De Novo Synthesis of Orthogonally-Protected C2-Fluoro Digitoxoses and Cymaroses: Development and Application for the Synthesis of Fluorinated Digoxin

Abstract

Inspired by Roush’s pioneering work on rare sugars, we have developed a scalable, stereoselective, de novo synthesis of orthogonally protected C2-fluoro digitoxose and cymarose, utilizing Sharpless kinetic resolution and organocatalytic fluorination as key steps. The utility of this strategy is demonstrated by the synthesis of a fluorinated analogue of digoxin, which indicates the fluorine on the sugar ring may have a significant impact on biological activity.

Preparation of glycosyl carboxylic acidsviastereoselective synthesis and oxidative cleavage ofC-vinyl glycosides

“…Notably, alkyl ether-type protecting groups such as MOM, MeO-, BnO and silyl ether-type protecting groups were compatible and the corresponding acids 20–23 were obtained in moderate yields (56%–68%). In contrast, the oxidation of 1b using our previous method afforded the over-oxidized product 2b in 51% yield 12 with a trace of 20 , as observed by TLC. Furthermore, a complex mixture was obtained when the TBS-protected substrate was treated with our previous method.…”

“…As part of our ongoing project on the synthesis and biological study of stable glycosides, 6 a , b ,7 b ,12 we report herein an improved cyanide-free strategy for the synthesis of glycosyl carboxylic acids using C -vinyl glycosylation 13 in lieu of C -aryl glycosylation (Scheme 1c) as the key step. The oxidative cleavage 14 only requires 4.5 equivalents of NaIO 4 and is compatible with electron-rich protecting groups.…”

Synthesis of 4‐Deoxy‐4‐Fluoro‐d‐Sedoheptulose: A Promising New Sugar to Apply the Principle of Metabolic Trapping

“…Recent examples of de novo synthetic strategies for the synthesis of fluorinated carbohydrate scaffolds led to impressive results regarding the obtained level of stereocontrol. [ 23 , 24 ] However, we did not choose a de novo synthetic approach for the synthesis of 4DFS as Yan et. al already showed that both manno and allo configured sugar epoxides can be used for fluorinations.…”