Peptide Functionalization Through the Generation of Selenocysteine Electrophile

Abstract

Herein we report the first example of a strategy for peptide functionalization through the generation of selenocysteine electrophile in 5‐ and 6‐endo‐dig cyclization reactions. This simple approach allows bio‐conjugation of selenocystine‐based peptides. The developed protocol is based on copper(II) bromide mediated reactions of selenocystine with either 2‐propargyl N‐heterocycles through 5‐endo‐dig closure or with 2‐ethynylbiaryls through 6‐endo‐dig closure. It allows construction of indolizinium moiety on selenocysteine residue as well as formation of polyaromatic fragment bonded to selenium in a simple one‐pot process under mild reaction conditions.

Selenocystine Peptides Performance in 5‐endo‐dig Reactions

“…However, CuBr 2 promoted cyclization led to the formation of 2‐phenyl‐3‐(phenyltellanyl)benzo[ b ]furan ( 2c ) in 50 % yield which is a considerable improvement comparing to FeCl 3 promoted phenyltellanyl electrophile generation (36 %). Based on previous studies we believe that electrophilic selenium species are formed via CuBr 2 ‐diselenide adduct A .…”

“…Boc‐ l ‐selenocystine, peptides 3a , b , c , 2‐(1‐alkynyl)anisoles 1a , b , 2‐(1‐alkynyl)phenols 1c , d , 2‐(1‐alkynyl)anilines 5a–c , f , g , h , i , j , and 7 were prepared according to literature procedures.…”

“…Boc-L-selenocystine, [39] peptides 3a,b,c, [25] 2-(1-alkynyl)anisoles 1a, [40] b, [41] 2-(1-alkynyl)phenols 1c,d, [42] 2-(1-alkynyl)anilines 5ac, [43] f, [44] g, [45] h,i, [46] j, [47] and 7 [34] were prepared according to literature procedures.…”

“…This approach is based on the electrophilic character of (5‐nitropyridylthio)‐Sec peptides and was used in Sec‐peptide and small molecule (including some indoles) late stage conjugation. Recently, our group demonstrated novel copper(II) bromide mediated method for the generation of selenocysteinyl electrophile from selenocystine containing peptides. The electrophilic species were used in 5‐ endo‐dig cyclization with 2‐propargyl N ‐pyridines forming corresponding indolizinium salts whereas 6 ‐ endo‐dig cyclization with 2‐ethynylbiaryls led to formation of polyaromatic systems containing Sec peptides.…”

Diorganyl Dichalcogenides and Copper/Iron Salts: Versatile Cyclization System To Achieve Carbo- and Heterocycles from Alkynes

“…The first work describing the use of seleno-cysteine electrophiles generation as a synthetic strategy to functionalize peptide derivatives via 5-endo-dig and 6-endo-dig cyclization processes was reported by Arsenyan and co-workers. 25 These protocols consist of the use of stoichiometry amounts of copper(II) bromide to promote the 5-endo-dig cyclization of 2propargyl N-heterocycles (Scheme 8) and the 6-endo-dig cyclization of 2-ethynyl-biaryls (Scheme 9). The advantage of these methods is the possibility to synthetize five-membered Nheterocycles 8 and six-membered carbocycles 9 just by performing slight modifications in the reaction conditions.…”