Divergence en Route to Nonclassical Annonaceous Acetogenins

Syntheses of the nonclassical annonaceous acetogenins, pyranicin, and pyragonicin from common latestage intermediates are presented. The construction of key elements relies on asymmetric HWE reactions, including the desymmetrization of a meso-dialdehyde and a parallel kinetic resolution of a racemic aldehyde. A stereoconvergent Pd-catalyzed substitution serves to install the C4 stereocenter in protected form with different orthogonal protective groups. A divergent strategy to form 1,4- and 1,6-diols, employing stereoselective Zn-mediated alkynylations, is used for completion of the core structures. Notably, the stereoselective coupling reaction toward pyragonicin proceeds with highly functionalized fragments. The methodology is further expanded by a divergent synthesis of all stereoisomers of the 2,3,6-trisubstituted tetrahydropyran subunit.