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. 2021 Apr 16;23(8):3110-3114.
doi: 10.1021/acs.orglett.1c00793. Epub 2021 Apr 5.

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

Joomyung V Jun  1 , Ronald T Raines  1
Affiliations

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

Joomyung V Jun et al. Org Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
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.
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.
Figure 3.
LC–MS analysis of the enzyme-catalyzed hydrolysis of γ-glutamyl ester 6 at pH 7.2 and 37 °C.
Scheme 1.
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.
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.
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