Design and synthesis of arylboronic acid 2, the first example of a permanently open “frustrated” benzoxaborole, is described along with an exploration of its application in the complexation of amines and amino acids, and protein modification.
Bioorthogonal click
reactions yielding stable and irreversible
adducts are in high demand for in vivo applications,
including in biomolecular labeling, diagnostic imaging, and drug delivery.
Previously, we reported a novel bioorthogonal “click”
reaction based on the coupling of ortho-acetyl arylboronates and thiosemicarbazide-functionalized
nopoldiol. We now report that a detailed structural analysis of the
arylboronate/nopoldiol adduct by X-ray crystallography and 11B NMR reveals that the bioorthogonal reactants form, unexpectedly,
a tetracyclic adduct through the cyclization of the distal nitrogen
into the semithiocarbazone leading to a strong B–N dative bond
and two new 5-membered rings. The cyclization adduct, which protects
the boronate unit against hydrolytic breakdown, sheds light on the
irreversible nature of this polycondensation. The potential of this
reaction to work in a live animal setting was studied through in vivo capture of fluorescently labeled molecules in vivo. Arylboronates were introduced into tissues through
intradermal injection of their activated NHS esters, which react with
amines in the extracellular matrix. Fluorescently labeled nopoldiol
molecules were administered systemically and were efficiently captured
by the arylboronic acids in a location-specific manner. Taken together,
these in vivo proof-of-concept studies establish
arylboronate/nopoldiol bioorthogonal chemistry as a candidate for
wide array of applications in chemical biology and drug delivery.
In this account, we describe the
synthesis of a series of BINOL-based
bis- and trisphosphoric acids 11d/e/f, which commonly feature an unusual phosphoric acid monoester
motif. This motif is generated by an acid-catalyzed 5-endo-dig cyclization of the 3-alkynyl-substituted BINOL
precursors to give the corresponding Furan-annelated derivatives,
followed by phosphorylation of the remaining phenolic alcohols. In
the cyclization reaction, we observed an unexpected partial racemization
in the bis- and tris-BINOL scaffolds, leading to mixtures of diastereomers
that were separated and characterized spectroscopically and by X‑ray
crystal structure analyses. The cyclization and racemization processes
were investigated both experimentally and by DFT-calculations, showing
that although the cyclization proceeds faster, the barrier for the
acid-catalyzed binaphthyl-racemization is only slightly higher.
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