Studies toward the total synthesis of ryanodine

The isolation of the alkaloid natural product ryanodine from Ryania Speciosa was reported over fifty years ago. Ryanodine's complex molecular structure, based on a pentacyclic core, with eleven contiguous stereocenters, five free hydroxyl groups, a hemiketal, and a pyrrolecarboxylic acid ester, makes it a formidable synthetic challenge. Herein are described efforts toward the total synthesis of this structurally intriguing natural product.; Starting from 3,6-dimethyl-7-hydroxy-1-indanone, the B-C-E ring system of ryanodine was constructed in an efficient manner, utilizing a phenolic oxidation as the key step. Stereocontrolled addition of singlet oxygen to the phenolic oxidation product concluded the introduction of the trans oxygen functionalities found at the B-C ring juncture of ryanodine. Key to the success of the overall strategy was the installation of a bromine blocking group at the para position of the phenol.; Having proven the viability and utility of the phenolic oxidation/singlet oxygen addition strategy for the assembly of the ryanodine B-C-E ring system, a more complex phenolic oxidation substrate which would allow the eventual construction of the complete carbon framework of ryanodine was designed. The relative stereochemistry of the main stereocenters present in the new system was set via a rhodium-mediated Claisen rearrangement. Extensive design and testing, especially on the part of the allylic alcohol involved in this reaction, was necessary, however, before the desired reactivity pattern was obtained.; The Claisen rearrangement product contains sixteen of the twenty diterpene carbon atoms found in the natural product, most notably lacking an isopropyl side chain, which is expected to be introduced via Grignard-type chemistry in the late stages of the synthesis. The relative stereochemistry of two of the eleven stereocenters has also been set and should guide the proper formation of any new stereocenters.; The task of carrying out the phenolic oxidation/singlet oxygen addition sequence on the new system and advancing the resulting intermediate to the natural product remains.