Total Synthesis of (+)-Cymbodiacetal: A Re-evaluation of the Biomimetic Route

A total synthesis of (+)-cymbodiacetal (1) has been completed from (R)-(+)-limonene oxide using a hetero-Diels−Alder cycloaddition as a key step. The key Diels−Alder cycloaddition proceeds with endo-selectivity (2:1, endo/exo) in quantitative yield, and the two diastereomeric spirochroman products are isolable, stable products. Furthermore, the exo- and the endo-hetero-Diels−Alder cycloaddition products (2 and 7) can be oxidized with m-CPBA to produce (+)-cymbodiacetal (1) and the C2-symmetric bis-hemiacetal structure 8, respectively. The isomeric hemiacetal 9 is produced in both oxidation reactions. The structures of (+)-cymbodiacetal (1), its C2-symmetric diastereoisomer 8, and the isomeric hemiacetal 9 were confirmed using X-ray crystallography.