Development of Novel Anticancer Therapeutics: Total Synthesis of Lactimidomycin and its Analogs and Synthetic Strategies Towards Diterpene Natural Products.

Abstract

In this dissertation, various glutarimide- and macrolactone-containing natural products are described in relation to their isolation, biological studies, and synthetic preparations. In particular, synthetic and biological studies on lactimidomycin (and related analogs) in regards to its previously reported activity as a cancer cell migration inhibitor compared to recently reporterd activity as a highly antiproliferic (cytotoxic) agent are discussed.

Furthermore, the studies culminating in the total synthesis of the glutarimide-containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route featured a Zn(II)-mediated intramolecular Horner-Wadsworth-Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12-membered macrolactone of lactimidomycin on nearly a half gram scale. The synthetic route featured a late-stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allowed for a quick generation of an extended chain lactimidomycin homolog, which was tested in various biological assays alongside lactimidomycin and its truncated precursors.

Finally, the biosynthetic origin, previous C-H modification, and synthetic studies towards isopimerane- and pimerane-containing natural diterpenes are discussed. The assymetric strategy towards a key chiral intermediate was achieved, establishing a highly scalable and convergent. Furthermore, previous studies along with preliminary model studies we have conducted demonstrated the feasibility of achieving a proposed key Michael-double reaction sequence to the core of isopimerane-containing natural products such as sphaeropsidin A and C, compactone, aspewentin A and B, and their derivitized analogs.

Overall, the development of enantioselective routes to lactimidomycin, its structural analogs, and diterpene-type intermediates has successfully been accomplished.