Safe and Scalable Continuous Flow Azidophenylselenylation of Galactal to Prepare Galactosamine Building Blocks

Abstract

Differentially protected galactosamine building blocks are key components for the synthesis of human and bacterial oligosaccharides. The azidophenylselenylation of 3,4,6-tri-O-acetyl-D-galactal provides straightforward access to the corresponding 2-nitrogenated glycoside. Poor reproducibility and the use of azides that lead to the formation of potentially explosive and toxic species limit the scalability of this reaction and render it a bottleneck for carbohydrate synthesis. Here, we present a method for the safe, efficient, and reliable azidophenylselenylation of 3,4,6-tri-O-acetyl-D-galactal at room temperature, using continuous flow chemistry. Careful analysis of the transformation resulted in reaction conditions that produce minimal side products while the reaction time was reduced drastically when compared to batch reactions. The flow setup is readily scalable to process 5 mmol of galactal in 3 h, producing 1.2 mmol/h of product.

Further Investigation of the 2‐Azido‐phenylselenylation of Glycals

“…Their ratio was calculated from integral intensities of the corresponding anomeric proton signals (Figure 1). The NMR data of compounds 2 – 5 correlated well with the published data [18,20] . Unfortunately, attempts to reproduce the reported high yield of 2 were unsuccessful, the total yield of only 48 % was achieved (entry 2, Table 1).…”

“…The NMR data of compounds 2-5 correlated well with the published data. [18,20] Unfortunately, attempts to reproduce the reported high yield of 2 were unsuccessful, the total yield of only 48 % was achieved (entry 2, Table 1). Poor scalability of heterogeneous APS was already mentioned earlier.…”

“…[19] An improved homogeneous version of APS was developed by Mironov et al who used trimethylsilylazide as a source of the azide radical. [19] Recently, Seeberger et al [20] proposed continuous flow APS as a safe and scalable alternative to conventional homogeneous APS. However, TMSN 3 is an expensive and toxic reagent and requires special reaction conditions such as low temperatures and an inert atmosphere.…”

“…who used trimethylsilylazide as a source of the azide radical [19] . Recently, Seeberger et al [20] . proposed continuous flow APS as a safe and scalable alternative to conventional homogeneous APS.…”

Zinc-Catalyzed Alkylation of Aromatic Amines in Continuous Flow

“…Microreactor technology is becoming more popular among chemists for its large surface-to-volume ratio and excellent process intensification. , The enhanced heat and mass transfer efficiencies in microreactors bring many advantages such as improved safety of the process, access to extreme reaction conditions, excellent reproducibility, straightforward scale-up, and automated operation. − As a result, microreactors are widely used in academic, pharmaceutical, and fine chemical production. Therefore, it is important to develop novel catalytic systems with low cost, high yield, and high selectivity in continuous flow. − Hence, we have developed a new approach for preparing DCDPA and its derivatives under continuous flow conditions.…”