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.

Keywords: Amino Acids; Phosphorylation; Photoredox Catalysis; Radical-Polar Crossover; Reaction Mechanisms.

Scheme 1

Bioactive examples and synthetic approaches to amino phosphonic acids.

Scheme 2

Optimized conditions and scope of the photocatalytic decarboxylative phosphorylation. Standard conditions: 3 (0.2 mmol), 4 (0.6 mmol), 4CzIPN (2 mol %), trifluoroacetic acid (TFA, 0.3 mmol), in acetonitrile (2.0 mL), 40 W blue LED, 2 h. Three letter code for parent N‐Boc amino acids shown. Yields are of isolated products. ^a Yield of large scale reaction (2.4 mmol); ^b tribenzyl phosphite used; ^c Ir[(dtbppy)(ppy)₂]PF₆ (1 mol %) used; ^d triethyl phosphite used; ^e starting 3 ac d.r.=5 : 1; Cy, cyclohexyl; Xan, xanthenyl; ^f reaction yield (¹H NMR) using conditions from current optimum methodology by Hernández et al. (see Supporting Information for protocol).

Scheme 3

A), B) Mechanism of desulfurization reactions providing additional evidence for radical intermediates and C) proposed mechanism.