Innovative Asymmetric Synthesis Routes toward Bioactive, Chiral Heterocyclic Compounds

The PhD project I am about to present focused on the development of five (photo)catalytic methodologies for the synthesis of chiral, polyfunctionalized heterocycles with potential biological activities. Capitalizing on a multidisciplinary approach spanning from organocatalysis, photoredox and biocatalysis, the work aimed to expand the synthetic toolbox available for the construction of complex, heterocyclic molecular architectures by exploring the peculiar reactivity of vinylogous systems. Central theme of my work focused on the strategic activation of π-extended enolate-type donor systems, such as silyl (poly)enol ethers and remotely enolizable heterocyclic-based scaffolds, which have demonstrated remarkable reactivity across both polar and radical domains. Chapter 3 describes the development of a stereoselective organocatalytic protocol for the synthesis of chiral, enantiopure 6,7-dihydrobenzo[d]imidazoles 3. Initially, a homosynergistic protocol − which involved the covalent, aminocatalytic activation of both an imidazole carbaldehyde 1 to the corresponding ortho-quinodimethane (oQDM) intermediate A (HOMO-raising) and a suitable enal 2 to the iminium ion B (LUMO-lowering) − was evaluated without success. Fortunately, dicyanovinylidenes 4, which were easily obtained from 1 via a Knoevenagel condensation with malononitrile, proved to be effective pronucleophiles. The increased acidity of the benzyl C(sp³)–H bond in 4 (the so-called malononitrile activation strategy) facilitated the efficient formation of the challenging imidazole-derived ortho-quinodimethane intermediate C (IM-oQDM). This species successfully reacted with the chiral iminium ion B in a stepwise [4+2] cycloaddition, enabling access to a wide range of enantioenriched products 3, obtained in moderate to good yields with excellent regioselectivity and stereocontrol. Furthermore, late-stage editing and telescoped one-pot functionalization of the targeted scaffolds 3 showcased the synthetic versatility of the disclosed methodology. Chapter 4 focuses on the synthesis and biological activity evaluation of chiral tetrahydroquinazolinedione derivatives of type 5 as potential inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Starting from a previously identified hit compound, a structure–activity relationship (SAR) study was conducted, supported by molecular docking and dynamics simulations. A second-generation library was so designed and synthesized, introducing variations at the N1/N3 and C7 positions. The antiviral activity of the obtained scaffolds was then evaluated in a series of in vitro assays in collaboration with Prof. Kurt Vermeire (Molecular Structural and Translational Virology group at the KU Leuven University). Chapter 5 introduces a novel, photocatalytic strategy for the benzylation of 2-silyloxyfurans 6 with N- (arylacetoxy) phthalimides 7 (NHPI esters), enabling access to various γ-benzyl butenolides 8 in good, isolated yields. Two complementary protocols were developed. The first relied on a radical–radical coupling enabled by an unprecedented photoinduced electron transfer (PET) oxidation of electron-rich silyloxyfurans 6 and was particularly suited for electron-deficient benzyl radical precursors 7. The second protocol, better suited for electron-rich 2- or 4-alkoxy substituted NHPI esters, capitalized on a radical–polar crossover pathway which generated a key benzyl carbocation intermediate which readily reacted with 6 preferentially at the γ-position. Both protocols were thoroughly optimized and applied to a broad substrate scope. Selected adducts were further transformed into bioactive polyphenol metabolites, such as hydroxyphenyl-γ-valerolactones and valeric acids, demonstrating the synthetic versatility and utility of the disclosed methodology. Chapter 6 describes a photoredox catalytic protocol for the regioselective γ-alkylation of 2- silyloxyfurans 6 with 2-bromoacetophenones 9, affording chiral ε-keto-γ-butenolides 10. The method relied on the coupling between electrophilic α-keto, open-shell intermediates 9• − generated from single electron reduction of radical precursors 9 upon visible light irradiation − with vinylogous silyloxyfurans 6 here acting as efficient, electron-rich SOMO-philes. The optimized conditions provided excellent regio- and chemoselectivity across a diversified substrate scope. The resulting butenolides were further transformed into fused heterobicyclic frameworks, highlighting their value as intermediates for accessing complex, heterocyclic frameworks. Finally, Chapter 7 describes the work I conducted on a six-month off-site experience as visiting PhD student at the University of Graz in Austria, under the supervision of Prof. Wolfgang Kroutil. Here, the catalytic potential of cytochrome P450 peroxygenases was explored for the enantioselective α- aminofunctionalization and α-hydroxylation of aromatic and aliphatic carboxylic acids 11. Despite extensive screening of natural and engineered enzymes, nitrogen donors, and reaction conditions, no aminated products were detected. Hydroxylation studies proved to be more effective, thus affording α-functionalized products 12 in moderate yields and excellent enantiocontrol. Sitedirected mutagenesis experiments were carried out to gain mechanistic insight into the biocatalyst mechanism.