Cycloisomerization of Olefins in Water

Abstract

Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel-Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.

Keywords: DNA; cobalt; isomerization; kinetics; water chemistry.

Figure 1:

MHAT hydrofunctionalization as a biocompatible reaction.

Figure 2:

Kinetic trace of the cyclization reaction with Co(salen)X under different conditions at 1 mM. Solid dots represent acquired data. Lines included for better visualization.

Figure 3:

Kinetic trace of the cyclization reaction at different overall concentrations. Traces overlayed with a logarithmic trendline for visualization.

Figure 4:

Pathways available for a radical after MHAT.

Figure 5.

Effect of reaction concentration on the yield of the cyclic isomer vs. linear isomer. ^aYield determined by ¹H NMR of the crude reaction mixture. ND = Not Determined.

Figure 6:

Scope under dilute aqueous conditions.^aReaction from the internal olefin. ^bMajor regiosiomer. See Supporting Information for regioselectivities in organic and aqueous conditions. ^cOnly PhH as the solvent. Yields at 1mM were determined by ¹H NMR using an internal standard or by LCMS using a calibrated internal standard. Boc = t-butyloxycarbonyl; Bn = benzyl

Figure 7:

Intermolecular examples and deallylation of amides. Yield determined by ¹H NMR of the crude reaction mixture. For procedures, see Supporting Information. ^aReaction ran at 1 mM. ^bReaction ran at 10 mM. SOAr = (R)-mesitylsulfinyl; Cy = cyclohexyl