A Phosphoramidite Analogue of Cyclotriphosphate Enables Iterative Polyphosphorylations

Abstract

An iterative polyphosphorylation approach is described, which is based on a phosphoramidite (P‐amidite) derived reagent (c‐PyPA) obtained from the cyclization of pyrophosphate with a reactive diisopropylaminodichlorophosphine. This type of reagent is unprecedented as it represents a reactive P‐amidite without protecting groups. The reagent proved to be stable in solution over several weeks. Its utility is described in the context of iterative monodirectional and bidirectional polyphosphorylations. The ensuing functionalized cyclotriphosphate can be opened with a variety of nucleophiles providing ready access to diverse functionalized polyphosphate chains of defined length with several tags, including both P‐N and P‐O labels. Their interaction with exo‐ and endopolyphosphatases is described.

Mild and Chemoselective Phosphorylation of Alcohols Using a PSI-Reagent

“…Alkynes (7), azides (8), thiophenes (9), aryl iodides (10), olefins (11), alkyl halides (12, 13), nitro arenes (17,19), and indoline (18) were unscathed upon P-O bond formation. Finally, four medicinally relevant substrates were phosphorylated (Table 2B): metronidazole (19), AZT (20), cholesterol (21), and a tyrosine-containing peptide bearing histidine, aspartamide, and glutamide side-chains. Prior routes to some of these compounds were either laborious or contained limited experimental data such as the preparation of 7 (three steps, 21 utility in biomolecule functionalization), 22 14 (three steps), 23 20 (most methods TABLE 2.…”

“…Finally, four medicinally relevant substrates were phosphorylated (Table 2B): metronidazole (19), AZT (20), cholesterol (21), and a tyrosine-containing peptide bearing histidine, aspartamide, and glutamide side-chains. Prior routes to some of these compounds were either laborious or contained limited experimental data such as the preparation of 7 (three steps, 21 utility in biomolecule functionalization), 22 14 (three steps), 23 20 (most methods TABLE 2. Scope of the -based alcohol phosphorylation method.…”

Four Phosphates at One Blow: Access to Pentaphosphorylated Magic Spot Nucleotides and Their Analysis by Capillary Electrophoresis

“…In the first part of this manuscript, we present a synthetic method to obtain pentaphosphorylated MSN and analogues with an unprecedented step economy 24 , 25 ( Figure 2 D). The synthetic core element relies on a simultaneous and regioselective one-flask introduction of four phosphates using a c yclic py rophosphoryl p hosphor a midite (cPyPA, 6 ) that has been used previously in polyphosphate and nucleotide synthesis, 26 − 28 in combination with regioselective enzymatic cyclophosphate hydrolysis by RNase T2. This key step, followed by chemoselective phosphoric anhydride construction, 29 enables access to a diverse array of important MSN tool compounds, which are then used in the second part of this study to develop a new analytical platform to study MSN.…”

Mild and Chemoselective Phosphorylation of Alcohols Using a PSI-Reagent

“…Alkynes (7), azides (8), thiophenes (9), aryl iodides (10), olefins (11), alkyl halides (12, 13), nitro arenes (17,19), and indoline (18) were unscathed upon P-O bond formation. Finally, four medicinally relevant substrates were phosphorylated (Table 2B): metronidazole (19), AZT (20), cholesterol (21), and a tyrosine-containing peptide bearing histidine, aspartamide, and glutamide side-chains. Prior routes to some of these compounds were either laborious or contained limited experimental data such as the preparation of 7 (three steps, 21 utility in biomolecule functionalization), 22 14 (three steps), 23 <35% yield 24a or multistep procedures 24b,c with one paper showing higher yield with POCl3 and characterization based only on UV spectrum; 24d enhanced HIV1 activity reported 25 ), and 21 (one 10c and three 26 step routes given with little characterization data).…”

“…Finally, four medicinally relevant substrates were phosphorylated (Table 2B): metronidazole (19), AZT (20), cholesterol (21), and a tyrosine-containing peptide bearing histidine, aspartamide, and glutamide side-chains. Prior routes to some of these compounds were either laborious or contained limited experimental data such as the preparation of 7 (three steps, 21 utility in biomolecule functionalization), 22 14 (three steps), 23 <35% yield 24a or multistep procedures 24b,c with one paper showing higher yield with POCl3 and characterization based only on UV spectrum; 24d enhanced HIV1 activity reported 25 ), and 21 (one 10c and three 26 step routes given with little characterization data). The limitations of this reaction (see SI for details) stem from lack of tolerance of preexisting functionality on the alcohol to basic conditions, and lower nucleophilicity of sterically hindered substrates (i.e.…”