Synthesis of Biologically Relevant Compounds Harboring Unusual Hydroxamate or Proline Amino Acid Residues

<p>This work explores the synthesis of two natural products possessing unusual amino acid residues, as well as a bioinspired unnatural prolyl residue.</p><p>Pseudouridimycin (PUM) is a naturally occurring C-nucleoside dipeptide antibiotic. PUM inhibits bacterial RNA polymerase (RNAP) <i>in vitro</i> at nanomolar concentrations while exhibiting >10-fold selectivity over human and viral RNAP. It also exhibits a 10-fold lower rate of spontaneous resistance in <i>S. pyogenes</i> RNAP compared to rifampicin (Rif). This natural product harbors a dipeptide tail that consists of <i>N</i>-guanidinoglycine and <i>N</i>-hydroxyglutamine (hGln) residues, as well as a β-pseudouridyl moiety. We report our total synthesis of PUM and the structure-based design of dipeptidyl analogues. We also explore conformation-activity relationships for PUM via modifications to the dipeptide hydroxamate bond.<a></a></p><p>As part of our continued interest in hydroxamate-containing residues, we devised the synthesis of an unnatural analogue of pipecolic acid (Pip), ε-oxapipicolic acid (oxaPip). Immunosuppressants FK506 and rapamycin are only biologically active when the amide bond preceding Pip adopts the <i>trans</i> conformation, highlighting a need for <i>trans</i>-inducing Pip surrogates. Utilizing model systems, we determined that oxaPip enhanced <i>trans</i> amide population in peptides, which we presumed was due to lone pair-lone pair repulsion between the amide carbonyl and the oxaPip ε oxygen. </p><p>We also pursued the total synthesis of eleganine A, a complex indole alkaloid natural product capable of inducing apoptosis in HUH-7 cancer cells. This molecule possesses an unusual ethylideneproline core with <i>E</i> alkene geometry. We devised a nickel-catalyzed route to this proline analogue that was highly selective for the desired alkene geometry, while also installing the necessary <i>trans</i> stereochemistry for the C2,C3 ring substituents. We successfully employed Larock heteroannulation to link the ethylideneproline ring to a substituted indole. Unfortunately, attempts to form the final intramolecular hemiaminal ether bond of eleganine A were unsuccessful, instead affording us an enamine dimer product. </p>