Synthesis of pyridines via [4 + 2] cycloadditions of vinylallenes with azadienophiles

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2015.Cataloged from PDF version of thesis.Includes bibliographical references.Pyridines are an important class of heterocycle with widespread applications. However, the efficient preparation of substituted pyridines remains a challenge in organic synthesis. This thesis describes new annulation strategies for the synthesis of highly substituted pyridines that involve [4 + 2] cycloadditions of vinylallenes with azadienophiles. Part II of this thesis describes a unimolecular, formal [2 + 2 + 2] cycloaddition strategy for the synthesis of tricyclic pyridines based on intramolecular propargylic ene/imino Diels-Alder reaction cascades. In this variant, unactivated oximino ethers and NN-dialkylhydrazones function as dienophiles in thermal Diels-Alder reactions. Part III of this thesis describes strategies for the synthesis of bicyclic and monocyclic 2-sulfonylpyrdines based on [4 + 2] cycloadditions of vinylallenes with tosyl cyanide. In addition, Part III discusses the synthetic elaboration of these 2- sulfonylpyridines via nucleophilic aromatic substitution reactions. Overall, annulation strategies based on [4 + 2] cycloadditions of vinylallenes with azadienophiles have been developed for the preparation of highly substituted pyridines in an efficient, convergent, and regioselective fashion.by Philip J. Hamzik.Ph. D

Endovascular stenting in malignant obstruction of superior vena cava

Introduction: Superior vena cava syndrome (SVCS) is obstruction of blood flow through the SVC. It is a medical emergency and most often manifests in patients with a malignant disease process within the thorax. A patient with SVCS requires immediate diagnostic evaluation and therapy. Presentation of case: A 33-years-old woman presented with complaints of dyspnoea and chest pain. Computer tomography revealed a large mass in the anterior mediastinum. This mass compressed surrounding structures. Stenting was indicated for early symptoms of SVCS. The diagnosis of Hodgkin’s lymphoma (HL) was confirmed with biopsy. The patient’s stage II HL has been subsequently treated with six cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), followed by radiotherapy. Presently she is doing well. Discussion: Although lymphomas are a common cause of SVCS but almost always SVCS is caused by non-Hodgkin’s lymphoma (NHL). HL despite its common presentation with mediastinal lymphadenopathy rarely causes SVCS. Conclusion: Lymphomas are a common cause of SVCS in young age. HL may present as SVCS. Pathological confirmation of diagnosis should be done before initiating therapy while dealing with a case of SVCS. SVC stenting is effective and has few complications in patients with SVCS

Electrical Changes in Deeper Cortical Structures During Balanced General Anesthesia with the Aim on Inhalation Anesthetics Effects

There are many theories that attempt to explain the mechanisms of the effects of inhalation anesthetics - from simpler, pursuing individual effects of anesthetics on the level of the ion channels, to more complex that are looking for uniform global changes in brain activity common to several agents. However, we still don’t have satisfactory and adequate conclusions

Aza Diels-Alder Reactions of Nitriles, N, N-Dimethylhydrazones, and Oximino Ethers. Application in Formal [2 + 2 + 2] Cycloadditions for the Synthesis of Pyridines

Metal-free, formal [2 + 2 + 2] cycloaddition st rategies for the synthesis of polycyclic pyridine derivatives are described. The overall transformation proceeds via a two-stage pericyclic cascade mechanism. In the first step, an intramolecular propargylic ene reaction generates a vinyl-allene that is necessarily locked in the s-cis conformation. This vinylallene exhibits exceptional reactivity as a Diels-Alder reaction partner and engages in [4 + 2] cycloadditions with normally unreactive aza dienophiles including unactivated cyano groups and heterosubstituted imine derivatives such as dimethylhydrazones and oximino ethers. Few examples of oximino ether Diels-Alder reactions have been reported previously and normal electron demand [4 + 2] cycloadditions of unactivated dialkylhydrazones are unprecedented. Overall this metal-free formal [2 + 2 + 2] cycloaddition provides access to polycyclic pyridine derivatives and complements transition metal-catalyzed [2 + 2 + 2] strategies.National Science Foundation (U.S.) (CHE-1111567)National Science Foundation (U.S.) (CHE-1464799)Amgen Summer Graduate FellowshipKenneth M. Gordon Summer FellowshipJapan Society for the Promotion of Science for Young Scientitist

The Effect of Hormonal Therapy on the Behavioral Outcomes in 47,XXY (Klinefelter Syndrome) between 7 and 12 Years of Age

47,XXY, also known as Klinefelter syndrome, is the most commonly occurring sex chromosomal aneuploidy (SCA). Hormonal replacement therapy (HRT) has been associated with improved neurodevelopmental capabilities in boys with 47,XXY, although studies investigating HRT\u27s possible positive effect on behavioral outcomes are scarce. This study explores the association between behavioral outcomes and HRT in boys ages 7-12. Patients were divided into 4 groups based on HRT status: untreated, early hormonal treatment (EHT), hormonal booster therapy (HBT), and both EHT and HBT. Analysis of Variance (ANOVA) and Kruskal-Wallis tests were conducted to determine group differences on the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF). The treated groups were found to have better scores in emotional control, initiative, organization of materials, behavioral rating index, metacognition index, and global executive composite than the untreated group on the BRIEF. On the CBCL, the treated groups presented better scores for somatic complaints, social problems, thought problems, attention problems, aggressive behavior, internalizing problems, total problems, affective problems, somatic problems, ADHD problems, oppositional defiant problems, and sluggish problems in comparison to the untreated group. These results offer evidence that HRT, specifically the combination of both EHT and HBT, may be successful in mitigating some undesirable behavioral outcomes. Further research is necessary to determine the efficacy of the combination of EHT and HBT regarding dosage, specific ages, and long-term benefits

Novel Neurocognitive Profile in a Minority of Boys with 47,XXY (Klinefelter Syndrome)

INTRODUCTION: 47,XXY, also known as Klinefelter syndrome, is the most commonly occurring sex chromosomal variation (1:660). The neurocognitive profile of boys with 47,XXY, in addition to verbal abilities, language skills, and general intelligence, has been explored in this study. METHODS: Fifty-five participants with 47,XXY were segregated into groups according to their performance on the Wechsler Intelligence Scale for Children (WISC): (1) those with a higher performance intelligence quotient (PIQ) in comparison with their verbal IQ (VIQ) and (2) those with a higher VIQ compared with their PIQ. Two-tailed independent t tests were completed to analyze group differences. RESULTS: Our study results demonstrate novel findings that one-third of subjects have higher verbal capabilities than perceptual skills. Those participants who showed the typical presentation of 47,XXY with increased PIQ in comparison with their VIQ excelled on perceptual and visual spatial subtests on the WISC and on nonverbal IQ on the Leiter International Performance Scale-III. In addition, it was found that expressive and receptive vocabulary skills were commensurate in both groups, which has not been reported previously. DISCUSSION: To the best of our knowledge, this is the first study to identify an alternative profile of 47,XXY with increased verbal capabilities in comparison with perceptual skills. In addition, previous research has found that boys with 47,XXY often show increased receptive vocabulary skills in comparison with their expressive vocabulary skills early in life. Therefore, our findings of commensurate expressive and receptive vocabulary skills suggest that age may be an impactful factor in vocabulary development. Further research is necessary to determine individualized treatment options for these patients, focusing on the specific cognitive profile they present

THERAPEUTIC APPROACH TO A CHILD WITH ACUTE RESPIRATORY DISTRESS SYNDROME: A REPORT OF TWO CASES

The course of a respiratory disorder in a child may end up in respiratory failure. There are also acute non-respiratory diseases which have a great influence on the respiratory functions and often lead to the acute lung injury and sometimes to the acute respiratory distress syndrome (ARDS). A feature of respiratory function deterioration is changed in the surfactant system. We often see inhibition of its synthesis or damage to its structure. Therapy of children suffering from ARDS should be complex and rapid. Despite many recently published studies explaining the principle of this disorder, the mortality of ARDS is still very high (30-50%). There are several studies documenting successful administration of exogenous surfactant as part of a complex combined therapy of patients with ARDS, which leads to decreased mortality, improved oxygenation, and decreased need for aggressive artificial pulmonary ventilation. The authors of this article present their own experience with administration of exogenous surfactant in therapy of children with ARDS

A longitudinal perspective of hormone replacement therapies (HRTs) on neuromotor capabilities in males with 47,XXY (Klinefelter syndrome)

PURPOSE: The purpose of this study was to delineate the effects of variable hormone replacement therapies on neuromotor function in a large cohort of males with 47,XXY from birth to adulthood. METHODS: A total of 270 participants aged 16 days to 17 years 11 months prenatally diagnosed with 47,XXY were assessed by their pediatric endocrinologist and were administered hormone replacement therapies accordingly. Infants and school-aged children with 47,XXY were administered neuromotor assessments during routine neurodevelopmental evaluations. For statistical analysis, participants were segregated on the basis of treatment status. Two-tailed t tests, 1-way analysis of variance, and post hoc analysis determined significant group differences on each assessment. RESULTS: In infants, the early hormonal treatment (EHT) group performed significantly better than the untreated group on fine motor and motor composite domains. In school-aged children, we observed significantly improved scores on fine motor control, coordination, agility, and strength domains among males treated with EHT (or any combination thereof) compared with those who did not receive early treatment. CONCLUSION: The highest treated combination group was associated with the highest neuromotor function, although the EHT group also often performed better than the other groups. This suggests EHT may be essential in promoting long-term optimal neuromotor outcome in males with an additional X