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

Formaldehyde (methylene) acetal derivatives can be conveniently prepared, on a small scale, using parent Annonaceous acetogenins which have 1,2-, 1,4-, and/or 1,5-diols along their aliphatic chains. The resulting 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 acetogenins) per-Mosher ester [methoxy(trifluoromethyl)phenyl acetate or MTPA] derivatives of the acetal derivatives can then be prepared and used to determine absolute configurations of the chiral positions which bear the remaining free hydroxyls. Prior knowledge of relative stereochemical relationships then permits assignments of absolute configurations to additional chiral centers along the chain of the molecules. This method has been particularly useful in solving the absolute configurations of several nonadjacent bis-THF and mono-THF acetogenins, viz. bullatanocin (1), (2,4-cis and trans)-bullatanocinones (2 and 3), bullatalicin (4), (2,4-cis and trans)-bullatalicinones (5 and 6), squamostatin A (7), squamocin (8), gigantetrocin A (9), and goniothalamicin (10). Most of the resulting acetals (vs the parent acetogenins) show enhanced, bioactivities, and their mode of action is, likewise, by mitochondrial inhibition.