Formation of highly substituted tetrahydropyranones: application to the total synthesis of cyanolide A.

A new tetrahydropyranone synthesis has been developed that leads to cis-2,6-disubstituted 3,3-dimethyltetrahydropyran-4-one rings by condensation of an aldehyde and a hydroxy silyl enol ether. The reaction works with a variety of aldehydes to produce the tetrahydropyranone products in moderate to high yields. This new method was applied to the enantioselective synthesis of cyanolide A and its aglycone.

Total synthesis of the cyanolide A aglycon.

The synthesis of the potent molluscicide cyanolide A has been achieved in 10 steps without the use of protecting groups. The synthesis features a key Sakurai macrocyclization/dimerization reaction that simultaneously forms both tetrahydropyran rings and the macrocycle of the natural product.

Symmetric macrocycles by a Prins dimerization and macrocyclization strategy.

A tandem dimerization/macrocyclization reaction utilizing the Prins cyclization has been developed. This reaction develops molecular complexity through the formation of highly substituted dimeric tetrahydropyran macrocycles. Mild conditions utilizing rhenium(VII) catalysts were explored for aromatic substrates, while harsher Lewis acidic conditions were used for aliphatic substrates.

Lewis Acid-Promoted Mukaiyama Aldol-Prins (MAP) Cyclizations of Acetals, Ketals, α-Acetoxy Ethers, and Orthoformates.

The Mukaiyama aldol-Prins (MAP) cyclization of acetals stereoselectively provided substituted tetrahydropyrans. The scope of the reaction has been expanded to include other electrophiles, including ketals and α-acetoxy ethers. Finally, a double MAP cyclization with orthoformates is described.