Studies in symmetry-driven synthesis of ryanodol: application of nucleophilic alkynylation for regio- and stereoselective desymmetrization

We developed a simple and novel desymmetrization strategy toward the total synthesis of ryanodol. The advanced intermediate 1 with six contiguous tetrasubstituted carbons was synthesized from the previously reported 3 by employing two key nucleophilic reactions. The first nucleophilic reaction to C2-symmetric tetraketone 2 installed the C6-tetrasubstituted carbon in a regio- and stereoselective fashion, leading to desymmetrized mono-alkynylated 8 without forming C2-symmetric bis-alkynylated 9. The second addition to triketone 8 also proceeded regio- and stereoselectively to construct the C2-tetrasubstituted stereocenter of 10.