Chemoselective N-Acylation via Condensations of N-(Benzoyloxy)amines and α-Ketophosphonic Acids under Aqueous Conditions

Abstract

A new amide-forming reaction with N-benzoyloxyamines and alpha-ketophosphonic acids was investigated. A mixed solvent of t-BuOH/water (1:1) at 40 degrees C provided the desired amide in high yield (71-96%). Both phosphonic acids ( 9, 12, or 13) and their disodium salts (e.g., 10) were shown to react with the respective N-benzoyloxyamines ( 1b and 4) in excellent yields. The phosphonic acid methyl ester monosodium salt 11 did not react under these conditions. However, compound 11 did provide the desired amide in 22% yield upon addition of 2 equiv of TFA. The N-acylation reaction is highly chemoselective for N-benzoyloxyamines as both aliphatic amines and N-hydroxylamines were shown not to react productively with the alpha-ketophosphonic acids under the conditions tested. Moreover, the alpha-ketophosphonic acids are more selective than the related alpha-ketocarboxylic acid systems, which react with both the N-hydroxylamines and N-benzoyloxyamines. In this regard, this novel phosphonic acid methodology provides a new high-yielding, chemoselective acylating reagent for further study.

KAHA Ligation at Serine

“…To overcome this, the improved type II KAHA ligation method was developed. This version involves the use of O‐substituted hydroxylamines, which allows the reaction to be performed in mixed solvents (e.g., t BuOH/H 2 O) . As an important example, 5‐oxaproline (5‐Opr) was found to be especially suitable for type II KAHA ligation.…”

Chemoselective Amide Formation Using O-(4-Nitrophenyl)hydroxylamines and Pyruvic Acid Derivatives

“…In an earlier report, we demonstrated that α-keto acids react cleanly with the related N -benzoyloxyamines (e.g., 1b ) and found improved yields and reactivity compared to 1a (Scheme ) . The scope of these reactions was also extended to include the related α-keto phosphonic acids (e.g., 3a , b ), which provided high yields of amides and exquisite chemoselectivity in their reactions with N -(benzoyloxy)amines.…”

“…Moreover, N -alkylhydroxylamines are not stable as their free bases, which complicates their purification by traditional methods. In contrast, O-substituted hydroxylamines are more robust to chromatography …”

“…In 2012, using selectively 18 O-labeled substrates, Bode et al provided support for the involvement of α-lactones ( 4a ) and oxaziridine ( 4b ) intermediates in the reactions of these O- un substituted hydroxylamine systems (type I) . In contrast, no intermediates have been observed in the related O -(benzoyloxy)hydroxylamine systems, presumably due to the high reactivity of their putative oximinium ion intermediates in water (e.g., 7 in Scheme ) …”

“…Even though we developed a direct entry to N -benzoyloxyamines from amines, , these systems have caveats associated with their use. While they show excellent utility in both siderophore and N -hydroxy-containing peptides synthesis, − they typically have high chemical reactivity. , Even though they can be stored for months in the freezer they slowly degrade at room temperature, which could limit their use as chemoselective reagents. Moreover, the ester motif can in principle react with biological amines to give benzamides and hydroxylamines.…”