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.

Cyclotribenzylene alkynylgold(I) phosphine complexes: synthesis, chirality, and exchange of phosphine.

Two different alkynyl-substituted C3-symmetric cyclotribenzylenes (CTB) were synthesized in racemic and enantiomerically pure forms, and six gold(I) phosphine complexes differing by the nature of the CTB and the phosphine were prepared and characterized, in particular by NMR spectroscopy, DOSY, electronic circular dichroism (ECD), and electrospray ionization mass spectrometry (ESI-MS). Their ECD patterns depended on the substitution of the starting CTBs and were shifted bathochromically by comparison with the latter. ESI-MS in the presence of HCO2H allowed us to detect the complexes as proton adducts. The intensities of the signals were stronger when the phosphine was more electron-rich. This technique was also used to investigate the exchange of phosphine betweeen pairs of CTB complexes. The scrambling reaction was demonstrated by the higher intensity of the signals of the complexes subjected to the exchange of a single phosphine ligand by comparison with the intensity of the signals of the starting complexes.

Physical Separation of Enantiomeric Products by Compartmentalized Parallel Kinetic Resolution.

Accessing each enantiomer of a chiral molecule starting from a racemic mixture remains a daunting challenge in chemistry. Indeed, until now, only a few solutions exist to separate enantiomers of an equimolar mixture of a chiral precursor. In this study, we establish a new strategy to prepare simultaneously and physically separate both enantioenriched enantiomers of a molecule starting from a racemic substrate. This process combines two enantiomeric catalytic systems, working in parallel, and separation by an achiral membrane with selective permeability. This unprecedented system was successfully applied to the simultaneous preparation of both enantiomers of chiral 1,2-diols starting from racemic epoxides using Jacobsen's hydrolytic kinetic resolution (HKR) in parallel.

Porphyrin- and Bodipy-helicene conjugates: syntheses, separation of enantiomers and chiroptical properties.

The synthesis of several new compounds containing a chromophore and a helicenic moiety is reported. The preparation, characterisation and some physico-chemical studies are detailed. In particular, the two enantiomers of several chiral molecules of this type were separated by chiral HPLC (both analytically and in a preparative way) and their racemisation rates were determined for short-lived species. Electronic circular dichroism (ECD) and circular polarised luminescence (CPL) measurements were performed for the compounds with a very long racemisation half-life. Chiral porphyrins and Bodipys both gave ECD and CPL responses over a large area of the visible spectrum.

C 2-Symmetric atropisomeric N-heterocyclic carbene-palladium(II) complexes: synthesis, chiral resolution, and application in the enantioselective α-arylation of amides.

The concept of atropisomeric N-heterocyclic carbene (NHC)-metal complexes was extended to NHCs possessing a C2-symmetry and implemented to prepare palladium-based complexes. An in-depth study of the NHC precursors and the screening of various NHC ligands enabled us to circumvent the issue associated with the formation of meso complexes. A set of 8 atropisomeric NHC-palladium complexes were prepared and then obtained with high enantiopurities, thanks to an efficient resolution by chiral HPLC at the preparative scale. These complexes displayed good activity in the intramolecular α-arylation of amides and various cyclic products were isolated with excellent enantioselectivities (up to 98% ee).

Synthesis and Chiroptical Properties of a Chiral Isotopologue of syn-Cryptophane-B.

We report the synthesis and absolute configuration (AC) of a chiral isotopologue of syn-cryptophane-B. Low chiral signatures were measured by polarimetry and electronic circular dichroism, whereas most significant chiroptical effects were observed by vibrational circular dichroism (VCD) and Raman optical activity (ROA). The comparison of experimental VCD and ROA spectra with those predicted by DFT calculations allows the determination of the AC of the two enantiomers as (-)589-MP-syn-2 and (+)589-PM-syn-2.

Assembly of Aggregation-Induced Emission Active Bola-Amphiphilic Macromolecules into Luminescent Nanoparticles Optimized for Two-Photon Microscopy In Vivo.

The (Z) and (E)-isomers of an extended tetraphenylethylene-based chromophore with optimized two-photon-induced luminescence properties are separated and functionalized with water-solubilizing pendant polymer groups, promoting their self-assembly in physiological media in the form of small, colloidal stable organic nanoparticles. The two resulting fluorescent suspensions are then evaluated as potential two-photon luminescent contrast agents for intravital epifluorescence and two-photon fluorescence microscopy. Comparisons with previously reported works involving similar fluorophores devoid of polymer side chains illustrate the benefits of later functionalization regarding the control of the self-assembly of the nano-objects and ultimately their biocompatibility toward the imaged organism.

Synthesis of a helicene-fused porphyrin leading to a π-extended chiral chromophore.

The preparation of several covalently linked [6]-helicene-porphyrins is reported. A fused [6]-helicene-porphyrin π-extended aromatic system was isolated, the enantiomers separated and the chiroptical properties determined. The oxidative cyclodehydrogenation proved to be very effective for six-membered fused helical systems, but not suited for the formation of five-membered fused systems.

Carbazole Isomerism in Helical Radical Cations: Spin Delocalization and SOMO-HOMO Level Inversion in the Diradical State.

We report a new molecular design to afford persistent chiral organic open-shell systems with configurational stability and an inversion in energy of the singly occupied molecular orbital (SOMO) and the highest doubly occupied molecular orbital (HOMO) for both mono- and diradical states. The unpaired electron delocalization within the designed extended helical π-conjugated systems is a crucial factor to reach chemical stabilities, which is not obtained using the classical steric protection approach. The unique features of the obtained helical monoradicals allow an exploration of the chiral intramolecular electron transfer (IET) process in solvents of different polarity by means of optical and chiroptical spectroscopies, resulting in an unprecedented electronic circular dichroism (ECD) sign inversion for the radical transitions. We also characterized the corresponding helical diradicals, which show near-infrared electronic circular dichroism at wavelengths up to 1100 nm and an antiferromagnetic coupling between the spins, with an estimated singlet-triplet gap (ΔEST) of about -1.2 kcal mol-1. The study also revealed an intriguing double SOMO-HOMO inversion (SHI) electronic configuration for these diradicals, providing new insight regarding the peculiar energetic ordering of radical orbitals and the impact on the corresponding (chiral) optoelectronic properties.

Helical Chiral N-Heterocyclic Carbene Ligands in Enantioselective Gold Catalysis.

The first chiral helicene-NHC gold(I) complexes efficient in enantioselective catalysis were prepared. The L-shaped chiral ligand is composed of an imidazo[1,5-a]pyridin-3-ylidene (IPy) scaffold laterally substituted by a configurationally stable [5]-helicenoid unit. The chiral information was introduced in a key post-functionalization step of a NHC-gold(I) complex bearing a symmetrical anionic fluoreno[5]helicene substituent, leading to a racemic mixture of complexes featuring three correlated elements of chirality, namely central, axial and helical chirality. After HPLC enantiomeric resolution, X-ray crystallography and theoretical calculations enabled structural and stereochemical characterization of these configurationally stable NHC-gold(I) complexes. The high potential in asymmetric catalysis is demonstrated in the benchmark cycloisomerization of N-tethered 1,6-enynes with up to 95 : 5 er.

Enantiopure, luminescent, cyclometalated Ir(III) complexes with N-heterocyclic carbene-naphthalimide chromophore: design, vibrational circular dichroism and TD-DFT calculations.

A series of chiral cyclometalated iridium complexes of the type [Ir(C^N)2(C^C:)], {(C^N) = ppy (2); dfppy (3)} featuring a naphthalimide N-heterocyclic carbene ligand (C^C:) = (Naphthalimide-NHC) are described and fully characterized. The racemic complexes rac-2 and rac-3 were resolved via chiral column chromatography techniques into their corresponding enantiopure species Δ-2, Λ-2, Δ-3, Λ-3 as confirmed by their CD curves. This unique class of molecules containing organic and inorganic chromophores might be used as a platform to probe the stereochemical effect on the photophysical properties. Vibrational circular dichroism (VCD) was used as an important tool to assign successfully the stereochemistry of the enantiomers. TD-DFT calculations are also advanced to support the experimental studies and to rationalize the observed results.

Alkynylgold(I) C3 -Chiral Concave Complexes: Aggregation and Luminescence.

Chiral gold(I) acetylide trinuclear complexes 1-3 based on the cyclotribenzylene platform and terminal PR3 ligands (R=Ph, Et, and Cy, respectively), were characterized and their light emission studied. They exhibited long-lived blue phosphorescence in CHCl3 and a weak fluorescence in the UV. In MeOH/CHCl3 mixtures of >1:1 volume ratio, 1 and 2 exhibited a new emission band at ca. 540 nm that developed at the expense of the UV emission. DLS studies demonstrated the presence of molecular aggregates of Ø 30-80 nm. The green emission observed in MeOH-rich solvent mixtures was therefore induced by aggregation, and could originate from Au⋅⋅⋅Au interactions. The AIE spectrum of 3 was observed only in solutions containing 99 % of MeOH, and correlated with its solid state emission. The AIE profiles of the enantiomers of 1 differed from that of rac-1, suggesting that the latter is a true racemate.

Transition metal complexes bearing atropisomeric saturated NHC ligands.

From achiral imidazolinium salts, chiral transition metal complexes containing an N-heterocyclic carbene (NHC) ligand were prepared (metal = palladium, copper, silver, gold, rhodium). Axial chirality in these complexes results from the formation of the metal-carbene bond leading to the restriction of rotation of dissymmetric N-aryl substituents about the C-N bond. When these complexes exhibited a sufficient configurational stability, a resolution by chiral high-performance liquid chromatography (HPLC) on preparative scale enabled isolation of enantiomers with excellent enantiopurities (>99% ee) and good yields. A study of the enantiomerization barriers revealed the effect of the backbone nature as well as the type of transition metal on its values. Nevertheless, the evaluation of palladium-based complexes in asymmetric intramolecular α-arylation of amides demonstrated that the ability to induce an enantioselectivity cannot be correlated to the configurational stability of the precatalysts.

Synthesis and Optical Resolution of Configurationally Stable Zwitterionic Pentacoordinate Silicon Derivatives.

Stereogenic silicon centres in functionalised tetracoordinated organosilanes generally exhibit very high configurational stability under neutral conditions. This stability drops completely when higher coordination states of the silicon centre are reached due to rapid substituent exchange. Herein we describe the synthesis of chiral and neutral pentacoordinate silicon derivatives with high configurational stability. The zwitterionic nature of these air- and water-tolerant species allows for the first time their direct and efficient optical resolution using chiral HPLC techniques. By means of this method, pentacoordinate silicon compounds exhibiting high Si-inversion have been obtained as single enantiomers. A rationalisation of the enantiomerisation pathways has been also carried out using DFT calculations.

Potential innate immunity-related markers of endometrial receptivity and recurrent implantation failure (RIF).

The successful implantation of the embryo into a receptive endometrium is essential for the establishment of a viable pregnancy while recurrent implantation failure (RIF) is a real challenge in assisted reproduction. The maternal innate immune system, specifically the Toll-like receptors (TLRs), are involved in maintaining immunity in the female reproductive tract (FRT) required for fertility. In this study, we aimed to investigate the importance of innate immunity-related gene expression in the regulation of human fertility and as a prediction of potential outcome of in vitro fertilization - embryo transfer (IVF-ET), thus, we assessed the gene expression levels of TLR signalling molecules using quantitative real-time PCR between endometrial biopsies of healthy fertile women, and the patients experiencing RIF. Interestingly, our results showed that, TRIB2 and TLR9 genes were differentially expressed between the endometrial biopsies of healthy women and those with RIF. However, comparing expression levels of same genes between pre-receptive and receptive healthy endometrial biopsies showed different genes (ICAM1, NFKBIA, VCAM1, LIF, VEGFB, TLR5) had significantly altered expression, suggesting their involvement in endometrial receptivity. Thus, further investigations will enable us to better understand the role of these genes in the biology of FRT and as a possible target for the improvement of infertility treatments and/or development of non-hormonal contraception.

Hemicryptophane Cages with a C1-Symmetric Cyclotriveratrylene Unit.

Two new hemicryptophanes combining a cyclotriveratrylene unit with either an aminotrisamide or a tris(2-aminoethyl)amine (tren) moiety have been synthesized. Although a conventional synthesis approach was used, the molecular cages obtained are devoid of the expected C3 symmetry. NMR analyses and X-ray crystal structure determination showed that these hemicryptophanes exhibited C1 symmetry due to the unusual arrangement of the substituents of the cyclotriveratrylene unit. This unprecedented arrangement is related to a change in the regioselectivity of the Friedel-Crafts reactions that led to the CTV cap. This constitutes an original approach to access enantiopure chiral molecular cages with low symmetry.

Exciton coupling chirality in helicene-porphyrin conjugates.

Enantiopure helicene-porphyrin conjugates were prepared. They show strong changes in their circular dichroic response as compared to classical helicene derivatives, with highly intense bisignate Exciton Coupling (EC) signal and Δε values up to 680 M-1 cm-1 for the Soret band. They also display circularly polarized fluorescence in the (far-)red region, with dissymmetry factors up to 7 × 10-4.

Are the Physical Properties of Xe@Cryptophane Complexes Easily Predictable? The Case of syn- and anti-Tris-aza-Cryptophanes.

We report the synthesis and optical resolution of C3-symmetrical tris-aza-cryptophanes anti-3 and syn-4, as well as the study of their interaction with xenon via hyperpolarized 129Xe NMR. These molecular cages are close structural analogues of the two well-known cryptophane-A (1; chiral) and cryptophane-B (2; achiral) diastereomers since these new compounds differ only by the presence of three nitrogen atoms grafted onto the same cyclotribenzylene unit. The assignment of their relative (syn vs anti) and absolute configurations was made possible, thanks to the combined use of quantum calculations at the density functional theory level and vibrational circular dichroism spectroscopy. More importantly, our results show that despite the large structural similarities with cryptophane-A (1) and -B (2), these two new compounds show a very different behavior in the presence of xenon in organic solutions. These results demonstrate that prediction of the physical properties of the xenon@cryptophane complexes, only based on structural parameters, remains extremely difficult.

On the Enantioselective Phosphoric-Acid-Catalyzed Hantzsch Synthesis of Polyhydroquinolines.

A reinvestigation of a chiral phosphoric-acid-catalyzed four-component Hantzsch enantioselective synthesis of polyhydroquinolines reported in 2009 is presented. In our hands, when the reaction was performed with fidelity to the original report using a chiral enantiopure phosphoric acid catalyst, no enantioselectivity was observed. Unlike in the original report, enantioselectivity results are backed by baseline separation of the enantiomers by HPLC analyses on chiral stationary phase with UV and chiroptical detection.

Circularly Polarized Fluorescent Helicene-Boranils: Synthesis, Photophysical and Chiroptical Properties.

Mono- and di-boranil-substituted helicenes were prepared by BF2 -borylation of the corresponding anils, readily synthesized by condensation of 2-amino- and 2,15-diamino-helicenes with 4-(diethylamino)salicylaldehyde. After enantiomeric resolution using HPLC, their chiroptical properties including circularly polarized fluorescence in solution and in PMMA films were investigated and rationalized with the help of NMR, X-ray and quantum-chemical calculations.