Development of a unified strategy for the asymmetric synthesis of lituarines A, B, and C. Progress towards the total synthesis of lituarine C

This dissertation describes the development and partial execution of a unified synthetic strategy for the total synthesis of the lituarines, A, B, and C, a small family of highly complex cytotoxic marine macrolides. Chapter one provides an introduction to the lituarine family of natural products. Specifically, the isolation, structure elucidation, and biological activity of the lituarines are discussed. Furthermore, a review of previous synthetic work relevant to the challenges that these macrolides pose is presented, concluding with a review of specific work aimed at the total synthesis of these natural products.* Chapter two provides a critical analysis of our synthetic approach to the lituarines and in particular a discussion of two of the key structural elements, the C(6,7)-trans epoxide and C(26–29) acyclic dienamide. The unified synthetic approach to the synthesis of the C(1–19) fragments of lituarines A, B, and C, highlighted by the iterative regio- and stereoselective functionalization of a trieneoate is then described. Using this protocol, the lituarine B/C C(1–19) iodide fragment (+)−188 has been constructed in a longest linear sequence of 24 steps proceeding in 10% overall yield.* The iterative functionalization of lituarine precursor trienoate (+)− 121 has been further extended through a substrate controlled regio- and stereoselective reduction to install the C(4–7) stereocenters requisite for further elaboration to the remaining member of the natural product family, lituarine A.* The potential application of this protocol for the stereodivergent synthesis of polyketide segments has been also been explored in the lituarine system. Investigation of the effect of preexisting stereocenters on the chemo and diastereoselectivity of trienoate functionalization was carried out using both antipodes of the chiral catalysts employed.* The remainder of Chapter 2 describes the synthesis of several functionalized dithianes corresponding to the common C(20–26) region of the lituarines. Novel dithioketalization conditions were developed for the conversion of α-chiral δ-lactols in the requisite dithianes. Starting from a common precursor, utilized in our spiroketal synthesis, four dithianes were constructed.* Chapter 3 describes our further progress towards the total synthesis of the lituarines, culminating in the synthesis of the C(1–29) macrolactone of lituarine C. Following fragment union via dithiane alkylation, homologation at the C(26) position led to installation of the C(26–29) E -eneyne, our precursor for late stage side chain elaboration. Oxidation to the C(23) ketone completed the functionality necessary for lituarine C. Further deprotection to provide the seco-acid, and Yamaguchi macrolactonization furnished the C(1–29) macrolactone of lituarine C in a longest linear sequence of 32 steps and an overall yield of 0.69%. Efforts are ongoing in our Laboratory with the goal of completing the total synthesis of all three members of this family of natural cytotoxins.* *Please refer to dissertation for diagrams