HETEROCYCLES

Short Paper | Special issue | Vol. 88, No. 2, 2014, pp. 1587-1594
Received, 29th July, 2013, Accepted, 25th September, 2013, Published online, 30th September, 2013.
DOI: 10.3987/COM-13-S(S)99

■ Glycosidation Reactions of Benzyl-Type Selenoglycoside Donors

Masanori Menjo, Hideki Tamai, Hiromune Ando,* Hideharu Ishida, Mamoru Koketsu, and Makoto Kiso*

Faculty of Applied Biological Sciences, Gifu University , 1-1 Yanagido, Gifu, Gifu 501-1193, Japan

Abstract

p-Methoxybenzyl (PMB), and p-nitrobenzyl (PNB) selenoglycosides of glucose were synthesized, and their glycosidation reactions were investigated. The Bn and PNB derivatives were successfully activated with IBr-AgClO4 to provide the glycosylated products in high yields. The glycosidation with the PMB derivatives required promotion with a metal triflate, such as (CuOTf)2·PhMe or In(OTf)3, and afforded the glycosylated products in medium to high yields.

Selenoglycosides are attractive potential glycosyl donors.1 The soft, highly nucleophilic selenium atom means that selenoglycosides can be activated by a wide range of soft electrophiles, and preferentially activated over thioglycosides.2 However, the lack of methods for the synthesis of selenoglycosides has limited their use as glycosyl donors.3 Namely, only phenylselenoglycoside donors have been utilized in the synthesis of carbohydrates. Previously, we have reported a facile synthetic method for alkyl selenoglycosides,4 which features the in situ chemoselective generation of an anomeric selenolate anion from β-p-methylbenzoyl selenoglycoside. Here, as a part of exploration of selenoglycoside donors, we report the glycosidation reactions of a benzyl selenoglycoside donor and its para-substituted analogues.

Three types of benzyl selenoglycosides (2-4) were synthesized according to our previously reported method.4 p-Methylbenzoyl 2,3,4,6-tetra-O-benzoyl-1-seleno-β-D-glucopyranoside (1) was reacted with the corresponding benzyl halide in the presence of piperazine and Cs2CO3 to afford selenoglycosides 2-4 in high yields (Scheme 1).

We examined the glycosidation reactions of the selenoglycoside donors with various glycosyl acceptors and promoters. Initially, the glycosidation with benzyl selenoglycoside 2 was attempted using various glycosylation promoters in the presence of 4 Å molecular sieves in CH2Cl2 (Table 1). The glycosidation promoted by PhSeOTf at -80 °C was sluggish and provided only a marginal yield of disaccharide 7 (45%, entry 1). The coupling yield was not improved by raising the reaction temperature. MeOTf required a higher temperature for the glycosylation, and produced 7 in low yield (36%) with orthoester 9 as a byproduct (entry 2). Surprisingly, NIS-TfOH generated orthoester 9 as the single major product (entry 3). However, IBr-AgClO45 provided the best yield of 7 (63%) at -80 °C (entry 4). For the reaction with the electron-rich hydroxyl group of compound 6, the yield of disaccharide 8 was 85% (entry 5).

Next, we compared the glycosidation of 5 with p-methoxybenzyl (PMB) selenoglycoside 3 with that of p-nitrobenzyl (PNB) selenoglycoside 4 (Table 2). NIS-TfOH did not produce disaccharide 7, whereas a good yield was obtained with IBr-AgClO4 for the PNB derivative 4 (entries 1-4). Although PhSeOTf

showed a better affinity for 3 and 4, the glycosidation yields remained low (entries 5 and 6). The reaction of 3 and PhSeOTf also produced asymmetric diselenide 11 and 6-O-p-methoxybenzylated compound 12 (entry 5) because of the preferential generation of the PMB cation instead of the oxocarbenium ion. When the reaction was promoted with MeOTf, PNB derivative 4 afforded an acceptable yield of 7, whereas PMB derivative 3 gave a complex mixture of products (entries 7 and 8).
The glycosidation of 3 and 4 was attempted in the presence of various metal triflates. Although electron-rich glycosyl donor 3 could be activated with AgOTf,6 Cu(OTf)2,7 and (CuOTf)2·PhMe, almost no product was observed for AgOTf, Cu(OTf)2. A moderate yield was observed for (CuOTf)2·PhMe (entries 9, 13, and 15). However, electron-deficient glycosyl donor 4 was not affected by any of the metal triflates (entries 10, 12, 14, 16, and 18). In contrast to 4, In(OTf)3 promoted the glycosidation of 3 with 10 to give disaccharide 138 in 88% yield.

In conclusion, we have synthesized three types of benzyl selenoglycosides (2-4). The Bn and PNB selenoglycoside donors were activated with IBr-AgClO4 or MeOTf, and afforded the corresponding glycoside in good yields. In addition, In(OTf)3 promoted the glycosidation with the PMB selenoglycoside donor 3, implying a possibility of the chemoselective activation of 3 over other selenoglycosides.

EXPERIMENTAL
1H and 13C NMR spectra were recorded with JEOL JNM-ECX400P, JNM-ECA500, and JNM-ECA600 spectrometers. Chemical shifts in the 1H NMR spectra are expressed in ppm (δ) relative to the Me4Si signal adjusted to δ 0.00 ppm. COSY methods were used to confirm the NMR peak assignments. Specific rotations were determined with a Horiba SEPA-300 high sensitivity polarimeter. High-resolution mass spectrometry (HRMS) was conducted with a Bruker Daltonics micrOTOF (ESI-TOF) system. Molecular sieves were purchased from Wako Chemicals Inc. and dried at 300 °C for 2 h in a muffle furnace prior to use. Solvents used in reactions were dried over molecular sieves and used without purification. TLC analysis was performed on Merck glass TLC plates (silica gel 60F254). Compounds were detected with UV light (253 nm) or by soaking in a 10% solution of H2SO4 in ethanol followed by heating. Silica gel (80 and 300 mesh) manufactured by Fuji Silysia Chemical Ltd. was used for flash column chromatography. The amount of silica gel was usually about 150- to 200-fold the weight of the sample. Solvent systems in chromatography are specified as volume ratios. Evaporation and condensation were carried out in vacuo.

Typical procedure of benzyl selenoglycosides: Piperazine (1.5 eq.) was added to a suspension of p-methylbenzoyl 2,3,4,6-tetra-O-benzoyl-1-seleno-β-D-glucopyranoside 1 (1.0 eq.), Cs2CO3 (2.0 eq.), and alkyl halide (2.0 eq.) in degassed DMA (50 mM) under Ar stream at ambient temperature. The reaction was monitored by TLC (n-Hexane/EtOAc = 2/1, developed twice). After stirred for 1 h, the reaction mixture was extracted with EtOAc. Then the organic layer was successively washed with H2O, 2 M HCl, satd. aq. NaHCO3, and brine. The organic solution was dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (n-Hexane/EtOAc = 5/1)

p-Methoxybenzyl 2,3,4,6-tetra-O-benzoyl-1-seleno-β-D-glucopyranoside (3): [α]D -22.5 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.05-6.76 (m, 22 H, Ar), 5.82 (dd, 1 H, J2,3 = 8.9 Hz, J3,4 = 9.7 Hz, H-3), 5.67 (dd, 1 H, J4,5 = 10.3 Hz, H-4), 5.63 (dd, 1 H, J1,2 = 10.3 Hz, H-2), 4.82 (d, 1 H, H-1), 4.64, (dd, 1 H, J5,6a = 2.8 Hz, Jgem = 12.4 Hz, H-6a), 4.51 (dd, 1 H, J5,6b = 5.5 Hz, H-6b), 4.04 (m, 2 H, H-5, SeCH2), 3.91 (d, 1 H, Jgem = 11.7 Hz, SeCH2), 3.79 (s, 3 H, OCH3); 13C NMR (150 MHz, CDCl3) δ 166.1, 165.8, 165.3, 165.2, 158.6, 133.4, 133.3, 133.2, 130.2, 129.9, 129.8, 129.7, 129.6, 129.6, 129.1, 128.8, 128.4, 128.3, 128.3, 114.0, 77.4, 77.1, 74.0, 71.4, 69.7, 63.5, 55.2, 26.3; 77Se-NMR (95 MHz, CDCl3) δ 377.4; HRMS (ESI): found [M+Na]+ 803.1370, C42H36O10Se calcd. for [M+Na]+ 803.1371.

p-Nitrobenzyl 2,3,4,6-tetra-O-benzoyl-1-seleno-β-D-glucopyranoside (4): [α]D -48.5 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.06-7.25 (m, 25 H, Ar), 5.88 (dd, 1 H, J2,3 = 9.0 Hz, J3,4 = 9.6 Hz, H-3), 5.71 (dd, 1 H, J4,5 = 10.3 Hz, H-4), 5.65 (dd, 1 H, J1,2 = 9.7 Hz, H-2), 4.93 (d, 1 H, H-1), 4.68 (dd, 1 H, J5,6a = 3.5 Hz, Jgem = 12.4 Hz, H-6a), 4.53 (dd, 1 H, J5,6b = 5.5 Hz, H-6b), 4.13 (m, 2 H, H-5, SeCH2), 4.00 (d, 1 H, Jgem = 11.7 Hz, SeCH2); 13C NMR (150 MHz, CDCl3) δ 166.0, 165.7, 165.3, 165.2, 146.8, 146.0, 133.5, 129.8, 129.6, 129.4, 128.7, 128.6, 128.6, 128.5, 128.4, 128.4, 128.3, 123.8, 76.8, 73.7, 71.3, 69.4, 63.1, 60.3, 25.5, 21.0, 14.1; 77Se-NMR (95 MHz, CDCl3) δ 388.1; HRMS (ESI): found [M+Na]+ 818.1113, C41H33O11Se calcd. for [M+Na]+ 818.1117.

Typical procedure for the glycosidation: A mixture of donor (1.0 eq.), acceptor (1.0 eq.), and desiccant (MS 4 Å or MS 5 Å, 100 mg/mL for solvent) in CH2Cl2 (40 mM) was stirred under Ar atmosphere at ambient temperature. Then, glycosylation promotor was added to the mixture at corresponding temperature. The completion of the reaction was monitored by TLC (toluene/EtOAc = 10/1). The reaction mixture was diluted with EtOAc. The mixture was then neutralized with satd. aq. NaHCO3. The mixture was filtered through a pad of celite and the filtrate was extracted with EtOAc. The organic layer was washed with H2O and brine, and dried over Na2SO4, and concentrated. The resulting residue was purified by silica gel column chromatography (toluene/EtOAc = 20/1).

2-(Trimethylsilyl)ethyl (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-(1→6)-2,3,4-tri-O-benzoyl-β-D-galactopyranoside (7): [α]D +80.0 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.13-7.29 (m, 35 H, Ar), 6.00 (d, 1 H, J3,4 = 4.8 Hz, H-4Gal), 5.97 (dd, 1 H, J2,3 = 10.3 Hz, J3,4 = 9.6 Hz, H-3Glc), 5.81 (dd, 1 H, J1,2 = 8.2 Hz, J2,3 = 10.3 Hz, H-2Gal), 5.76 (t, 1 H, J4,5 = 9.6 Hz, H-4Glc), 5.64-5.61 (m, 2 H, H-3Gal, H-2Glc), 5.04 (d, 1 H, J1,2 = 8.3 Hz, H-1Glc), 4.78 (d, 1 H, H-1Gal), 4.70 (dd, 1 H, J5,6a = 2.8 Hz, Jgem = 11.7 Hz, H-6aGlc), 4.42 (dd, 1 H, J5,6b = 4.8 Hz, H-6bGlc), 4.27 (dd, 1 H, J5,6a = 4.8 Hz, H-5aGal), 4.21-4.17 (m, 2 H, H-5Glc, H-6aGal), 4.02 (m, 2 H, H-6bGal, OCH2CH2Si), 3.55 (m, 1 H, OCH2CH2Si), 0.91, 0.82 (m, 2 H, OCH2CH2Si), 0.00 (s, 9 H, 3 CH3); 13C NMR (150 MHz, CDCl3) δ 166.0, 165.7, 165.5, 165.4, 165.2, 165.1, 164.9, 133.4, 133.2, 133.1, 133.0, 129.9, 129.8, 129.7, 129.6, 129.5, 129.2, 129.1, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.2, 128.1, 101.1, 100.8, 73.1, 72.8, 72.3, 71.9, 71.8, 69.9, 69.4, 68.7, 68.3, 67.5, 62.7, 17.7, -1.5; HRMS (ESI): found [M+Na]+ 1193.3594, C66H62O18Si calcd. for [M+Na]+ 1193.3598.

Methyl (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-(1→3)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (8): [α]D -19.4 (c 1.8, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.02-7.00 (m, 35H, Ar), 5.93 (t, 1 H, H-3Glc, J2,3 = J3,4 = 9.8 Hz), 5.71 (t, 1 H, H-4Glc, J4,5 = 9.8 Hz), 5.67 (dd, 1 H, H-2Glc, J1,2 = 8.0 Hz), 5.30 (d, 1 H, H-1Glc), 5.01 (d, 1 H, OCH2Ph, Jgem = 11.3 Hz), 4.65 (dd, 1H, H-6aGlc, Jgem = 12.1 Hz, J5,6a = 3.1 Hz), 4.53 (dd, 1 H, H-6bGlc, J5,6b = 5.7 Hz), 4.52 (d, 1 H, OCH2Ph, Jgem = 11.3 Hz), 4.44 and 4.43 (2 d, 2 H, 2 OCH2Ph, Jgem = 11.3 Hz), 4.36 (d, 1 H. H-1Gal, J1,2 = 3.7 Hz), 4.35 (d, 1 H, OCH2Ph, Jgem = 11.4 Hz), 4.19 (dd, 1 H, H-3Gal, J2,3 = 10.2 Hz, J3,4 = 3.0 Hz), 4.14 (ddd, 1 H ,H-5Glc), 4.09 (d, 1 H, OCH2Ph, Jgem = 12.5 Hz), 3.98 (d, 1 H, H-4Gal), 3.79 (dd, 1 H, H-5Gal, J5,6a = 6.5 Hz, J5,6b = 5.7 Hz), 3.77 (dd, 1 H, H-2Gal), 3.47 (dd, 1 H, H-6aGal, Jgem = 9.7 Hz), 3.37 (dd, 1 H, H-6bGal) ; 13C NMR (125 MHz, CDCl3) δ 166.0, 165.8, 165.2, 165.0, 138.6, 138.3, 138.1, 133.4, 133.2, 133.2, 133.1, 129.8, 129.7, 129.5, 129.2, 129.0, 128.8, 128.7, 128.6, 128.4, 128.4, 128.4, 128.3, 128.3, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 125.3, 101.9, 98.5, 78.1, 77.3, 77.2, 76.3, 75.0, 73.8, 73.3, 72.9, 72.2, 72.1, 69.7, 69.3, 69.2, 62.7, 55.1; HRMS (ESI): found [M+Na]+ 1065.3667, C62H58O15 calcd. for [M+Na]+ 1065.3668.

3,4,6-Tri-O-benzoyl-α-D-glycopyranose 1,2-[2-(trimethylsilyl)ethyl 2,3,4-tri-O-benzoyl-β-D-galactopyranosid-6-yl orthobenzoate] (9): [α]D -60.4 (c 2.6, CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.18-7.29 (m, 35 H, Ar), 6.01 (d, 1 H, J1,2 = 3.2 Hz, H-1Glc), 5.93 (dd, 1 H, J2,3 = 3.0 Hz, J3,4 = 1.4 Hz, H-3Glc), 5.77 (m, 2 H, H-2Gal, H-4Gal), 5.61 (dd, 1 H, J2,3 = 8.5 Hz, J3,4 = 3.2 Hz, H-3Gal), 5.51 (dd, 1 H, J4,5 = 8.7 Hz, H-4Glc), 4.87 (dd, 1 H, H-2Glc), 4.83 (d, 1 H, J1,2 = 7.7 Hz, H-1Glc), 4.53 (dd, 1 H, J5,6a = 3.2 Hz, Jgem = 11.9 Hz, H-6aGlc), 4.39 (dd, 1 H, J5,6b = 5.0 Hz, H-6bGal), 4.11 (m, 3 H, H-5Glc, H-6aGal, OCH2CH2Si), 3.64 (m, 3 H, H-5Gal, H-6bGal, OCH2CH2Si), 0.96 (m, 2 H, OCH2CH2Si), 0.00 (s, 9 H, 3 CH3); 13C NMR (150 MHz, CDCl3) δ 165.9, 165.6, 165.5, 165.2, 165.1, 164.5, 134.4, 133.6, 133.4, 133.4, 133.1, 132.9, 130.1, 129.9, 129.9, 129.7, 129.7, 129.6, 129.6, 129.2, 129.1, 129.0, 128.9, 128.5, 128.4, 128.3, 128.2, 128.2, 126.1, 121.0, 101.0, 97.5, 77.2, 72.2, 71.9, 71.7, 69.9, 68.9, 68.3, 67.9, 67.7, 67.5, 64.0, 61.3, 29.7, 18.0, -1.5; HRMS (ESI): found [M+Na]+ 1193.3597, C66H62O18Si calcd. for [M+Na]+ 1193.3598.

2-(Trimethylsilyl)ethyl 2,3,4-tri-O-benzoyl-6-O-p-methoxybenzyl-β-D-galactopyranoside (12): [α]D +96.0 (c 0.5, CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.03-6.74 (m, 19 H, Ar), 5.93 (d, 1 H, J3,4 = 3.4 Hz, H-4), 5.73 (dd, 1 H, J1,2 = 8.2 Hz, J2,3 = 8.6 Hz, H-2), 5.54 (dd, 1 H, H-3), 4.78 (d, 1 H, H-1), 4.47 and 4.35 (2 d, 2 H, Jgem = 11.0 Hz, OCH2Ar), 4.10 (m, 2 H, H-6a, OCH2CH2Si), 3.71 (s, 3 H, OCH3), 3.65 (m, 3 H, H-5, H-6b, OCH2CH2Si), 0.92 (m, 2 H, OCH2CH2Si), -0.06 (s, 9 H, 3 CH3); 13C NMR (150 MHz, CDCl3) δ 165.6, 165.5, 165.2, 159.2, 133.3, 133.1, 133.0, 129.9, 129.7, 129.7, 129.6, 129.5, 129.5, 129.3, 128.9, 128.4, 128.2, 128.2, 113.7, 101.0, 73.2, 72.7, 72.0, 70.0, 68.4, 67.7, 67.5, 55.1, 18.0, -1.5; HRMS (ESI): found [M+Na]+ 735.2597, C42H36O10Se calcd. for [M+Na]+ 735.2596.

ACKNOWLEDGEMENTS
The iCeMS is supported by World Premier International Research Center Initiative (WPI), MEXT, Japan. This work was financially supported in part by MEXT of Japan (a Grant-in-Aid for Scientific Research (B) No. 22380067 to M.K., and a Grant-in-Aid for Young Scientists (A) No. 23688014 and Grant-in-Aid on Innovative Areas No. 24110505, Deciphering sugar chain-based signals regulating integrative neuronal functions to H.A.). We thank Ms. Kiyoko Ito (Gifu Univ.) for providing technical assistance.

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