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.

Absolute Configuration of the Polyketide Natural Product (-)-Enterocin.

The absolute configuration of the polyketide natural product (-)-enterocin was established by two independent approaches. In the first approach, synthetic enterocin with a defined configuration was compared to the natural product. While identical in all scalar properties, the compound displayed an opposite specific rotation and a different chiral HPLC retention time when compared with (-)-enterocin. In a second approach, the vibrational circular dichroism (VCD) of the natural product was measured and shown to be opposite to the calculated VCD of its enantiomer.

Biomimetic Total Synthesis of Enterocin.

The first chemical total synthesis of the highly oxygenated polyketide enterocin has been accomplished. The key step of the synthesis was a late-stage biomimetic reaction cascade involving two intramolecular aldol reactions in which each step proceeded in 52 % yield (averaged) and which established four of the seven stereogenic centers. The pivotal precursor for the cascade reaction was assembled from three readily available building blocks. A chiral dithioacetal with two stereogenic centers originating from L-arabinose represented the core fragment to both ends of which the other building blocks were attached by aldol reactions. The remaining stereogenic center was installed by Davis oxygenation immediately prior to the key step.