17 research outputs found
Synthesis of Fmoc-Protected Arylphenylalanines (Bip Derivatives) via Nonaqueous Suzuki-Miyaura Cross-Coupling Reactions
A one-step synthesis
of Fmoc-protected aryl/heteroaryl-substituted
phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed
Suzuki–Miyaura cross-coupling (SMC) reaction of Fmoc-protected
bromo- or iodophenylalanines is reported. This protocol allows for
the direct formation of a variety of unnatural biaryl-containing amino
acids in good to excellent yield, which can be readily used in subsequent
Fmoc solid-phase peptide synthesis. The synthetic utility of this
method is also demonstrated by the SMC reaction of bromophenylalanine-containing
tripeptides
Ligand-Enabled β‑C(sp<sup>3</sup>)–H Olefination of Free Carboxylic Acids
An acetyl-protected
aminoethyl phenyl thioether has been developed
to promote CÂ(sp<sup>3</sup>)–H activation. Significant ligand
enhancement is demonstrated by the realization of the first PdÂ(II)-catalyzed
olefination of CÂ(sp<sup>3</sup>)–H bonds of free carboxylic
acids without using an auxiliary. Subsequent lactonization of the
olefinated product via 1,4 addition provided exclusively monoselectivity
in the presence of multiple β-C–H bonds. The product
γ-lactone can be readily opened to give either the highly valuable
β-olefinated or γ-hydroxylated aliphatic acids. Considering
the challenges in developing Heck couplings using alkyl halides, this
reaction offers a useful alternative
Ligand-Enabled β‑C–H Arylation of α‑Amino Acids Using a Simple and Practical Auxiliary
Pd-catalyzed β-C–H functionalizations
of carboxylic
acid derivatives using an auxiliary as a directing group have been
extensively explored in the past decade. In comparison to the most
widely used auxiliaries in asymmetric synthesis, the simplicity and
practicality of the auxiliaries developed for C–H activation
remains to be improved. We previously developed a simple <i>N</i>-methoxyamide auxiliary to direct β-C–H activation,
albeit this system was not compatible with carboxylic acids containing
α-hydrogen atoms. Herein we report the development of a pyridine-type
ligand that overcomes this limitation of the <i>N</i>-methoxyamide
auxiliary, leading to a significant improvement of β-arylation
of carboxylic acid derivatives, especially α-amino acids. The
arylation using this practical auxiliary is applied to the gram-scale
syntheses of unnatural amino acids, bioactive molecules, and chiral
bisÂ(oxazoline) ligands
Combination indices of EI-1 with HCV replication inhibitors.
a<p>NS5A, BMS-790052; NS3, BMS-605339.</p>b<p>Mean of 8 independent experiments.</p>c<p>Loewe combination index at the combined EC<sub>50</sub> level.</p
E1 and E2 amino acid changes that emerged during selection with EI-1.
a<p>Fold increase in EC<sub>50</sub> compared to wild-type virus. Values represent the mean of ≥3 experiments.</p
Schematic diagram of the HCV E2 protein and sequences of the region encompassing the EI-1 resistance residue.
<p>Previously defined regions of the protein are indicated by the shaded boxes. Numbers correspond to the HCV polyprotein amino acid positions in E2. HVR1, hypervariable region 1. HVR2, hypervariable region 2. pFP<sub>1</sub> and pFP<sub>2</sub>, putative fusion peptide regions. igVR, intergenotypic variability region. HR, heptad repeat. TMD, transmembrane domain. The asterisk indicates the position of residue 719 that is involved in EI-1 resistance. The protein sequence alignment from amino acids 709–729 for each of the HCVpp genotype isolates from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001086#ppat-1001086-g002" target="_blank">Figure 2</a> is shown. The shaded residues are part of the TMD.</p
EI-1 resistance levels of site-directed changes engineered into HCVcc or HCVpp.
a<p>Fold increase in EC<sub>50</sub> compared to wild-type virus. Values represent the mean of ≥3 experiments.</p
Activity of EI-1 in infectious virus assays.
a<p>Mean of ≥4 independent experiments.</p
Effect of EI-1 on HCV cell-to-cell spread.
<p>(A) Huh-7.5 cells were infected with 0.001 ffu/cell HCVcc-1a/2a at 37°C. At 12 hrs post infection, the inoculum was removed and replaced with medium +1% agarose overlay containing EI-1 (0.5 µM) or DMSO and the cultures were incubated at 37°C for 2, 3 or 4 days. Infected cells were labeled by indirect immunofluorescence using an anti-HCV core monoclonal antibody (green) and nuclei were stained with Hoechst 3325 (red). Images were captured using a Nikon Eclipse TE300 inverted epi-fluorescence microscope. (B) The mean number and standard deviation of infected cells/focus was determined from visual counting of infected cells in ≥100 foci for each time point. (C) The mean number and standard deviation of foci/well was determined at 2 and 4 days post infection.</p
Structure-activity-relationship of the EI-1 chemotype.
a<p>Mean of ≥3 independent experiments.</p>b<p>R, aniline ring substituent (<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001086#ppat-1001086-g001" target="_blank">Fig 1A</a>).</p