Group 5 alkyltantalum and ureate catalyst systems : hydroaminoalkylation reactivity and applications in selective syntheses of structurally diverse amines

Alkyltantalum precatalysts for intermolecular hydroaminoalkylation reactions between alkene and amine substrates are explored to gain insight into catalyst structure/activity relationships and to develop new methods for the regioselective and diastereoselective synthesis of amines and N-heterocycles. This thesis addressed significant challenges with widespread adoption of hydroaminoalkylation towards synthesizing products that display concrete applications in agricultural or pharmaceutical industries. First, we synthesized alkyltantalum starting materials and combined them with new ureate ligand salts for in situ catalyst mixtures that display promising reaction rates. Substrate scope in this section emphasized reactivity using switchable ureate salts for either terminal or internal alkenes while maintaining chemoselectivity with diene substrates. We then probed reaction scope changes that resulted from varying ligand steric and electronic factors. We extended this to study chiral cyclic ureate ligands to attempt enantioselective catalysis, these ligands resulted in poor ee’s, but presented unprecedented reactivity with challenging aliphatic amine substrates. Comparative hydroaminoalkylation reactivity with different Ta halides revealed that a brominated Ta started material is slightly more reactive than its chlorinated counterpart, while a fluorinated complex was not active at all. Catalysis with a new chiral ureate salt accomplished highly chemo- and regioselective C- C bond formation between substituted N-methylanilines and either limonene or pinene. We confirmed that hydroaminoalkylation does not racemize allylic stereocentres and can be selective for terminal alkenes. Further, pinene-containing products were consistently generated with high diastereoselectivity. All products were isolated using a simple filtration protocol. iii The catalyst system highlighted towards the end of this thesis was the first generally reactive hydroaminoalkylation system. Reactivity was excellent with aromatic or aliphatic amines, terminal or internal alkenes, and most importantly saturated N-heterocycles. Exploring substrate scope with these N-heterocycles resulted in consistently good yields, with good regio- and diastereoselectivity when unactivated alkene partners are used. However, additional data highlighted the linear dependence of regioisomer product ratios as a function of alkene electronic factors when combining piperidine with styrene partners. This discovery of substrate-controlled product selectivity allowed for only linear product to be obtained in select cases. Final results applied N-heterocycle reactivity to a two-step, one-pot catalytic, regiodivergent synthesis of indolizine and quinolizine alkaloids.Science, Faculty ofChemistry, Department ofGraduat

Latent profile analysis of cognitive decline and depressive symptoms after intracerebral hemorrhage

International audienceBackground: Cognitive impairment and depressive symptoms are highly prevalent after Intracerebral Hemorrhage (ICH). We leveraged Latent Profile Analysis (LPA) to identify profiles for cognitive decline and depression onset after ICH. We also investigated differences in clinical, genetic and neuroimaging characteristics across patients' profiles. Methods: We analyzed data from the ICH study conducted at Massachusetts General Hospital between January 1998 and December 2019. We collected information from electronical health records, follow-up interviews, CT and MRI imaging, and APOE genotype. We conducted LPA and multinomial logistic regression analyses to: 1) identify distinct profiles for cognitive decline and depression onset after ICH; 2) identify clinical, neuroimaging and genetic factors predicting individuals' likelihood to express a specific profile. Results: We followed 784 ICH survivors for a median of 45.8 months. We identified four distinct profiles in cognitive and depressive symptoms after ICH: low depression and dementia risk, early-onset depression and dementia, lateonset depression and dementia, high depression with low dementia risk. Cerebral small vessel disease severity and APOE genotype were specifically associated with the late-onset profile (both p < 0.05). Acute hematoma characteristics (size, intraventricular extension) and functional disability were specifically associated with the early-onset profile (all p < 0.05). Conclusion: We identified four distinct profiles for cognitive and depressive symptoms after ICH, each displaying specific associations with individual patients' clinical, genetic and neuroimaging data. These associations reflect separate biological mechanisms influencing dementia and depression risk after ICH. Our findings support employing LPA in future ICH studies, and is likely applicable to stroke survivors at large

White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy

Objective:To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA).Methods:Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri-basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression.Results:The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic regression, presence of multiple subcortical spots was associated with lobar CMBs (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.01-1.50, p = 0.039) and high degree of centrum semiovale EPVS (OR 2.43; 95% CI 1.56-3.80, p < 0.0001). By contrast, age (OR 1.05; 95% CI 1.02-1.09, p = 0.002), deep CMBs (OR 2.46; 95% CI 1.44-4.20, p = 0.001), total WMH volume (OR 1.02; 95% CI 1.01-1.04, p = 0.002), and high BG EPVS degree (OR 8.81; 95% CI 3.37-23.02, p < 0.0001) were predictors of peri-BG WMH pattern.Conclusion:Different patterns of subcortical leukoaraiosis visually identified on MRI might provide insights into the dominant underlying microangiopathy type as well as mechanisms of tissue injury in patients with ICH.Paroxysmal Cerebral Disorder

APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review

International audienceBACKGROUND: Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD). OBJECTIVE: We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature. METHODS: We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and performed a comprehensive literature review of all cases reported with the same APP mutation. RESULTS: We screened APP in 61 unrelated French patients. Three mutations, located in the Aβ coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation. CONCLUSIONS: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature