Facile Conversion of α‐Amino Acids into α‐Amino Phosphonates by Decarboxylative Phosphorylation using Visible‐Light Photocatalysis

Abstract

Amino phosphonates exhibit potent inhibitory activity for a wide range of biological processes due to their specific structural and electronic properties, making them important in a plethora of applications, including as enzyme inhibitors, herbicides, antiviral, antibacterial, and antifungal agents. While the traditional synthesis of α-amino phosphonates has relied on the multicomponent Kabachnik-Fields reaction, we herein describe a novel and facile conversion of activated derivatives of α-amino acids directly to their respective α-amino phosphonate counterparts via a decarboxylative radical-polar crossover process enabled by the use of visible-light organophotocatalysis. The novel method shows broad applicability across a range of natural and synthetic amino acids, operates under mild conditions, and has been demonstrated to successfully achieve the late-stage functionalization of drug molecules.

Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap “BecaP”

“…We subsequently investigated the versatility of BecaP by applying it to decarboxylative phosphonylations. ,, Since carboxylic acids are readily available feedstock chemicals, and a common source of alkyl radicals in visible light photocatalysis, their use would significantly increase the reach of this chemistry . We recently reported a photoredox-catalyzed decarboxylative phosphonylation of N -hydroxyphthalimide (NHP) esters derived from α-amino acids . This reaction proceeded through a radical–polar crossover pathway, where C–P bond formation occurred via the reaction of trimethyl phosphite with an intermediate iminium ion, which limited its application to the formation of α-amino phosphonate esters .…”

“… 22 We recently reported a photoredox-catalyzed decarboxylative phosphonylation of N -hydroxyphthalimide (NHP) esters derived from α-amino acids. 23 This reaction proceeded through a radical–polar crossover pathway, where C–P bond formation occurred via the reaction of trimethyl phosphite with an intermediate iminium ion, which limited its application to the formation of α-amino phosphonate esters. 21 We reasoned that using BecaP in place of trimethyl phosphite would enable a radical-mediated C–P bond formation and therefore significantly expand the scope of decarboxylative phosphonylations beyond α-amino acids.…”

Radical Redox Annulations: A General Light-Driven Method for the Synthesis of Saturated Heterocycles

“…Then, anti -Markovnikov addition of this nascent radical to the partner aryl alkene would forge a new bond and yield a linear intermediate bearing both a benzylic radical and the tethered nucleophile. Finally, an ORPC event would follow, wherein single-electron oxidation of the benzylic radical by the oxidized state of the photocatalyst furnishes a reactive carbocation. − Cyclization would then occur through addition of the tethered nucleophilic group to the electrophilic cation to yield the desired annulation product. Importantly, this reaction design should accommodate the use of both a variety of radical types and numerous nucleophilic functional groups with varying tether lengths.…”