Stereoselective Synthesis of Densely Substituted Tetrahydroquinolines by a Conjugate Addition Nitro-Mannich Reaction with Carbon Nucleophiles

Conjugate addition of an alkyl group to a series of 2-imino-nitrostyrenes and then addition of trifluoroacetic acid initiates a nitro-Mannich cyclisation to give cis,cis-2,3,4-substituted tetrahydroquinolines in good yield and high diastereoselectivity

Intramolecular conjugate addition nitro-mannich reaction: Towards the synthesis of schizozygine

Part 1: The introduction of this thesis describes in detail the development of the nitro-Mannich reaction, in particular organocatalytic methodologies and its use in the synthesis of N-heterocycles. Additionally a current review of cascade cyclisations to furnish tetrahydroquinolines is detailed. The results and discussion describes the strategies involved in synthesising sensitive nitrostyrenes tethered onto an imine. It was found that classical disconnections to nitrostyrenes, involving the Henry reaction, were successful but low yielding and with poor substrate scope. An alternative disconnection involving a condensation between 2- vinylanilines and aldehydes, then subsequent nitration with AgNO2/TEMPO provided the desired nitrostyrene. It was found that this reaction sequence gave various substituted nitrostyrenes in high yields and was scalable. The cascade cyclisation was then investigated using hydride and carbon nucleophiles. This was highly selective for either the cis or cis,cis diastereomer. Use of a simple thiourea catalyst and a Hantzsch ester as the hydride source gave access to these cis-tetrahydroquinolines in high enantioselectivities (up to >99% ee). Investigation into using chiral phosphine ligands for the enantioselective addition of carbon nucleophiles, such as dialkylzincs, failed to give any stereoselectivity. Briefly an enantioselective approach to cis,cis-tetrahydroquinolines is discussed, using a standard intramolecular nitro-Mannich reaction. / Part 2: The introduction to this section describes the Schizogane family of alkaloids, the approaches to their total synthesis and a review of both the nitro-Mannich reaction and the nitro group in total synthesis. The results and discussion then details our approach to Schizozygine, the major alkaloid in the Schizogane family. Our retrosynthesis utilizes an intramolecular Pd catalyzed C-N bond formation and the enantioselective synthesis of syn,anti-nitroamines, both methodologies have been developed within our group. The main body of this work describes the approaches for an enantioselective synthesis of the syn,anti-nitroamine and its use in the synthesis of a key piperidine intermediate

Asymmetric Intramolecular Conjugate Addition Nitro-Mannich Route to cis-2-Aryl-3-nitrotetrahydroquinolines

Reductive cyclization of 2-iminonitrostyrenes (from the condensation of 2-aminostyrenes with an aldehyde and subsequent nitration of the alkene) using a bifunctional thiourea catalyst and tert-butyl-Hantzsch ester leads to an intramolecular conjugate hydride addition nitro-Mannich reaction to give the corresponding cis-2-aryl-3-nitrotetrahydroquinolines as single diastereoisomers in high yields and enantioselectivities

Base-Controlled Diastereoselective Synthesis of Either anti- or syn-β-Aminonitriles

Deprotonation of secondary alkane nitriles with nBuLi and addition to aryl imines gives kinetic anti-β-aminonitriles. Use of LHMDS allows reversible protonation of the reaction intermediate to give syn-β-aminonitriles. The pure diastereosiomers can be isolated in good yields, and the mechanism was elucidated

Reductive conjugate addition nitro-Mannich route for the stereoselective synthesis of 1,2,3,4-tetrahydroquinoxalines

A concise, high yielding and structurally divergent synthesis of complex 1,2,3,4-tetrahydroquinoxalines with excellent diastereoselectivity is described. A wide array of nitroalkenes and imines derived from commercially available aromatic aldehydes and 2-chloroanalines were subjected to a key reductive conjugate addition nitro-Mannich reaction to give diastereomerically pure β-nitro amines. Sequential reduction of the nitro function followed by Pd-catalyzed intramolecular N-arylation of the resultant primary amine onto the 2-chloroanailine gives highly substituted 1,2,3,4-tetrahydroquinoxalines. Non basic imines were found to participate better in the nitro-Mannich reaction if the stronger acid methanesulfonic acid was used to promote the reaction. The 3 step reaction sequence should be useful for the array synthesis of drug like scaffolds

Widespread adaptive evolution during repeated evolutionary radiations in New World lupins

The evolutionary processes that drive rapid species diversification are poorly understood. In particular, it is unclear whether Darwinian adaptation or non-adaptive processes are the primary drivers of explosive species diversifications. Here we show that repeated rapid radiations within New World lupins (Lupinus, Leguminosae) were underpinned by a major increase in the frequency of adaptation acting on coding and regulatory changes genome-wide. This contrasts with far less frequent adaptation in genomes of slowly diversifying lupins and all other plant genera analysed. Furthermore, widespread shifts in optimal gene expression coincided with shifts to high rates of diversification and evolution of perenniality, a putative key adaptation trait thought to have triggered the evolutionary radiations in New World lupins. Our results reconcile long-standing debate about the relative importance of protein-coding and regulatory evolution, and represent the first unambiguous evidence for the rapid onset of lineage- and genome-wide accelerated Darwinian evolution during rapid species diversification

Asymmetric synthesis of piperidines using the nitro-Mannich reaction

A method for the synthesis of functionalized piperidines containing 3 contiguous stereocentres in the 2-,3- and 4- positions uses a diastereoselective nitro-Mannich to control stereochemistry. The nitro-Mannich reaction between a β-aryl/heteroaryl substituted nitroalkanes and glyoxylate imine provides β-nitro-amines with good selectivity (70:30 to >95:5) for the syn, anti-diastereoisomers. Reductive cyclisation with BF3.OEt2 and Et3SiH gave, after purification, stereochemically pure piperidines in 19–57% yield for ten examples with different 4-aryl/heteroaryl substituents

Dyspneic athlete

Breathing concerns in athletes are common and can be due to a wide variety of pathology. The most common etiologies are exercise-induced bronchoconstriction (EIB) and paradoxic vocal fold movement disorder (PVFMD). Although some patients may have both, PVFMD is often misdiagnosed as EIB, which can lead to unnecessary treatment. The history and physical exam are important to rule out life threatening pulmonary and cardiac causes as well as common conditions such as gastroesophageal reflux disease, sinusitis, and allergic etiologies. The history and physical exam have been shown to be not as vital in diagnosing EIB and PVFMD. Improvement in diagnostic testing with office base spirometry, bronchoprovocation testing, eucapnic voluntary hyperpnea (EVH) and video laryngoscopy are essential in properly diagnosing these conditions. Accurate diagnosis leads to proper management, which is essential to avoid unnecessary testing and save healthcare costs. Also important to the physician treating dyspnea in athletes is knowing regulations on medications, drug testing, and proper documentation needed for certain organizations. The differential diagnosis of dyspnea is broad and is not limited to EIB and PVFMD. Ruling out life threatening cardiac and pulmonary causes with a proper history, physical, and appropriate testing is essential. The purpose of this review is to highlight recent literature on the diagnosis and management of EIB and PVFMD as well as discuss other potential causes for dyspnea in the athlete

Sleep patterns and sleep-related complaints of Brazilian interstate bus drivers

Sleep-related complaints have become a highlight for physicians as well as public health administrators. Studies of sleep patterns and sleep-related complaints of shift workers have been useful in minimizing reduction in the quality of life due to the warping of the sleep-wake cycle. The objective of the present study was to assess patterns of sleep, sleep-related complaints as well as physical activity and scoring rates for depression and anxiety in interstate bus drivers. Data were obtained with a sleep questionnaire, with the Beck inventory for depression, and the State-Trait Anxiety Inventory (STAI). A total of 400 interstate bus drivers from the northern, southern, central-western and south-eastern regions of Brazil were interviewed. Sixty percent of the subjects interviewed presented at least one sleep-related complaint, 16% admitted to have dozed at the wheel while on duty, and 41% stated that they exercised on a regular basis. Other sleep disturbance complaints reported were: sleep latency 29'17"; physical fatigue, 59.8%; mental fatigue, 45.4%; sleepiness, 25.8%; irritability, 20.6%; insomnia, 37.5%, respiratory disturbances, 19.25% and snoring, 20.75%. Scores for anxiety and depression were not in the pathological range. The present data reinforce the view that bus drivers are generally discontent with shift work and its effects on sleep. Consequently, it is very important to establish an appropriate work schedule for drivers, besides implementing photo-therapy and physical activities in order to minimize sleepiness when driving