UC Berkeley

This dissertation describes our application of C–C bond cleavage methodology on carvone-derived cy- clobutanols to access functionalized cyclohexenones, which have been utilized toward 1) the syntheses of analogs of the plant hormone abscisic acid, and 2) syntheses of the taxagifine-like natural products, a subclass of the taxoid family of natural products. In Chapter 1, we review the most recent applications of transition metal-catalyzed C–C single bond cleavage in natural product synthesis, highlighting how the strategic use of C–C bond cleavage can streamline retrosynthetic efforts. Ten total syntheses from 2014–2019 are discussed, with examples including the use of C–C bond cleavage on both the core and the periphery of synthetic intermediates.

In Chapter 2, we discuss our efforts toward the syntheses of rationally designed analogs of abscisic acid. This chapter first outlines the biology of and previous synthetic efforts toward abscisic acid and its analogs; our computation-aided design of 5’,5’-spirocyclic ABA analogs with higher expected potency and metabolic stability, informed by this background, is then described. Our synthetic strategy toward these analogs involves the C–C bond cleavage/olefination of a carvone-derived cyclobutanol to yield a cyclohexenone with various functional groups in place to facilitate further derivatization. We describe the implementation of this strategy to a late stage at the end of this chapter.

In Chapter 3, we review the history, biology, and previous syntheses of the taxoid natural products. While, of the taxoid natural products, taxol has historically been the focus of both biological studies and synthetic work, special emphasis is placed in this chapter on the taxagifine-like natural products, which possess an additional bridging ether ring between C12 and C17. The high in vitro bioactivity of originally isolated member taxagifine, despite its myriad structural differences with taxol, suggest that the mechanism of action of the taxagifine-like natural products may involve their adoption of a distinct orientation in the binding site of tubulin; trying to understand this alternative binding yet comparable activity provides a motivation for the pursuit of syntheses of these natural products, which to date have not been reported.

In Chapter 4, we detail the construction of a highly oxygenated 6/8/6/5 tetracyclic core of taxagifine, with C–C bond cleavage/cross-coupling and aldol addition reactions forming two key C–C bonds between two carvone-derived A- and C-ring precursor fragments. Our investigations of numerous alternative cross- coupling partners and cyclization strategies are also described.

Finally, in Chapter 5, we describe our efforts toward the late-stage functionalization of the tetracyclic core of taxagifine. Specifically, we describe our efforts to 1) introduce the C9,C10-trans-diol motif found in taxagifine, 2) install oxidation at C5 and C2, and 3) transpose the C3–C4 alkene while stereoselectively placing a hydrogen atom at C3. Our investigations have culminated in the synthesis of a C10,C2-oxidized late-stage intermediate, whose conversion to natural products taxagifine III and 4-deacetyltaxagifine III in large part involves synthetic transformations that we have studied on model systems. Our examination of methods to introduce C14 and C19 oxidation, as well as to convert the tetracyclic core of taxagifine to other, less oxidized taxoid cores, is also discussed.