Metal-Catalyzed Enantioconvergent Transformations.

Enantioconvergent catalysis has expanded asymmetric synthesis to new methodologies able to convert racemic compounds into a single enantiomer. This review covers recent advances in transition-metal-catalyzed transformations, such as radical-based cross-coupling of racemic alkyl electrophiles with nucleophiles or racemic alkylmetals with electrophiles and reductive cross-coupling of two electrophiles mainly under Ni/bis(oxazoline) catalysis. C-H functionalization of racemic electrophiles or nucleophiles can be performed in an enantioconvergent manner. Hydroalkylation of alkenes, allenes, and acetylenes is an alternative to cross-coupling reactions. Hydrogen autotransfer has been applied to amination of racemic alcohols and C-C bond forming reactions (Guerbet reaction). Other metal-catalyzed reactions involve addition of racemic allylic systems to carbonyl compounds, propargylation of alcohols and phenols, amination of racemic 3-bromooxindoles, allenylation of carbonyl compounds with racemic allenolates or propargyl bromides, and hydroxylation of racemic 1,3-dicarbonyl compounds.

Catalytic asymmetric synthesis of 1,2-diamines.

The asymmetric catalytic synthesis of 1,2-diamines has received considerable interest, especially in the last ten years, due to their presence in biologically active compounds and their applications for the development of synthetic building blocks, chiral ligands and organocatalysts. Synthetic strategies based on C-N bond-forming reactions involve mainly (a) ring opening of aziridines and azabenzonorbornadienes, (b) hydroamination of allylic amines, (c) hydroamination of enamines and (d) diamination of olefins. In the case of C-C bond-forming reactions are included (a) the aza-Mannich reaction of imino esters, imino nitriles, azlactones, isocyano acetates, and isothiocyanates with imines, (b) the aza-Henry reaction of nitroalkanes with imines, (c) imine-imine coupling reactions, and (d) reductive coupling of enamines with imines, and (e) [3+2] cycloaddition with imines. C-H bond forming reactions include hydrogenation of CN bonds and C-H amination reactions. Other catalytic methods include desymmetrization reactions of meso-diamines.

Synthesis of Vicinal anti-Amino Alcohols from N-tert-Butanesulfinyl Aldimines and Cyclopropanols.

The stereoselective synthesis of vicinal amino alcohols derivatives from 1-substituted cyclopropanols and chiral N-tert-butanesulfinyl imines is described. Cyclopropanols are easily prepared from carboxylic esters upon reaction with ethylmagnesium bromide in the presence of titanium tetraisopropoxide and undergo carbon-carbon bond cleavage by means of diethylzinc to produce, upon base deprotonation, enolized zinc homoenolates, which react with chiral sulfinyl imines in a highly regio- and stereoselective manner.

Multimodal neuroimaging in post-COVID syndrome and correlation with cognition.

Brain changes have been reported in the first weeks after SARS-CoV-2 infection. However, limited literature exists about brain alterations in post-COVID syndrome, a condition increasingly associated with cognitive impairment. The present study aimed to evaluate brain functional and structural alterations in patients with post-COVID syndrome, and assess whether these brain alterations were related to cognitive dysfunction. Eighty-six patients with post-COVID syndrome and 36 healthy controls were recruited and underwent neuroimaging acquisition and a comprehensive neuropsychological assessment. Cognitive and neuroimaging examinations were performed 11 months after the first symptoms of SARS-CoV-2. Whole-brain functional connectivity analysis was performed. Voxel-based morphometry was performed to evaluate grey matter volume, and diffusion tensor imaging was carried out to analyse white-matter alterations. Correlations between cognition and brain changes were conducted and Bonferroni corrected. Post-COVID syndrome patients presented with functional connectivity changes, characterized by hypoconnectivity between left and right parahippocampal areas, and between bilateral orbitofrontal and cerebellar areas compared to controls. These alterations were accompanied by reduced grey matter volume in cortical, limbic and cerebellar areas, and alterations in white matter axial and mean diffusivity. Grey matter volume loss showed significant associations with cognitive dysfunction. These cognitive and brain alterations were more pronounced in hospitalized patients compared to non-hospitalized patients. No associations with vaccination status were found. The present study shows persistent structural and functional brain abnormalities 11 months after the acute infection. These changes are associated with cognitive dysfunction and contribute to a better understanding of the pathophysiology of the post-COVID syndrome.

Coronary microvascular dysfunction is associated with impaired cognitive function: the Cerebral-Coronary Connection study (C3 study).

BACKGROUND: It remains unknown whether the presence of coronary microcirculatory dysfunction (CMD) correlates with its equivalent condition in the brain, cerebral small vessel disease (CSVD). The cerebral-coronary connection (C3), a prospective blinded study, investigated the prevalence of CMD in patients with coronary artery disease (CAD) and its association with CSVD and cognitive function. METHODS AND RESULTS: Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were performed. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR (<2.0) (55.2%) showed higher burden of white-matter hyperintensities: 43.2 vs. 20.0% (P = 0.044). After statistical adjustment, low CFR was associated with lower grey matter volume (P = 0.024) and with parameters of white-matter microstructural damage in diffusion-tensor imaging (lower fractional anisotropy and higher mean diffusivity, P = 0.029 and P = 0.032, respectively). Low CFR was associated with higher resistive (P = 0.027) and pulsatility (P = 0.043) values on TCD, and worse neurocognitive test scores (lower mini mental state examination, P = 0.025, and slower Trail Making Test A, P = 0.034). CONCLUSIONS: Coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04131075.

Unraveling brain fog in post-COVID syndrome: Relationship between subjective cognitive complaints and cognitive function, fatigue, and neuropsychiatric symptoms.

BACKGROUND AND PURPOSE: "Brain fog" is a frequent and disabling symptom that can occur after SARS-CoV-2 infection. However, its clinical characteristics and the relationships among brain fog and objective cognitive function, fatigue, and neuropsychiatric symptoms (depression, anxiety) are still unclear. In this study, we aimed to examine the characteristics of brain fog and to understand how fatigue, cognitive performance, and neuropsychiatric symptoms and the mutual relationships among these variables influence subjective cognitive complaints. METHODS: A total of 170 patients with cognitive complaints in the context of post-COVID syndrome were evaluated using a comprehensive neuropsychological protocol. The FLEI scale was used to characterize subjective cognitive complaints. Correlation analysis, regression machine-learning algorithms, and mediation analysis were calculated. RESULTS: Cognitive complaints were mainly attention and episodic memory symptoms, while executive functions (planning) issues were less often reported. The FLEI scale, a mental ability questionnaire, showed high correlations with a fatigue scale and moderate correlations with the Stroop test, and anxiety and depressive symptoms. Random forest algorithms showed an R2 value of 0.409 for the prediction of FLEI score, with several cognitive tests, fatigue and depression being the best variables used in the prediction. Mediation analysis showed that fatigue was the main mediator between objective and subjective cognition, while the effect of depression was indirect and mediated through fatigue. CONCLUSIONS: Brain fog associated with COVID-19 is mainly characterized by attention and episodic memory, and fatigue, which is the main mediator between objective and subjective cognition. Our findings contribute to understanding the pathophysiology of brain fog and emphasize the need to unravel the main mechanisms underlying brain fog, considering several aspects.

Pseudo-multicomponent 1,3-dipolar cycloaddition involving metal-free generation of unactivated azomethine ylides.

The pseudo-multicomponent reaction between propargyl amine, an aldehyde and an electron-deficient alkene is described. The C-H activation takes place thermally and allows the obtaining of cycloadducts in very good yields with high diastereoselectivities. The relative configuration is determined by X-ray diffraction analysis of the chiral molecule, obtained as a single diastereoisomer, using a chiral maleimide. A brief study of the stability of the possible ylides involved in the process is also mentioned, confirming the high diastereoselectivity observed. The high functional group density of these cycloadducts permits the synthesis of complex heterocycles. After allylation or propargylation of the pyrrolidine nitrogen atom, RCM-DA cycloaddition or cyclotrimerization with an alkyne is studied, respectively. In this last example, the resulting tetracyclic structures are of potential interest as drugs for the treatment of cystic fibrosis.

Stereoselective Synthesis of 1-Substituted Homotropanones, including Natural Alkaloid (-)-Adaline.

The stereocontrolled synthesis of 1-substituted homotropanones, using chiral N-tert-butanesulfinyl imines as reaction intermediates, is described. The reaction of organolithium and Grignard reagents with hydroxy Weinreb amides, chemoselective N-tert-butanesulfinyl aldimine formation from keto aldehydes, decarboxylative Mannich reaction with ß-keto acids of these aldimines, and organocatalyzed L-proline intramolecular Mannich cyclization are key steps of this methodology. The utility of the method was demonstrated with a synthesis of the natural product (-)-adaline, and its enantiomer, (+)-adaline.

Persistent olfactory dysfunction after COVID-19 is associated with reduced perfusion in the frontal lobe.

BACKGROUND: Olfactory dysfunction is common during SARS-CoV-2 infection. The pathophysiology of the persistence of this symptom and the potential relationship with central nervous system involvement is unknown. AIM OF THE STUDY: To evaluate the neural correlates of persistent olfactory dysfunction in a series of patients with post-COVID syndrome. METHODS: Eighty-two patients with post-COVID syndrome were assessed with the Brief Smell Identification Test and a multimodal MRI study including 3D-T1, T2-FLAIR, diffusion-tensor imaging, and arterial spin labeling. Olfactory and neuroimaging examinations were performed 11.18 ± 3.78 months after the acute infection. Voxel-based brain mapping analyses were conducted to correlate the olfactory test with brain volumes, white matter microstructure, and brain perfusion. RESULTS: Olfactory dysfunction was associated with lower tissue perfusion in the orbital and medial frontal regions in the arterial spin labeling sequence. Conversely, no statistically significant findings were detected in brain volumes and diffusion-tensor imaging. Mild changes in paranasal sinuses and nasal cavities were detected in 9.75% of cases, with no association with olfactory deficits. CONCLUSIONS: We provide new insights regarding the pathophysiology of persistent olfactory dysfunction after COVID-19, involving the main brain regions associated with the olfactory system.

Enantioselective 1,3-Dipolar Cycloaddition Using (Z)-α-Amidonitroalkenes as a Key Step to the Access to Chiral cis-3,4-Diaminopyrrolidines.

The enantioselective 1,3-dipolar cycloaddition between imino esters and (Z)-nitroalkenes bearing a masked amino group in the ß-position was studied using several chiral ligands and silver salts. The optimized reaction conditions were directly applied to the study of the scope of the reaction. The determination of the absolute configuration was evaluated using NMR experiments and electronic circular dichroism (ECD). The reduction and hydrolysis of both groups was performed to generate in an excellent enantiomeric ratio the corresponding cis-2,3-diaminoprolinate.

Chiral N-tert-Butylsulfinyl Imines: New Discoveries.

In this account the reactions of chiral N-tert-butylsulfinyl imines with organometallic reagents such as organoalkaline (lithium, sodium, potassium and cesium derivatives), organomagnesium, organozinc, organoboron, organoaluminium, organoindium and organosilicon compounds is comprehensively described. The reactivity in all cases is derived to synthetic applications in order to prepare interesting organic nitrogenated molecules, especially in the field of alkaloid compounds.

Conjugated Ynones in Organic Synthesis.

This review article will consider the preparation and application of ynones in synthetic organic chemistry. Concerning the preparation of these bifunctional compounds, several methodologies starting from propargyl alcohols, acyl derivatives, both by using alkynylmetal reagents or by transition metal (mainly palladium and copper) catalyzed alkynylations, carbon monoxide (carbonylation of terminal alkynes and alkenes), and other substrates will be discussed. The reactivity and synthetic applications of ynones will be focused on conjugate additions with boron-, carbon-, nitrogen-, oxygen-, and other heteroatom-containing nucleophiles, as well as radicals. Then, cycloaddition processes will include [2 + 2] cycloadditions, [3 + 2] 1,3-dipolar cycloadditions (with azides, nitrones, azomethine imines and ylides, nitrile oxides, diazo compounds, and other dipoles), and [4 + 2] cycloadditions (mainly Diels-Alder-type reactions). The reduction of the triple bond, addition to the carbonyl group (using carbon- and heteronucleophiles and reductions), and other not so commonly used processes (such as aldol reactions, cyclizations, and isomerizations) will be considered at the end.

Chemodivergent reactions.

An important strategy for the efficient generation of diversity in molecular structures is the utilization of common starting materials in chemodivergent transformations. The most studied solutions for switching the chemoselectivity rely on the catalyst, ligand, additive, solvent, temperature, time, pressure, pH and even small modifications in the substrate. In this review article several processes have been selected such as inter- and intramolecular cyclizations, including carba-, oxa-, thia- and oxazacyclizations promoted mainly by Brønsted or Lewis acids, transition metals and organocatalysts, as well as radical reactions. Catalyst-controlled intra- and intermolecular cyclizations are mainly described to give five- and six-membered rings. Cycloaddition reactions involving (2+2), (3+2), (3+3), (4+1), (4+2), (5+2), (6+2) and (7+2) processes are useful reactions for the synthesis of cyclic systems using organocatalysts, metal catalysts and Lewis acid-controlled processes. Addition reactions mainly of carba- and heteronucleophiles to unsaturated conjugated substrates can give different adducts via metal catalyst-, Lewis acid- and solvent-dependent processes. Carbonylation reactions of amines and phenols are carried out via ligand-controlled transition metal-catalyzed multicomponent processes. Ring-opening reactions starting mainly from cyclopropanols, cyclopropenols and epoxides or aziridines are applied to the synthesis of acyclic versus cyclic products under catalyst-control mainly by Lewis acids. Chemodivergent reduction reactions are performed using dissolving metals, sodium borohydride or hydrogen transfer conditions under solvent control. Oxidation reactions include molecular oxygen under solvent control or using different dioxiranes, as well as chemodivergent palladium catalyzed cross-coupling reactions using boronic acids are applied to aromatic and allenic compounds. Other chemodivergent reactions such as alkylations and allylations under transition metal catalysis, dimerization of acetylenes, bromination of benzylic substrates, and A3-couplings are performed via catalyst- or reaction condition-dependent processes.

Stereoselective Synthesis of δ- and ε-Amino Ketone Derivatives from N-tert-Butanesulfinyl Aldimines and Functionalized Organolithium Compounds.

The addition of functionalized organolithium compounds derived from 5-chloro-2-methoxy-1-pentene and 6-chloro-2-methoxy-1-hexene to N-tert-butanesulfinyl aldimines imines, and a subsequent hydrolysis of the enol ether moiety, yielded different δ- and ε-amino ketone derivatives, respectively, in moderate yields and diastereoselectivities. The application of these compounds in organic synthesis was demonstrated by the preparation of 2-substituted 6-methylpiperidines in a stereoselective manner, among them natural alkaloids (+)- and (-)-isosolenopsin A.

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles.

The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format.

Stereodivergent routes in organic synthesis: carbohydrates, amino acids, alkaloids and terpenes.

The natural occurrence of enantiomers and diastereomers is often encountered. In addition, the synthesis of these stereoisomers is important for structure determination and for the study of structure-activity relationships. Stereodivergent routes simplify the access to these molecules starting from a common material. This review is focused on the synthesis of carbohydrates, amino acids, alkaloids and terpenes using this efficient strategy. In the case of carbohydrates, such as monosaccharides, carbasugars, aminosugars and azasugars, carbohydrates are usually employed as common starting materials. As a very common strategy, configurations of hydroxy groups are inverted by SN2 methods playing with protection and deprotection processes. For the synthesis of acyclic α-AAs, diastereoselective methods using mainly Garner's aldehyde have been described. Diastereodivergent routes allowed the synthesis of ß-hydroxy- and ß-amino-α-amino acids, as well as of ß- and γ-amino acids. Heterocyclic and cyclic amino phosphonic acids were synthesized using diastereodivergent routes. Alkaloids containing five- and six-membered saturated azaheterocycles needed multistep stereodivergent routes and other alkaloids, such as enantiomers of balanol, vincamine, anatoxin and codeine, and diastereomeric isochaetominines C and galanthamines. In the terpene field, sesquiterpenes ß-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes.

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds.

Enantio- and diastereodivergent routes to marine-origin natural products with different sizes of cyclic ethers and lactones have been used in order to assign stereochemical features. Kainoid amino acids such as isodomoic acids have been synthesized using diastereodivergent routes. The bis(indole) alkaloid dragmacidin F has been prepared by enantiodivergent strategies as well as furanoterpenes and the tetracyclic agelastatin A. Natural products containing five-membered lactones like quercus lactones, muricatacins, goniofufuranones, methylenolactocins and frenolicin B have been synthesized using stereodivergent routes. Macrolides are very abundant lactones and have been mainly prepared from the corresponding seco-acids by lactonization, such as lasiodiplodin, zaeralanes, macrosphelides and haloprins, or by ring-closing metathesis, such as aspercyclides, microcarpalides, macrolides FD-891 and 892, and tetradic-5-en-9-olides. Other natural products including cyclic ethers (such as sesamin, asarinin, acetogenins, centrolobines and nabilones), alcohols (such as sulcatol), esters (such as methyl jasmonates), polycyclic precursors of fredericamycin, amino alcohols (such as ambroxol and sphingosines), isoprostanes, isofurans, polyketide precursors of anachelins, brevicomins, gummiferol, shikimic acid and the related compounds, and the pheromone disparlure have been synthesized stereodivergently. Heterocyclic systems such as epoxides, theobroxides and bromoxones, oxetan-3-ones, 5- to 8-membered cyclic ethers, azetidones, γ-lactams, oxazolidinones, bis(oxazolines), dihydropyridoisoindolines and octahydroisoquinolines have been prepared following stereodivergent routes. Stereodivergent routes to unnatural compounds such as alkenes, dienes, allenes, cyclopropanes, alcohols, aldols, amines, amino alcohols, ß-amino acids, carboxylic acids, lactones, nitriles and α-amino nitriles have been considered as well.

Stereodivergent Catalysis.

This review covers diastereo- and enantiodivergent catalyzed reactions in acyclic and cyclic systems using metal complexes or organocatalysts. Among them, nucleophilic addition to carbon-carbon and carbon-nitrogen double bonds, α-functionalization of carbonyl compounds, allylic substitutions, and ring opening of oxiranes and aziridines are considered. The diastereodivergent synthesis of alkenes from alkynes is also included. Finally, stereodivergent intramolecular and intermolecular cycloadditions and other cyclizations are also reported.

Metal-catalyzed regiodivergent organic reactions.

Metal-catalyzed regiodivergent reactions allow control over regioselectivity in the synthesis of a wide range of organic products. Starting from the same material, it is possible to prepare different regioisomers just by appropriately choosing the catalyst or by modifying the reaction conditions. Therefore, these regiodivergent methodologies should be included as the key factor in the concept of efficiency and atom economy in synthetic organic chemistry. The synthetic potential of this subject has been demonstrated mainly in addition reactions to unsaturated carbon-carbon bonds, allylic and propargylic nucleophilic substitutions, C-H activation reactions, cross-couplings, and intramolecular or intermolecular cyclizations. This review article overviews the development and rationalization of regiodivergence in these fundamental reactions in the last 15 years.

Discriminating Alzheimer's disease progression using a new hippocampal marker from T1-weighted MRI: The local surface roughness.

Hippocampal atrophy is one of the main hallmarks of Alzheimer's disease (AD). However, there is still controversy about whether this sign is a robust finding during the early stages of the disease, such as in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Considering this background, we proposed a new marker for assessing hippocampal atrophy: the local surface roughness (LSR). We tested this marker in a sample of 307 subjects (normal control (NC) = 70, SCD = 87, MCI = 137, AD = 13). In addition, 97 patients with MCI were followed-up over a 3-year period and classified as stable MCI (sMCI) (n = 61) or progressive MCI (pMCI) (n = 36). We did not find significant differences using traditional markers, such as normalized hippocampal volumes (NHV), between the NC and SCD groups or between the sMCI and pMCI groups. However, with LSR we found significant differences between the sMCI and pMCI groups and a better ability to discriminate between NC and SCD. The classification accuracy of the LSR for NC and SCD was 68.2%, while NHV had a 57.2% accuracy. In addition, the classification accuracy of the LSR for sMCI and pMCI was 74.3%, and NHV had a 68.3% accuracy. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on hippocampal markers and conversion times. The LSR marker showed better prediction of conversion to AD than NHV. These results suggest the relevance of considering the LSR as a new hippocampal marker for the AD continuum.