A First Total Synthesis of Ganglioside HLG‐2

Abstract

A neuritegenic ganglioside from sea cucumber, HLG-2 (see figure), has been synthesized for the first time. The unique tandem of sialic acids, Neu5Gc-alpha(2,4)-NeuAc, was established by the combination of a reactive N-Troc sialyl donor and a 1,5-lactamized sialyl acceptor. The ceramide counterpart was assembled in a stereoselective manner. Direct connection of the trisaccharide and the ceramide successfully afforded a precursor of HLG-2, which was converted to ganglioside HLG-2 in pure form.A first synthesis of the neuritegenic ganglioside HLG-2, which was identified in extracts of the sea cucumber Holothuria leucospilota, is described. The characteristic sequence of the trisaccharide part, alpha-N-glycolylsialyl-(2,4)-alpha-N-acetylsialyl-(2,6)-glucoside, was efficiently assembled by coupling of a highly active N-2,2,2-trichloroethoxycarbonyl (Troc)-protected sialyl donor and a 1,5-lactamized sialyl acceptor with high stereoselectivity. The corresponding trisaccharyl imidate donor was directly glycosidated with the primary hydroxyl group of the ceramide part, producing protected HLG-2 in relatively high yield, global deprotection of which furnished ganglioside HLG-2 in highly pure form.

A Synthetic Challenge to the Diversity of Gangliosides for Unveiling Their Biological Significance

“…Similarly, modifying the C5 amine with tri uoroacetyl and Troc groups increased the reactivity of the C4 or C8 hydroxyl groups. 7,19 The 1,5 lactamized sialyl acceptor was used with the N Troc sialyl donor in the total synthesis of ganglioside HLG 2, in which a tandem composed of two sialic acid species, Neu5Gc and NeuAc, was incorporated into the glycan moiety (Scheme 7). To construct the α (2,4) linked disialic acid, the 1,5 lactam sialyl acceptor was investigated, and diol derivative 23 was identi ed as the most suitable.…”

“…Following protecting group manipulation, the trisaccharyl donor was subjected to direct glycosylation with Cer to afford the framework of HLG 2, which then underwent global deprotection, providing ganglioside HLG 2. 19 The synergic use of the N Troc sialyl donor and 1,5 lactam sialyl acceptor also allowed us to synthesize of Hp s6 glycan, which has a partially modied α (2,8) linked disialic acid residue, 8 sulfo NeuAcα (2,8) Neu. …”

Glycolipids from Marine Invertebrates

“…Synthesis of the pentasaccharide moiety of AG-2 isolated from the starfish Acanthaster planci was reported in 2009 (Hanashima et al, 2009a), but no information is yet available concerning the total synthesis or biological assay. Also during 2009, the first total synthesis was reported for HLG-2 isolated from the sea cucumber Holothuria leucospilota (Iwayama et al, 2009) but, again, the biological assays of these synthesized compounds remain unreported. Synthesis of the sugar moiety of HPG-1 and HPG-7, isolated from the sea cucumber Holothuria pervicax, has also been reported, and the total synthesis and biological assays are currently under way Shimizu et al, 2011).…”

The Total Synthesis of the Neurogenic Ganglioside LLG‐3 Isolated from the Starfish Linckia laevigata

“…[3] Recently, we were the first to synthesize the neurogenic ganglioside HLG-2, which is found in the sea cucumber. [4] Herein we report the first total synthesis of ganglioside LLG-3 (1; Scheme 1), [5] which contains the 8-O-Me-Neu5Aca(2,11)Neu5Ac structure, by using Neu5Troc chemistry combined with the glucosyl ceramide (Glc-Cer) cassette approach.…”

“…[15] The synthesis of the Glc-Cer portion (30) was conducted in accordance with our earlier report. [4,9] The (R)-2-hydroxytricosanoic acid derivative 23 was successfully assembled Scheme 1. Retrosynthetic scheme for target molecule 1.…”