Synthetic Study Directed toward the Squalene Synthase Inhibitor Zaragozic Acid and Squalestatin

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Studies toward the synthesis of the bicyclic core of the zaragozic acids (squalestatins) have been carried out by the utilization of verstile building blocks, chiral furylglycerols. The key features are the diastereoselective dihydroxylation followed by reduction of (2S, 3S)-6-tert-butyldimethylsiloxy-2-[(4S')-2', 2'-dimethyl-1', 3'-dioxolan-4'-y]-4, 5-bis (methoxymethoxy-methyl)-6H-pyran-3 (2H)-one to control the stereochemistries at the C4-C6 positions of the target molecule. Addition of lithium acetylide at the stereocenter C3 provided (3R, 4R, 5R, 6S)-1, 7-diacetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-8-nonyn-2-one-5, 6-bis[spiro-4'-(2', 2'-dimethyl-1', 3'-dioxolane)], a potent intermediate in the synthesis of the bicylic core of zaragozic acids (squalestatins).During the course of the synthetic studies, the Wittig rearrangement of furylmethyl ethers has been found. The Witting rearrangement of 3-furylmethyl ethers proceeded efficiently to give 3-methyl-2-furylmethanols or 3-furylethanols depending on the basicity of the butyllithium used. Synthesis of a furanosesquiterpenoid dendrolasin has been achieved with the 1, 2-rearrangement of 3-furylmethyl geranyl ether as a key step.