Substituent Effects on the Regiochemical and Stereochemical Course of the Nussbaumer-Frater Variation of the Prins Cyclization

Eleven vinylogous carbonates were examined in the Nussbaumer-Frater variation of the Prins cyclization to provide 2,3,4,6-tetrasubstituted tetrahydropyrans.Results indicate that substrate olefin geometry is a more reliable control element than preset substrate vicinal stereochemistry for establishing C 2 -C 3 vicinal stereochemistry in tetrahydropyran products.The Prins cyclization has been developed into an effective route for the preparation of complex tetrahydropyrans. 1 Refinements of this methodology are plentiful in the recent literature. 2Consequently, subtle aspects of reactions have been revealed and numerous applications in the field of natural products synthesis have been reported. 3,4 ot surprisingly, the Nussbaumer-Frater variant of the Prins cyclization has become increasingly popular. 5,6 e recently reported a study of this reaction that revealed a variety of reaction pathways that compete with the usual cyclization to provide tetrahydropyrans. 6For example, when vinylogous carbonates (1a and 1b) were subjected to the Nussbaumer-Frater conditions, the major products were 3a (50%) and 4 (41%), respectively, rather than the expected tetrahydropyrans (2a and 2b) (both formed in lesser amounts) (Scheme 1).In addition, both cyclization substrates (1a and 1b) gave both dioxabicyclo[3.2.1]octanes (3a and 3b), indicating that stereochemistry across the initial C 2 -C 3 bond had been compromised.