TOTAL SYNTHESIS OF ZARAGOZIC ACID-A (SQUALESTATIN S1) - SYNTHESIS OF THE RELAY COMPOUND

Compound 2 has been prepared from the 1,6-anhydropyranohexose 3. The k ey process for elaborating the 1,7-dioxabicyclo[3.2.1]octane core of t he zaragozic acids is addition of an organometallic reagent to lactone 6 and treatment of the resulting 1,2,3-trihydroxy-6-oxo ethylene acet al with acid. Use of the cerium(III) reagent of 4-bromo-1-butene in th is process provided 7 in excellent yield, unaccompanied by the isomeri c 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 vi nyllithium to ketone 10. The latter addition was shown by 2D H-1 NMR e xperiments to provide the relative configuration found in the zaragozi c acids. Similar stereoselective additions were observed with 2-furyll ithium and (5-methyl-2-furyl)-lithium, but the resulting adducts are r esistant to ozonolysis. The synthesis of 2 completes a total synthesis of zaragozic acid A (squalestatin S1) (1).