DETERMINING ABSOLUTE-CONFIGURATIONS OF STEREOCENTERS IN ANNONACEOUS ACETOGENINS THROUGH FORMALDEHYDE ACETAL DERIVATIVES AND MOSHER ESTER METHODOLOGY

Formaldehyde (methylene) acetal derivatives can be conveniently prepar ed, on a small scale, using parent Annonaceous acetogenins which have 1,2-, 1,4-, and/or 1,5-diols along their aliphatic chains. The resulti ng cyclic acetal protons give NMR signals which allow characterization of the relative stereochemistries of the two stereogenic centers that originated from the diols. Less complicated (vs the parent acetogenin s) per-Mosher ester [methoxy(trifluoromethyl)phenyl acetate or MTPA] d erivatives of the acetal derivatives can then be prepared and used to determine absolute configurations of the chiral positions which bear t he remaining free hydroxyls. Prior knowledge of relative stereochemica l relationships then permits assignments of absolute configurations to additional chiral centers along the chain of the molecules. This meth od has been particularly useful in solving the absolute configurations of several nonadjacent bis-THF and mono-THF acetogenins, viz. bullata nocin (1), (2,4-cis and trans)-bullatanocinones (2 and 3), bullatalici n (4), (2,4-cis and trans)-bullatalicinones (5 and 6), squamostatin A (7), squamocin (8), gigantetrocin A (9), and goniothalamicin (10). Mos t of the resulting acetals (vs the parent acetogenins) show enhanced, bioactivities, and their mode of action is, likewise, by mitochondrial inhibition.