Total synthesis of (+)-phyllanthocin: Strategy, implementation and extension

A feasible approach to the construction of the phyllanthocin framework with the relative and absolute stereochernistry of four stereogenic centers (C3, C5, C6 and C8) established has been developed. The key transformations include nucleophilic addition of an alpha-alkoxy lithio anion derived from the corresponding stannane, stereoselective nucleophilic epoxidation, regioselective epoxide cleavage and acid catalyzed spiroketalization. The strategy has successfully been implemented in a formal total synthesis of (+)-phyllanthocin in twenty eight steps from commercially available starting materials, in twenty steps from known compounds including a linear sequence of sixteen steps. A novel lanthanide triflate catalyzed Diels-Alder Maction exhibiting excellent regioselectivity (50:1) and stereoselectivity (92% de) has been developed to synthesize a chiral cyclohexenal precursor for (+)-phyllanthocin. A long range reverse Brook rearrangement of an alpha-alkoxysilyloxy lithio anion has also been identified. Formation of spiroketals via acid catalyzed ketalization of 1,2-diketone intermediates has been further developed as a general approach to the synthesis of bicyclic alpha-keto ketals. The synthetic utility of bicyclic alpha-keto ketals has been demonstrated by developing a novel regioselective deoxygenation of bicyclic alpha-keto ketals. High degrees of regioselective deoxygenation have been achieved using samarium diiodide in the presence of a tertiary amine bearing proton source.