Music is a universal human trait and ubiquitous in everyday life. However, about 4% of the population is afflicted with a rare perceptual disorder of music perception and production, referred to as congenital amusia. Scientific research about this lifelong disorder has developed only recently, and its behavioral and cerebral underpinnings are still under-investigated. The major deficit in congenital amusia is linked to the processing of the pitch dimension in the auditory signal, thus having destructive consequences for music processing. Pitch discrimination thresholds are generally abnormally high in amusic individuals, and this has been initially interpreted as evidence for a primary deficit in pitch perception. More recent findings have revealed a deficit in short-term memory of pitch information, which seems to be the principal impairment as it can occur without pitch perception deficits. Our present research project will investigate behavioral and cerebral correlates of pitch perception and memory with two major goals: Firstly, we aim at deciphering the deficits as well as the spared processes linked to pitch perception and memory in congenital amusia by combining behavioral measures and brain imaging studies (with both functional and anatomical methods). Secondly, we intend to pave the way towards a rehabilitation program for amusic individuals, informed by the knowledge already acquired about the perceptual and memory deficits in amusia and by the knowledge about cross-modal interactions and benefits we have gained in previous research. Our project has three novel, original aspects in comparison to previous research. 1) We will investigate pitch perception and memory in the amusic brain and the normal brain by combining three approaches, namely behavioral, anatomical, and functional imaging methods in the same participants. 2) Our investigations will be using not only, as classically done, explicit investigation methods, but also implicit, indirect investigation methods. The power of implicit processing despite observed explicit failures and deficits has been reported in neuropsychology for a long time in visual perception, language processing and memory, and has been recently extended to music processing, which we will now investigate for congenital amusia. 3) Based on the spared implicit processing capacities, we will combine the investigation of auditory processing with cross-modal interactions. Previously reported audio-visual interactions motivate the development of a research project that exploits cross-modal influences to boost auditory (pitch) processing with concurrent visual information. This allows us to develop and test training methods that should benefit pitch perception and memory. Beyond these perspectives concerning congenital amusia per se, our research program will more generally deepen our understanding of perceptual and memory processes and their cerebral underpinnings. It will benefit to the understanding of basic brain functioning for the perception and memory of auditory information (music, language), but also its interaction with visual information. Finally, the rehabilitation procedures that we aim to develop could further be transposed to pathologies that also encompass deficits in the processing of the pitch dimension in the auditory signal, such as cochlear hearing loss (in particular for people receiving cochlear implants) or dyslexia.

Multicomponent reactions (MCR) have recently garnered a lot of attention, these processes offering an efficient access to a broad range of molecular diversity in a limited number of operations. While MCRs based on ionic and organometallic reactions have enjoyed a wide interest, such is not the case for multicomponent reactions relying on free-radical processes. In this project, we propose two novel free-radical mediated three-component processes that we called carbo-alkenylation and alkynylation. These reactions are based on the coupling between an electrophilic radical species, generated from the corresponding halide or xanthate, an electron-rich olefin and an electron-poor acceptor (unsaturated sulfones and nitroolefins). In the first part of the program, the nature of the different partners will be varied as to determine the best reacting system. In parallel, DFT calculations will be performed to establish a reactivity scale between the different components and to study the mechanism of the addition of nucleophilic radicals onto vinyl- and alkynylsulfones. Experimental and theoretical reactivity scale will be compared as to establish a predictive tool for these free-radical MCRs. A diastereocontrolled version of the carbo-alkenylation and alkynylation above will then be devised using chiral allylsilanes and allylic alcohols that should provide an access to enantioenriched adducts. We also envision, as a long-term objective, developing organocatalyzed enantiocontrolled carbo-alkenylation and alkynylation. Such a process has no precedent in the literature and appears as very challenging. We will thus start our study by devising an enantioselective version of a carbo-oximation reaction that we developed recently. Enantioselective carbo-alkenylation and alkynylation will be studied subsequently based on these preliminary results. For this purpose, activation of the electrophilic radical precursor and/or activation of the acceptor will be investigated using chiral Lewis and Brønsted acids. The last part of the project will finally focus on the development of new domino processes involving two successive multicomponent reactions. Our objective is to perform such post-functionalizations in a single pot, the adduct generated during the first MCR serving as a new component for a second MCR. Three different types of domino processes will be investigated. We will first study a free-radical carbo-alkenylation/1,4-addition/olefination domino process, relying on Julia or Horner-Emmons olefinations. Using acylsilanes as radical precursors, we will also develop an unprecedented cascade where a 1,4-addition of a nucleophile onto a vinylsulfone, followed by a cyclisation onto the acylsilane, will trigger a Brook rearrangement, to eventually provide functionalized silyl enol ethers. Finally, a third domino process will be developed based on an intramolecular Michael-type cyclisation/olefination sequence that should afford new unsaturated cyclic or polycyclic systems. These domino processes will be first tested on model compounds and their value illustrated with straightforward synthesis of small natural products. As a summary, we plan developing new free-radical additions of functionalized carbon fragments across the pi-system of non activated olefins. Such processes result in the neat formation of two new C-C bonds and the generation of a stereogenic center, which stereochemistry should be controlled using organocatalysis. On the whole, this project proposes to tackle fundamental aspects of radical chemistry, including the reactivity of olefins and the enantiocontrol in C-C bond formation under radical conditions.