Synthesis of a novel glucose-conjugated 15-crown-5 ether with a spiro ketal structure

Article abstract of DOI:10.3390/molecules13081840

This paper describes a synthetic approach to a novel glucose-conjugated 15-crown-5 ether having a spiroketal structure starting from a 1-C-vinylated glucose derivative. The approach consists of the glycosylation of the vinylated glucose derivative to give an ethyleneoxy spacer derivative using bismuth(III) triflate, the conversion of the 1-C-vinyl group of the glucoside produced into a carboxylic acid group, and the intramolecular condensation between the carboxyl group and the terminal hydroxyl group in the ethyleneoxy spacer. A D-glucose-conjugated 15-crown-5 ether having a unique spiroketal structure was thus successfully synthesized.

Full text of DOI:10.3390/molecules13081840

Molecules 2008, 13, 1840-1845 manuscripts; DOI: 10.3390/molecules13081840
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
Synthesis of a Novel D-Glucose-Conjugated 15-Crown-5 Ether
with a Spiro Ketal Structure
Takashi Yamanoi *, Yoshiki Oda, Hitomi Muraishi and Sho Matsuda
The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan; E-mails:
odayoshiki@noguchi.or.jp (Yoshiki Oda), hitommy-heart@bridge.ocn.ne.jp (Hitomi Muraishi),
s.matsuda@noguchi.or.jp (Sho Matsuda)
* Author to whom correspondence should be addressed. E-mail: tyama@noguchi.or.jp; Fax:
(+81) 3 5944 3213.
Received: 18 July 2008; in revised form: 12 August 2008 / Accepted: 19 August 2008 / Published: 22
August 2008
Abstract: This paper describes a synthetic approach to a novel D-glucose-conjugated 15-
crown-5 ether having a spiroketal structure starting from a 1-C-vinylated glucose
derivative. The approach consists of the glycosylation of the vinylated glucose derivative
to give an ethyleneoxy spacer derivative using bismuth(III) triflate, the conversion of the
1-C-vinyl group of the glucoside produced into a carboxylic acid group, and the
intramolecular condensation between the carboxyl group and the terminal hydroxyl group
in the ethyleneoxy spacer. A D-glucose-conjugated 15-crown-5 ether having a unique
spiroketal structure was thus successfully synthesized.
Keywords: Crown ether; Spiroketal; 1-C-Vinylated glucose; Glycosylation
Introduction
Crown ether molecules with saccharide moieties are interesting as chiral phase-transfer catalysts
[1-2]. An enzymatic approach for synthesizing these types of crown ethers provides the cyclofructan
family (cycloβ(2J1)-D-fructooligosaccharides) via the digestion of inulin. The cyclofructan contains a
structurally interesting crown ether framework in its central core [3-4]. It is noteworthy that this is the

Molecules 2008, 13
1841
first example of saccharide-based crown ethers which have spiroketal structures. Many saccharide-
based crown ether molecules have also been synthesized by chemical procedures [5-7]. As these
chemical methods bind the original hydroxyl groups of the saccharide with an ethyleneoxy spacer,
they cannot produce however crown ether compounds having spiroketal structures.
Sugar derivatives (1-C-vinylated sugars) having a vinyl group at the anomeric center, which are
readily prepared by the addition of organometallic reagents, such as vinylMgX, to a suitably protected
sugar lactone, are a synthetically useful tool in carbohydrate chemistry [8-11]. Our recent studies have
shown that these 1-C-vinylated sugar derivatives were good precursors for preparing some
fuctionalized exo-glycal derivatives [12] and naturally occurring anhydroketopyranoses [13]. For the
purpose of further exploring the utility of the 1-C-vinylated sugars, we investigated the synthesis of a
novel crown ether molecule from a 1-C-vinylated D-glucose derivative 1. The D-glucose-conjugated
15-crown-5 ether 2 that we designed is a dicyclic compound with a unique spiroketal structure
derived from the structural characteristic of 1, i.e., its spiro carbon atom corresponds to the anomeric
carbon atom. This paper describes our synthetic approach to a novel 15-crown-5 ether 2 having a
spiroketal structure from a 1-C-vinylated glucose derivative (1).
Results and Discussion
The synthetic approach to compound 2 from 1 is shown in Scheme 1. It consists of the following
reaction steps: 1) introduction of the ethyleneoxy spacer, tetraethyleneglycol monobenzoate (3) onto
the vinylated D-glucopyranose derivative 1 by the glycosylation reaction; 2) conversion of the vinyl
group at the anomeric center of 4 to a carboxyl group, and 3), intramolecular condensation between the
carboxyl group and the terminal hydroxyl group in the ethyleneoxy spacer to produce the desired 2.
The glycosylation of 1 to 3 (1.3 equiv.) using bismuth(III) triflate (Bi(OTf)3) (0.05 equiv.) in the
o
presence of anhydrous CaSO4 in dichloromethane at 0 C for 24 h afforded the desired glucoside 4
[14], which was purified by preparative TLC (ethyl acetate/hexane = 1/2) in 81% yield. The
glycosylation proceeded with an α-stereoselectivity. The high α-stereoselectivity of the glycosylation
using 1 was in agreement with our previously reported observation [15]. The α-anomeric configuration
of 4 was determined by the NOE interaction between the H-2 and the H-1’.
The ozone oxidation of 4 in dichloromethane at -78 oC for 5 h and treatment with
triphenylphosphine (3.4 equiv.) at room temperature for 19 h gave the crude aldehyde product. The
subsequent oxidation using NaClO2 (12 equiv.)-NaH2PO4 (3 equiv.) in t-butyl alcohol-H2O (4/1)
produced the carboxylic acid derivative 5, which was purified by preparative TLC (CHCl3/MeOH =
5/1) in 85% yield.
Deprotection of the benzoyl group of 5 was performed using 0.5 M NaOH/THF to afford 6 in 83%
yield. The cyclization of 6 using (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluoro-
phosphate (PyBOP) (2.5 equiv.) and DIEA (1.8 equiv.) in dichloromethane for 24 h afforded the
desired 2, which was purified by preparative TLC (CHCl3/MeOH = 20/1) in 84% yield.
In conclusion, we have demonstrated the synthesis of a novel 15-crown-5 ether 2 having a spiro
ketal structure from a 1-C-vinylated D-glucose derivative. This compound 2 is expected to function as
a chiral phase-transfer catalyst.

Molecules 2008, 13
1842
Scheme 1. Synthetic approach to 2.
NOE
OBn
OBn
H
O 1
H
O 1
3 BnO
i)
BnO
BnO
BnO
BnO
1'
3
BnO
OH
O
O
OBz
O
O
1
4
ii)
OBn
OBn
O 2
O
5
O
O 1
14'
BnO
BnO
BnO
BnO
1'
iv)
O
OH
O
1
BnO
4
O
BnO
O
O
O
OR
O
O
O
R = Bz; 5
= H ; 6
iii)
2
Reagents and conditions: i) Bi(OTf)3 (0.05 equiv.), Bz(OCH2CH2)4OH 3 (1.3 equiv.), CH2Cl2, 0
°C, 24 h, 81%; ii) (a) O3, -78 °C, 5 h, CH2Cl2, then Ph3P (3.4 equiv.), rt, 19 h. (b) Me2C=CHMe
(4.5 equiv.), NaClO2 (12 equiv.), NaH2PO4 (3 equiv.), t-BuOH-H2O, rt, 24 h, 85%; iii) 0.5 M
NaOH (13 equiv.), THF, rt, 3 h, 83%; iv) PyBOP (2.5 equiv.), DIEA (1.8 equiv.), CH2Cl2, 24 h,
84%.
Experimental
General
1H-NMR (600 MHz) and 13C-NMR (150 MHz) spectra were recorded using a JEOL ECA-600
spectrometer in CDCl3 with TMS as the internal standard. The optical rotations were recorded by a
JASCO DIP-360 digital polarimeter. The HRMS were obtained using a Mariner spectrometer
(PerSeptive Biosystems Inc.). Preparative TLC was performed using Merck silica gel 60GF254.
Column chromatography was conducted using silica gel 60 N (40~50 μm, Kanto Chemical Co., Inc.).
Bi(OTf)3 was purchased from Sigma-Aldrich. All anhydrous solvents were purified according to
standard methods.
11-Benzoyloxy-3,6,9-trioxaundecyl 2,3,4,6-tetra-O-benzyl-1-C-vinyl-α-D-glucopyranoside (4): To a
stirred solution of Bi(OTf)3 (15 mg, 0.023 mmol) in CH2Cl2 (3.5 mL) were added tetraethyleneglycol
monobenzoate (3) (165 mg, 0.55 mmol) and 2,3,4,6-tetra-O-benzyl-1-C-vinyl-α-D-glucopyranose (1)
(257 mg, 0.42 mmol) in the presence of anhydrous CaSO4 (280 mg) under an Ar atmosphere. The
resulting mixture was stirred at 0 oC for 24 h. The reaction was then quenched by the addition of a sat.

Molecules 2008, 13
1843
NaHCO3 solution (5 mL). The reaction mixture was extracted with CH2Cl2 (three times), and the
organic layer was washed with water and a sat. NaCl solution. After the organic layer was dried over
Na2SO4, the solvent was evaporated under reduced pressure. The crude product was purified by
preparative silica gel TLC (ethyl acetate/hexane = 1/2) to give 4 (311 mg, 81% yield) as a colorless
25
1
oil. [α]D = +3o (c 4.7, CHCl3); H-NMR: δ 3.34 (d, 1H, J = 9.6 Hz, H-2), 3.48-3.70 (m, 14H, H-4,
Ha-6, CH2CH2), 3.76-3.79 (m, 3H, Hb-6, CH2CH2), 3.85 (m, 1H, H-5), 4.10 (t, 1H, J = 9.7 Hz, H-3),
4.43-4.91 (m, 8H, CH2Ph), 5.27 (dd, 1H, J = 2.0 Hz, J = 11.0 Hz, CH=CHaHb), 5.54 (dd, 1H, J = 2.1
Hz, J = 17.9 Hz, CH=CHaHb), 5.99 (m, 1H, CH=CH2), 7.19-7.54, 8.04-8.05 (m, 25H, Ph); 13C-NMR:
δ 61.1 (CH2CH2), 64.1 (CH2CH2), 68.8 (C-6), 69.2 (CH2CH2), 70.0 (CH2CH2), 70.6 (CH2CH2), 70.64
(CH2CH2), 70.7 (CH2CH2), 71.5 (C-5), 73.4 (CH2Ph), 75.0 (CH2Ph), 75.5 (CH2Ph), 75.8 (CH2Ph),
78.5 (C-4), 83.0 (C-3), 84.3 (C-2), 99.5 (C-1), 118.8 (CH=CH2), 127.5-133.0 (Ph), 135.3 (CH=CH2),
138.1-138.4 (Ph), 166.5 (C=O); HRMS (ESI) m/z calcd for C51H58NaO11 869.3871 [M +Na]+, found
869.3865.
(11-Benzoyloxy-3,6,9-trioxaundecyl 3,4,5,7-tetra-O-benzyl-α-D-gluco-hept-2-ulopyranosid)onic acid
(5): Ozone was bubbled through a stirred solution of 4 (224 mg, 0.26 mmol) in CH2Cl2 (15 mL) at -78
o
oC for 5 h. After triphenylphosphine (230 mg, 0.88 mmol) was added at -78 C and the reaction
temperature was raised to room temperature, the reaction mixture was stirred for 19 h. The solvent was
then evaporated under reduced pressure. To a solution of the crude product in t-butyl alcohol (4 mL)-
H2O (1 mL) were added NaClO2 (277 mg, 3.1 mmol), NaH2PO4 (124 mg, 0.8 mmol) and 2-methyl-2-
butene (123 μL, 1.2 mmol). After the reaction mixture was stirred for 24 h, the reaction was quenched
by adding 2 M HCl (1 mL) and water (5 mL). The reaction mixture was then extracted with CH2Cl2
(three times), and the combined organic solvent was dried over anhydrous Na2SO4. The organic
solvent was filtered and evaporated under reduced pressure. The crude product was purified by
preparative silica gel TLC (CHCl3/MeOH = 5/1) to afford 5 (194 mg, 85% yield) as a colorless oil.
25
1
[α]D = +21o (c 3.9, CHCl3); H-NMR: δ 3.54-4.08 (m, 20H, H-3, H-4, H-5, H-6, H-7, CH2CH2),
4.41-4.49 (m, 2H, CH2CH2), 4.51-5.28 (m, 8H, CH2Ph), 7.03-7.53 (m, 23H, Ph), 8.03-7.53 (d, 2H, J =
6.8 Hz, Ph); 13C-NMR: δ 64.0 (CH2CH2), 69.1 (C-7), 69.9 (CH2CH2), 70.2 (CH2CH2), 70.3 (CH2CH2),
70.4 (CH2CH2), 70.5 (CH2CH2), 70.6 (CH2CH2), 72.6 (CH2CH2), 75.19 (CH2Ph), 75.20 (CH2Ph), 75.4
(CH2Ph), 75.5 (CH2Ph), 77.6 (C-6), 80.9 (C-5), 82.7 (C-3, C-4), 99.3 (C-2), 126.0-139.2 (Ph), 166.5
(C(O)Ph), 177.7 (C-1); HRMS (ESI) m/z calcd for C50H56NaO13 887.3613 [M +Na]+, found 887.3653.
(11-Hydroxy-3,6,9-trioxaundecyl 3,4,5,7-tetra-O-benzyl-α-D-gluco-hept-2-ulopyranosid)onic acid (6):
A 0.5 M NaOH solution (4 mL, 2 mmol) was added to a solution of 5 (142 mg, 0.16 mmol) in THF (4
mL). After the reaction mixture was stirred for 3 h at room temperature, the reaction was quenched by
adding 2 M HCl (1 mL) and water (5 mL). After the reaction mixture was extracted with CH2Cl2 (three
times), the combined organic solvent was dried over anhydrous Na2SO4. The organic solvent was
filtered and evaporated under reduced pressure. The crude product was purified by preparative silica
gel TLC (CHCl3/MeOH = 5/1) to afford 6 (103 mg, 83% yield) as a colorless oil. [α]D25 = +25o (c 1.8,
1
CHCl3); H-NMR: δ 3.37-4.00 (m, 22H, H-3, H-4, H-5, H-6, H-7, CH2CH2), 4.44-4.84 (m, 8H,
CH2Ph), 6.94-7.43 (m, 20H, Ph); 13C-NMR: δ 60.4 (CH2CH2), 62.6 (CH2CH2), 68.5-70.4 (CH2CH2, C-
7), 72.4 (CH2Ph), 73.4 (CH2Ph), 74.9 (CH2Ph), 75.3 (CH2Ph), 78.1 (C-6), 82.4 (C-5), 82.9 (C-3, C-4),

Molecules 2008, 13
1844
99.7 (C-2), 127.3-128.4, 137.8-138.9 (Ph), 172.3 (C-1); HRMS (ESI) m/z calcd for C43H52NaO12
783.3351 [M +Na]+, found 783.3396.
(1R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-D-glucitol-1,2’-[3,6,9,12]tetraoxatetradecan]-14’-olide
(2): To a solution of 6 (20 mg, 0.027 mmol) in CH2Cl2 (3 mL) were added 4-dimethylaminopyridine
(5.9 mg, 0.048 mmol) and PyBOP (35 mg, 0.067 mmol). After the reaction mixture was stirred for 24
h. The reaction was then quenched by the addition of a sat. citric acid solution (5 mL). The reaction
mixture was extracted with EtOAc and the organic layer was washed with water and a sat. NaCl
solution. After the organic layer was dried over Na2SO4, the solvent was evaporated under reduced
pressure. The crude product was purified by preparative silica gel TLC (CHCl3/MeOH = 20/1) to give
2 (17 mg, 84% yield) as a colorless oil. [α]D25 = +11o (c 0.15, CHCl3); 1H-NMR: δ 3.48-3.71 (m, 15H,
H-4, H-5, H-6, CH2CH2), 3.73-3.75 (m, 1H, CH2CH2), 3.81 (d, 1H, J = 9.6 Hz, H-2), 3.87-3.92 (m,
1H, CH2CH2), 3.94-3.98 (m, 1H, CH2CH2), 4.00-4.05 (m, 1H, CHaHbCH2), 4.06-4.07 (m, 1H, H-3),
4.31-4.34 (m, 1H, CHaHbCH2), 4.54-4.65 (m, 4H, CH2Ph), 4.79-4.89 (m, 4H, CH2Ph), 7.16-7.35 (m,
20H, Ph); 13C-NMR: δ 63.6 (CH2CH2), 65.2 (CH2CH2), 68.3 (CH2CH2), 68.4 (C-6), 69.6 (CH2CH2),
70.1 (CH2CH2), 70.4 (CH2CH2), 70.9 (CH2CH2), 71.2 (CH2CH2), 73.41 (C-5), 73.44 (CH2Ph), 75.1
(CH2Ph), 75.2 (CH2Ph), 75.6 (CH2Ph), 78.0 (C-4), 82.2 (C-2), 82.7 (C-3), 99.7 (C-1), 127.5-128.4
(Ph), 137.9-138.5 (Ph), 173.5 (C-1’); HRMS (ESI) m/z calcd for C43H50NaO11 765.3245 [M +Na]+,
found 765.3247.
References and Notes
1.
Mako, A.; Szollosy, A.; Keglevich, G.; Menyhard, D. K.; Bako, P.; Toke, L. Synthesis of
methyl-α-D-glucopyranoside-based azacrown ethers and their application in enantioselective
reactions. Monatsh. Chem. 2008, 139, 525-535. Their other references cited in therein.
Itoh, T.; Shirakami, S. Synthesis of chiral crown ethers derived from α-D-glucose and their
catalytic properties on the asymmetric michael addition. Heterocycles 2001, 55, 37-43.
Takai, Y.; Okumura, Y.; Tanaka, T.; Sawada, M.; Takahashi, S.; Shiro, M.; Kawamura, M.;
Uchiyama, T. Binding characteristics of a new host family of cyclic oligosaccharides from
inulin: Permethylated cycloinulohexaose and cycloinulohepaose. J. Org. Chem. 1994, 59, 2967-
2975. Their other references cited in therein.
2.
3.
4.
It has also been reported the cyclo(2J1)-D-fructodisaccharides have spiro ketal structures. Louis,
F.; Garcia-Moreno, M. I.; Balbuena, P.; Mellet, C. O.; Garcia-Fernandez, J. M. Stereoselective
synthesis of nonsymmetrical difructose dianhydrides from xylylene-tethered D-fructose
precursors. Tetrahedron 2008, 64, 2792-2800.
5.
6.
7.
Mani, N. S.; Kanakamma, P. P. Synthesis of novel chiral macrocycles: Crown ethers derived
from D-glucose. Tetrahedron Lett. 1994, 35, 3629-3632.
Faltin, F.; Fehring, V.; Miethchen, R. Chiral crown ethers based on galactopyranosides.
Synthesis 2002, 1851-1856 and the numerous references cited therein.
Dumont-Hornebeck, B.; Joly, J.P.; Coulon, J.; Chapleur, Y. Synthesis of ethoxy-linked pseudo-
disaccharides incorporating a crown ether macrocycles and lectin recognition. Carbohydr. Res.
1999, 321, 214-227.

Molecules 2008, 13
1845
8.
9.
Tomooka, K.; Nakamura, Y.; Nakai, T. [2, 3]-Wittig rearrangement using glucose as a chiral
auxiliary: asymmetric transmission from the anomeric center. Synlett. 1995, 321-322.
Lay, L.; Meldal, M.; Nicotra, F.; Panza, L.; Russo, G. Stereoselective synthesis of the C-
analogue of β-D-glucopyranosyl serine. Chem. Commun. 1997, 54, 1469-1470.
10. van Hooft, P. A. V.; Oualid, F. E.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H.;
Leeuwenburgh, M. A. Synthesis and elaboration of functionalised carbohydrate-derived
spiroketals. Org. Biomol. Chem. 2004, 2, 1395-1403.
11. Li, X. L.; Ohtake, H.; Takahashi, H.; Ikegami, S. A facile synthesis of 1′-C-alkyl-α-
disaccharides from 1-C-alkyl-hexopyranoses and methyl 1-C-methyl-hexopyranosides.
Tetrahedron 2001, 57, 4297-4309.
12. Yamanoi, T.; Nara, Y.; Matsuda, S.; Oda, Y.; Yoshida, A.; Katsuraya, K.; Watanabe, M.
Synthetic approach to exo-glycals from 1-C-vinyl-D-glycopyranose derivatives via an SN1′-
substitution mechanism. Synlett. 2007, 785-789.
13. Matsuda, S.; Matsumura, K.; Watanabe, M.; Yamanoi, T. Synthesis of a partially benzylated
derivative of the anhydro-D-altro-heptulose found in Coriaria japonica A. Tetrahedron Lett.
2007, 48, 5807-5810.
14. Yamanoi, T.; Inoue, R.; Matsuda, S.; Katsuraya, K.; Hamasaki, K. Synthesis of trehalose mimics
by bismuth(III) triflate or bis(trifluoromethane)sulfonimide-catalyzed 1-C-methyl-D-
hexopyranosylation. Tetrahedron Asymmetry 2006, 17, 2914-2918.
15. Yamanoi, T.; Oda, Y.; Matsuda, S.; Yamazaki, I.; Matsumura, K.; Katsuraya, K.; Watanabe, M.;
Inazu, T. Synthesis of 1-C-alkyl-α-D-glucopyranosides by Lewis acid- or Brønsted acid-
catalyzed O-glycosidation. Tetrahedron 2006, 62, 10383-10392.
Sample Availability: Samples of the compounds are available from the authors
© 2008 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).