Two-Step Synthesis of α-Aryl-α-diazoamides as Modular Bioreversible Labels

Abstract

α-Aryl-α-diazoamides were synthesized in two steps under mild conditions. This expeditious route employs Pd-catalyzed C-H arylation of N-succinimidyl 2-diazoacetate to obtain N-succinimidyl 2-aryl-2-diazoacetates, followed by aminolysis. The ensuing diazo compounds can esterify carboxyl groups in aqueous solution, and the ester products are substrates for an esterase. The broad scope of the synthetic route enables the continued development of diazo compounds in chemical biology.

Figure 1.

(A) Bioreversibility of protein esterification by an α-aryl-α-diazoacetamide. (B) Two-step synthesis of α-aryl-α-diazoacetamides. EDG, electron-donating group.

Figure 2.

(A) Aminolysis of N-succinimidyl α-aryl-α-diazoacetates with secondary amines. (B) Scope of the ensuing N,N-disubstituted α-aryl-α-diazoamides.

Figure 3.

LC–MS analysis of the enzyme-catalyzed hydrolysis of γ-glutamyl ester 6 at pH 7.2 and 37 °C.

Scheme 1.

Scope of the C–H Arylation of Diazo Compound 1 ^aReaction conditions: 10 mol% Pd(OAc)₂ 20 mol% P(2-Fu)₃.

Scheme 2.

Scope of the Aminolysis of N-Succinimidyl α-Aryl-α-diazoacetates with Primary Amines; Isolated Yields Are Reported ^aReaction conditions: 1.0 equiv of H₂NR.