Construction of the Zaragozic Acids Core Bicycle

Abstract

Concise synthesis of the bicyclic core of zaragozic acids has been accomplished by the utilization of (2S, 3S)-furylglycerol 7. The key features are based on the diastereoselective dihydroxylation of enone S followed by reduction of ketone 11 to control the stereochemistries at the C4-C6 positions of the target molecule. Addition of lithium trimethylsilylacetylide to aldehyde 20 provided propargyl alcohol 21, which was further transformed into the bicyclic core 25, a potent intennediate for the synthesis of zaragozic acids During the screening of fungi for inhibitors of squalene synthase, structurally related novel compounds, zaragozic acidsl and squalestatins 2 were isolated independently from Sporormiella intermedia and Phoma sp. C 2932 by Merck and Glaxo groups, respectively.(Figure l) These natural products exhibited potent activity against mammalian squalene synthase, a key enzyme in cholesterol biosynthesis lb,2c These compounds share a common 4,6,7-trihydroxy2,8-dioxabicyclo[3.2. I Joctane-3,4,5-tricarboxylic acid core and differ at C-1 alkyl and C-6 O-acyl side chains. The interest in both the novel structural feature and the significant activity has provoked a large number of synthetic studies3 and has resulted in total syntheses of zaragozic acids A4 and C5 by 6 groups. For ongoing studies directed to the synthesis of physiologically active natural compounds using chiral furylcarbinols 6 we have been interested in the synthesis of the squalene synthase inhibitor zaragozic acid. Here we report a facile method for the construction of the bicyclic core of zaragozic acids 7 Figure I . O ~:~ 0.6 OH OAC 5 1 Ph H02C O H02C 3 c02H OH zaragozic acid A / squalestatin S1 A typical member of the zaragozic acid and squalestatin family HO HO HO RO. OH 7 O OH 3 cO1 unlt