Studies directed toward the total synthesis of tedanolide and studies of conformationally controlled E2 elimination reactions in acyclic systems.

This dissertation describes research directed toward the total synthesis of the marine natural product tedanolide; specifically focusing on the synthesis of a C(1)--C(12) fragment that will be used in a highly selective methyl ketone aldol reaction. In addition to these efforts, studies concerning the regioselectivity of conformationally controlled E2 elimination reactions in acyclic systems is discussed. At the outset of the synthesis of the C(1)--C(12) fragment of tedanolide, it was envisioned that a highly regioselective E2 elimination reaction could be utilized to install the C(8)--C(9) E-trisubstituted olefin. Unfortunately, it was discovered that steric shielding coupled with free rotation around the polypropionate backbone resulted in the highly selective formation of the undesired Z-oelfin. Therefore, it was necessary to design a polypropionate system that would provide a better model for the synthesis of E-trisubstituted olefins. This was accomplished by the synthesis of a ten carbon chain with methyl substituents at C(2,4,6 and 8; having a 1,3 anti relationship) and oxygen substituents at C(3,5 and 7; having a 1,3 anti relationship). The activation of the C(5) hydroxyl by its transformation to a mesylate allowed for an extensive study on the regioselectivity of an E2 elimination governed by conformational control through steric interactions. The E2 elimination did prove to be selective, however, a predominating Grob fragmentation limited the scope and utility of this methodology. Ultimately, this methodology was abandoned and an emphasis was placed on the synthesis of the C(1)--C(12) fragment through more traditional synthetic methods. During the synthesis of the C(1)--C(12) fragment of tedanolide vinyl anion, Horner-Wadsworth-Emmons and aldol coupling strategies were examined. Finally, a selective ethyl ketone aldol reaction for the installation of the C(6)--C(7) bond afforded the most concise and selective synthesis of the C(1)--C(12) fragment. Coupling of the C(1)--C(12) methyl ketone fragment with the C(13)--C(21) aldehyde fragment proved to be efficient and highly selective. Examination of post coupling modifications provided insight into the final strategy of the tedanolide synthesis, but were ultimately unsuccessful.Ph.D.Organic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/130244/2/3042141.pd