Total Synthesis of (-)-5-Deoxyenterocin and Attempted Late-Stage Functionalization Reactions

The first total synthesis of (-)-5-deoxyenterocin has been accomplished starting from pentane-1,3,5-triol (16 steps in the longest linear sequence, 0.2 % overall yield). (-)-Menthone served as the source of chirality to distinguish the enantiotopic hydroxymethyl groups of the substrate. Key steps of the synthesis include two aldol reactions to either end of the C5-skeleton, a diastereoselective hydroxylation reaction and a biomimetic twofold intramolecular aldol reaction as the final step. Although this step suffered from geometrical constraints and was low yielding (10 %), enough synthetic material could be secured to substantiate the relative and absolute configuration of the natural product. Additional experiments were directed toward a C-H functionalization at carbon atom C5. Despite the fact that several protocols could be successfully applied to (3aR)-(+)-sclareolide as model substrate, (-)-5-deoxyenterocin withstood any selective functionalization. The polyketide natural product (-)-5-deoxyenterocin (2) was stereoselectively synthesized from aldehyde 1, which was in turn obtained from pentane-1,3,5-triol and (-)-menthone. An attempted functionalization at position C5 remained futile, although several C-H activation methods could be successfully applied to (3aR)-(+)-sclareolide (3).image

Automated summary

The first total synthesis of (-)-5-deoxyenterocin has been accomplished, starting from pentane-1,3,5-triol with a linear sequence of 16 steps and an overall yield of 0.2%. Key steps of the synthesis include aldol reactions, hydroxylation reactions, and an intramolecular aldol reaction. Despite attempts, a functionalization reaction at position C5 was unsuccessful.