Catalytic olefin metathesis is a transformative transformation with many unique attributes, one being the possibility of converting a ring to a modifiable acyclic diene by ring-opening cross-metathesis (ROCM). However, the existing methods are rare and limited to those that generate E-enoates. To the best of our knowledge, there are no available methods for ROCM reactions that can be used to access Z-alkenes from reactions involving five- to eight-membered rings. To address this, we will develop a ROCM method for converting the small rings to readily alterable acyclic dienes efficiently and in high Z:E ratios. On the basis of preliminary (unpublished) results, a set of molybdenum alkylidene complexes recently designed by the host group will be utilized. We will investigate and develop a method for ROCM of cyclohexene with several commercially available Z- and E-alkenyl halides. The strategy will then be extended to five-, seven- and eight-membered ring alkenes. The diene products can be used for rapid synthesis of bioactive compounds, such as antitumor tetrahydrosiphonodiol, and their specifically altered analogs. Another notable aspect of the project will be application to precise skeletal alterations of polycyclic bioactive compounds. We will exploit the presence of an olefin within a bioactive compound as the launching point for brief sequences leading to various specific modifications. This will obviate the need for lengthy and tedious de novo synthesis of each analog. More specifically, we will develop the open ring modify close ring (OMC) strategy, and by using it prepare an assortment of specifically modified analogs of androstadiene and vindoline. Through collaboration with experts, these compounds will be tested for in vitro bioactivity. Catalyst and method development will thus be applied to accessing formerly uncharted chemical space, which is central to new lead discovery and drug development.

With most bioactive molecules, such as pharmaceuticals, and agrochemicals, being complex amines, efficient synthesis and functionalization is of crucial importance. Although much progress has been achieved, conventional strategies, especially those targeting the functionalizations of less reactive sites, are particularly ineffective. The current methods typically require forcing conditions, such as strong oxidizing agents and stoichiometric organometallic reagents or the installation of directing groups and N-protected functionalities, that jeopardize their utility in practical synthesis. To address these limitations, herein, we propose a new strategy for the direct and efficient functionalization of amine frameworks at their otherwise unreactive sites. Specifically, I will explore the dual Mn/Ni-catalytic systems, where the unique features of the Mn complexes drive the temporary activation of an amine generating a transient reactive imine intermediate, which in turn undergoes the functionalization step enabled by the Ni complexes. Attractively, the overall transformation employs Earth-abundant metals and occurs directly in ‘one pot’ without any stochiometric activating reagents, thereby underscoring the high atom economy enabled by multicatalysis. The mechanistic studies will be used to untangle catalytic aspects assisting the rational methodology development. Attractively, a range of functionalizations, including arylation, alkylation, olefination, and halogenations at different sites can be achieved, which will open up innovative routes to industrially important and value-added chemicals. This highly original project combines the strengths of complex systems chemistry with the power of catalysis to address the current limitations of organic synthesis, yielding a project of excellent, innovative science that will exploit my unique expertise in Mn catalysis while providing me extensive training in multicatalysis, reaction networks, and computations.

MS2DCOFO will offer a highly talented and promising young researcher with a PhD in chemistry and an outstanding track record a world-class training through research in the cross-disciplinary, supra-sectoral and burgeoning field of multifunctional 2D semiconducting covalent organic frameworks (COFs). MS2DCOFO’s overall mission is to coach the fellow to become a mature and independent scientist and to prepare him for a leading position in academia or industry in Europe. Organic field-effect transistors are crucial elements for the fabrication of flexible, wearable, and biocompatible electronic devices. As miniaturization is approaching its limits, bringing an end to Moore’s law, beyond-CMOS devices, “More-than-Moore” technologies aimed at functional diversification are emerging as technologically viable strategy to boost the data storage capacity in tomorrow’s digital electronics. 2D COFs, as crystalline porous organic polymers built by covalently connecting organic building units, represent ideal platforms to incorporate simultaneously different switchable units into a given 2D skeleton with a atomically precise and robust structure. Thus, on the long term, multiresponsive semiconducting 2D COFs can become crucial components in neuromorphic devices and synaptic arrays to meet the present and future requirements of higher computational density that cannot be achieved by scaling down CMOS transistors. In this framework, the making of multiresponsive semiconducting 2D COFs represents a grand challenge that can offer a major technological advancement for next-generation electronic devices. Towards this ambitious goal, we will first design and synthesize multiresponsive 2D COFs, whose switchable properties and stabilities will be carefully characterized. The related high-quality 2D COF films fabricated via interfacial, in-situ solvothermal, or exfoliation methods, will be integrated and tested into multifunctional semiconducting devices for complex logic operations.

Allogeneic tissue graft (hematopoietic cell transplantation; HCT) and solid organ transplantation (SOT) (Kidney, Heart, Lung,..) save tens of thousands of lives annually. Yet their success is compounded by a high incidence of the potentially fatal graft-versus-host disease (GvHD) in HCT and chronic rejection (CR) in SOT. This is primarily due to the existence of yet unknown histocompatibility loci which have escaped detection - besides certain immunogenic peptides - since the identification of the Major Histocompatibility Complex (MHC; also called Human Leukocyte antigen “HLA” in man) in 1940-1950s. The identification of these hitherto unknown histocompatibility loci in man is the major aim of this proposal. Our contribution to MHC genetics includes the identification of the sole, non-HLA, MHC-encoded, class I molecules; the MHC class I chain-related MIC genes (A second lineage of mammalian major histocompatibility complex class I genes. | PNAS), which we recently qualified as a bona fide histocompatibility gene (The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation | Nature Medicine). Here we aim to identify the totality of histocompatibility loci embedded within our genome. We will apply a pluri-omics approach (successfully applied elsewhere Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort (science.org)) on deeply phenotyped cohorts of kidney transplants and HCT. Identified candidate loci will be validated based on their ability to be presented by MHC molecule and to elicit T- and/or B-cell responses. In contrast to the classical, hypothesis-driven approaches, which have collectively failed to identify universally applicable such loci in the past 70 years, our approach is unbiased, data-driven and unprecedented in the field. It shall have direct relevance in our understanding of the primum movens of GvHD and CR and shall lead to a personalized therapy of the transplant patient.

Organofluorine compounds are scarce in natural products, but they are central to therapeutic science, agrochemical development and materials research. Incorporation of fluorine atoms within an organic molecule can have profound effects on pharmacokinetic and pharmacodynamic properties. Enantiomerically enriched fluoro amino acids possess physiochemical and biological properties that distinguish them from canonical amino acids and are key to advances in biological sciences, including peptide and protein engineering. On another front, many azasugars that have high pharmacological potential suffer from weak binding affinities and inferior pharmacokinetic properties; this problem may be addressed through glycomimetics. A promising strategy in glycomimetics entails H-to-F and OH-to-CF2H exchange. A compelling objective in modern chemistry, therefore, is the development of efficient, and practical strategies for diastereo- and enantioselective synthesis of readily modifiable organofluorine fragments that have a CF2H moiety. However, while enantioselective methods that can be used to form a C(sp3)–CF2H stereocenter are available, none apply to the formation of products bearing a fully substituted carbon stereogenic center that has a CF2H and a F substituent. To address this problem, we will develop a robust, practical, and scalable catalytic strategy for practical, efficient, diastereo- and enantioselective conversion of nitriles to homoallylic amines with a CF2H- and F-substituted allylic carbon. Our investigations will focus on an important but severely underdeveloped class of transformations, namely, catalytic diastereo- and enanantioselective addition of a carbon-based nucleophile to nitriles. We plan to utilize the new catalytic approach as the key design element in highly efficient diastereo- and enantioselective syntheses of polyfluoro α-amino acids, and aza-sugars, bearing a fully substituted carbon stereogenic center that has a CF2H and a F substituent.