Acylation of sucrose

Figure 6.1 Chemo- and/or regioselective acylation of sucrose (1), salicin (2), and adenosine (3) catalyzed by subtilisin.

Other authors have attempted to rationalize the enzyme selectivity toward sugar derivatives by simulating the interaction of the substrates with the enzyme by molecular modeling [100], although this is not an easy task [101]. The first published example related to the regioselective acylation of sucrose [102]. However, the two observed acylation sites of sucrose were not on the same monosaccharide unit, and therefore a possible explanation of subtilisin selectivity could reside in the different steric hindrances. 

Other Carboxylic Esters. Selective 2-0-acylation of sucrose has been achieved by way of the 2-oxyanion compound. Treatment of sucrose in DMF with 3-lauryl-, 3-stearyl-, 3-hydrocinnamoyl-, and 3-(4-phenylbutyryl)-thiazolidine-2-thione derivatives and sodium hydride produced the corresponding 2-0-acyl derivatives in good yield (69). Syntheses of 6-O-acylsucroses were also achieved by acylation with 3-acylthiazolidine-2-thione and 3-acyl-5-methyl-1,3,4-thiadiazole-2(3ff)-thione derivatives in the presence of sodium hydride in DMF, followed by acyl migration using l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or aqueous triethyl amine. 6-0-Acylsucroses were obtained directly when onlyDBU was used (70). 

M. Ferrer, M. A. Cruces, M. Bernabe, A. Ballesteros, and F. J. Plou., Lipase-catalyzed regioselective acylation of sucrose in two-solvent mixtures, Biotechnol. Bioeng., 65 (1999) 10-16. 

The major problem associated with the enzymatic acylation of sucrose is the incompatibility of the two reactants sucrose and a fatty acid ester. Sucrose is hydrophilic and readily soluble in water or polar aprotic solvents such as pyridine and dimethylformamide. The former is not a feasible solvent for (trans)esterifi-cations, for obvious thermodynamic reasons, and the latter are not suitable for the manufacture of food-grade products. The selective acylation of sucrose, as a suspension in refluxing tert-butanol, catalyzed by C. antarctica lipase B, afforded a 1 1 mixture of the 6 and 6 sucrose monoesters (Fig. 8.39) [208]. Unfortunately, the rate was too low (35% conversion in 7 days) to be commercially useful. 

Regioselectively protected cytidine derivatives have been prepared from the peracetylated nucleoside using lipase and esterase reactions. There have been reports on the use of bacterial proteases for the selective acylation of sucrose to produce a variety of different acyl and acrylate esters. 8-Aminooctyl 5-5-coniferyl-5-thio-a-L-arabinofuranoside(27) attached to sepharose proved to be a selective affinity ligand for feruloyl esterase A. niger ... 

Acylation of sucrose generally is performed with the appropriate acid anhydride or acyl halide in pyridine at or below room temperature. The most common acyl derivatives of sucrose used are acetates and ben-... 

Acetylsucrose [63648-81-7] has been prepared in 40% yield by direct acetylation of sucrose using acetic anhydride in pyridine at 40° C (36). The 6-ester has subsequently been obtained in greater than 90% yield, by way of 4,6-cycHc orthoacetate. Other selective methods for the 6-acylated derivatives include the use of alkyl tin reagents such as dibutyl tin oxide (37) and of dibutyl stannolane derivatives (38). Selective acetylation of sucrose by an enzymic process has also been described. Treatment of sucrose with isopropenyl acetate in pyridine in the presence of Lipase P Amano gave, after chromatography, 6-0-acetylsucrose (33%) and 4/6-di-O-acetylsucrose (8%). The latter compound has been obtained in 47% yield by the prolonged treatment (39). 

Enzymatic acylation reactions offer considerable promise in the synthesis of specific ester derivatives of sucrose. For example, reaction of sucrose with an activated alkyl ester in /V, /V- dim ethyl form am i de in the presence of subtilisin gave 1 -0-butyrylsucrose, which on further treatment with an activated fatty acid ester in acetone in the presence of Hpase C. viscosum produced the 1, 6-diester derivative (71,72). 

Orthoesters. The value of cycHc orthoesters as intermediates for selective acylation of carbohydrates has been demonstrated (73). Treatment of sucrose with trimethylorthoacetate and DMF in the presence of toluene-/)-sulfonic acid followed by acid hydrolysis gave the 6-0-acetylsucrose as the major and the 4-0-acetylsucrose [63648-80-6] as the minor component. The latter compound underwent acetyl migration from C-4 to C-6 when treated with an organic base, such as / fZ-butylamine, in DMF to give sucrose 6-acetate in >90% yield (74). When the kinetic reagent 2,2-dimethoxyethene was used,... 

The value of methylation studies in structural determination of carbohydrates is well known. Methylation of sucrose has generally been achieved by the use of dimethyl sulfate-sodium hydroxide,34,35 methyl iodide-silver oxide-acetone,20 sodium hydride-methyl io-dide-N,N-dimethylformamide,35 or diazomethane-boron trifluoride etherate.36,37 The last method (already applied to monosaccharides38,39) has been found particularly useful for sucrose, because it proceeds without concomitant migration of acyl groups. The reaction of 2,3,6,T,3, 4, 6 -hepta-0-acetylsucrose (21) and 2,3,4,6,1, 3, 4 -hepta-O-acetylsucrose (22) with diazomethane in dichloromethane in the presence of a catalytic proportion of boron trifluoride etherate for 0.5 h at —5° gave the corresponding 4-methyl (23) and 6 -methyl (24)... 

Trityl ethers and acetals of sucrose have generally been used as precursors for the synthesis of partially acylated derivatives of sucrose. Deacetalation of 3,4,3, 4 -tetra-0-acetyl-2,l 6,6 -di-0-(diphenylsilyl)sucrose (33) and 3,3, 4, 6 -tetra-0-acetyl-2,l 4,6-di-0-isopropylidenesucrose (35) with aqueous acetic acid for 25 min at 50° gave 3,4,3, 4 -tetra-0-acetylsucrose27 (34) and 3,3, 4, 6 -tetra-0-ace-tylsucrose32 (36), respectively. Synthesis of 2,3,4,3, 4 -penta-0-acetyl-... 

An enzymatic reaction intermediate formed by acylation of an acetal hydroxyl group. Such an intermediate is thought to occur in a number of reactions involving carbohydrates. The sucrose phosphorylase reaction is thought to proceed by way of an acyl-glucosyl intermediate. 

Another representative highlight of the regioselective O-acylation work undertaken at QEC can be found in Richardson s selective O-pivaloylation of sucrose, which led to two papers with Les Hough and Manjit Chowdhary. One of these was on the regioselective O-pivaloylation itself, the other on the applications of the pivalate products in the preparation of various ring-modified sucrose derivatives. 

The most important of the acyl derivatives of sucrose is doubtless sucrose octaacetate. This is represented by formula LXIV, the consti-... 

The rather complex furylvinylcarbinol derivative 76 shown in Scheme 4.28 was required in enantiopure form as a key intermediate in the synthesis of the natural product cneorin. The carbinol moiety is heavily substituted with sterically demanding groups. Therefore attempts to resolve the furylvinylcarbinol with CALB or lipase PS-II led to very slow reactions. However, the rarely used enzyme Candida antarctica lipase A (CALA), which is known to act on sterically hindered substrates offers an alternative. Thus acylation of the furylvinylcarbinol 76 with 2,2,2-trifluoroethyl butanoate catalyzed by CALA (immobilized on celite with sucrose at pH 7.9) furnished the enantiomerically enriched propanoate of S-76 and R-76 (Scheme 4.28) [90]. Small-scale experiments gave E > 300. 

Some very efficient resolutions of P-aminoesters using CALA as acylating catalyst are exemplified in Scheme 4.39. The enzyme is immobilized on Celite in the presence of sucrose or on polypropylene (Accurel EP-100). 

Methyl Ethers. Methylation of sucrose is generally conducted under basic conditions. Etherification occurs initially at the most acidic hydroxyl groups, HO-2, HO-T, and HO-3f, followed by the least hindered groups, HO-6 and HO-6. Several reagents have found use in the methylation of sucrose, including dimethyl sulfate—sodium hydroxide (18,19), methyl iodide—silver oxide—acetone, methyl iodide—sodium hydride in N, N- dimethyl form amide (DMF), and diazomethane—boron trifluoride etherate (20). The last reagent is particularly useful for compounds where mild conditions are necessary to prevent acyl migration (20). 

Partial sulfation of sucrose can be also achieved. Thus, reaction of sucrose with SOCl2 afforded a mixture of diastereoisomeric cyclic sulfites, which are readily oxidized to sulfates. Treatment of these latter compounds with fatty acids and potassium carbonate provided the ester with the sulfate group placed on 0-4. The sulfate function can be also introduced at other positions as demonstrated by reaction of 6-<9-acyl sucrose and l -O-acylsucrose with S03-pyridine (Scheme ll).150... 

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