Studies on the total synthesis of (+/-)-cameroonan-7alpha-ol and presilphiperfolan-8-ol and discovery of a novel stereoselective Prins cyclization of delta,epsilon-unsaturated ketones.

摘要

Interest in the structures and biogenetic relationships of silphinane sesquiterpenes has prompted investigations into the synthesis of cameroonanol and presilphiperfolan-8-ol. The first total synthesis of (±)-cameroonan-7α-ol was completed and solvolytic rearrangement of its methanesulfonate derivative afforded prenopsanol, nopsanol, silphiperfol-6-ene, and silphiperfolan-7β-ol. Two separate routes to synthesize presilphiperfolan-8-ol were investigated resulting in the synthesis of nor-presilphiperfolan-2-one. As part of these investigations, a syn-selective Prins cyclization of δ,ϵ- and ϵ,ζ-unsaturated ketones to 1,3-chlorohydrins was discovered.; The first total synthesis of (±)-cameroonan-7α-ol was completed in eight steps and 5% overall yield from 3,5,5-trimethylcyclopentenone. Key steps of the synthesis involved installation of the third carbon ring of the cameroonanol skeleton accomplished by Sakurai addition, radical hydrobromination, and enolate cyclization. The Sakurai addition proceeded in good yield but poor stereoselectivity. The secondary methyl epimer and C15-nor analogs of cameroonanol were synthesized and characterized.; Solvolytic rearrangement of a mixture of cameroonanyl mesylate epimers provided prenopsanol, nopsanol, silphiperfol-6-ene, and silphiperfolan-7β-ol supporting the proposed structures and biogenetic relationships of these sesquiterpenes. Kinetic analysis revealed that the C7β-mesylate undergoes solvolysis at a rate 26 times faster than the C7α-mesylate. The rate difference was rationalized via sigma-bond participation to aid in displacement of the mesylate. Solvolysis of an epimeric mixture of nor-cameroonanyl mesylates gave results analogous to those above.; The synthesis of presilphiperfolan-8-ol was attempted via two separate routes. The first strategy employed a Prins cyclization reaction as the key step that unfortunately only provided products containing the triquinane skeleton. The second strategy entailed a cyclozirconation/carbonylation sequence to construct the presilphiperfolane carbon skeleton. The cyclozirconation/carbonylation reaction of a model compound resulted in the synthesis of nor-presilphiperfolan-2-one. However, this strategy was not successful with the fully elaborated substrate owing to difficulties incurred during the cyclozirconation reaction.; A novel stereoselective Prins cyclization reaction of unsaturated ketones was discovered. It was found that reaction of TiCl₄ with δ,ϵ- or ϵ,ζ-unsaturated ketones at low temperature followed by buffered methanolysis provided monocyclic and bicyclic cis 3-chlorocyclohexanols. Testing of ten unsaturated ketones and four acid activators provided evidence for substrate generality while the stereoselectivity was rationalized by intramolecular delivery of the nucleophile.