Multi-Component One-Pot Synthesis of the Tumor-Associated Carbohydrate Antigen Globo-H Based on Preactivation of Thioglycosyl Donors

Abstract

Two efficient routes for rapid assembly of the tumor-associated carbohydrate antigen Globo-H hexasaccharide 2 by the pre-activation based iterative one pot strategy are reported. The first method involves the sequential coupling of four glycosyl building blocks, leading to the desired hexasaccharide in 47% overall yield in one-pot. Although model study on constructing the challenging Gal-α-1,4-Gal linkage in Gb3 trisaccharide yielded the desired α linkage almost exclusively, similar approach to assemble the hexasaccharide led to formation of significant amount of β anomer. As an alternative, the second synthesis utilizes three components in one pot with the Gal-α-1,4-Gal linkage pre-formed, producing the desired hexasaccharide in a similar overall yield as the four component approach. Both methods demonstrate that oligosaccharides containing α and β linkages within the same molecule can be constructed in one pot via the pre-activation based approach with higher glyco-assembly efficiencies than the automated solid phase synthesis strategy. Furthermore, because glycosylations can be carried out independent of anomeric reactivities of donors, it is not necessary to differentiate anomeric reactivities of building blocks through extensive protective group adjustment for chemoselective glycosylation. This confers great flexibilities in building block design allowing matching of the donor with the acceptor leading to improved overall yield.

Multi-Bond Forming Processes in Efficient Synthesis

“…A good example of consecutive reactions can be found in the total synthesis of oligosaccharides by Huang and coworkers. [18] Up to four glycosides can be united in a onepot sequence of consecutive couplings (Scheme 1e). The onepot process circumvents costly purifications, and achieves a comparable outcome to automated solid phase synthesis.…”

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

“…The synthesis of trisaccharide 24 was achieved via glycosidation with the fucosyl donor 22 18 and acceptor 23 (Scheme 3). For the synthesis of 23 an approach originally described by Matta and co-workers was used.…”

Cowpea Mosaic Virus Capsid: A Promising Carrier for the Development of Carbohydrate Based Antitumor Vaccines

“…Previously we encountered difficulties in simultaneously reducing azide and benzyl groups by catalytic hydrogenolysis. [67,69] Thus, we tested the direct conversion of azide to acetamide via treatment of thioacetic acid, [62] resulting in amide 9 in 85 % yield. However, the cleavage of the benzyl ester from 9 by catalytic hydrogenolysis turned out to be very inconsistent, presumably due to the poisoning of the Pd catalyst by trace amounts of sulfur-containing impurities in 9, despite repeated purifications.…”