Good timing in total synthesis: The case of phoslactomycin A

Article abstract of DOI:10.1002/chem.201000104

The importance for the right order of functional group introduction and manipulation (good timing) was demonstrated in the course of a total synthesis of phoslactomycin A. The synthetic strategy comprised a Cu^Ithiophene carboxylate (CuTC, Liebeskind's reagent)-mediated coupling to introduce the Z, Z-diene at the final stage of the synthesis in the presence of a protected phosphate. Key features for the assembly of the C1-C13 fragment were an asymmetric dihydroxylation, an Evans-aldol reaction and an advanced protective group strategy. The C14-C21 fragment was accessible via an asymmetric 1, 2-addition to cyclohexenone and a subsequent diastereoselective ketone reduction. One crucial task was the dihydroxylation of the C8-C9 alkene, the introduction of the C6-C7 double bond and the generation of the C25-nitrogen functionality. A second example consisted of the best sequence for the generation of the functional groups in the core part (first phosphorylation, second iodo-olefination, third azide/carbamate conversion). The synthetic solutions from this approach are compared with the already existing contributions in the phoslactomycin area.