Total Synthesis of Zaragozic Acid A (Squalestatin S1). Synthesis of the Relay Compound

Abstract

Compound 2 has been prepared from the 1,6-anhydropyranohexose 3. The key process for elaborating the 1,7-dioxabicyclo[3.2.1]octane core of the zaragozic acids is addition of an organometallic reagent to lactone 6 and treatment of the resulting 1,2,3-trihydroxy-6-oxo ethylene acetal with acid. Use of the cerium(III) reagent of 4-bromo-1-butene in this process provided 7 in excellent yield, unaccompanied by the isomeric 1,6-anhydropyranose isomer. The remaining two carboxy groups of the zaragozic acid core were added by addition of the lithium enolate of 8 to formaldehyde, to obtain 9, and cerium(III)-mediated addition of vinyllithium to ketone 10. The latter addition was shown by 2D 1H NMR experiments to provide the relative configuration found in the zaragozic acids. Similar stereoselective additions were observed with 2-furyllithium and (5-methyl-2-furyl)lithium, but the resulting adducts are resistant to ozonolysis. The synthesis of 2 completes a total synthesis of zaragozic acid A (squalestatin S1) (1).