The zaragozic acids and squalestatins are a family of naturally occurring fungal metabolites isolated and characterized independently by researchers at Merck and Glaxo. These natural products are potent inhibitors of squalene synthase and have potential as therapeutic agents for the treatment of hypercholesterolemia. All the zaragozic acids and squalestatins show a common 2,8-dioxabicyclo[3.2.1]octane core with an array of six stereogenic centers including contiguous quaternary carbons, and are different only at the C1 alkyl and C6 acyl side chains. Zaragozic acid A (squalestatin S1) (1) is a representative example of this novel class of compounds. Herein, we wish to report the efficient, convergent synthesis of 1 highlighting acetal [1,2]-Wittig rearrangement to join the C4-C5 bond with a simultaneous creation of the contiguous quaternary carbons as the key steps. Core part synthesis Our synthesis begins from the O-glycoside 4, which can be prepared from in four steps from protected L-arabino-γ-lactone 3 and bis(ethynyl)carbinol. The [1,2]-Wittig rearrangement of O-glycoside 4 to afford the (S, β)-C-glycoside 5 (87% dr) in 55% yield. The major isomer, separated by column chromatography was then converted to the key precursor 7 as follows. Hydroalumination of the TBDPS-substituted ethynyl group of 5 followed by ozonolysis gave the aldehyde which was then subjected to the Grignard reaction (vinyl magnesium bromide) to afford the desired alcohol 7 as a single diastereomer. Further oxidations of ethynyl, vinyl and α-oxy carbon (C1) gave the desired lactone 11, successfully. C1 side chain synthesis C1 side chain segment 15 has been synthesized from (S)-methyl lactate via [1,2]-Wittig rearrangement as a key step. C6 side chain synthesis C6 side chain segment 20 has been synthesized from the chiral α,β-unsaturated imide 16 via the sequential allylation/Cope rearrangement as a key step. Union of segments Generation of the alkyllithium C1 side chain derived from iodide 15 followed by addition of lactone 11 provided hemiketal 21 as a mixture of anomers. Oxidative cleavage of MPM ether followed by acetylation of the C4' hydroxyl completed the assemblage of hemiketal 22, precursor to the bicyclic core and associated C1 side chain. Hydrolysis/ketalization of hemikatal 22 with TFA, followed by the esterification and TBAF treatment to provide the desired bicyclic ketal 23. Protection of C7 hydroxyl with Boc group followed by the acylation with C6 side chain 20, acid treatment afforded the zaragozic acid A (1), whose spectral and chromatographic properties are identical with those of a comparison sample of the natural product.
