| This dissertation describes research which was targeted toward the total synthesis of the natural product (−)-spinosyn A. Spinosyn A is a structurally complex natural product that has significant insecticidal activity. Key features of the tetracyclic structure of the natural product include the following: an octahydro-as-indacene system which has six stereocenters, a twelve-membered lactone appended to the tricyclic indacene core, and finally, two glycosidic residues affixed to two secondary alcohols. In Chapter 1, the proposed biosynthesis of spinosyn A and synthetic studies by other research groups are presented. Chapter 2 summarizes initial approaches which utilize a tandem ring contraction and transannular Diels-Alder reaction of a tetraene macrolide to prepare a decahydro-as-indacene tricycle. Chapter 3 describes application of this same strategy to a more complex substrate, designed to deliver the indacene core by virtue of two directing groups incorporated into the cyclic tetraene precursor. While this strategy was not as selective as anticipated, it was found that by simply performing the transannular Diels-Alder reaction first, the decahydro-as-indacene core of the natural product could be prepared as a single stereoisomer. Chapter 4 delineates an entirely new approach toward spinosyn A: preparation of the octahydro- as-indacene core by an intramolecular double Michael reaction using a catalytic nucleophile. By first exploiting a stereoselective intramolecular Diels-Alder reaction on a sensitive pentaene precursor, the subsequent Morita-Baylis-Hillman reaction of the hexahydroindene delivers the tricyclic core of spinosyn A with high selectivity. |
