Abstract
Chapter 1: Allylic boronates undergo stereoselective allylboration with aldehydes, which proceeds through a closed six-membered Zimmerman-Traxler transition state to generate homoallylic alcohols. Analogous to this, cyclopropylcarbinyl boronates react similarly with aldehydes to generate bishomoallylic alcohols stereoselectively. Optically pure α-substituted cyclopropylcarbinyl boronates lead to the enantioselective synthesis of E-alkenes. In the case of α-aryl substituents, the boronates rearrange to styrene byproducts with electron-rich arenes favoring this rearrangement. In addition, while γ-alkyl substituted boronates lead to the expected diastereoselective homoallylation, an anomalous cyclopropylcarbinylation was observed with γ-aryl substituted boronates which was determined to proceed through a mechanism involving ring opening and reclosure. Tuning the electronic properties of the arene substituent can revert the reactivity back to homocrotylation.
Chapter 2: The biosynthesis of clickable peptides requires the use of noncanonical alkynyl amino acid homopropargylglycine (HPG). These peptides can be bioconjugated to azide-containing compounds by copper-catalyzed azide-alkyne cycloaddition (CuAAC). One example of this is the generation of peptide libraries for directed evolution of mRNA-displayed glycopeptides that mimic the glycosylated viral protein on the HIV virion surface and induce an immune response. Solid-phase peptide synthesis (SPPS) of evolved peptide sequences requires multigram quantities of the noncanonical alkynyl amino acid Fmoc-L-HPG-OH. An optimized multigram synthesis of Fmoc-L-HPG-OH (18 g, 72% yield over 5 steps) is described herein. A double N-Boc protection was optimized for high material throughput, and the key Seyferth-Gilbert homologation is optimized to avoid racemization.