Publication
Strained ring systems such as cyclobutanes offer unique opportunities for synthetic innovation. Its significant ring strain, caused by compressed bond angles, presents synthetic challenges; however, this same strain renders the ring a valuable handle for activation and subsequent functionalization for the construction of complex molecular structures that would otherwise be difficult to obtain through conventional methods. As such, the development of efficient strategies to construct and transform cyclobutane scaffolds remains a compelling area of research, with broad implications for the synthesis of complex, bioactive molecules.
Heteroatoms play a major role in medicinal chemistry by modulating the physicochemical properties of drug candidates, including electronic properties, hydrogen bonding potential, and metabolic stability. In this context, heteroatom-substituted cyclobutanes are increasingly used in pharmaceuticals and agrochemicals, where they exhibit strong pharmacological potential. In particular, β-disubstituted cyclobutanes have gained considerable attention due to their conformational rigidity induced by the cyclobutane ring. Nevertheless, general synthetic access to heteroatom-substituted β-cyclobutanes remains largely underexplored and generally lacks efficiency, selectivity, and broad applicability.
The first objective of this thesis was to establish a synthesis of novel donor-acceptor amino-cyclobutane monoesters, and to use these new compounds in catalytic, diastereoselective [4+2] annulation reaction with indoles as partners. The silylium-catalyzed methodology developed was applied both inter- and intramolecularly, with the latter yielding divergent alkaloid scaffolds depending on the reaction temperature. DFT studies rationalized this divergent outcome, and the synthetic utility of the method was demonstrated in the divergent synthesis of structurally diverse alkaloids, starting from simple and commercially available starting materials.
The second part of this thesis focused on expanding the scope of available aminocyclobutane esters. The previously developed approach, relying on in situ dehydrobromination and subsequent Michael addition, to synthesize donor-acceptor aminocyclobutane monoesters was streamlined and expanded to a wide variety of relevant N-heterocycles, such as imidazoles, azoles, and nucleobase derivatives, allowing the elaboration of a new library of aminocyclobutane esters and amides.
The scope of this approach using other hetero-atom nucleophiles, such as sulfur nucleophiles, was then investigated. As a result, we developed the diastereoselective synthesis of thiocyclobutane esters and amides. Moreover, we achieved the enantioselective version of the sulfa-Michael addition onto cyclobutenes using a chiral cinchona squaramide organocatalyst, affording 1,2-substituted thiocyclobutanes with high enantioselectivity.
Finally, attention was turned to the synthesis of multi-substituted aminocyclobutane esters