Extending the glucosyl ceramide cassette approach: application in the total synthesis of ganglioside GalNAc-GM1b

Abstract

The development of a novel cyclic glucosyl ceramide cassette acceptor for efficient glycolipid syntheses was investigated. p-Methoxybenzyl (PMB) groups were selected as protecting groups at C2 and C3 of the glucose residue with the aim of improving the functionality of the cassette acceptor. The choice of the PMB group resulted in a loss of β-selectivity, which was corrected by using an appropriate tether to control the spatial arrangement and the nitrile solvent effect. To investigate the effect of linker structure on the β-selectivity of intramolecular glycosylation, several linkers for tethering the glucose and ceramide moiety were designed and prepared, namely, succinyl, glutaryl, dimethylmalonyl, and phthaloyl esters. The succinyl ester linker was the best for accessing the cassette form. The newly designed glucosyl ceramide cassette acceptor was then applied in the total synthesis of ganglioside GalNAc-GM1b.

Figure 1

Structure of our previously reported cyclic GlcCer cassette acceptor (left). Structure of newly designed cyclic GlcCer cassette acceptor (right).

Scheme 1

Synthesis of the 2,3-di-O-PMB-protected glucose derivative.

Scheme 2

Tethering between the glucose residue and ceramide derivative by various types of dicarboxylate linkers.

Figure 2

Structure of ganglioside GalNAc-GM1b and key disconnections for total synthesis.

Scheme 3

Synthesis of the non-reducing end glycan sequence of GalNAc-GM1b.

Scheme 4

Final glycosylation using the GlcCer cassette approach and global deprotection.