Abstract
Coumarin-based compounds are found in many terrestrial plants and marine organisms. It forms the core of many biologically active compounds, including meranzin hydrate and ulopterol, and it is of great interest to the synthetic research community due to its wide range of biological significance. Interest in meranzin hydrate and ulopterol arises from the fact that they are regio-isomers of each other and possess a stereogenic centre on the isopentyl glycol group attached to the 6th carbon of the coumarin for ulopterol and the 8th carbon of meranzin hydrate. Although these two compounds were isolated several times from various parts of plants and evaluated for biological activities, no stereoselective syntheses have been reported thus far. This dissertation describes a divergent approach to the total stereoselective syntheses of meranzin hydrate and ulopterol.
Various strategies and synthetic approaches for assembling the two natural products were evaluated, which eventually led to the enantioselective synthesis of meranzin hydrate. One of the key reactions was the Claisen rearrangement, which gave a mixture of regio-isomers the 6-allyl-7-hydroxycoumarin and 8-allyl-7-hydroxycoumarin, precursors to ulopterol and meranzin hydrate, respectively. 8-Allyl-7-hydroxycoumarin was the major product in the Claisen rearrangement, obtained in 87% yield. This compound was then elaborated into meranzin hydrate through 4 steps: methylation of the phenolic group (96% yield), Grubbs-II catalyst-mediated alkene cross-metathesis with a pre-prepared benzyl-protected citronellol to give osthol (90%), then Sharpless asymmetric dihydroxylation (SAD) to enantioselectivity introduce the chiral secondary alcohol and both enantiomers were made in yields of 61% and 41% when using AD-mix-α and AD-mix-β, respectively.
The successful synthesis of meranzin hydrate validates our divergent approach and the same transformations can be used for the synthesis of ulopterol from 6-allyl-7-hydroxycoumarin.