Synthesis of carbolines and analogues via rhodhium-catalyzed [2+2+2] cycloaddition with alkynyl-ynamides : application to the total synthesis of alkaloids

The main research theme of this dissertation is the synthesis of g- and b-carbolines using a metal-catalyzed [2+2+2] cycloaddition strategy of tethered alkynyl-ynamides (diynes) with nitriles. g- and b-carbolines form the core of a large group of natural product and represent important targets for organic chemists. Many of these carbolines showed pharmacological effects ranging from anti-tumor to anxiolytic and anti-HIV activity. A model study with N-Ethynyl-N-tosyl-2-(2-phenylethynyl)aniline and methyl cyanoformate showed that rhodium-based catalysts promote efficiently the reaction. A further optimization showed that the regioselectivity of the reaction can be tuned by the choice of the solvent or by the catalytic system. Application to a larger scope of diynes showed that the regioselectivity strongly depends on the type of substitution of the alkynyl moieties, giving regioselectivities in the range g:b = 1/0 to g:b = 0/1. This [2+2+2] cycloaddition approach for the synthesis of the g- and b-carboline cores was successfully applied to the first total synthesis of Isoperlolyrine and the total synthesis of Perlolyrine. Extension of this strategy to heterocumulenes as cycloaddition partners allowed the synthesis of a g-carbolinone, a thiopyrano[3,4-b]indol-3-imine and thiopyranothiones.

Long-term potentiation and neural network activity in the neonatal rat cerebral cortex in vivo

Long-term potentiation in the neonatal rat rnbarrel cortex in vivo rnLong-term potentiation (LTP) is important for the activity-dependent formation of early cortical circuits. In the neonatal rodent barrel cortex LTP has been so far only studied in vitro. I combined voltage-sensitive dye imaging with extracellular multi-electrode recordings to study whisker stimulation-induced LTP for both the slope of field potential and the number of multi-unit activity in the whisker-to-barrel cortex pathway of the neonatal rat barrel cortex in vivo. Single whisker stimulation at 2 Hz for 10 min induced an age-dependent expression of LTP in postnatal day (P) 0 to P14 rats with the strongest expression of LTP at P3-P5. The magnitude of LTP was largest in the stimulated barrel-related column, smaller in the surrounding septal region and no LTP could be observed in the neighboring barrel. Current source density analyses revealed an LTP-associated increase of synaptic current sinks in layer IV / lower layer II/III at P3-P5 and in the cortical plate / upper layer V at P0-P1. This study demonstrates for the first time an age-dependent and spatially confined LTP in the barrel cortex of the newborn rat in vivo. These activity-dependent modifications during the critical period may play an important role in the development and refinement of the topographic map in the barrel cortex. (An et al., 2012)rnEarly motor activity triggered by gamma and spindle bursts in neonatal rat motor cortexrnSelf-generated neuronal activity generated in subcortical regions drives early spontaneous motor activity, which is a hallmark of the developing sensorimotor system. However, the neuronal activity patterns and functions of neonatal primary motor cortex (M1) in the early movements are still unknown. I combined voltage-sensitive dye imaging with simultaneous extracellular multi-electrode recordings in the neonatal rat S1 and M1 in vivo. At P3-P5, gamma and spindle bursts observed in M1 could trigger early paw movements. Furthermore, the paw movements could be also elicited by the focal electrical stimulation of M1 at layer V. Local inactivation of M1 could significantly attenuate paw movements, suggesting that the neonatal M1 operates in motor mode. In contrast, the neonatal M1 can also operate in sensory mode. Early spontaneous movements and sensory stimulations of paw trigger gamma and spindle bursts in M1. Blockade of peripheral sensory input from the paw completely abolished sensory evoked gamma and spindle bursts. Moreover, both sensory evoked and spontaneously occurring gamma and spindle bursts mediated interactions between S1 and M1. Accordingly, local inactivation of the S1 profoundly reduced paw stimulation-induced and spontaneously occurring gamma and spindle bursts in M1, indicating that S1 plays a critical role in generation of the activity patterns in M1. This study proposes that both self-generated and sensory evoked gamma and spindle bursts in M1 may contribute to the refinement and maturation of corticospinal and sensorimotor networks required for sensorimotor coordination.rn