In the frame of this research program, carried out at the Institute of Molecular Sciences (ISM) at the University of Bordeaux (UB), we propose a strategy directed towards the first total synthesis of leucophyllidine, a cytotoxic alkaloid recently isolated from L. griffithii. From the retrosynthetic analysis of the target, two fragments where identified that will be prepared then connected in the last stage of the synthesis, following a biomimetic approach. The “North-fragment” will be synthesized relying on a coupling between a key-aldehyde moiety and tryptamine through a Pictet-Spengler reaction/lactamization cascade. The “South-fragment” will be elaborated using a Friedländer-type condensation between a piperidinone, and an ortho-aminobenzonitrile. The key-aldehyde and the piperidinone will be elaborated using a unified strategy, including a novel stereoselective free-radical carbo-oximation process, which will install quaternary centers present in North and South fragments. Incorporation of the vinyl motif on the naphthyridine ring, through a Suzuki coupling, should complete the synthesis of the south-fragment. Both fragments will finally be connected, following a biomimetic Mannich-type strategy, which should provide sufficient quantities of this potent anticancer agent and analogues for future biological screening. Key objectives of this research program are the development of an access to new plant anticancer drugs for potential clinical use and the training of future leading experts in the field of natural product–derived drugs discovery, a domain in which Europe must remain competitive in the 21st century as cancer-related diseases are rapidly increasing with population’s life expectancy.
Landslides, the violent motion of large masses of debris, rock or snow, are an ever-present danger in mountainous regions the world over. After the landslide material falls down the mountainside, it will run out some distance away from the mountain even on relatively flat surfaces until the energy it gained from falling is dissipated by friction with the terrain. Although a simple energy balance argument suggests that a single rock cannot travel farther than the height from which it fell, many landslide runouts extend their ruin to seemingly safe distances far removed from their origin. These long runout landslides have baffled scientists for over a century, ever since Albert Heim recorded his study of the Elm rock landslide that devastated the village of Elm, Switzerland in 1881. There are many explanations for this phenomenon, such as lubrication by an interstitial fluid, but none of these satisfactorily addresses how a completely dry landslide can run out so far. Not understanding how and when long runouts will occur makes hazard mitigation and prediction extremely difficult, highlighting the urgency of this issue. Recently, Melosh and coworkers have provided support for a mechanism borrowed from the fluidization of impact craters, “acoustic fluidization”, by using idealized 2D simulations of circular disks, but more work is needed to show that this mechanism is a feature of real 3D flows and robust for a range of conditions. We will perform laboratory experiments and fully 3D simulations of granular flows using simultaneous pressure and velocity measurements to test the acoustic fluidization hypothesis. We will also look for a crossover between this dry mechanism and the lubrication mechanisms for wet landslides. Besides application to landslide engineering, we will also explore for the first time how fundamental features of granular flows such as shear flow instabilities (clustering and longitudinal stripes) affect the rheology of landslides and long runouts.
The concentration of carbon dioxide (CO2) in the atmosphere depends on carbon cycle processes, i.e. sources and sinks of carbon. The future evolution of the carbon sinks is not well known, which inhibits robust quantification of future atmospheric CO2 concentration and the resulting climate change. Understanding warm past periods is essential to constrain climate models and accurately predict future changes. During the last million years, warmer periods, called interglacials, happened every ~100,000 years. CO2 levels measured in interglacials before the mid-Bruhnes event (MBE), a large climate shift taking place ~430,000 years ago, are lower than the CO2 in interglacials after the MBE. The cause for this drastic evolution is still unexplained, resulting in uncertainty in the carbon cycle response to global warming. To resolve that issue, we propose to combine data and model simulations including new key processes. We suggest that a major mechanism was a slower circulation during interglacials before the MBE, resulting in more ocean carbon storage and lower atmospheric CO2. We also hypothesize that sea-level changes played a considerable role by altering carbon sinks from land vegetation and shallowing ocean carbonate sedimentation. We will include these mechanisms in a state-of-the-art climate model applicable to long timescales, and compare its modified behaviour with paleoclimate data and more complex models used for projections. This will provide a step change in our understanding of the impact of ocean circulation and sea-level changes on the carbon cycle. It will benefit the European and international scientific community by shedding new light on these processes, and by setting the basis to include these new mechanisms in climate models used for projections. The excellence of the experienced researcher in carbon cycle modelling combined with the expertise in ocean modelling and paleoclimate data from the host institution will ensure the success of this project.