Branched cyclodextrins

2 Branched Cyclodextrins. - From the 6 6 -di-0-(dimethoxytrityl)-peracetates the corresponding set of 6, 6 -di-0-a-D-Gal-Y -CD derivatives were made by trichloroacetimidate glycosylation following detritylation.  

By use of debranching enzyme acting in reverse the trisaccharide p-D-Gal-(l- 4)-a-D-Glc-(l- 4)-D-Glc was substituted into P-CD at 0-6 and the three disubstituted products were also observed, the AC and AD isomers predominat-ing. Similar work with a-D-Man -(l- 6)-a-D-Glc-(1 4)-a-D-Glc-(l- 4)-D-Glc gave products with one and two tetrasaccharide branches introduced into p-CD.  

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Tosylcyclomaltoheptaose (15 a) treated with 2 eq of the sodium salt of either 1-thio-a- (16a) or l-thio- -n-glucopyranose (16b) in DMPU at 70 °C for 5 h afforded the expected branched cyclodextrins (17a, 17b) in 66 and 60% yield respectively [23] (Scheme 6). 

The branched cyclodextrins (CDs, 17 a, 17 b) and their analogues with D-galactosyl and a-D-mannosyl residues (17c, 17d) have also been prepared under mild conditions by the approach depicted in Scheme 6 [24,25]. Selective in situ S-deacetylation and activation was obtained by treatment of peracetylated 1-thioglycoses (10a, 8e, 8g) by cysteamine in the presence of diAioerythritol in HMPA [26]. This method was very efficient for ffie synthesis of branched CDs (17a) (80%), (17b) (60%), and (17c) (85%) when the acceptor molecule (15b) bearing primary iodide was used. However, peracetylated 1-thioa-D-mannose (8f) failed as a donor under these conditions, but tetra-O-acetyl-l-thio-a-mannose (8 b) afforded the expected CD (17d) in high yield (83%). 

Branched cydodextrins are also used to increase the solubility of complexes. Two methods are used to make branched cydodextrins, an enzymic method and a pyrolytic method. In the enzymic method, a starch debranching enzyme, such as pul-lulanase, is added to a solution of cyclodextrin and a large excess of D-glucose or maltose to force the reaction to proceed in the reverse direction, i.e. to add rather than remove a branch.69 Since the equilibrium favors the debranching reaction, yields are low and the product typically contains —15% branched cyclodextrin and —85% glucose or maltose. Purification is difficult because of the high solubility of both the glucose or maltose and the branched cyclodextrin, but much of the unreacted cyclodextrin can be removed by crystallization. 

Branched cydodextrins can also be formed by heating dry cyclodextrin in the presence of a small amount of hydrogen chloride.70 The pyrolysis product is dissolved in a small amount of water to dissolve the branched cyclodextrin, leaving behind most of the (3-cyclodextrin which has limited solubility. 

Okada, Y, Kubota, Y, Koizumi, K. et al. Some properties and inclusion behaviour of branched cyclodextrins. Chem. Pharm. Bull. 1988, 36, 2176-2185. 

Imata, H., Kubota, K., Hattori, K. et al. The specificity of association between concanavalin A and ohgosaccharide-branched cyclodextrins with an optical biosensor. Bioorg. Med. Chem. Lett. 1997, 7, 109-112. 

Ajisaka, N, K Hara, K Mikuni and H Hashimoto (2000). Effects of branched cyclodextrins on the solubility and stability of terpenes. Bioscience, Biotechnology, and Biochemistry, 64(4), 731-734. 

Kara, K, K Fujita, H Nakano, N Kuwahara, T Tanimoto, H Hashimoto, K Koizumi and S Kitahara (1994). Acceptor specificities of a-Mannosidases from jack bean and almond, and trans-mannosylation of branched cyclodextrins. Bioscience Biotechnology and Biochemistry, 58(1), 60-63. 

K. Kiozumi, T. Utamura, T. Kuroyanagi, S. Hirzukuri, and J. Abe, Analysis of branched Cyclodextrins by high-performance liquid and thin-layer chromatography, J. Chromatogr. 360 397-406 (1986). 

A branched cyclodextrin, 6-0-a-maltosyl cyclodextrin (G2-CD), was produced from a-D-maltosyl fluoride and a cyclodextrin by the transglycosylation reaction catalyzed by pullulanase or isoamylase [100, 101]. 

A new and exciting application to the synthesis of branched cyclodextrins has recently been reported, whereby acarbose (68), the known potent inhibitor of glu-coamylase, has been tethered to a cyclodextrin via flexible spacers of different length [46]. The functionalized spacers (69 and 70) were S-deacetylated and the corresponding thiolates coupled easily to 6-deoxy-6-iodocyclodextrin (53), affording the branched fully acetylated cyclodextrins 71 (76%) and 72 (64%), respectively. 

These were refunctionalized as their iodides (73 and 74) and elongation of 73 with the spacer 69 under similar conditions generated the trityl ether 75 and thence the iodide 76, The thioacetate derivative of acarbose (77), was coupled to the cyclodextrin 53 and branched cyclodextrins 73, 74, and 76, and then subsequently de-protected, readily affording the acarbose tethered branched cyclodextrins 78 (63%), 79 (88%), 80 (83%) and 81 (84%), respectively, in a good yield (Scheme 16). 

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