C₂-Symmetric Macrocyclic Carbohydrate/Amino Acid Hybrids through Copper(I)-Catalyzed Formation of 1,2,3-Triazoles

Abstract

An efficient method was developed for the preparation of macrocyclic carbohydrate/amino acid hybrids by macrocyclization with copper(I)-catalyzed 1,2,3-triazole formation. Methyl 2-amino-6-azido-3,4-di-O-benzoyl-2,6-dideoxy-beta-D-glucopyranoside was prepared and coupled to two different N-propiolyl dipeptides (propiolyl-Tyr-Tyr-OH and propiolyl-Arg(Mtr)-Tyr-OH) to obtain bifunctional molecules carrying one azido group and one terminal alkyne. These bifunctional molecules were cyclodimerized using Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes to form macrocycles containing two 1,2,3-triazoles. Various cyclization methods were evaluated, and the most efficient conditions were found to be CuI and N,N-diisopropylethylamine in CH3CN.

Significant rate accelerated synthesis of glycosyl azides and glycosyl 1,2,3-triazole conjugates

“…Glycosyl 1,2,3-triazole derivatives derived from glycosyl azides using "Click chemistry" [15][16][17][18][19][20][21][22] have appeared as useful molecules of medicinal interest because of their potential to act as inhibitors for galectins [23][24][25][26], RNA binding molecules [27] and carbonic anhydrase antagonists [28]. Most commonly, glycosyl triazole derivatives are prepared by the 1,3-dipolar cycloaddition of glycosyl azides and alkynes under "Click chemistry" conditions, which is a powerful technique for the preparation of triazole linked neoglycoconjugates [29], cyclodextrin analogs [30,31] and linking of carbohydrate moieties with proteins to generate glycoconjugates [32,33] in glycobiology research.…”

Synthesis of Triazole‐Epothilones by Using Cu2O Nanoparticles to Catalyze 1,3‐Dipolar Cycloaddition

“…= broad, m = multiplet), coupling constants, and integration. 13 C NMR spectra were recorded with a Bruker AC-P 300 (75 MHz) or AV 400 spectrometer (100 MHz) using CDCl 3 or MeOD as the solvent. Chemical shifts (δ) are reported in ppm measured relative to the solvent peak.…”

“…[1,2] In particular, the click reaction provides a facial approach for construction of macrocyclic molecules through intramolecular cycloaddition. The catalyst systems that are employed in this type of ring formation includes: CuSO 4 /NaAsc, [2c] CuI/DIEA, [3] Cu(CN) 4 PF 6 , [4] and CuBr/ 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU). [5] Chen and Kong [6] recently reported the use of Cu 2 O nanoparticles (Cu 2 O-NPs) to catalyze this reaction either under physiological conditions or in acetonitrile.…”

“…A model reaction to form a fourteen-membered heterocycle 10 was applied to explore the best conditions for the intramolecular CuAAC reaction (Scheme 2). Exposure of the key intermediate 9 to CuI/DIEA [3] or [Cu(CN) 4 PF 6 ] [4] either provided the cyclization product in only trace amounts or no reaction was observed. However, compound 10 was successfully obtained in 64 % yield when the reaction was catalyzed by Cu 2 O-NPs.…”

“…[19] Treatment of 18 with p-toluenesulfonyl chloride (TsCl) to generate a TsO leaving group, followed by NaN 3 replacement, afforded 2 in 87 % yield for two steps. [20] Exposure of the key intermediate 2 to conventional catalyst systems (Scheme 6, entries 1-3), CuI/DIEA, [3] CuSO 4 / NaAsc, [2c] or CuBr/DBU, [5] either provided the cyclization product in only trace amounts or no reaction was observed. The best approach was to apply [Cu(CN) 4 PF 6 ] (Scheme 6, entry 4), which provided the product 19 in 36 % yield.…”