Challenges in the Conversion of Manual Processes to Machine-Assisted Syntheses: Activation of Thioglycoside Donors with Aryl(trifluoroethyl)iodonium Triflimide

Abstract

The steps needed to adapt a stable iodonium promoter for use in automated fluorous-assisted solution-phase oligosaccharide synthesis are described. Direct adaptation of the originally reported batch procedure resulted in the formation of an orthoester or protecting group transfer to the glycosyl acceptor. Fortunately, the addition of inexpensive β-pinene as an acid scavenger avoided both of these side reactions. The utility of this newly developed protocol was applied to the automated solution-phase synthesis of a β-glucan fragment.

Synthesis of protected glucose derivatives from levoglucosan by development of common carbohydrate protecting group reactions under continuous flow conditions

“…Thioglycosides are important anomeric constituents that can be activated for glycosylation [46,47]. Their range of stabilities under basic and acidic conditions [48], ability to be activated with various promoters such as N -iodosuccinimide (NIS), hypervalent iodine and pentavalent bismuth (V) [49–53], their orthogonal activation over common glycosyl donors [54], and their ability to be preactivated and coupled selectively in the presence of other thioglycosides [55] makes them ideal for building block production and oligosaccharide synthesis. The stereoselective ring opening of functionalized levoglucosan with bis (trimethylsilyl) sulfide, trimethylsilyl azide, and aryl (halo)-alanes under batch conditions has been reported [31–33], although the production of thiol substrates requires 4–6 h in CH 2 Cl 2 [31].…”

Using Neighboring-Group Participation for Acyclic Stereocontrol in Diastereoselective Substitution Reactions of Acetals

“…With the more polar solvents MeCN and EtCN, significant quantities of undesired dioxolane product 16a were formed (Table ). , The major diastereomer of acyclic substitution product 15a in the nitrile solvents was the same as for reactions with CH 2 Cl 2 as the solvent, which indicates that there is no special influence of the nitrile solvent. − The nonpolar solvent toluene gave the highest proportion of desired acyclic product 15a (Table ). This observation is consistent with studies of product distributions as a function of solvent for carbohydrates with neighboring acyloxy groups .…”

“… , The major diastereomer of acyclic substitution product 15a in the nitrile solvents was the same as for reactions with CH 2 Cl 2 as the solvent, which indicates that there is no special influence of the nitrile solvent. − The nonpolar solvent toluene gave the highest proportion of desired acyclic product 15a (Table ). This observation is consistent with studies of product distributions as a function of solvent for carbohydrates with neighboring acyloxy groups . Lower concentrations (0.1 M), which favor neighboring-group participation in reactions of carbohydrates, gave the highest stereoselectivities.…”

Automated, Multistep Continuous‐Flow Synthesis of 2,6‐Dideoxy and 3‐Amino‐2,3,6‐trideoxy Monosaccharide Building Blocks

“…Recently, our labs reported on the challenges associated with converting batch processes into machine-assisted syntheses [7] and using continuous flow conditions to carry out protecting group manipulations (Scheme 1). [8,9] By taking advantage of the many benefits of flow chemistry, [10][11][12][13][14][15] such as increased reaction efficiency [16,17] and avoiding unwanted exotherms, [18] the continuous flow processes resulted in significantly faster reaction times than was possible under standard batch-phase conditions.…”