The First Total Synthesis of Cytopiloyne, an Anti‐Diabetic, Polyacetylenic Glucoside

Abstract

The first total synthesis of cytopiloyne 1, a novel bioactive polyacetylenic glucoside isolated from the extract of Bidens pilosa, is described. The structure of cytopiloyne was determined to be 2-β-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne by using various spectroscopic methods, but the chirality of the polyyne moiety was unknown. Herein, the convergent synthesis of two diastereomers of cytopiloyne by starting from commercially available 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-diozolane is described. The synthetic sequence involved two key steps: stereoselective glycosylation of the glucosyl trichloroacetimidate with 1-[(4-methoxybenzyl)oxy]hex-5-yn-2-ol to give the desired β-glycoside and the construction of the glucosyl tetrayne skeleton by using a palladium/silver-catalyzed cross-coupling reaction to form the alkyne-alkyne bond, the first such use of this reaction. Comparison between the observed and published characterization data showed the 2R isomer to be the natural product cytopiloyne.

Polyacetylene Glycosides: Isolation, Biological Activities and Synthesis

“…Undoubtedly, cytopiloyne, 8 is one of the most studied natural PAGs, and several biological applications of this compound have been reported. From this perspective, Kumar and coworkers [179] described a convergent synthesis of two diastereoisomers of cytopiloyne. The synthesis involved ten sequential steps, in which the key step was a stereoselective glycosylation to give β-glycoside 97 in 86 % yield.…”

Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases

“…Its synthesis is shown in Scheme 5 . By alkylating 2-chloro-4-nitro-1 H -imidazole with (4 R )-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane ( 44 ) [ 71 ], the chiral acetal product 45 was readily converted into the R -epoxide 47 by successive hydrolysis to diol 46a , tosylation at the primary hydroxyl ( 46b ), and internal substitution to form the oxirane ring. This was then elaborated to 50 by reaction with 2-bromo-5-hydroxypyridine to give 48 , ring closure to 49 , and Suzuki coupling.…”

Palladium-Mediated Total Synthesis of Bioactive Natural Products

“…The construction of the tetrasaccharide was achieved by an iterative diastereoselective palladium-catalyzed glycosylation, Luche reduction, dia-stereoselective dihydroxylation, and regioselective acylation as key steps for the assembly of the L-rhamnotrisaccharide building block. The anthrax tetrasaccharide was thus achieved in a comparatively shorter route (25 steps and in 13% overall yield) from the same achiral starting material acetylfuran (98).…”

“…This effectively controls and prevents type 1 diabetes in non-obese diabetic mice and also effective in controlling type 2 diabetes in dβ/dβ mice. 97 Lee and co-workers described 98 the first total synthesis of two diastereomers of cytopiloyne (113a and 113b) and assigned the absolute stereochemistry (at C2) of the natural product on the basis of the following disconnection approach (Scheme 23).…”