Development of a Modular Synthetic Strategy for Saturated Polyisoprenoid Natural Products

Naturally occurring polyisoprenoid compounds bearing highly methyl-branched arrays are found in glycolipids, vitamins, archaeal lipids, and insect pheromones. Significant synthetic effort has been directed toward their synthesis, as access to these compounds facilitates biological investigations and structure–activity relationship (SAR) studies. Two major challenges in polyisoprenoid synthesis are the efficient elongation of saturated aliphatic chains and the precise control of multiple remote stereocenters. To address these challenges, our group developed a modular strategy for the stereocontrolled synthesis of polyisoprenoid compounds based on the Mitsunobu reaction with a stabilized phosphorane reagent, cyanomethylenetrimethylphosphorane (CMMP). In this strategy, 1,3-benzodithiol tetraoxide (BDT) serves as a versatile carbon pronucleophile for assembling chiral alcohol building blocks with precise stereocontrol. Differentially protected alcohols are essential for the efficient elongation of chiral methyl-branched arrays. The utility of this modular approach is demonstrated through the total syntheses of two representative targets: α-tocopherol, which features a chroman core bearing a saturated isoprenoid side chain with three stereocenters, and mycoketide, which possesses five methyl-branched stereocenters arranged in a 1,5-syn relationship along an extended saturated carbon chain. Furthermore, the combination of chiral alcohol building blocks with different stereochemical configurations enables stereodivergent access to polyisoprenoids and other structurally related natural products.