UCLA

Chapter 1 provides an introduction to the biological significance of natural product prodiginines such as streptorubin, roseophilin, and the marineosins. This includes a brief discussion of structural features and biological mechanisms of action. The prodiginine of interest in our synthetic studies concerned marineosin A. This chapter then discusses how we used our previously published route to scale up the synthesis of marineosin A, challenges encountered, and how we were able to accomplish one of our goals of accessing novel synthetic analogs. We then segue into mechanistic studies concerning an atypical acid-promoted migration of a hydroxy-propyl sidechain that affords a new unprecedented class of synthetic rearranged prodiginines. We then postulate a potential operative mechanism based on data obtained experimentally and computationally. Chapter 2, we show that unprotected peptides react with commercial octafluorocyclopentene (OFCP) to afford fluorinated macrocycles via successive ipso substitutions of vinyl fluoride. We quantify relative reaction rates and establish sequence variations having combinations of cysteine, tyrosine, histidine, and serine residues. Compounds bearing permutations of these functional groups are shown to react rapidly at room temperature to give stable, isolable products. We also introduce our initial discoveries involving polysubstitution cascades with OFCP. Chapter 3, we further probe and diversify our polysubstitution cascades of linear unprotected peptides with OFCP to generate complex fluorinated polycycles. The reactions occur in a single flask at 0–25 �C and require no catalysts or heavy metals. OFCP can directly polycyclize linear sequences using native functionality, or fluorospiroheterocyclic intermediates can be intercepted with exogenous nucleophiles. The latter tactic generates molecular hybrids composed of peptides, sugars, lipids, and heterocyclic components. Building on this strategy we also develop novel small-molecules as inserts to afford orthogonal cyclizations and diversify our synthetic outcomes. This platform can create stereoisomers of both single- and double-looped macrocycles. Calculations indicate that the latter can mimic diverse protein surface loops. Subsets of the molecules have low energy conformers that may shield their polar surface area through intramolecular hydrogen bonding. A significant fraction of OFCP-derived macrocycles tested show moderate to high passive permeability in parallel artificial membrane permeability assays (PAMPA).