Tunable thiofumarate stereoselective cycloadditions via aminomefloquine catalysis†

Abstract

Norcamphane is a bicyclic, lipophilic motif present in widely used drugs. It also serves as an adamantane substitute, expanding the structural diversity of biologically active compounds. Despite its potential, norcamphane has received little synthetic attention, with related six-membered ring systems dominating research. Jørgensen et al. developed asymmetric synthesis of norcamphane using a Cinchona-derived amine, but its single-enantiomer nature limited pharmaceutical applications, and fumarates enable only limited enantioselectivity. Here, we introduce a highly selective approach using aminomefloquine as an organocatalyst and thiofumarates as electrophiles. Both aminomefloquine enantiomers efficiently catalyze the reaction, yielding norcamphane thioesters as single regio- and diastereoisomers in both enantiomeric forms. This strategy overcomes previous limitations, offering improved selectivity and broader applicability. Moreover, thioesters act as versatile oxo-ester equivalents with enhanced reactivity. We also show that the yields can be improved by mechanochemical methods (ball milling) when compared to solution phase reactions, albeit with slightly lower enantioselectivity. Finally, based on dispersion-corrected density functional theory (DFT) calculations, we demonstrate that the mechanism can be classified as stepwise subsequent Michael additions, with the amine playing a dual role in enamine and imine formation, ensuring facial selectivity. The proposed computational protocol allowed us to accurately reproduce specific product yields based on kinetic modelling, and it can be further used to scan for other effective variants and catalysts for related reactions. This work presents catalysts that operate via the same molecular principles as 9-amino-9-deoxy-epi-quinine, enabling the efficient synthesis of bicyclic ring systems and expanding the scope of organocatalytic strategies.