Regioselective Carbohydrate Acylation

In one of our research programs aimed at preparing new trimodular nonionic surfactants made of a sugar with a lipophilic tail linked by an aminoacid residue (30), several esterifications of suitable sugar derivatives have been attempted using different lipases.

The potential of lipases as catalysts for the acylation of carbohydrates is currently of considerable interest, as the reaction occurs selectively at the primary hydroxyl group of the sugar. The need for protection and deprotection steps of the nonfavorable secondary hydroxyl groups is avoided, allowing a reduction in the number of steps. In recent years, various reports have been published on the enzymatic transesterifications of carbohydrates using activated donors, such as trihaloethyl, vinyl, and oxime esters or acid anhydrides (31). For example, 6-0-acyl derivatives of alkyl glucopyranosides, useful as biodegradable nonionic surfactants, were synthesized from fatty acids and the corresponding 1-0-ethyl-glucopyranosides in the presence of a thermostable lipase from Candida antarctica (CAL) (32,33) (see Subheading 3.7.). This lipase also catalyzed the regioselective acylation of 1-0-octyl-a-D-glucopyranoside by ethyl acrylate using zeolite CaA for selective adsorption of the produced ethanol or water; a 99% conversion and a 99% selectivity were observed in 4 h (34).

Native enzymes such as Porcine pancreatic lipase (PPL), C. antarctica lipase (CAL), and proteinase N (crude subtilisin) or immobilized enzymes such as Lipozyme® (lipase from Mucor miehei adsorbed on anionic resin) or Novozyme SP 435 (immobilized C. antarctica lipase) were tested for regioselective acylation of the primary hydroxy group of a sugar (present in excess). The biocatalysis was carried out in organic solvents or in solvent-free systems under nearly anhydrous conditions, which favor lipase-catalyzed process. Nevertheless, the problem of carbohydrate solubility in these media created difficulties for choosing the appropriate conditions to perform the reaction. Glucose and others alkyl glucopyrannosides such methyl, ethyl, or 1,2-isopropylidene glucopyrannosides were not soluble. Consequently, the sugar used was butyl a-D-glucopyranoside, prepared enzymatically using almond meal (35). As the melting point of butyl a-D-glucopyrannoside was low (65 °C), experiments in the solvent-free system were performed on melted compounds for the efficient preparation of 6-0-lauroyl derivatives of butyl a-D-glucopyranoside (see Subheading 3.8.).

For our purpose of producing new surfactants, spacers used for the sugar acylation were bromoacetic acid and its active esters (see Subheading 3.9.), succinic acid esters (see Subheading 3.10.), and adipic acid, dodecanedioi'c acid and hexadodecanedioi'c acid (see Subheading 3.11.); increasing the length of the chain (2, 4, 6, 12, or 16 carbons, respectively) increased the lipophilicity of the compounds, giving better substrates for lipases. Proteinase N, catalyzing regioselective esterification of sugars in anhydrous N,N-dimethylformamide (36), was not an efficient biocatalyst (data not shown).

Lipozyme in the presence of excess of bromoacetate catalyzed the acylation of butyl a-D-glucopyranoside in a solvent-free system, at 70°C in just 8 h (yield = 60%). With short diacids, this acylation was difficult. It was reported in 1993 that sugar acylation with succinic acid anhydride can be achieved, but with low regioselectivity, yielding only 7% for the C6 monoester (37). Unfortunately, the high melting point of this acid anhydride (120°C) prevented working in a solvent-free system. The active ester 2,2,2-trichloroethylsuccinate has a lower melting point (86°C). Two products were obtained resulting from an esterification followed by a transesterification: the butyl 6-0-succinoyl-a-D-glucopyranoside and the butyl 6-0-(2,2,2-trichloroethylsuccinate)-a-D-gluco-pyranoside.

With adipic acid (n = 4), dodecanedioic acid (n = 10) and hexadecanedioic acid (n = 14), sugar acylation using Lipozyme or PPL were performed (respectively 0%, 35%, and 60% yields), resulting in the formation of mixture of diesterified and triesterified sugars.There is a literature precedent showing that the length of the fatty chain plays a major role in the lipase-catalyzed reactions.

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