Synthesis of Maradolipid

Abstract

The first synthesis of maradolipid, a unique dissymmetrically 6,6'-di-O-acylated trehalose glycolipid isolated from C. elegans, is accomplished in five steps starting from trehalose in 45% overall yield. The short synthesis relies on dissymmetrization of trehalose core via regioselective acylation of a 2,3,4,2',3',4'-hexa-O-TMS trehalose 6,6'-diol derivative as a key step.

TMSOTf‐Catalyzed Silylation: Streamlined Regioselective One‐Pot Protection and Acetylation of Carbohydrates

“…and 12.0 equiv., respectively) were sufficient to persilylate 17 and 19, regioselective per-2,6-di-O-trimethylsilylations were observed and afforded the corresponding products 18 [18] and 20 [18] smoothly, notwithstanding their polyhydroxy systems (Entries 11 and 12). The regioselectivity was confirmed by careful comparison of the obtained 1 H and 13 C spectra with literature data [18] and the cross-signals between the free hydroxy groups and H3 observed in the 1 H-1 H COSY spectra of 18 and 20 (see the Supporting Information).…”

“…More importantly, silylation of the d-glucosamine derivative 7 could be achieved in excellent yield to afford the silylated product 8 without its trichloroacetamido functionality being affected (Entry 6). The full silylation of α,αЈ-trehalose (9) to afford the corresponding product 10 [13] was also excellent (Entry 7). It was noticed that longer reaction times were needed for d-glucose (11), d-galactose (13), and d-mannose (15), probably due to the weaker nucleophilicities of their anomeric oxygen atoms and their lower solubilities in CH 2 Cl 2 (Entries 8 to 10).…”

“…[9] A onepot stereoselective glycosylation protocol by way of per-Otrimethylsilylated glycosyl iodides [10] generated in situ and more recently the regioselective nonenzymatic acetylation of monosaccharides [11] with involvement of per-O-TMS monosaccharides have been established by Gervay-Hague et al Furthermore, selective removal of the primary 6,6Ј-TMS ethers of per-O-TMS trehalose has been applied in various syntheses of 6,6Ј-symmetrically [12] and dissymmetrically [13] substituted trehalose-based glycolipids. However, these methodologies cannot proceed with unprotected sugars, which because of their multiple hydroxy groups are insoluble in most organic solvents.…”

The Caenorhabditis elegans lipidome

“…Especially for the maradolipids and several dafachronic acids no commercial standards are available. Though, synthesis protocols for both have been described [54,[101][102][103]. Interestingly, ceramides with 2-OH-fatty acid are available, but not with C17:0iso base.…”

The Uptake of Trehalose Glycolipids by Macrophages Is Independent of Mincle

“…These conditions gave the monoester 6 in 41 % yield along with the corresponding diester (19 %) and starting material (30 %), with the products being readily separated by silica gel flash column chromatography. Whereas others have reported slightly improved yields for the monoesterification of 5 and were able to directly esterify 4 when using shorter-chain acids, [25,26] we encountered difficulties in solubilising the longer-chain acid and the formation of the Steglich esterification product [27] despite exploring a variety of reaction conditions. The second esterification reaction was then undertaken with 11-azido-undecanoic acid (8), itself prepared in 91 % yield by treating 11-bromoundecanoic acid (7) with NaN 3 .…”