Title: Reagents and Strategies for the Total Synthesis of Halogenated Natural Products
Description: Chapter 1. Introduction Natural product total synthesis has long fulfilled many roles in synthetic organic chemistry, one of the foremost being inspiration of the development of novel methods and strategies to access particular structures. The halogenated natural products represent one class of secondary metabolites that can serve to inspire new chemical methods. Although nature's enzymatic machinery is capable of installing halogen atoms onto organic frameworks efficiently, synthetic chemists often lack these same tools. In particular, the development of halonium-induced polyene cyclization, asymmetric halogenation, and medium-ring haloether formation would facilitate access to hundreds of halogenated natural products, but these reactions have traditionally proven challenging. Chapter 2. The Discovery of BDSB and Initial Investigations into Halonium-Induced Polyene Cyclizations Currently available electrophilic bromination reagents are often not suitable initiators for halonium-induced polyene cyclizations, likely due to competing inter- and intramolecular processes.

As such, we explored bromosulfonium salts for this purpose and in doing so developed a novel bromonium reagent (BDSB, bromodiethylsulfonium bromopentachloroantimonate). This easily synthesized and handled reagent proved capable of cyclizing an array of polyene precursors rapidly, in good yield, and with high diastereocontrol. The chlorinated analogue (CDSC) proved somewhat successful for initiating the analogous chloronium-induced polyene cyclizations. Chapter 3. The Total Syntheses of 4-Isocymobarbatol, Peyssonol A, and Peyssonoic Acid A, and Evaluation of Peyssonol A Analogues for Anti-HIV Activity Our novel reagent, BDSB, was applied to the successful total syntheses of three brominated natural products (4-isocymobarbatol, peyssonol A, and peyssonoic acid A). These syntheses were predicated upon bromonium-induced polyene cyclizations of substrates of increasing complexity. The total synthesis of peyssonol A uncovered a structural mischaracterization, one that would require the synthesis of four diastereomeric final products to rectify.

Given that the anti-HIV properties of peyssonol A have been documented, we undertook an exploration of the structure-activity relationship of peyssonol A utilizing the many synthetic precursors and analogues at our disposal. These studies indicated that both the aromatic and aliphatic portions of peyssonol A contributed to its observed bioactivity. Chapter 4. Enantioselective Halogenation Chiral variants of BDSB, CDSC, and IDSI (the iodinated analogue) were synthesized from chiral sulfides and applied to halonium-induced polyene cyclizations and other asymmetric halogenation reactions. While no enantioselectivity was observed for cyclization reactions, moderate e.e. values (up to 63%) were observed for both asymmetric dichlorination and asymmetric iodohydroxylation of alkenes. Additionally, we developed an effective two-step surrogate for asymmetric halonium-induced polyene cyclizations that proved capable of affording the desired cyclic products in good yield and with moderate enantiomeric excess (up to 81%).

Chapter 5. Bromonium-Induced Ring Expansion for Accessing 8-Membered Bromoethers and Application of this Reaction to the Formal Total Synthesis of (E)- and (Z)-Pinnatifidenyne A fortuitous rearrangement led to the development of a novel method for bromonium-induced ring expansion, one that transforms tetrahydrofurans into brominated oxocanes (8-membered ring ethers). This BDSB-mediated process is high yielding and both regio- and diastereoselective, making it ideal for application to the synthesis of lauroxocanes: a large family of natural products built around an 8-membered ring bromoether core. This synthetic utility was demonstrated during the application of this strategy to the formal total synthesis of (E)- and (Z)-pinnatifidenyne; the completed route represents the most expedient total synthesis (of more than two dozen) of any lauroxocane natural product.