37 research outputs found
Rapid Assembly of the Salvileucalin B Norcaradiene Core
Preparation of the polycyclic core of the cytotoxic natural product salvileucalin B is described. The key feature of this synthetic strategy is a copper-catalyzed intramolecular arene cyclopropanation to provide the central norcaradiene. These studies lay the foundation for continued investigations toward an enantioselective total synthesis of 1
Enantioselective Total Synthesis of (+)-Salvileucalin B
An enantioselective total synthesis of the diterpenoid natural product (+)-salvileucalin B is reported. Key findings include a
copper-catalyzed arene cyclopropanation reaction to provide the unusual
norcaradiene core and a reversible retro-Claisen rearrangement of a
highly functionalized norcaradiene intermediate
Buchner and Beyond: Arene Cyclopropanation as Applied to Natural Product Total Synthesis
Buchner and Curtius first reported the cyclopropanation of arenes in 1885. Since the initial discovery, the Buchner reaction has been the subject of significant research by both physical and synthetic organic chemists. Described herein is a brief overview of the Buchner reaction and related arene cyclopropanation processes, with an emphasis on their application to natural product total synthesis
A cationic cysteine-hydrazide as an enrichment tool for the mass spectrometric characterization of bacterial free oligosaccharides
In Campylobacterales and related ε-proteobacteria with N-linked glycosylation (NLG) pathways, free oligosaccharides (fOS) are released into the periplasmic space from lipid-linked precursors by the bacterial oligosaccharyltransferase (PglB). This hydrolysis results in the same molecular structure as the oligosaccharide that is transferred to a protein to be glycosylated. This allowed for the general elucidation of the fOS-branched structures and monosaccharides from a number of species using standard enrichment and mass spectrometry methods. To aid characterization of fOS, hydrazide chemistry has often been used for chemical modification of the reducing part of oligosaccharides resulting in better selectivity and sensitivity in mass spectrometry; however, the removal of the unreacted reagents used for the modification often causes the loss of the sample. Here, we develop a more robust method for fOS purification and characterize glycostructures using complementary tandem mass spectrometry (MS/MS) analysis. A cationic cysteine hydrazide derivative was synthesized to selectively isolate fOS from periplasmic fractions of bacteria. The cysteine hydrazide nicotinamide (Cyhn) probe possesses both thiol and cationic moieties. The former enables reversible conjugation to a thiol-activated solid support, while the latter improves the ionization signal during MS analysis. This enrichment was validated on the well-studied Campylobacter jejuni by identifying fOS from the periplasmic extracts. Using complementary MS/MS analysis, we approximated data of a known structure of the fOS from Campylobacter concisus. This versatile enrichment technique allows for the exploration of a diversity of protein glycosylation pathways
α‑Diazo-β-ketonitriles: Uniquely Reactive Substrates for Arene and Alkene Cyclopropanation
An
investigation of the intramolecular cyclopropanation reactions
of α-diazo-β-ketonitriles is reported. These studies reveal
that α-diazo-β-ketonitriles exhibit unique reactivity
in their ability to undergo arene cyclopropanation reactions; other
similar acceptor–acceptor-substituted diazo substrates instead
produce mixtures of C–H insertion and dimerization products.
α-Diazo-β-ketonitriles also undergo highly efficient intramolecular
cyclopropanation of tri- and tetrasubstituted alkenes. In addition,
the α-cyano-α-ketocyclopropane products are demonstrated
to serve as substrates for S<sub>N</sub>2, S<sub>N</sub>2′,
and aldehyde cycloaddition reactions
Electrophile-Integrating Smiles Rearrangement Provides Previously Inaccessible C4′‑<i>O</i>‑Alkyl Heptamethine Cyanine Fluorophores
New synthetic methods to rapidly
access useful fluorophores are
needed to advance modern molecular imaging techniques. A new variant
of the classical Smiles rearrangement is reported that enables the
efficient synthesis of previously inaccessible C4′-<i>O-</i>alkyl heptamethine cyanines. The key reaction involves <i>N</i>- to <i>O</i>- transposition with selective electrophile
incorporation on nitrogen. A representative fluorophore exhibits excellent
resistance to thiol nucleophiles, undergoes productive bioconjugation,
and can be used in near-IR fluorescence imaging applications
A Near-IR Uncaging Strategy Based on Cyanine Photochemistry
The development of photocaging groups
activated by near-IR light
would enable new approaches for basic research and allow for spatial
and temporal control of drug delivery. Here we report a near-IR light-initiated
uncaging reaction sequence based on readily synthesized C4′-dialkylamine-substituted
heptamethine cyanines. Phenol-containing small molecules are uncaged
through sequential release of the C4′-amine and intramolecular
cyclization. The release sequence is initiated by a previously unexploited
photochemical reaction of the cyanine fluorophore scaffold. The uncaging
process is compatible with biological milieu and is initiated with
low intensity 690 nm light. We show that cell viability can be inhibited
through light-dependent release of the estrogen receptor antagonist,
4-hydroxycyclofen. In addition, through uncaging of the same compound,
gene expression is controlled with near-IR light in a ligand-dependent
CreER<sup>T</sup>/LoxP-reporter cell line derived from transgenic
mice. These studies provide a chemical foundation that we expect will
enable specific delivery of small molecules using cytocompatible,
tissue penetrant near-IR light