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. Both aldehydes and acetals are shown to be viable substrates for this reaction. Oxacyclic macrodimers are an important class of natural products that offer a wide array of structural complexity and bioactivity.1 These macrolides have become popular targets for synthetic chemists.2 The most direct way to construct these molecules is through the union of two monomeric species in a tandem dimerization and macrocyclization reaction. The most common version of this strategy utilizes two esterification reactions between an activated acid and an alcohol, the initial dimerization followed by a macrolactonization.3 While often successful, this approach does not greatly enhance the complexity of the intermediate through the formation of carbon-carbon bonds. Alternative bond-forming reactions, such as Suzuki coupling and olefin metathesis have been used with occasional success in dimerization and macrocyclization strategies.4,5 Herein we describe a new dimerization and macrocyclization strategy based on the Prins cyclization reaction. The Prins cyclization is a powerful reaction that forms cis-2,6-disubstituted tetrahydropyrans (THPs) through the addition of an olefin to an oxocarbenium ion generated from the condensation of an aldehyde with a homoallylic alcohol.6 Recently, intramolecular Prins cyclizations have been utilized as key macrocyclization steps in the synthesis of several THP containing natural products (Figure 1 A).7 We report the extension of this methodology to the formation of oxacyclic macrodimers through sequential Prins dimerization and macrocyclization reactions (Figure 1 B). This synthetic strategy has been applied to a model for the marine macrodiolide clavosolide A