After an elegant retrosynthetic plan, we designed a route based on an enantio- and diastereoselective Diels–Alder reaction between carefully engineered diene and dienophile partners.
• Diene synthesis:
A modular approach employing two consecutive Wittig reactions was developed, starting from β-ketoesters and stabilized ylides. Optimization of temperature and reagent equivalents led to high yields and improved (E)-selectivity, suppressing undesired regioisomers. The final step involved ester reduction, affording functionalized diene building blocks in good to excellent yields.
• Dienophile synthesis:
Substituted acroleins were prepared via a retro-Diels–Alder strategy on cyclic acetal precursors. This sequence was demonstrated on multi-gram scale, enabling reliable access to volatile aldehyde dienophiles required for the cycloaddition.
• Diels–Alder reaction (racemic):
Initial screening with Lewis acids showed limited reactivity, subsequent modification promoted the desired cycloaddition to give bicyclic lactols in moderate yields as single regioisomers. Oxidation to the corresponding lactones was optimized by proper choice of an oxidant, providing synthetically versatile intermediates.
• Enantioselective Diels–Alder reaction:
Chiral BINOL, SPINOL, and related diol ligands were explored in combination with aluminium complexes. Reaction parameters such as ligand structure, catalyst preformation, solvent, temperature, and acrolein addition rate were systematically optimized, identifying promising directions for further improvement.
• Protecting group effects:
Both free-OH and O-protected dienes were evaluated, bulkier protecting groups were detrimental. Free OH substrates remain the most versatile for subsequent transformations.
• Post-cycloaddition transformations:
Oxidation of lactols to lactones and subsequent Dieckmann or bromination sequences demonstrated access to advanced spirotetronate scaffolds. Although structural complexity introduced challenges (side reactions, rearrangements), several promising intermediates were isolated, including tricyclic cores and brominated derivatives resembling natural product motifs.
• Catalyst development:
To overcome the limitations of axially chiral phosphoric acids (BINOL, SPINOL, VAPOL, TADDOL), we initiated the synthesis of novel helically chiral phosphoric acids. A scalable synthesis of racemic biaryl-diol was achieved, followed by resolution to afford enantiopure material. Subsequent functionalization delivered a first library of helically chiral phosphoric acids, representing a new class of catalysts for enantioselective Diels–Alder and other organocatalytic transformations.
