The
mechanisms of general anesthetics have been debated in the
literature for many years and continue to be of great interest. As
anesthetic molecules are notoriously difficult to study due to their
low binding affinities and multitude of binding partners, it is advantageous
to have additional tools to study these interactions. Fropofol is
a hydroxyl to fluorine-substituted propofol analogue that is able
to antagonize the actions of propofol. Understanding fropofol’s
ability to antagonize propofol would facilitate further characterization
of the binding interactions of propofol that may contribute to its
anesthetic actions. However, the study of fropofol’s molecular
interactions has many of the same difficulties as its parent compound.
Here, we present the synthesis and characterization of ortho-azi-fropofol (AziFo) as a suitable photoaffinity
label (PAL) of fropofol that can be used to covalently label proteins
of interest to characterize fropofol’s binding interactions
and their contribution to general anesthetic antagonism.
The
highly Lewis basic amidine-based catalyst DHIP promotes the
rearrangement of S-phenacyl thiocinnamate and related
thioesters into dihydrothiophene derivatives. In contrast to previously
explored rearrangements of thioesters, the reaction proceeds via a
novel Dieckmann-like cyclization pathway. An alternative two-component
synthesis of the same products has also been developed.
Several additional examples of cascade cyclizations of α,β-unsaturated thioesters proceeding are reported, which proceed via two distinct mechanistic pathways: enantioselective acyl transfer promoted by amidine-based catalysts (ABCs) and a racemic chain mechanism mediated by a thiolate nucleophile. Note pubs.acs.org/joc
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