Dithiocarbamates
(DTCs) are ligands known to chelate with Cu and
other transition metals to form insoluble complexes. Wastewater treatment
protocols have utilized DTCs to remove trace (ppb) metals from waste
streams. We have extended the applicability of DTCs to a protocol
that readily enables control of the residual Cu in isolated material
in a quick and cost-effective manner. Formation of the chelate complex
typically results in purging of Cu and a variety of other metals in
an array of reaction media to ≤10 ppm. Furthermore, the simplicity
of the method makes it very attractive for large-scale applications
late in a synthetic sequence because of the low toxicity and efficient
removal of the metal complex by filtration.
We report herein a facile and efficient method of the construction of the cis-1,2-oxazadecaline system, distinctive of (pre)trichodermamides, aspergillazine A, gliovirin and FA-2097. The formation of the 1,2-oxazadecaline core was accomplished by a 1,2-addition of an αC-lithiated O-silyl ethyl pyruvate oxime to benzoquinone, that is followed by an oxa-Michael ring-closure. The method was successfully applied to the concise total synthesis of trichodermamide A (in gram quantities), trichodermamide B, as well as the first synthesis of trichodermamide C.
Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of pro-inflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found 7 molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. Molecular docking simulations have suggested the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as a target of these compounds. These molecules also inhibited the production of TNF-α, IL-6 and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.
A comprehensive
mechanistic analysis of the copper-catalyzed azide–alkyne
cycloaddition to form 5-protio-1,2,3-triazoles (from terminal alkynes)
or 5-iodo-1,2,3-triazoles (from 1-iodoalkynes) is presented. Through
various mechanistic probes, we elucidate several salient features
of this well-known reaction that have yet to be fully articulated
in the literature: Kinetic evidence is provided that supports (i)
the copper-catalyzed cycloadditions to form 5-protiotriazoles and
5-iodotriazoles are mechanistically distinct, (ii) the catalyst counterion
has a linchpin role in facilitating the chemoselective generation
of 5-iodotriazoles from 1-iodoalkynes in the presence of terminal
alkynes, (iii) “activation” of the requisite catalyst
for protiotriazole synthesis is highly influenced by the nature of
the catalyst counterion, and last (iv) a more nuanced interpretation
of the role of copper acetylides in triazole synthesis is required.
An expanded reaction manifold is offered to provide the most comprehensive
image to date of the different copper-catalyzed processes active during
triazole synthesis, which are obscured behind what appears to be a
simple catalytic system. Ultimately, mechanistic and kinetic insight
is provided that can be utilized in the development of chemoselective
methods where 1-iodoalkynes and terminal alkynes are simultaneously
present.
Detailed
kinetic profiles of the copper-catalyzed exchange between
the acetylenic proton and iodide of terminal and 1-iodophenylacetylenes
are reported. The electronic nature of the alkynes does not influence
the equilibrium of the exchange (K
eq =
1), only the rate of equilibration. Notably, the profiles are the
same for electron-rich, methyl-substituted phenylacetylenes but are
divergent for electron-deficient, trifluoromethyl-substituted variants.
The heretofore unreported exchange process yields practical considerations
regarding reactions involving iodo and terminal alkynes.
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