The Aryne Phosphate Reaction**

Abstract

Condensed phosphates are ac ritically important class of molecules in biochemistry.Non-natural analogues are important for various applications,s uch as single-molecule real-time DNAs equencing.O ften, such analogues contain more than three phosphate units in their oligophosphate chain. Consequently,investigations into phosphate reactivity enabling new ways of phosphate functionalization and oligophosphorylation are essential. Here,w es crutinizet he potential of phosphates to act as arynophiles,paving the way for follow-up oligophosphorylation reactions.The aryne phosphate reaction is ap owerful tool to-depending on the perspective-(oligo)phosphorylate arenes or arylate (oligo-cyclo)phosphates. Based on Kobayashi-type o-silylaryltriflates,t he aryne phosphate reaction enables rapid entry into ab road spectrum of arylated products,l ike monophosphates,d iphosphates,p hosphodiesters and polyphosphates.T he synthetic potential of these new transformations is demonstrated by efficient syntheses of nucleotide analogues and an unprecedented one-flask octaphosphorylation.

Non‐Hydrolysable Analogues of Cyclic and Branched Condensed Phosphates: Chemistry and Chemical Proteomics

“…The aryne phosphate reaction provides direct access to arylated metaphosphates of controllable ring-size without the need for an additional activation step and was therefore initially tested as method to modify non-hydrolysable analogues of metaphosphates. [21] Since substitution of the bridging oxygen of a phosphoanhydride bond by a CF 2 -group retains the correct polarity, while it is reversed with CH 2 as the bridging unit, bis(difluoromethylene)triphosphate ( 17) was synthesized following a procedure of Olah [24] and the corresponding tetrabutylammonium (TBA) salt of 17 cyclized in 64 % yield using DCC for condensation (Scheme 2a). To avoid linearization of the esterified metaphosphate-analogue in accordance with previous reports, [12,13,15,21,27] arylation at the phosphinate oxygen was desired (Scheme 2a, marked in green).…”

“…[21] Since substitution of the bridging oxygen of a phosphoanhydride bond by a CF 2 -group retains the correct polarity, while it is reversed with CH 2 as the bridging unit, bis(difluoromethylene)triphosphate ( 17) was synthesized following a procedure of Olah [24] and the corresponding tetrabutylammonium (TBA) salt of 17 cyclized in 64 % yield using DCC for condensation (Scheme 2a). To avoid linearization of the esterified metaphosphate-analogue in accordance with previous reports, [12,13,15,21,27] arylation at the phosphinate oxygen was desired (Scheme 2a, marked in green). CF 2 -trimetaphosphonate 18 was reacted with the alkynylated Kobayashi-type aryne precursor 19 to enable subsequent further functionalization by copper-catalysed 1,3-dipolar cycloaddition (CuAAC) resulting in a complex mixture instead of monoarylated 20.…”

“…[48,55] The corresponding TBA salt was obtained as an oil, which slowly crystallized during storage at 4 °C allowing for X-ray analysis (Scheme 4). Regarding the functionalization of 15, we were interested to study whether an aryne reaction would result in O-arylated products as in the aryne phosphate reaction [21] or in PÀ C bond formation as observed for phosphinates and phosphonate esters by insertion of arynes into PÀ O bonds. [56] Using Kobayashi-type o-silylphenyltriflate aryne precursors, we found O-arylation and mono-to trisarylated products with formation of phosphonate monoester preferred over diester formation under the applied conditions (Scheme 4).…”

“…[18][19][20] Avoiding the need for an additional activation step, aryne chemistry enables direct modification of metaphosphates with different ring-sizes representing a broadly applicable method. [21] Yet, metaphosphate esters are susceptible to nucleophiles, including water, and such reactions lead to linearization usually within minutes to hours, depending on the nucleophile. This reactivity is detrimental to their use as pull-down probes in proteomics studies.…”

“…Considering larger ring‐sizes, tetrametaphosphate esters are accessible from the reaction of a nucleophile with the anhydride P 4 O 11 2− as the activated form [18–20] . Avoiding the need for an additional activation step, aryne chemistry enables direct modification of metaphosphates with different ring‐sizes representing a broadly applicable method [21] . Yet, metaphosphate esters are susceptible to nucleophiles, including water, and such reactions lead to linearization usually within minutes to hours, depending on the nucleophile.…”