Tandem Electrochemical Oxidative Azidation/Heterocyclization of Tryptophan‐Containing Peptides under Buffer Conditions

Abstract

As the aromatic tryptophan (Trp) side chain plays a pivotal role in influencing the structure and function of peptides and proteins, it has become an attractive target for the late-stage modification of these important biomolecules. Herein, we report an electrochemical approach for late-stage functionalization of peptides containing a Trp side chain through manganese-catalyzed tandem radical azidation/heterocyclization. This electrochemical oxidative strategy provides access to azide-substituted tetrazolo[1,5-a]indole-containing peptides with broad functional group tolerance, high site selectivity, and good yields of products (up to 87 %) under mild buffer conditions. Moreover, the modified Trp-containing peptides bearing an azide functionality are promising building blocks, paving the way for the construction of various derivatives, such as "click" chemistry products.

Electrochemical synthesis of vicinal azidoacetamides

“…Under the standard electrolytic conditions, the oxidation of styrene ( 1 , E p/2 = 1.92 V vs. Ag/AgCl) was favored over that of TMSN 3 ( 2 ) as no obvious oxidation peak of TMSN 3 could be observed. This contradicted our previous observation that TMSN 3 was readily oxidized in the presence of HFIP, 15 suggesting that a different mechanism was operative. In addition, product ( 3 ) exhibited a much lower oxidation potential ( E p/2 = 0.95 V vs. Ag/AgCl) than those of the raw materials, suggesting that the overoxidaiton of the product was the reason for the low yields obtained.…”

“…To this end, we have achieved the electrochemical azidotetrazolation of a variety of olefins, in which the products have been shown as versatile building blocks and potentially stable high-energy materials. 15 The other possible diamine derivatives, i.e. , vicinal azidoacetamides via the hydrolysis of the β-azido Ritter intermediate, were either only formed in trace amounts or completely not observed in our previous electrochemical settings.…”

An electrochemical multicomponent reaction toward C–H tetrazolation of alkyl arenes and vicinal azidotetrazolation of alkenes

“…When applied to alkenes, the corresponding vicinal azidotetrazoles were readily obtained, which have been demonstrated to be versatile building blocks and potential high-energy materials. 27 The current work indicates that the e-MCR might be broadly applicable for the facile syntheses of diverse nitrogen-containing heterocycles.…”

Electrochemical Late-Stage Functionalization

“…Very recently, Weng and co-workers developed an electrochemical LSF of tryptophan-containing peptides with NaN 3 to afford azide-substituted tetrazolo [1,5-α]indolecontaining peptides (Scheme 23). 222 This reaction used an earth abundant Mn catalyst under mild buffered conditions. This strategy was applicable for a wide range of peptides with good functionalgroup tolerance and high site-selectivity.…”