TOTAL SYNTHESIS OF THE REPORTED STRUCTURE OF NEAUMYCIN B

Neaumycin B is a macrocyclic polyketide natural product that has shown potent activity against U87 human glioblastoma cell. In this dissertation, the first stereoselective total synthesis of the reported structure of Neaumycin B is reported in a 2.3% overall yield on 90-mg scale. The synthesis features a convergent strategy via union of smaller fragments. Key transformations in the total synthesis involves a gram-scale nickel-catalyzed reductive cross-coupling/spiroketalization to construct the axial/equatorial (A/E) spirocyclic core of Neaumycin B, and a sequential Carreira asymmetric alkynylation/trans-reduction to forge the linear southern hemisphere of the macrocycle.Comparison of the NMR data of synthetic Neaumycin B and that of the natural sample, however, displayed significant deviations. In addition, the reported synthetic Neaumycin B showed no anti-proliferative activity against Glioblastoma cells. The stereo structures that span C3-C6, C8-C14 and C20-C41 of synthetic Neaumycin B were unambiguously confirmed by X-ray crystallography, and C7 stereogenicity was individually verified via Mosher ester analysis. Based on the evidences above, we are confident that synthetic Neaumycin B I prepared as described in this dissertation matches the reported structure, and a future revision on the proposed structure of this natural product will be necessary.