A unified strategy for penostatin (Bio)synthesis and forays in computational chemistry

Abstract

<bold>PART 1</bold>: Comprising Chapters I&ndash;IV, the studies described in the first part of this Thesis have as their overarching goal the utilization of organic synthesis to address questions of biosynthetic import. The impetus for this work has been provided by the penostatins A&ndash;I, a family of biologically active, structurally atypical, polyketide-derived secondary metabolites isolated from the fungus <italic>Penicillium</italic> sp. OUPS-79. Critical mechanistic and structural analyses have compelled the hypothesis that the penostatins arise via spontaneous (i.e., <italic>non</italic> enzyme-catalyzed) pericyclic reaction cascades that emanate from a single biogenetic precursor. Part 1 is inaugurated with a concise summary of the isolation, structure determination, and biological activity of the penostatins (Chapter I). In addition, a discussion of others' previous synthetic efforts toward members of the family is presented. Chapter II describes a campaign that has culminated in the stereoselective synthesis and study of the putative biosynthetic precursor to penostatins A and B, which constitutes the vast majority of the work conducted during the author's tenure. A pertinent model study that involved the design, synthesis, and subsequent investigation of (the enolates derived from) a pair of model dihydropyran substrates is detailed in Chapter III. This work has tentatively supported the notion that penostatins I and F arise via spontaneous [3,3]-sigmatropic (Claisen) rearrangements. Finally, Chapter IV documents progress toward the synthesis of a model substrate relevant to the biosynthesis of penostatins G and H. <bold>PART 2</bold>: The ability to reliably deduce the constitution and relative configuration of newly isolated organic molecules lies at the very core of all endeavors in the fields of synthetic organic and natural products chemistry. Nuclear magnetic resonance (NMR) spectroscopy is unarguably the single most powerful spectroscopic tool for this task; however, the unambiguous assignment of these structural properties via spectroscopic data alone is rarely a trivial matter. In Part 2 of this Thesis, the power and utility of DFT-based computational methods for the structure determination of small organic molecules are showcased. Chapter V includes a short discussion of the motivation for these studies and previous work from the Hoye/Cramer team. Then, in Chapter VI, computed proton (<super>1</super>H) and carbon (<super>13</super>C) NMR chemical shifts (&delta;) are employed to address structural issues that have arisen from two concurrent synthetic endeavors in the Hoye group. On the basis of the computational results described therein, reassignments of (i) the structures of the &lsquo;Jones isomers&rsquo; and (ii) the relative configuration within (at least) the AB ring system of phomopsichalasin are strongly recommended. Additionally, a reexamination of the reported <super>1</super>H NMR chemical shift assignments for patchouli alcohol has emerged from a collaborative effort with the Cramer group.