C-furanoside synthesis via intramolecular cyclization

Article abstract of DOI:10.1055/s-1999-3157

Polysubstituted C-furanoside 8, with the correct absolute configuration is readily available from diacetone-D-glucose. This C-furanoside after deprotection should be a useful synthon for natural product synthesis.

Full text of DOI:10.1055/s-1999-3157

LETTER
435
C-Furanoside Synthesis via Intramolecular Cyclization
David Egron, Thierry Durand, Arlene Roland, Jean-Pierre Vidal, Jean-Claude Rossi
Laboratoire de Chimie Biomoléculaire et Interactions Biologiques associé au C.N.R.S., Université Montpellier I, Faculté de Pharmacie,
15 Av. Ch. Flahault, F-34060 Montpellier, France
Fax +33 (4) 67548625; E-mail: Thierry.Durand@pharma.univ-montp1.fr
Received 1 November 1998
and also the temperature applied during the Wittig reac-
Abstract. Polysubstituted C-furanoside 8, with the correct absolute
tion.
configuration is readily available from diacetone-D-glucose. This
C-furanoside after deprotection should be a useful synthon for nat-
ural product synthesis.
HO
O
O
O
O
HO
O
c
a
O
b
O
Key words: C-furanoside, intramolecular cyclization, absolute
configuration steady-state NOE, diacetone-D-glucose
OH
O
O
O
O
O
O
3
1
2
TBDPSO
HO
TBDPSO
TBDPSO
I
I
O
C-Furanosides are found in many natural products as
polyether antibiotics,1 acetogenins2a as well as C-glyco-
sides,2b in a wide range of stereochemical complexity.
Due to their biological importance, the synthesis of such
valuable compounds has attracted the attention of organic
synthetic chemists. A variety of different approaches to-
wards these furanosides, has been developed,3,4 using the
“chiral pool”5 and other strategies with substituents both
at C-2 and C-5. Non-natural tetrahydrofurans might be in-
teresting from a biological point of view, especially, on
account of their applications as potential synthons in dif-
ferent classes of natural compounds including phospho-
glycerides and analogues.6,7 These tetrahydrofuran
analogues, in which the Protein Activating Factor (PAF)
moiety is restricted as a part of the heterocyclic skeleton,
have been shown to be very potent agonists of PAF.8
e
d
O
O
OH
O
O
O
OH
O
6
5
4
OTBDPS
I
HO
TBDPSO
CO2Me
f
O
or
OH OH
7
8
CO2Me
a) NaH/THF/imidazole/CS2/MeI then Bu3SnH/toluene reflux, 3 h,
85%. b) aq. AcOH 70%, 7 h, 92%. c) TBDPSCl/DMF/imidazole, 2 h
at 0°C then rt, 100%. d) I2/Ph3P/imidazole/xylene, 15 min at reflux,
91% e) aq. H2SO4 10%, THF-dioxane (3:1), 4 h, 80%. f)
Ph3P=CHCO2Me 2 eq. in dry THF, 11 h at rt, 75% of 7 or
Ph3P=CHCO2Me 3 eq. in dry THF, 24 h at reflux, 100% of 8.
Scheme 1
The synthesis of 8 (Scheme 1) starts with the commercial
1,2:5,6-di-O-isopropylidene-a-D-glucofuranose 1, which
was transformed to the corresponding 3-deoxy-sugar 2 in
85% yield using the Barton-McCombie procedure.13 A se-
lective deprotection of the isopropylidene group in 5,6 po-
sition was accomplished in the presence of 70% aq. acetic
acid in 92% yield. Protection of the primary alcohol at C-
6 of derivative 3 using 1.1 eq. of tert-butyldiphenylsilyl
chloride in freshly distilled DMF in the presence of 2.8 eq.
of imidazole led to the pure mono silyl ether 4 in 100%
yield. Introduction of iodine at C-5 was carried out using
the procedure that we have developed earlier14 (I2, Ph3P,
imidazole, xylene) and led to compound 5 in 91% yield.
Hydrolysis of the isopropylidene group in 1,2 position
was achieved in the presence of 10% aq. sulfuric acid in
THF-dioxane (3:1) to afford the diol 6 in 80% yield.
Carbohydrates have been used extensively as precursors
in C-furanoside synthesis. Ring closure by attack of an
OH or OR-group at an activated double bond, normally
the most applied method to prepare the furan moiety, has
been used in few cases within the carbohydrates.9 A gen-
eral method to create hydroxylated furans from carbohy-
drates is the nucleophilic attack of an OH-group on a
suitably introduced leaving group. Wittig reactions with
sugars have been described in the literature and, depend-
ing on the reaction conditions and the reagents employed,
open-chain10 or C-furanoside11 derivatives can be ob-
tained. We have found that the reaction of diol 6 in the
presence of 3 equivalents of methoxycarbonylmethylene
triphenylphosphorane gave quantitatively 8 (Scheme 1).
The use of cyclic chiral precursors such as 8 presents cer-
tain potential advantages such as a considerable degree of
stereocontrol of the three asymmetric centers.
Finally, when 6 was stirred at room temperature with two
equivalents of methoxycarbonylmethylene triphenylphos-
phorane in dry THF for 11h 75% of 715 was obtained,
whereas, using three equivalents of the Wittig reagent and
refluxing the solution for 24 h 100% of the C-furanoside
816 was produced in 55% overall yield after 6 steps.
In the course of our ongoing research on the total synthe-
sis of isoprostaglandins,12 we have investigated the in-
tramolecular nucleophilic cyclization of iodo derivative 6
under Wittig conditions. Hence, the observed results
(Scheme 1) are different with regards to the amount of
methoxycarbonylmethylene triphenylphosphorane used
Synlett 1999, No. 4, 435–437 ISSN 0936-5214 © Thieme Stuttgart · New York

436
D. Egron et al.
LETTER
In conclusion, we consider this intramolecular nucleo-
philic cyclization, as a useful straightforward way to ob-
tain chiral C-furanoside 8 substituted at C-2, C-3, C-5
with the 4R,6S,7R configuration. This C-furanoside after
deprotection should be a useful synthon for natural prod-
uct synthesis.
OTBDPS
HO
I
a
TBDPSO
O
7
CO2Me
OH
O -
9
8
CO2Me
Scheme 2
Acknowledgement
The mechanism that we propose for the formation of the
C-furanoside 8 is shown in the Scheme 2. After formation
of derivative 7 and under the basic conditions of the Wit-
tig reaction, alcoholate 9 was generated in situ followed
by intramolecular nucleophilic cyclization on the iodo
leaving group to afford the C-furanoside 8. We have con-
firmed the structure of this compound 8 by a NMR studies
in 1D (1H and 13C) and 2D (HQMC and HMBC) and ele-
mental analysis.
We wish to thank the Direction des Recherches Etudes et Tech-
niques for financial support (grant N° 94135/DRET) and the Mini-
stère de l'Education Nationale, de l’Enseignement Supérieure et de
la Recherche for financial support of one of us (AR).
References and Notes
(1) Westley, J. W., Polyether Antibiotics : Naturally Occurring
Acid Ionophores, vols. I and II Marcel Dekker, New York,
1982
Finally, we have determined and confirmed the 4R,6S,7R
configuration of compound 8 (Figure 1 and Table 1) by
steady-state NOE difference spectroscopy (DNOES) ex-
periments, which have previously been employed by our
group.17 Concerning the relative configuration of the
chains situated at C-7 and C-4, the irradiation of 7-H (to
3.94 ppm) induced a NOE of 1.0% on 4-H (to 4.74 ppm).
This result is in agreement with a relative cis configura-
tion between these two chains. The irradiation of 6-H (to
4.44 ppm) induced a NOE of 0.4% on 8-H (to 3.59 ppm)
and of 3.9% on 5’-H (to 1.87 ppm), and the irradiation of
3-H (to 6.92 ppm) also induced a NOE of 0.1% on 5’-H (to
1.87 ppm). These observations allowed us to confirm the
relative trans configuration of the hydroxyl group and the
chains situated in C-7 and C-4 positions.
(2) a) Cavé, A.; Cortes, D.; Figadère, B.; Hocquemiller, R.;
Laprévote, O.; Laurens, A.; Leboeuf, M. Phytochemical
Potential of Tropical Plants; Recent Advances in Phytochemi-
stry, 27, Bownum, K. R.; Romeo, J.; Stafford H. H. A. Eds.,
Plenum Press, New-York, 1993; b) Postema, M. H. D. Tetra-
hedron 1992, 48, 8545
(3) Harmange, J. C.; Figadère, B. Tetrahedron: Asymmetry 1993,
4, 1711
(4) Boivin, T. L. B. Tetrahedron 1987, 43, 3309
(5) See for example a) Choi, S. S.; Myerscough, P. M.; Fairbanks,
A. J.; Skead, B. M.; Bichard, C. J. F.; Mantell, S. J.; Son, J. C.;
Fleet, G. W. J.; Sanders, J.; Brown, D. J. Chem. Soc., Perkin
Trans. 1 1992, 3023.
(6) Demopoulos, C. A.; Pinckard, R. N.; Hanahan, D.J. J. Biol.
Chem. 1979, 254, 9355;
(7) Benveniste, J.; Tence, M.; Varenne P.; Bidault, J.; Boullet, C.;
Polonsky, J. C. R. Acad. Sci. 1979, 289D, 1037
(8) Kobayashi, S; Sato, M.; Eguchi, Y; Ohno, M. Tetrahedron
Lett. 1992, 33, 1081
(9) For example; Wilson, P.; Shan, W.; Mootoo, D. R. J. Carbo-
hydr. Chem. 1994, 13, 133.
(10) a) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. Tetrahedron Lett.
1979, 2327; b) Sun, K. M.; Fraser-Reid, B. Can. J. Chem.
1980, 58, 2732.
(11) a) Kochetkov, N. K.; Dmitriev, B. A. Tetrahedron Lett. 1965,
21, 803; b) Hanessian, S.; Ogawa, T.; Guindon, Y. Carbohydr.
Res. 1974, 38, C-12; c) Ohrui, H.; Jones, G. H.; Moffatt, J. G.;
Maddox, M. L.; Christensen, A. T.; Byram, S. K. J. Am.
Chem. Soc. 1975, 97, 4602.
(12) a) Roland, A.; Durand, T.; Rondot, B.; Vidal, J.P.; Rossi, J.C.
Bull. Soc. Chim. Fr. 1996, 113, 1149; b) Guy, A; Durand, T;
Roland, A; Cormenier, E; Rossi, J.C; Tetrahedron Lett. 1998,
39, 6181
(13) Barton, D. H. R.; Mc Combie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
(14) Rondot, B.; Durand, T.; Rossi, J.C.; Rollin, P. Carbohydr.
Res. 1994, 261, 149.
3.9%
0.12%
H3
H3CO2C
H2
H5'
0.4%
H6
H5
OH
O
(15) Compound 7: To a solution of diol 6 (564 mg, 1.1 mmol) in
dry THF (15 ml) was added methoxycarbonylmethylene
triphenylphosphorane (730 mg, 2.2 mmol). The reaction mix-
ture was stirred for 11 h at room temperature. Concentration
under reduced pressure followed by purification by flash
chromatography (Silica gel, Hex-EtOAc 8:2) gave 7 (468 mg,
75%)
H4
8
OTBDPS
1.0%
H7
Figure 1
1H-NMR (360 MHz, CDCl3) d : 7.62-7.6 (m, 4H, Ph), 7.37-
7.46 (m, 6H, Ph), 6.87-6.92 (dd, J=15.8 and 4.7 Hz, 1H, H-3),
6.07-6.11 (dd, J=1.4 Hz, 1H, H-2), 4.54-4.57 (m, 2H, H-4),
Synlett 1999, No. 4, 435–437 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
4.12-4.16 (m, 1H, H-7), 3.96-4.03 (m, 1H, H-8), 3.72 (s, 3H,
C-Furanoside Synthesis via Intramolecular Cyclization
437
7.43 (m, 6H, Ph), 6.89-6.95 (dd, J=15.6 and 3.6 Hz, 1H, H-3),
6.03-6.08 (dd, J=1.7 Hz, 1H, H-2), 4.72-4.75 (m, 2H, H-4),
4.42-4.46 (m, 2H, H-6), 3.92-3.96 (m, 1H, H-7), 3.71-3.78 (m,
1H, H-8), 3.71 (s, 3H, OCH3), 3.57-3.62 (dd, J=10.8, and 5.9
Hz, 1H, H-8), 2.02-2.11 (ddd, J=12.9, 5.9 and 2 Hz, 1H, H-5),
1.85-1.90 (ddd, J=9.9 and 5.7 Hz, 1H, H-5), 1.02-1.05 (s, 9H,
(CH3)3C). 13C-NMR (90 MHz, CDCl3) d : 166.84 (C-1),
147.43 (C-3), 135.54 (Ph); 133.02 (Ph), 129.84 (Ph), 127.87
(Ph), 120.34 (C-2), 87.31 (C-7), 76.91 (C-4), 73.91 (C-6),
64.53 (C-8), 51.57 (OCH3), 40.77 (C-5). 26.84 (t-Bu), 19.2 (t-
Bu) IR (film) (umax): 1720 (C=O), 1650 (C=C) Anal.Calcd.
For C25H32O5Si C, 68.15; H, 7.33; O, 18.17; Found C, 68.02;
H, 7.36; O, 18.15.
OCH3), 3.58-3.60 (d, J=10.8, and 5.9 Hz, 1H, H-6), 1.68-1.86
(m, 1H, H-5), 1.07 (s, 9H, (CH3)3C). 13C-NMR (90 MHz,
CDCl3) d : 167 (C-1), 149.2 (C-3), 135.7 (Ph); 132.7 (Ph);
132.3 (Ph), 130.1 (Ph), 128 (Ph), 120.1 (C-2), 71.4 (C-4), 70.1
(C-6), 67.5 (C-8), 51.7 (OCH3), 42.7 (C-7) 42.5 (C-5). 26.9 (t-
Bu), 19.2 (t-Bu) IR (film) (umax): 3515 (OH), 1730 (C=O),
1650 (C=C) Anal.Calcd. For C25H33O5ISi C, 52.82; H, 5.85;
O, 14.07; Found C, 52.82; H, 5.87; O, 14.02.
(16) Compound 8 : To a solution of diol 6 (110 mg, 0.22 mmol) in
dry THF (10 ml) was added methoxycarbonylmethylene
triphenylphosphorane (220 mg, 0.66 mmol). The reaction
mixture was stirred for 24 h at 80°C. Concentration under re-
duced pressure followed by purification by flash chromatogra-
phy (Silica gel, Hex-EtOAc 8:2) gave 8 (95.2 mg, 100%)
1H-NMR (360 MHz, CDCl3) d : 7.63-7.65 (m, 4H, Ph), 7.36-
(17) Rondot, B; Durand, T; Vidal J. P; Girard, J. P; Rossi, J. C; J.
Chem. Soc., Perkin Trans. 2 1995, 1589.
Synlett 1999, No. 4, 435–437 ISSN 0936-5214 © Thieme Stuttgart · New York