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

This work explores the synthesis of two natural products possessing unusual amino acid residues, as well as a bioinspired unnatural prolyl residue.

Pseudouridimycin (PUM) is a naturally occurring C-nucleoside dipeptide antibiotic. PUM inhibits bacterial RNA polymerase (RNAP) in vitro 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 S. pyogenes RNAP compared to rifampicin (Rif). This natural product harbors a dipeptide tail that consists of N-guanidinoglycine and N-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.

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 trans conformation, highlighting a need for trans-inducing Pip surrogates. Utilizing model systems, we determined that oxaPip enhanced trans amide population in peptides, which we presumed was due to lone pair-lone pair repulsion between the amide carbonyl and the oxaPip ε oxygen.

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 E 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 trans 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.