Supramolecular fullerene sponges as catalytic masks for regioselective functionalization of C60

Isomer-pure poly-functionalized fullerenes are required to boost the development of fullerene chemistry in all fields. On a general basis, multi-adduct mixtures with uncontrolled regioselectivity are obtained, and the use of chromatographic purification is prohibitively costly and time consuming, especially in the production of solar cells. Single-isomer poly-functionalized fullerenes are only accessible via stoichiometric, multistep paths entailing protecting-unprotecting sequences. Herein, a nanocapsule is used as a supramolecular tetragonal prismatic mask to exert full control on the reactivity and the equatorial regioselectivity of Bingel-Hirsch cyclopropanation reactions of a confined C guest. Thus, equatorial bis-, tris-, and tetrakis-C homo-adducts are exclusively obtained in a stepwise manner. Furthermore, isomer-pure equatorial hetero-tetrakis-adducts or hetero-Th-hexakis-adducts are synthesized at will in one-pot synthesis for the first time. This work provides a synthetically valuable path to produce a plethora of new pure-isomer poly-functionalized C-based compounds as candidates for testing in solar cell devices and biomedical applications

A three-shell supramolecular complex enables the symmetry-mismatched chemo- and regioselective bis-functionalization of C60

Molecular Russian dolls (matryoshkas) have proven useful for testing the limits of preparative supramolecular chemistry but applications of these architectures to problems in other fields are elusive. Here we report a three-shell, matryoshka-like complex—in which C60 sits inside a cycloparaphenylene nanohoop, which in turn is encapsulated inside a self-assembled nanocapsule—that can be used to address a long-standing challenge in fullerene chemistry, namely the selective formation of a particular fullerene bis-adduct. Spectroscopic evidence indicates that the ternary complex is sufficiently stable in solution for the two outer shells to affect the addition chemistry of the fullerene guest. When the complex is subjected to Bingel cyclopropanation conditions, the exclusive formation of a single trans-3 fullerene bis-adduct was observed in a reaction that typically yields more than a dozen products. The selectivity facilitated by this matryoshka-like approach appears to be a general phenomenon and could be useful for applications where regioisomerically pure C60 bis-adducts have been shown to have superior properties compared with isomer mixtures.This work was supported by grants from MINECO-Spain (CTQ2016-77989-P and PID2019-104498GB-I00 to X.R., RTI2018-095622-B-100 to D.M. and I.I., and EUR2019-103824 to F.G.), Generalitat de Catalunya (2017SGR264 and a PhD grant to C.F.-E.) and the Severo Ochoa Center of Excellence Program (Catalan Institute of Nanoscience and Nanotechnology, grant SEV-2017-0706). X.R. is also grateful for ICREA-Acadèmia awards. M.v.D. is grateful for financial support from the Deutsche Forschungsgemeinschaft (project number 182849149-SFB953 ‘Synthetic Carbon Allotropes’), the Fonds der Chemischen Industrie (FCI), the University of Ulm and the Deutscher Akademischer Austauschdienst (PhD fellowship to O.B.). E.U. thanks Universitat de Girona for a PhD grant and we thank Serveis Tècnics de Recerca, Universitat de Girona for technical support.Peer reviewe

Purification of Uranium-based Endohedral Metallofullerenes (EMFs) by Selective Supramolecular Encapsulation and Release

Supramolecular nanocapsule 1⋅(BArF) is able to sequentially and selectively entrap recently discovered U@C and unprecedented ScCU@C, simply by soaking crystals of 1⋅(BArF) in a toluene solution of arc-produced soot. These species, selectively and stepwise absorbed by 1⋅(BArF), are easily released, obtaining highly pure fractions of U@C and ScCU@C in one step. ScCU@C represents the first example of a mixed metal actinide-based endohedral metallofullerene (EMF). Remarkably, the host-guest studies revealed that 1⋅(BArF) is able to discriminate EMFs with the same carbon cage but with different encapsulated cluster and computational studies provide support for these observations

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Supramolecular nanocapsules as platforms for molecular recognition and reactivity in confined spaces

The use of self-assembly to bring simple building blocks together into complex product, has led to the preparation of an increasing number of sophisticated and functional 3D supramolecular nanocapsules. By understanding the selectivity of these different coordinative bond-forming reactions and interactions between the subcomponents, complex supramolecular scaffolds by design are cleanly generated from simple building blocks. Important prospective applications of metal-organic capsules are the development of low-energy methodologies for chemical separations and purification of target molecules, and the reactivity modulation of confined guests for the efficient and selective production of valuable compounds. In the first part, this thesis builds upon expanding the capabilities of 1a·(BArF)8 (Pd(II)-based tetragonal prismatic nanocapsule) as a supramolecular mask, to gain full regio-functionalization control and modulate the reactivity of Bingel cyclopropanation reactions on confined fullerene C60. The confinement effect not only allows a very precise control of the regiochemistry in the synthesis of poly-functionalized C60 adducts, but also, completely precludes the over-reactivity commonly observed without mask. In this manner, fully equatorial bis-, tris- and tetrakis- homo and heteroadducts have been synthesized for the first time, as well as hekakis-heteroadducts. Afterwards, the Cu(II)-based tetragonal prismatic nanocapsule 5·(OTf)8, analogue of the 1a·(BArF)8, was prepared and fully characterized. As a consequence of the inherent lability of the Cu(II)-carboxylate coordinative bonds present in the metal nodes of 5·(OTf)8, this nanocapsule is able to reversibly encapsulate large fullerenes and EMFs in homogeneous and heterogeneous (host in solid and guest in solution) systems. The different affinities displayed by 5·(OTf)8 towards the species present in a Sc3N-based soot, allows for the straightforward purification of Sc3N@C80 in a single step. Then, 5·(OTf)8 nanocapsule was derivatized by exchanging its OTf counter-anions by BArF- , yielding 1b·(BArF)8. We investigated the ability of 1b·(BArF)8 as a selective host in the purification of U/Sc-based EMF soots. The very precise and divergent selectivity shown by 1b·(BArF)8 towards U2@C80 and unprecedented Sc2CU@C80 guests allows their sequential and selective uptake in a single and operationally simple step. The obtained results demonstrate that 1b·(BArF)8 is able to discriminate EMFs bearing exactly the same carbon cage and differing exclusively in the endohedral clusters. In the final part of this thesis, the ability of 1b·(BArF)8 to purify challenging EMFs directly from complex mixtures has been further exemplified by the selective encapsulation and purification of U-based C78 EMFs in the presence of U-based C80 ones. The molecular recognition events observed in the heterogeneous (host in solid and guest in solution) host-guest systems, were dictated by the enhanced electrostatic interactions between the host and the EMFs guests possessing ellipsoidal fullerene cages, such as U-based C78 EMFs, compared to spherical C80 species. Moreover, further host-guest experiments demonstrate that 1b·(BArF)8 is able to distinguish among EMF with very similar endohedral clusters, i.e. U2@D3h-C78 versus U2C@D3h C7L'ús de reaccions d'autoensamblatge ha facilitat la preparació de nombroses càpsules supramoleculars 3D. La comprensió d'aquestes reaccions, permet dissenyar i sintetitzar de manera selectiva aquestes estructures supramoleculars usant subcomponents senzills. Aquestes càpsules d'alta complexitat, mostren un gran potencial en el desenvolupament de metodologies de separació/purificació de productes químics, així com, en la síntesi millorada de productes d'alt valor afegit, gràcies al confinament dels precursors sintètics en les cavitats internes de les càpsules i la peculiar reactivitat que es dóna en aquests espais confinats. La primera part d'aquesta tesi doctoral es focalitza en l'expansió de les capacitats de 1a·(BArF)8 (càpsula tetragonal prismàtica basada en Pd (II)) com a màscara supramolecular, per exercir un control total de la regioselectivitat i la reactivitat en reaccions de ciclopropanació en el ful·lerè C60, mitjançant el seu confinament. Aquest confinament del substrat, no només permet controlar de manera precisa la regioselectivitat durant la formació de derivats poli funcionalitzats de C60, sinó que també exerceix un control de la quimioselectivitat del procés. D'aquesta manera, s'han sintetitzat per primera vegada bis-, trista i tetrakis- homo- i heteroadductos completament equatorials, així com hekakis-heteroadductos. Posteriorment, es va preparar i caracteritzar una nova càpsula de Cu (II) (5·(OTf)8), anàloga a 1a·(BArF)8. Gràcies a la inherent labilitat dels enllaços de coordinació present en els nodes metàl·lics d'aquesta estructura, es va aconseguir encapsular de manera reversible ful·lerens i EMFs de grans dimensions (usant 5·(OTf)8 en solució o en estat sòlid). Gràcies a l'afinitat divergent que mostra 5·(OTf)8 davant les diferents espècies presents en un cru de reacció de EMFs basats en clústers de "Sc3N", es va aconseguir purificar en un sol pas de reacció el compost Sc3N@C80. El següent pas en aquesta tesi doctoral, va ser derivatitzar la càpsula 5·(OTf)8 mitjançant l'intercanvi del seu contra-anió (OTf- per BArF-), generant la càpsula 1b·(BArF)8. Seguidament, es van estudiar les capacitats que mostrava 1b·(BArF)8 per encapsular les diferents espècies presents en un cru de reacció d’EMFs basats en clústers de "U/Sc", amb l'objectiu de purificar lo. Gràcies a la gran selectivitat que mostra 1b·(BArF)8 cap U2@C80 i Sc2CU@C80, es va aconseguir encapsular de manera seqüencial i selectiva aquests dos EMFs, finalment purificant-los en un sol pas de reacció. Els resultats obtinguts en aquest projecte van evidenciar la capacitat de 1b·(BArF)8 per distingir entre espècies d’EMFs que únicament difereixen en els seus clústers interns, mostrant exactament la mateixa caixa de carboni. A la part final d'aquesta tesi, les capacitats de 1a·(BArF)8 per purificar espècies d’EMFs directament de crus de reacció, va ser clarament evidenciada amb l'encapsulació selectiva i purificació d'uns nous EMFs basats en U i caixes de carboni C78. Cal destacar, que l'afinitat de 1b·(BArF)8 per a aquests nous EMFs, és encara més gran que l'observada per U2@C80. Els esdeveniments de reconeixement molecular que mostra 1b·(BArF)8 en sistemes heterogenis (1b·(BArF)8 en estat sòlid i els EMFs en solució), són dirigits per les interaccions electroestàtiques de major eficiència que es donen entre 1b·(BArF)8 i els EMFs que posseeixen caixes de carboni el·lipsoidals (com ara els EMFs basats en urani i caixes de carboni C78), en comparació amb aquelles caixes de carboni més esfèriques (com el C80). A més, l'estudi de reconeixement molecular que es va dur a terme va demostrar que 1b·(BArF)8 es pot distingir entre EMFs amb clústers interns molt similars, tal com U2@D3h-C78 versus U2C@D3h-C78Programa de Doctorat en Químic