Stereoselective synthesis of alkyl pyranosides on a laboratory scale

The one-pot reaction of per-acetylated glycopyranosyl bromides with alcohols in light-protected flask leads to the stereoselective synthesis of deacetylated alkyl pyranosides in good yields.


Introduction
For a long time, the importance of fatty acids and fatty acid derivatives was limited to their occurrence in mono-, di-and triacylglycerides. The real and greater importance of this class of compounds was finally given by lipidomics. Lipidomics unveils the complexity of the lipidome in metabolic diseases [1][2][3][4][5] . Since then, fatty acid derivatives have increasingly come into the focus of scientific interest, and their importance has increased. For example, glycolipids not only hold many biological functions, including signaling and recognition but also cell adhesion [6][7][8] .
Recently, it demonstrates that the potential of -unsaturated fatty acids as inhibitors of the enzymes acetyl-and butyrylcholinesterase 9 , and the antimicrobial and cytotoxic activity of (thio)alkyl hexopyranosides was described 10,11 These glycolipids are known to destabilize biological membranes resulting most often in antifungal or antibacterial properties 12 . It was shown that especially tetradecyl and hexadecyl -D-glucopyranosides hold good antimicrobial activity against some strains of Grampositive bacteria. Their cytotoxicity, however, increases with an increasing chain length of the aglycon 10 . The number of reports dealing with the antimicrobial activity of alkyl glycosides is rare [13][14][15][16] .
Today, the selective synthesis of or -configured glycosides usually does not pose a significant challenge, since a variety of methods exist that allow stereoselective syntheses in good to excellent yields. Unfortunately, these methods have hardly found their way into the synthesis of long-chain alkyl glycosides. Within the scope of an extensive study on the cytotoxicity of this class of compounds, we were particularly interested in a rapid stereoselective synthesis of -configured glycosides. The method had to be scalable holding reasonable short reaction times, mild conditions and acceptable yields.

Results and discussion
Our investigations began with the synthesis of methyl glycosides. Fischer glycosidation, the direct reaction of aldoses with boiling methanol in the presence of an acid as a catalyst, usually leads to a mixture of the corresponding  and  anomers, and the yields are moderate to low. The reactions proceed fast, but rather time-consuming separations of the anomers cannot be avoided [17][18][19][20] . As an alternative chemo-enzymatic glycosidations have been suggested [21][22][23][24] . These reactions proceed very slowly, and they rarely give acceptable yields 25 . Furthermore, the glycosidases responsible for the creation of the glycosidic bond are not readily commercially available or have to be identified as far as they are yet unknown.
Methanolyses of 2,3,4,6-tetra-O-acetyl--D-glucopyranosyl bromide in the presence of silver salts (e.g. silver(I)triflate) 26 or mercury salts (Königs-Knorr conditions) 27 have been widely used [28][29][30][31][32][33] . However, the use of silver salts for large scale preparations is expensive, and the use of mercury salts raises ecological concern. Additionally, the tin chloride catalysed reaction of 1,2,3,4,6-penta-O-acetyl-D-glucopyranose, however, led to -D-glycopyranosides only when 1,2,3,4,6-penta-O-acetyl--Dglucopyranose was used as a starting material 34 . A couple of years ago, the synthesis of methyl -D-glucopyranoside from peracetylated -D-glucopyranosyl bromide was re-investigated by H. Weidmann 35 . The scale and the yield were good, but the reported protocol was restricted to the synthesis of methyl -D-glucopyranoside. Due to our need in considerable amounts of -configurated alkyl glycosides, we became interested in the further development of this procedure.
Our investigations started with the synthesis of methyl -D-glucopyranoside (5, Scheme 1) from 2,3,4,6-tetra-O-acetyl--D-glucopyranosyl bromide (4). This compound can be obtained from D-glucose (1) by a two-step synthesis consisting of acetylation of D-glucose (leading to an anomeric mixture of the corresponding per-acetates 2 and 3) followed by their treatment with hydrobromic acid. The reaction of 4 with dry methanol in a light-protected flask at room temperature for four days furnished 85% of pure 5 being identical with an authentic sample (commercial). Only slight drops of yields were observed upon scaling up of the reaction (up to the amount of ca. 100 g product prepared in a single flask reaction). The reaction of a mixture of 2 and 3 with methanol at room temperature in the presence of BF3 . Et2O gave a mixture of the anomeric methyl glycosides in 89% yield.

Conclusion
The reaction of glycosyl bromides in the presence of the corresponding alcohols leads to the respective glycosides in good yields. Starting from D-glucose, D-galactose and lactose, the -configured glycosides are stereoselectively obtained.
While the corresponding -configured product is obtained from D-mannose. The method described here is simple, can be easily scaled up for more considerable preparations and offers the advantage of not requiring additional metal salt or base catalysis.