Thionyl Fluoride-Mediated One-Pot Substitutions and Reductions of Carboxylic Acids.

Thionyl fluoride (SOF2) is an underutilized reagent that is yet to be extensively studied for its synthetic applications. We previously reported that it is a powerful reagent for both the rapid syntheses of acyl fluorides and for one-pot peptide couplings, but the full scope of these nucleophilic acyl substitutions had not been explored. Herein, we report one-pot thionyl fluoride-mediated syntheses of peptides and amides (35 examples, 45-99% yields) that were not explored in our previous study. The scope of thionyl fluoride-mediated nucleophilic acyl substitutions was also expanded to encompass esters (24 examples, 64-99% yields) and thioesters (11 examples, 24-96% yields). In addition, we demonstrate that the scope of thionyl fluoride-mediated one-pot reactions can be extended beyond nucleophilic acyl substitutions to mild reductions of carboxylic acids using NaBH4 (13 examples, 33-80% yields).

Halide-Accelerated Acyl Fluoride Formation Using Sulfuryl Fluoride.

Herein, we report a new one-pot sequential method for SO2F2-mediated nucleophilic acyl substitution reactions starting from carboxylic acids. A mechanistic study revealed that SO2F2-mediated acid activation proceeds via the anhydride, which is then converted to the corresponding acyl fluoride. Tetrabutylammonium chloride or bromide accelerate the formation of acyl fluoride. Optimized halide-accelerated conditions were used to synthesize acyl fluorides in 30-80% yields, and esters, amides, and thioesters in 72-96% yields without reoptimization for each nucleophile.

New sulfuryl fluoride-derived alkylating reagents for the 1,1-dihydrofluoroalkylation of thiols.

Herein, we report a new method for the one-pot synthesis of 1,1-dihydrofluoroalkyl sulfides by bubbling sulfuryl fluoride (SO2F2) through a solution of the corresponding alcohol and thiol. The reaction proceeds through a new class of bis(1,1-dihydrofluoroalkyl) sulfate reagents, to afford the desired 1,1-dihydrofluoroalkyl sulfides in 55-90% isolated yields. The bis(1,1-dihydrofluoroalkyl) sulfates are highly chemoselective for thiol alkylation, and are unreactive with competing, unprotected nucleophiles, including amines, alcohols, and carboxylic acids.

In Vitro Assessment of Putative PD-1/PD-L1 Inhibitors: Suggestions of an Alternative Mode of Action.

The programmed cell death protein 1 (PD-1) signaling axis is among the most important therapeutic targets in modern oncology. Aurigene Discovery Technologies Ltd. (Aurigene) has patented a series of peptidomimetic small molecules derived from the PD-1 protein sequence for use in targeting the interaction between PD-1 and its ligand, PD-L1. We evaluated three of Aurigene's most potent compounds in SPR binding assays. Our results showed that these compounds-each of which is known to be potently effective in a splenocyte recovery assay-do not directly inhibit the PD-1/PD-L1 interaction nor do they appear to bind to either of the constituent proteins, indicating that another mechanism is at play. As a result of these studies and upon consideration of structural features within the PD-1/PD-L1 complex, we hypothesize that the Aurigene molecules may interact with a currently unknown protein capable of regulating the PD-1 axis.