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

Doctoral Dissertation
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Abstract

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.

Attributes

Attribute NameValues
Author Christopher F. Cain
Contributor Juan R. Del Valle, Research Director
Contributor Brian Blagg, Committee Member
Contributor Bradley Smith, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Chemistry and Biochemistry
Degree Name Doctor of Philosophy
Banner Code
  • PHD-CHEM

Defense Date
  • 2022-12-07

Submission Date 2022-12-08
Record Visibility Public
Content License
  • All rights reserved

Departments and Units
Catalog Record

Digital Object Identifier

doi:10.7274/xs55m904d26

This DOI is the best way to cite this doctoral dissertation.

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