1490 Send Orders for Reprints to [email protected] Current Organic Chemistry, 2016, 20, 1490-1501 ISSN: 1385-2728 eISSN: 1875-5348 Sugar-Functionalized Fullerenes Impact Factor: 2.157 Shengju Zhou1,3, Piotr Trochimczyk2, Lili Sun2, Sen Hou2,* and Hongguang Li1,* BENTHAM SCIENCE 1Laboratory of Clean Energy Chemistry and Materials, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China; 2Institute of Physical Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; 3University of Chinese Academy of Sciences, Beijing 100049, China Abstract: Being the first member in the family of nanocarbon superstructures, fullerene C60 (refers to C60 hereaf- ter) continues to be a research focus in physics, chemistry, materials science, biology and life science. The readily available functionalization methods that can be realized on C60 further expand the potential applications of C60 in various fields. Carbohydrates distribute widely in a variety of forms in mammalian animals and the glycan-protein interactions play important roles in many biological processes. Covalently attaching sugar units to C60 yields glyco- fullerenes, which exhibit interesting physicochemical properties and biological activities. Here, we give a compre- hensive review on the syntheses, properties and applications of this novel class of C60 derivatives. Directions in which efforts should be devoted to in near future have also been discussed. Keywords: Fullerene C60, carbohydrates, glycofullerenes, biological activities, cycloaddition. INTRODUCTION Here, we summarize the studies on sugar-functionalized C60 carried out during the past decades. Although such topics have par- Since its discovery [1] and large-scale production [2], fullerene tially been mentioned in the review papers by Nierengarten et al. C (refers to C hereafter) has received much attention due to its 60 60 and Roy et al., respectively [21, 22], emphases have been put on highly symmetric geometry and unique physicochemical properties. recently developed globular fullerene sugar balls. A comprehensive Its appearance strengthens interests of scientists on cage molecules. review reflecting all the aspects of sugar-functionalized C is still Moreover, it induces the subsequent revolution of nanocarbon ma- 60 needed. In this review, we would like to first give a brief introduc- terials, during which a variety of nanocarbon superstructures with tion of the chemical reactivity of C , followed by a detailed presen- different dimensionalities and properties have been discovered [3]. 60 tation of glycofullerenes organized mainly by the type of reactions These include carbon nanotubes (CNTs), graphene and carbon through which the sugar units are covalently attached. Hopefully quantum dots. this review can serve as a guide for those who are interested on When comprehensive investigations on C60 start in different fullerene chemistry and/or sugar-containing hybrid materials. disciplines, its poor solubility becomes a big obstacle. This is espe- cially true for the studies in aqueous solutions due to the extremely -24 -1 CHEMICAL REACTIVITY OF C60 low solubility of C60 in water, which is only ~2 10 molL [4]. Post-functionalization is thus mandatory before a variety of poten- The discovery of C60 introduces a thoroughly new and intrigu- tial applications, especially its biological activities [5-10], can be ing substrate for organic synthesis. Investigations on its chemical realized. This triggers the interests on the syntheses of water soluble reactivity were initiated soon after its production in gram-scale. C60 derivatives which bear a variety of hydrophilic groups such as Earlier studies indicated that C60 has some aromaticity [23]. How- quaternary ammonium salts [11, 12], carboxylic groups [13-15] and ever, deeper investigations revealed that it is more like an electron- oligo-(ethylene oxide)s [16]. deficient alkene and can accept up to six electrons [24]. C60 also Sugars are important components in mammalian cells. They are acts like a radical sponge and can react with various radicals utmost important due to their biological activities such as glycan- through addition reaction [25]. This occurs easily especially when protein interactions [17-19]. However, such interaction between a C60 is exposed to the light. One of the disadvantages of the radical single sugar unit and protein is normally quite weak and multivalent addition reaction, however, is the formation of a mixture with mul- display is thus required [20]. Aromatic scaffolds have recently been tiple functional groups attached onto C60 in a single reaction, which recognized as ideal candidates for multivalent glycoconjugate syn- makes subsequent purification quite sophisticated or impossible. theses and applications [21], among which sugar-functionalized Recently, this obstacle has been partially solved by applying transi- tion metal-based catalysts, leading to the formation of well-defined C60, i.e., glycofullerenes, received special attention. Grafting sugar C monoadducts [26]. units to C60 can not only impart C60 water solubility to realize its 60 intriguing biological activities, but also give the hybrid the ability The most comprehensively studied and useful reactions on C60 for molecular recognition through glycan-protein interactions. are probably the various cycloadditions. Accordingly to the reaction pathway and the number of atoms involved in the ring which bridges C and the addends, they can be categorized by [1+2], *Address correspondence to these authors at the Institute of Physical Chemistry Polish 60 Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; Tel: + 0048 [3+2] and [4+2] cycloadditions, respectively. Typical examples in 790662634; E-mail: [email protected] and Laboratory of Clean Energy Chemis- each case include Bingle-Hirsch reaction [27, 28], Prato reaction try and Materials, Lanzhou Institute of Chemical Physics, Chinese Academy of Sci- [29] and Diels-Alder reaction [30], respectively. To date, glyco- ences, Lanzhou 730000, China; Tel: +86-931-4968829 Fax: +86-931-4968163; E-mail: [email protected] fullerenes have been prepared mainly through these cycloadditions. Current Organic Chemistry 1875-5348/16 $58.00+.00 © 2016 Bentham Science Publishers Sugar-Functionalized Fullerenes Current Organic Chemistry, 2016, Vol. 20, No. 14 1491 Scheme 1. In the following, the presentation will be divided mainly based on was then subjected to react with 1,2:3,4-di-O-isopropylidene-D- the reaction pathway and/or the sugar-based precursors, which will galactopyranose-6-chloroformate to give glycofullerene 6 through then be ended with C60 derivatives functionalized with - amide coupling (Scheme 2) [35]. cyclodextrin (-CD), a cyclic oligosaccharide with seven -D- Besides preparation of glycofullerene through amide coupling glucopyranoside units linked through 1,4-glucosidic bonds. Finally, between acyl chloride-based sugar unit and C60 amine as demon- conclusions will be given together with a brief discussion of per- strated in Scheme 2, a more popular synthetic pathway involves spectives. installing an azide group onto the sugar units which were then di- rectly subjected to react with C60 (Scheme 3). For the monoadducts REACTION WITH DIAZONIUMS obtained this way, theoretically there are four isomers, i.e., 5.6- The first report on glycofullerenes appeared in 1992, i.e., one open, 5,6-close, 6,6-open and 6,6-close. In most reports accom- plished by different authors, however, only one (or two) dominant year after the report on the gram-scale production of C60 [31]. In this work, Vasella et al. prepared O-benzyl (Bn) and O-pivaloylated isomer(s) have been claimed, among which 5.6-open and/or 6,6- (Piv) protected sugar units which bear diazoniums, which were then close are the most popular. It is also claimed that alkyl azides prefer to afford 5,6-addition type glycofullerenes while acyl azides prefer- subjected to react with C60 to give glycofullerene 1 and 2 (Scheme 1). The mechanism involved in the reaction between fullerene and entially give the adducts with 6,6-addition pattern [34-37]. Mean- diazonium will not be repeated here. For details, one can refer to a while, bisadduct can be also obtained where the two addends are recent paper co-authored by Olmstead, Balch, Wudl and Echegoyen joint at the end of the C=C double bond in between two six- et al., which discusses the regioselective synthesis of easily isolable membered rings on C60 (Scheme 3). pure bismethano derivatives of fullerene C60 and C70 with high Kobayashi et al. prepared a series of glycofullerenes in 13-28% steric congestion using 1,3-dibenzoylpropane bis-p-toluenesulfonyl yields by reacting C60 with per-O-acetyl glycosyl azide of D- hydrazone as the addend precursor [32]. The protecting groups on glucopyranose, D-galactopyranose, lactose, maltose, and maltotri- the sugar units were later expanded to 4,6-O-benzylidene (3) and ose, respectively (Scheme 3, 7-11) [38]. The glycofullerenes were 2,3:4,6-di-O-isopropylidene (4), and glycofullerene 5 with unpro- identified to be 5,6-addition type due to the absence of the signals 3 tected sugar unit was also prepared [33]. from sp carbons of C60 which should appear between 80-90 ppm as well as the disappearance of the bands between 420-440 nm in UV- REACTION WITH AZIDES vis absorptions. Even though the addition pattern has been fixed, the authors found by 1H NMR analysis that each of these glyco- The addition of azides to C60 was demonstrated by Prato and fullerenes is a mixture of two steroisomers with a molar ratio of Wudl in 1993 [34]. Utilizing this synthetic route, Taylor et al. re- ~2:1. ported the preparation of an isolable and stable C derivative, az- 60 In another work, Kobayashi and Shinohara et al. prepared gly- iridino[2,3:1,2]C (6a), by thermal elimination of isobutene and 60 cofullerenes carrying mono- and bis--D-mannosyl linkages on the CO from N-tert-butoxycarbonylaziridino[2,3:1,2]C (6b). 6a 2 60 surface via the reaction between 2-azidoethyl -D-mannoside and 1492 Current Organic Chemistry, 2016, Vol.