, were synthesized via two distinct routes from either dihydroxy benzoates or toluene-3,4-dithiol. Racemic mixtures of the fully protected amino acids were separated by chiral HPLC into the corresponding enantiomers. The absolute configuration of both 3,4- and 2,3-analogues could be assigned based on X-ray crystallography and VCD/DFT measurements. Thioketal groups were deprotected upon reaction with mercury oxide and aqueous tetrafluoroboric acid followed by treatment with H2S gas under an argon atmosphere to obtain the corresponding dimercapto amino acids. The optically pure l-Fmoc-protected 3,4-analogue (S- enantiomer) was successfully incorporated into a decapeptide using standard solid-phase peptide synthesis. Therefore, dithiolene-functionalized peptides are now accessible from a simple synthetic procedure, and this should afford new molecular tools for research into the catalysis, diagnostic, and nanotechnology fields.

Absolute configuration and host-guest binding of chiral porphyrin-cages by a combined chiroptical and theoretical approach.

Porphyrin cage-compounds are used as biomimetic models and substrate-selective catalysts in supramolecular chemistry. In this work we present the resolution of planar-chiral porphyrin cages and the determination of their absolute configuration by vibrational circular dichroism in combination with density functional theory calculations. The chiral porphyrin-cages form complexes with achiral and chiral viologen-guests and upon binding one of the axial enantiomorphs of the guest is bound selectively, as is indicated by induced-electronic-dichroism-spectra in combination with calculations. This host-guest binding also leads to unusual enhanced vibrational circular dichroism, which is the result of a combination of phenomena, such as rigidification of the host and guest structures, charge transfer, and coupling of specific vibration modes of the host and guest. The results offer insights in how the porphyrin cage-compounds may be used to construct a future molecular Turing machine that can write chiral information onto polymer chains.

Simultaneous Control of Central and Helical Chiralities: Expedient Helicoselective Synthesis of Dioxa[6]helicenes.

An expedient synthesis of a new family of configurationally stable dioxa[6]helicenes was established using a sequential helicoselective organocatalyzed heteroannulation/eliminative aromatization via enantioenriched fused 2-nitro dihydrofurans featuring both central and helical chiralities. Starting from simple achiral precursors, a broad range of these previously unknown chiral heterocyclic scaffolds were obtained with good efficiency, and their aromatization proceeded with very high enantiopurity retention in most cases.

Stereoselective Syntheses, Structures, and Properties of Extremely Distorted Chiral Nanographenes Embedding Hextuple Helicenes.

We report a molecular design and concept using π-system elongation and steric effects from helicenes surrounding a triphenylene core toward stable chiral polycyclic aromatic hydrocarbons (PAHs) with a maximal π-distortion to tackle their aromaticity, supramolecular and molecular properties. The selective syntheses, and the structural, conformational and chiroptical properties of two diastereomeric large multi-helicenes of formula C90 H48 having a triphenylene core and embedding three [5]helicene units on their inner edges and three [7]helicene units at their periphery are reported based on diastereoselective and, when applicable, enantiospecific Yamamoto-type cyclotrimerizations of racemic or enantiopure 9,10-dibromo[7]helicene. Both molecules have an extremely distorted triphenylene core, and one of them exhibits the largest torsion angle recorded so far for a benzene ring (twist=36.9°).

Strategic Stereoselective Halogen (F, Cl) Insertion: A Tool to Enhance Supramolecular Properties in Polyols.

To improve the supramolecular properties of organic compounds, chemists continuously need to identify new tools. Herein, the influence of the stereoselective insertion of halogen atoms (F or Cl) on different supramolecular properties is analyzed. Inserting anti-halohydrins in polyols considerably strengthens the H-bonding networks and other supramolecular interactions. This behavior resulted in improved anion binding, H-bonding catalysis, or organogel properties of the designed polyols with strong perspectives for applications in other classes of substrates.