Carbohydrate Research 410 (2015) 36e46

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Efficient regioselective O3-monodesilylation by hydrochloric acid in cyclodextrins Jiamin Gu, Tong Chen, Qifang Wang, Tieyu Chen, Chang-Chun Ling* Alberta Glycomics Centre, Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 March 2015 Received in revised form 6 April 2015 Accepted 7 April 2015 Available online 16 April 2015

An efficient O3-monodesilylation method has been developed for the derivatization of per-3-O-silylated cyclodextrin (CD) derivatives. Using hydrochloric acid as a reagent, the O3-monodesilylation was found to be regioselective, mild, practical and general as it can be applied to all a-, b- and g-CDs. The advantage of the methodology is that the acid-catalyzed O3-desilylation can be carried out in a stepwise manner so that different types of functional groups can be introduced to a CD molecule at different stage of the O3desilylations. This makes the current methodology flexible and versatile. This current methodology constitutes one of the few methodologies available for the regioselective modification of CDs at the secondary face. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Cyclodextrins O3-Desilylation Silyl protecting group Hydrochloric acid Regioselectivity

1. Introduction Regioselective modification at a single O3-position of cyclodextrins (CDs) is still a challenge because of the higher reactivity1e13 of hydroxyl groups at O2- and O6-positions. As a result, only few synthetic methodologies are available in the literature for the regioselective O3-modification of CDs. Early work on direct O3monotosylation of a-CD provided the mono-3-tosylate in only 17% yield using tosyl chloride in aqueous alkaline solution; the 2- or 6tosylates were also obtained as minor side products.14e17 On the other hand, by taking advantage of the inclusion properties of CDs in aqueous media, specific sulfonylation agents such as 2naphthalenesulfonyl chloride have been shown to monofunctionalize O3-position of a- and b-CDs in 18e29% yields using sodium hydroxide in aqueous acetonitrile conditions.18e20 For the analogous O3-sulfonylation of g-CD, dansyl chloride was reported to be the reagent of choice.21 However, the reaction provided poor regioselectivity and very low yields as the 3-dansylate was isolated in only 7% yield along with the 2-dansylate (13% yield). After obtaining the 3- or 2-sulfonates of CDs, usually the derivatives were further elaborated and converted to the corresponding 2,3-allo- or 2,3-manno-epoxides, which then underwent a nucleophilic attack

* Corresponding author. Tel.: þ1 403 220 2768; fax: þ1 403 289 9488. E-mail address: [email protected] (C.-C. Ling). http://dx.doi.org/10.1016/j.carres.2015.04.003 0008-6215/© 2015 Elsevier Ltd. All rights reserved.

to open the strained three-membered ring, resulting in the introduction of a functional group at either 3- or 2-position.22,23 However, it is important to note that the formed products by this fashion were derivatives of altrose. Jindrich and Tislerova later reported24 a direct synthesis of mono-3-O-cinnamylated b-CD (29% yield) in aqueous sodium hydroxide along with the formation of a large amount of polysubstituted by-products. More recently, Masurier et al. reported25 a novel method to regioselectively modify one of the O3-positions of native b-CD based on the formation of a temporary copper(II)-b-CD complex; the methodology appears to be only suitable for bulky electrophiles such as benzylic and 3brominated allyl groups to afford the O3-monoalkylated b-CDs in 38e42% yields, together with some O2-substituted by-products. Remarkably, a de-O-benzylation method by using iodineetriethylsilane (I2eEt3SiH) as the reagent has been reported to regioselectively deprotected all O3- benzyl groups from per-2,3,6benzylated a-CD.26 Other less direct methods were also reported. For example, one benzylidene acetal group has been introduced to simultaneously protect an adjacent O2 and O3 pair of the contiguous D-glucopyranosyl residues in a CD.27e29 a,a-Dibromo-o-xylylene can also be regioselectively introduced to O2 and O3 of one glucose unit of CDs30,31 to form O2,O3-capped derivatives (28e33% yields), and the o-xylylene can be advantageously removed by hydrogenation. More recently, diisobutylaluminum hydride (DIBAL-H) has been shown to reductively remove either methyl groups from both O2 and O3 positions of per-O-methylated CDs32

J. Gu et al. / Carbohydrate Research 410 (2015) 36e46

or benzyl groups from per-2,3,6-O-benzylated a-CD;33 in the latter case, the benzyl groups were removed in a sequential fashion to form 3A,6A,6D-tri-O-debenzylated a-CD derivative. In this paper, we report a general, practical and efficient method to monofunctionalize O3-position of CDs by taking advantage of the easily accessible per-3-O-silylated CD34,35 derivatives as well as the acid-sensitivity of O-silyl ether group.36,37 Previously, we have reported the acidcatalyzed stepwise O-desilylation from per-3,6-O-silylated CD derivatives,38 which gave consistent O6-desilylations but inconsistent O3-desilylations. This work further expands the scope of the acidcatalysed O-desilylation. 2. Results and discussion Previously, we have shown that DIBAL-H could be used to reductively remove 1e2 primary O-silyl groups in a regioselective manner from per-6-O-silylated CDs12,13 in good to excellent yields. The methodology has a general applicability to CD substrates containing either tert-butyldimethylsilyl (TBS) or thexyldimethylsilyl (TDS) groups at primary face. An important advantage of the methodology is its chemoselectivity, as different alkyl groups (such as methyl, benzyl and allyl group) could be present in the molecule during the reductive O-desilylation without being affected. Therefore, we wondered if this methodology could be applied to CD substrates containing O-silyl groups at secondary face. A per-2,6-O-methylated a-CD derivative 2 that contained six TBS groups at O3 positions was designed as a test (Scheme 1). Compound 2 was prepared in 57% yield from the easily accessible hexol 138 by carrying out a per-6-O-methylation using iodomethane as the reagent and sodium hydride as the base. Unfortunately, when compound 2 was subjected to a reaction with DIBAL-H (2e48 equiv) in anhydrous toulene using previously published conditions,12 a series of products were formed from the reduction, with no product isolated as a major. High resolution mass spectrometry revealed that the initially formed

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intermediates had a loss of 1e2 methyl groups, followed by a further loss of one TBS group. Due to the complexity of formed reaction mixtures, the DIBAL-mediated reaction was not investigated further. We thus turned our attention to the acid-catalyzed O-desilylation methodology,38 which has been shown to exhibit interesting regioselectivity in CD chemistry for per-3,6-O-silylated CD derivatives. In a mixture of chloroformemethanol and under mild acidic condition (pH 2e3, ~3 h), the primary O6-TBS groups were progressively removed without affecting the secondary O3-TBS groups. The last primary O6-TBS group was observed to be slightly more resistant to the hydrolysis than the rest; thus this intermediate could be isolated along with the symmetric product that had all primary O6-TBS groups removed. On the other hand, if the reaction time was prolonged to 18 h, in some cases, one of the secondary O3-TBS groups was found to be more labile than the rest. However, the reaction pattern was not consistent. The presence of numerous O-TBS groups in previously used CD substrates (typically 12e16 OTBS groups) made the O-desilylation process rather complexes, which afforded multiple intermediates. Consequently, the yield of each isolated product was low. We thus turned our attention to CD substrates containing less O-TBS groups; as this could reduce complexity of the reaction mixtures, allowing O-desilylated products to form in higher yields. The per-3-O-silylated a-CD derivative 2 was thus subjected to different acidic conditions in a 3:1 mixture of chloroformemethanol (Scheme 2). As expected, in strong acidic condition (pH2), it was observed that the reactions did not proceed at all even after 24 h. More interestingly, when the acidity of the reaction mixture was controlled to be in the range of pH 1~2, the rate of O-desilylation was observed to proceed slowly, and the progress of reaction could be effectively monitored by TLC. After 14 h, the O3-monodesilylated compound 3 was easily isolated in 37% yield by chromatography on silica gel.

Scheme 1. Attempted reductive O3-desilylations using DIBAL-H as a reagent.

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J. Gu et al. / Carbohydrate Research 410 (2015) 36e46

Scheme 2. Hydrochloric acid-mediated partial O3-desilylation from per-3-O-silylated a-, b- and g-CD substrates.

To demonstrate the general applicability of the methodology, other per-3-O-silylated CD analogs 5e8 derived from a-, b- or g-CD were also prepared. These substrates were per-functionalized with allyl or methyl groups at O6/O2 positions. To our delight, when all compound 5e8 were subjected to a treatment with hydrochloric chloride as above, the O3-monodesilylated CD derivative was obtained in each case. The isolated yield for the O3-monodesilylated a-CD (9) was 57% yield, while the other similarly O3monodesilylated analogs 10e12 were obtained in 38e42% yields (Scheme 2). More encouragingly, the acid-mediated regioselective O-desilylations could be scaled up to gram quantities. For example, by using b-CD derivative 6 as a substrate, the O3-monodesilylation was successfully carried out in a near 2-g scale to afford desired alcohol 11 in 43% yield. The reaction was observed to progress slightly slower at this scale, and the optimal time required for the reaction can be carefully monitored by thin-layer chromatography (TLC) on silica gel. Compared to the DIBAL-H-mediated O-desilyaltion methodology, the acid-mediated O-desilylation could be advantageous in some aspects. For example, DIBAL-H reagent was known to reduce propargyl39 and azide;40,41 in these cases, the acid-mediated Odesilylation could preserve these functionalities. To demonstrate the utility, we thus designed two b-CD derivatives containing per6-azido-6-deoxy and per-6-O-propargyl 15 and 17 for our studies. Both compounds could be very useful as they are both trifunctionalized. The per-6-azido compound 15 was prepared from the easily accessible compound 1342 by carrying out a regioselective O2-persilylation using TBS chloride in DMF (/14, 45% yield). The obtained product was subsequently treated with sodium hydride and allyl bromide to provide the desired substrate 15, which was formed after a complete migration of silyl groups from O2 to O3 positions, and finally perallylation at all O2 positions. The

synthesis of O6-perpropargylated compound 17 was directly prepared from the previously obtained heptol 1638 by carrying out a per-6-O-propargylation using conventional conditions (70% yield). As shown in Scheme 3, the acid-mediated O3-mondesilylations worked very well for both substrates 15 and 17. The corresponding alcohols 18 and 19 were obtained in 37% and 34% yields. The most importantly added value of the current methodology is the provided opportunities to perform stepwise O-desilylations at the secondary face of CDs, so that different chemical functionalities could be precisely introduced to the secondary face of a CD. Scheme 4 shows examples of such applications using b-CD alcohol 10 as a substrate. After uncovering the first secondary alcohol at the C3-position, a functional group could be introduced. For example, a methyl group or the more useful propargyl group could be smoothly introduced via conventional alkylation conditions in 83% (/20) and 61% (/21) yields, respectively. By subjecting both compounds to a stronger acidic treatment (pH