gem-Dihalocyclopropanes as building blocks in natural-product synthesis: Enantioselective total syntheses of ent-erythramine and 3-epi-erythramine

ent-Erythramine ((-)-1), the enantiomer of the alkaloid erythramine, was prepared in 15 steps from known compounds. The first of three pivotal bond-forming steps in the synthesis was a Suzuki-Miyaura cross-coupling reaction of the starting materials to give a bis-silyl ether. The second involved silver(I)-induced electrocyclic ring opening of the gem-dichlorocyclo-propane formed in the next step and trapping of the ensuing π-allyl cation by the tethered nitrogen atom to give, following cleavage of the allyloxycarbonyl protecting group, an approximately 5:6 mixture of the chromatographically separable diastereoisomeric spirocyclic products. In the third critical bond-forming reaction, the iodide formed from one of the diastereoisomers underwent a radical-addition/ elimination reaction sequence that led to (-)-1 in 89% yield. The application of the same sequence of transformations to the other diastereoisomer afforded 3-epi-(+)-erythramine (3-epi-(+)-1).