Chiral Pool/Henry/Enzymatic Routes to Acetogenin Synthons

Enantiospecific and enantioselective approaches to the natural (16R,19R)- and the unnatural (16S,19S)- THF core of the bioactive acetogenin annonacin are described which utilizes both a chiral pool synthesis and enzymatic transformations. In the antipodal (2S,5S) THF series derived from D- (+)-glucosamine, the semi-protected THF aldehyde synthon allows for two-directional synthetic elaboration through a Henry reaction with a lipid-like nitroalkane. The resulting nitroalcohol having the unnatural (2S,5S)-THF core was oxidized to the corresponding α-nitroketone using a modified Collins oxidation. The intermediate α-nitroketone has potential for the preparation of the C15-C32 core and analogues through subsequent removal of the nitro group and reduction of the carbonyl.