1,2-Diacetals in Synthesis: Total Synthesis of a Glycosylphosphatidylinositol Anchor of Trypanosoma brucei

Abstract

A full account on a total synthesis of GPI anchor 1 employing butanediacetal (BDA) groups and a chiral bis(dihydropyran) is presented. The reactivity of selenium and thio glycosides was tuned by the use of BDA groups. This allowed the assembly of an appropriately protected GPI anchor precursor 2 in just six steps from the six building blocks 5 ± 10 including only one protecting group manipulation (see Scheme 1). myo-Inositol was desymmetrised with the bis(dihydropyran) derivative 15 and appropriately protected to give inositol acceptor 21 in nine steps and 17 % overall yield (see Scheme 3). The use of common starting materials and BDA-protections give efficient access to building blocks 5, 6, 7 and 8 (see Scheme 5). A new and improved synthesis of the glucosamine donor 28 is included. In summary, a highly convergent and efficient synthesis of GPI anchor 1, which is clearly adaptable to other GPI anchors, has been reported.

Total synthesis of the fully lipidated glycosylphosphatidylinositol (GPI) anchor of malarial parasite Plasmodium falciparum

“…Arguably, the most demanding aspect of the GPI synthesis has been to access suitably protected glucosamine-inositol block requiring optically pure protected D-myo-inositol acceptor and 2-azido-2-deoxyglucosyl donor. This has mainly been accomplished by previous workers [8][9][10][11][12] either by the a priori resolution of bis-cyclohexylidene-myo-inositols by chiral auxiliaries and enzymes or through a multi-step synthesis from D-glucose by the Ferrier reaction.…”

“…Compound 20 was prepared by the coupling of tetra-O-benzyl-a-D-mannosyl trichloroacetimidate 28 (13, prepared from known 29 allyl mannopyranoside 10 by perbenzylation, allyl deprotection, and trichloroacetimidation) with allyl-3-O-benzyl-4,6-O-benzylidene-a-D-mannoside (15, prepared from 10 by 4,6-benzylidenation, 30 The mannobiose intermediate 26 was synthesized (Scheme 5) by glycosylation of allyl-2,3,4-tri-O-benzyl-a-D-mannopyranoside (24) (prepared from D-mannose by anomeric allylation 29 (10), selective tritylation at the 6-OH, and perbenzylation followed by the removal of trityl group) with known 31 pentenyl mannose orthoester (22).…”

“…Although a number of approaches have been reported [8][9][10][11][12] by various leading groups for the synthesis of GPI anchors of various parasitic species, including our own approach, 13 the GPI molecules of the malarial parasite present increasing challenges due to the presence of a third fatty acid group at the 2-position of the myo-Dinositol residue. For this reason, so far only one total synthesis of fully lipidated Pf-GPI has been reported (Seeberger et al).…”

Assembly of a Series of Malarial Glycosylphosphatidylinositol Anchor Oligosaccharides

“…Synthesis of GPI glycans of varying length : Disaccharide 3 , the shortest GPI glycan to be prepared, was readily accessible from known pseudo‐disaccharide 11 13 (Scheme ). Benzylation of 11 to afford disaccharide 15 was followed by removal of the allyl group with palladium( II ) chloride in wet acetic acid to provide 16 25.…”

“…Many GPI structures have been synthesized by using various chemical methodologies and protective group combinations 12–22. Structural studies on GPIs were the basis for substantial synthetic work, resulting in total syntheses of the T. brucei anchor,12, 13 rat‐brain Thy‐1 anchor,14–16 a ceramide‐linked yeast anchor,17 a GPI core structure lacking the phosphoethanolamine,18 non‐lipidated Toxoplasma gondii anchor,19 the sperm CD52 anchor containing an acylated inositol,20 and a GPI structure containing an acylated inositol ring as well as lipid moieties 21. 22…”