Highly stereoselective synthesis of C-vinyl furanosides through acid-catalyzed SN2 inversion at the C-3 position of 1,2-dideoxy-hept-1-enitols

Article abstract of DOI:10.1016/j.carres.2008.08.017

A highly stereoselective synthesis of C-vinyl furanosides through the S_N2 inversion at the C-3 position of the 1,2-dideoxy-hept-1-enitols is disclosed. Treatment of the 1,2-dideoxy-hept-1-enitols with diphenylammonium trifluoromethanesulfonate as the acid catalyst produced the C-vinyl furanosides (3,6-anhydro-1,2-dideoxy-hept-1-enitol derivatives) via a subsequent S_N2 intramolecular debenzyloxyation-cycloetherification reaction at the C-3 position.

Full text of DOI:10.1016/j.carres.2008.08.017

Carbohydrate Research 343 (2008) 2985–2988
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Highly stereoselective synthesis of C-vinyl furanosides through acid-catalyzed
SN2 inversion at the C-3 position of 1,2-dideoxy-hept-1-enitols q
*
Hitoshi Tsuchiya, Noriaki Asakura, Yasunori Ikeda, Hidetoshi Yamada
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2008
Received in revised form 11 August 2008
Accepted 13 August 2008
Available online 22 August 2008
A highly stereoselective synthesis of C-vinyl furanosides through the SN2 inversion at the C-3 position of
the 1,2-dideoxy-hept-1-enitols is disclosed. Treatment of the 1,2-dideoxy-hept-1-enitols with diphenyl-
ammonium trifluoromethanesulfonate as the acid catalyst produced the C-vinyl furanosides (3,6-anhy-
dro-1,2-dideoxy-hept-1-enitol derivatives) via a subsequent SN2 intramolecular debenzyloxyation–
cycloetherification reaction at the C-3 position.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
C-Vinyl furanosides
1,2-Dideoxy-hept-1-enitols
SN2 intramolecular debenzyloxyation–
cycloetherification
Diphenylammonium
trifluoromethanesulfonate
.
C-Furanosides possess a wide array of applications, and some of
them have remarkable biological activities as C-nucleosides.1 Syn-
thetically, C-vinyl furanosides are some of the potentially useful
intermediates leading to a variety of C-furanosides,2 and thus sev-
eral stereocontrolled synthetic approaches toward the C-vinyl fur-
anosides have been previously reported.3,4 Among them, Martin
et al.3a and Yang et al.3b independently developed a synthetic
method for C-vinyl furanosides through the SN2 inversion at the
C-6 position of the 3,4,5,7-tetrabenzyloxy-6-hydroxyhept-1-enes,
which are hereafter abbreviated to 1,2-dideoxy-hept-1-enitols
(Scheme 1, left-hand pathway). Because of the high stereoselectiv-
ity and easy availability of the starting 1,2-dideoxy-hept-1-enitols,
an inversion of the reaction site would double the available diaste-
reomers starting from a single substrate. We herein describe the
development of a highly stereoselective synthesis of C-vinyl fur-
anosides through the SN2 inversion at the C-3 position of the 1,2-
dideoxy-hept-1-enitols (Scheme 1, right-hand pathway).
was developed by Tanabe and co-workers.6 However, despite our
intention to achieve first an inter- and then an intramolecular
bis-macrolactonization of the diol 1, no desired product was
OH
BnO
BnO
OBn
R
S
OBn
1,2-dideoxy-hept-1-enitols
Tf2O, pyridine
protonation
H
Tf
O
OH
+
BnO
OBn
BnO
BnO
O Bn
6
6
We stumbled across the stereoselective cycloetherification dur-
ing examinations for esterification of partly protected 1,2-dideoxy-
3
BnO
3
OBn
OBn
D
-gluco-hept-1-enitol (1) with (1,10-diphenyl)-2,20-dicarboxylic
acid using diphenylammonium trifluoromethanesulfonate (DPAT)
with respect to the synthetic approach of corilagin (Scheme 2).5
DPAT is an effective and practical reagent for esterification, which
BnO
BnO
O
O
R
R
S
S
q
BnO
OBn
BnO
OBn
Detailed general methods and NMR spectra for compounds 2 and 8 are given in
the Supplementary data section.
* Corresponding author. Tel.: +81 79 565 8342; fax: +81 79 565 9077.
E-mail address: hidetosh@kwansei.ac.jp (H. Yamada).
Scheme 1. Left-hand pathway: Martin’s or Yang’s procedure; right-hand pathway:
this study.
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.08.017

2986
H. Tsuchiya et al. / Carbohydrate Research 343 (2008) 2985–2988
solution of DPAT in toluene using a syringe pump afforded 4 in
HO2C CO2H
60% yield (entry 7). Intermolecular reactions were prevented by
keeping a low concentration of substrate 3. However, even with
this slow addition method, an increase of the catalyst did not indi-
cate further positive effects (entries 8 and 9). Attempts using sev-
eral other Lewis and protic acids also provided 4 as a single
diastereomer, but the yields were lower than that with the use of
DPAT (entries 10–14). Although generation of unidentified side
products was observed in all cases, fortunately, 4 was easily iso-
lated from each reaction mixture by simple column chromatogra-
phy on silica gel. Therefore, the conditions of entry 7 were selected
for the following applications. It is not clear why diol 1 reacted
more smoothly than 3.
HO
OH
OPMB
BnO
O
R
3
BnO
HO
DPAT (0.25 equiv)
toluene, 90 °C, 1 d
BnO
OH
1
2
O
O
O
O
OPMB
OBn
This reaction was applicable to 1,2-dideoxy-hept-1-enitols de-
rived from
D
-mannose and
D
-galactose. Thus, 1,2-dideoxy-
D-man-
BnO
no-hept-1-enitol (5)3 and 1,2-dideoxy-
D
-galacto-hept-1-enitol (6)9
were similarly treated with DPAT to provide the cyclized products
78 and 8, respectively, with inversion of C-3 stereochemistry
(Scheme 3). The structure of 8 was confirmed by its conversion
to the known 9.10
We concluded that the reaction passed the SN2 attack of the O-6
at the secondary allylic carbon, that is the C-3 position, following
the protonation of the benzyloxy group (Scheme 1), because both
BnO
BnO
OBn
OH
BnO
O
R
DPAT (0.1 equiv)
toluene, 90 °C, 1 h
3
BnO
BnO
OBn
3
4
D-glucose-derived 3 and its C-3 epimer, D-mannose-derived 5, pro-
Scheme 2. Detection of the C-furanosylation. DPAT = diphenylammonium
duced C-3-(R)-4 and C-3-(S)-7, respectively. Recently, Cribiú and
Cumpstey reported a similar inversion of the allylic stereochemis-
try in a trifluoroacetic acid-mediated debenzylative cycloetherifi-
cation.4a Our results here using the 1,2-dideoxy-hept-1-enitols
supported the generality of the SN2 inversion at the allylic position.
Further, this study revealed that such cycloetherification is possi-
ble using a catalytic amount of the acidic reagent in contrast to
the Cribiú–Cumptsey method, which used trifluoroacetic acid as
a part of the reaction solvent. These results are in apparent contrast
to method described by Martin et al.3a and Yang et al.3b which in-
volves the SN2 inversion at C-6. Thus, these two complementary
methods provide different diastereomers stereoselectively starting
from the same substrate.
trifluoromethanesulfonate.
produced. Instead, a C-furanoside 2 was detected in 79% yield as a
single diastereomer. The R stereochemistry at C-3 was predicted
because its DPFGSE (double pulse field gradient spin echo) 1D-
NOESY spectra indicated the correlation between H-2 and -4, be-
tween H-2 and -6, and between H-3 and -5. Similar intramolecular
etherification proceeded using the more readily available sub-
strate, 1,2-dideoxy-D
-gluco-hept-1-enitol (3),7 and DPAT to provide
48 in 49% yield, whose C-3 stereochemistry is R.
Optimization of the reaction conditions increased the yield of 4
to 60% (Table 1). Use of equimolar amounts of 3 and DPAT did not
increase the yield (entry 1). The reaction was accelerated at ele-
vated temperature with a catalytic amount of DPAT; however,
the yields were not affected (entries 2–6). On the other hand, a
technical elaboration in addition of reagents increased the yield.
Thus, the slow addition of a toluene solution of 3 into a heated
In summary, the accidentally found C-furanosylation proceeded
through the SN2 inversion at the C-3 position. This reaction could
be applied to the substrates derived from
D-glucose, mannose,
and galactose, to produce the corresponding C-vinyl furanosides.
Despite their moderate yields, the isolation of each product was
Table 1
Optimization of the reaction conditions
BnO
DPAT (0.1 equiv)
BnO
BnO
OBn
OH
O
S
BnO
OBn
OH
BnO
Man
Gal
Acid
O
R
BnO
3
BnO
BnO
toluene
70 °C, 20 h
70%
BnO
OBn
toluene
5
7
BnO
OBn
3
4
BnO
DPAT (0.1 equiv)
OBn
BnO
Entry
Acid (equiv)
Temperature (°C)
Time (h)
Yield (%)
O
R
OH
BnO
1
2
3
4
5
DPAT (1.0)
DPAT (0.1)
DPAT (0.1)
DPAT (0.1)
DPAT (0.1)
DPAT (0.1)
DPAT (0.1)
DPAT (0.2)
DPAT (0.5)
BF3ꢀOEt2 (0.1)
Cu(OTf)2 (0.2)
Sn(OTf)2 (0.1)
Yb(OTf)3 (0.1)
TfOH (0.2)
90
rt
40
60
90
110
80
70
70
60–100
70
70
80
40
3.5
48
15
3
45
0
BnO
toluene
70 °C, 19 h
84%
47
48
49
45
60
58
52
31
33
37
40
56
BnO
OBn
6
8
1
6
0.083
21
12
12
48
21
24
24
24
7a
8a
9a
10
11a
12a
13a
14a
1) OsO4, NMO
THF/H2O (1/1)
rt, 6 h
BnO
O
CHO
2)
NaIO4, MeOH
BnO
OBn
rt, 10 h, 73%
9
a
A toluene solution of 3 was slowly added to a heated solution of the acid in
Scheme 3. C-Furanosylation using derivatives of
NMO = N-methylmorpholine-N-oxide.
D-mannose 5, and D-galactose 6.
toluene by syringe pump.

H. Tsuchiya et al. / Carbohydrate Research 343 (2008) 2985–2988
2987
easy. The combination of this and the previously known methods
has stereoselectively doubled the available diastereomers starting
from a single starting material.
oxy-6-hydroxyhept-1-ene (5) (100 mg, 0.186 mmol) in toluene
(10 mL) at 70 °C using a syringe pump at the rate of 0.5 mL/h dur-
ing a period of 20 h. The mixture was poured into water, and it was
extracted with Et2O. The organic layer was successively washed
with water, satd aq NaHCO3, and brine, dried over MgSO4, filtered
through a cotton pad, and evaporated. The resulting residue was
purified by column chromatography on silica gel (SiO2: 3 g, eluant:
7:1 hexane–EtOAc) to give 7 (57 mg, 70% yield) as a pale-yellow
syrup. The NMR spectra of the compound were identical to those
reported.8
1. Experimental
1.1. General methods
All commercially available reagents were used without further
purification. All reactions were performed under a positive pres-
sure of nitrogen. Column chromatography was performed on E.
Merck Silica Gel 60 (0.063–0.200 mm, 70–230 mesh). The 1H
NMR data are indicated by a chemical shift with the multiplicity,
the coupling constants, and the integration in parentheses in this
order. The multiplicities are abbreviated as s, singlet; d, doublet;
t, triplet; m, multiplet; and br, broadened. The 13C NMR data are re-
ported as the chemical shift with the hydrogen multiplicity ob-
tained from the DEPT spectra.
1.2.4. 3,6-Anhydro-4,5,7-tri-O-benzyl-1,2-dideoxy-D-talo-hept-
1-enitol (8)
To a stirred solution of DPAT (13 mg, 41 lmol) in toluene
(20 mL) was added a solution of (3S,4R,5S,6R)-3,4,5,7-tetrabenzyl-
oxy-6-hydroxyhept-1-ene (6) (201 mg, 0.373 mmol) in toluene
(12 mL) at 70 °C using a syringe pump at the rate of 2 mL/h dur-
ing a period of 6 h. After completion of the addition, the mixture
was further stirred for 13 h. The mixture was poured into water,
and extracted with EtOAc. The organic layer was successively
washed with satd aq NaHCO3 and brine, dried over MgSO4, fil-
tered through a cotton pad, and evaporated. The resulting residue
was purified by column chromatography on silica gel (SiO2: 5 g,
gradient elution with 15:1 to 8:1 hexane–EtOAc) to give 8
1.2. Preparative procedures and characterization of
compounds
1.2.1. 3,6-Anhydro-5-O-benzyl-1,2-dideoxy-D-manno-hept-1-
enitol (2)
(135 mg, 84% yield) as a pale-yellow syrup: ½a D23
ꢁ
–18.1 (c 1.2,
A mixture of (3S,4R,5S,6R)-3,5-dibenzyloxy-4,7-dihydroxy-6-
(4-methoxybenzyl)oxyhept-1-ene (1) (31.8 mg, 66.4
mol), (1,10-
diphenyl)-2,20-dicarboxylic acid (16.1 mg, 66.5
mol), and di-
phenylammonium trifluoromethanesulfonate (DPAT, 5.2 mg,
16.3 mol) in toluene (7 mL) was stirred at 90 °C for 1 day. The
CHCl3); IR (ZnSe, thin film): 3088, 3063, 3030, 2919, 2864,
1497, 1454, 1092, 737, 698 cmꢂ1 1H NMR (CDCl3, 400 MHz): d
;
l
l
7.35–7.26 (m, 15 H), 5.82 (ddd, J = 17.2, 10.3, 6.9 Hz, 1H; H-2),
5.38 (ddd, J = 17.2, 1.4, 1.4 Hz, 1H; H-1), 5.19 (ddd, J = 10.3, 1.4,
1.4 Hz, 1H; H-1), 4.76 (d, J = 11.9 Hz, 1H; Bn), 4.61 (d,
J = 11.9 Hz, 1H; Bn), 4.59 (d, J = 12.1 Hz, 1H; Bn), 4.59 (d,
J = 11.9 Hz, 1H; Bn), 4.54 (d, J = 12.1 Hz, 1H; Bn), 4.50 (d,
J = 11.9 Hz, 1H; Bn), 4.49 (br t, J = 7.1 Hz, 1H; H-3), 4.27 (ddd,
J = 6.6, 6.2, 4.1 Hz, 1H; H-6), 4.10 (dd, J = 4.1, 4.1 Hz, 1H; H-5),
3.78 (dd, J = 9.8, 6.2 Hz, 1H; H-7), 3.75 (dd, J = 7.3, 4.1 Hz, 1H;
H-4), 3.69 (dd, J = 9.8, 6.6 Hz, 1H; H-7); 13C NMR (CDCl3,
100 MHz): d 138.3 (s), 138.2 (s), 137.8 (s), 137.0 (d), 128.4-
127.6 (many doublets, 15 C), 117.5 (t), 83.6 (d), 80.8 (d), 78.7
(d), 77.2 (d), 73.5 (t), 73.4 (t), 72.5 (t), 69.0 (t); HRESIMS (m/z):
[M+Na]+ calcd for C28H30O4, 453.2042; found, 453.2022.
l
mixture was poured into water, and it was extracted with AcOEt.
The organic layer was successively washed with water and brine,
dried over MgSO4, filtered through a cotton pad, and evaporated.
The resulting residue was purified by column chromatography on
silica gel (SiO2: 2.5 g, eluant: 2:1 to 1:1 hexane–EtOAc) to give 2
(13.1 mg, 79% yield): ½a D24
ꢁ
+52.9 (c 0.895, CHCl3); 1H NMR (CDCl3,
400 MHz): d 7.41–7.29 (m, 5 H), 5.95 (ddd, J = 17.6, 10.4, 7.2 Hz,
1H), 5.30 (d, J = 17.6 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.66 (d,
J = 11.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.39 (dd, J = 7.2, 3.6 Hz,
1H), 4.17 (ddd, J = 3.2, 3.2, 2.8 Hz, 1H), 4.11 (dd, J = 3.6, 3.2 Hz,
1H), 3.97 (dd, J = 3.2, 3.2 Hz, 1H), 3.81 (dd, J = 12.0, 2.8 Hz, 1H),
3.64 (dd, J = 12.0, 3.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d 137.7
(s), 136.0 (d), 128.5 (d, 2C), 127.9 (d), 127.6 (d, 2C), 117.1 (t),
87.2 (d), 86.2 (d), 83.4 (d), 79.4 (d), 72.1 (t), 63.0 (t); HRESIMS
(m/z): [M+NH4]+ calcd for C14H18O4, 268.1549; found, 268.1547.
1.2.5. Preparation of 2,5-anhydro-3,4,6-tri-O-benzyl-
D
-talose
mol),
(9)10
A mixture of 8 (115 mg, 0.276 mmol), OsO4 (1.5 mg, 5.9
l
4-methylmorpholine-N-oxide (90 mg, 0.77 mmol) in 1:1 THF–H2O
(10 mL) was stirred for 6 h at rt. Then, MeOH (10 mL) and NaIO4
(171 mg, 0.798 mmol) were added to the mixture, and it was stir-
red at rt for 10 h. After evaporation to remove THF and MeOH, the
aqueous mixture that remained was extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4, filtered
through a cotton pad, and evaporated. The resulting residue was
purified by column chromatography on silica gel (SiO2: 3 g, gradi-
ent elution with 3:1 to 1:1 hexane–EtOAc) to give 9 (83.2 mg, 73%
yield) as a pale-yellow syrup. The NMR spectra of the compound
were identical to those reported.10
1.2.2. Preparation of 3,6-anhydro-4,5,7-tri-O-benzyl-1,2-
dideoxy-
To a stirred solution of DPAT (6.0 mg, 19
D
-manno-hept-1-enitol (4)8 (Table 1, entry 7)
lmol) in toluene
(5 mL) was added a solution of (3S,4R,5R,6R)-3,4,5,7-tetrabenzyl-
oxy-6-hydroxyhept-1-ene (3) (100 mg, 0.186 mmol) in toluene
(4.2 mL) at 80 °C using a syringe pump at the rate of 1 mL/h. After
completion of the addition, the mixture was further stirred for
17 h. The mixture was poured into water and extracted with
EtOAc. The organic layer was successively washed with water, satd
aq NaHCO3, and brine, dried over MgSO4, filtered through a cotton
pad, and evaporated. The resulting residue was purified by column
chromatography on silica gel (SiO2: 3 g, eluant: 15:1 to 5:1 hex-
ane–EtOAc) to give 4 (48 mg, 60% yield) as a pale-yellow syrup.
The NMR spectra of the compound were identical to those
reported.8
Acknowledgment
This work was partly supported by the Grant-in-Aid for Scien-
tific Research on Priority Areas (17035086) from MEXT.
1.2.3. Preparation of 3,6-anhydro-4,5,7-tri-O-benzyl-1,2-
Supplementary data
dideoxy-
To a stirred solution of DPAT (5.9 mg, 19
(10 mL) was added a solution of (3R,4R,5R,6R)-3,4,5,7-tetrabenzyl-
D
-gluco-hept-1-enitol (7)8
l
mol) in toluene
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2008.08.017.

2988
H. Tsuchiya et al. / Carbohydrate Research 343 (2008) 2985–2988
(e) Dehmlow, H.; Mulzer, J.; Seilz, C.; Strecker, A. R.; Kohlmann, A. Tetrahedron
References
Lett. 1992, 33, 3607–3610; (f) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc.
1981, 103, 3963–3964.
1. (a) Pankiewicz, K. W. Curr. Med. Chem. 1999, 6, 514–634; (b) Townsen, L. B.
Chemistry of Nucleosides and Nucleotides; Plenum: New York, 1988.
2. (a) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G.; Pierron, J.; Loiseleur,
O. Tetrahedron 2006, 62, 5201–5214; (b) Sisu, E.; Sollogoub, M.; Mallet, J.-M.;
Sinaÿ, P. Tetrahedron 2002, 58, 10189–10196; (c) Molander, G. A.; Haas, J.
Tetrahedron 1999, 55, 617–624; (d) Oikawa, Y.; Nishi, T.; Yonemitsu, O. J. Chem.
Soc., Perkin Trans. 1 1985, 7–17.
3. (a) Martin, O. R.; Yang, F.; Xie, F. Tetrahedron Lett. 1995, 36, 47–50; (b)
Yang, B.-H.; Jiang, J.-Q.; Ma, K.; Wu, H.-M. Tetrahedron Lett. 1995, 36,
2831–2834.
5. 5a Yamada, H.; Nagao, K.; Dokei, K.; Kasai, Y.; Michihata, N. J. Am. Chem. Soc.
2008, 130, 7566–7567; (b) Ikeda, Y.; Nagao, K.; Tanigakiuchi, K.; Tokumaru, G.;
Tsuchiya, H.; Yamada, H. Tetrahedron Lett. 2004, 45, 487–489.
6. Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y. Tetrahedron Lett. 2000, 41,
5249–5252.
7. (a) Lancelin, J.-M.; Pougny, J.-R.; Sinaÿ, P. Carbohydr. Res. 1985, 136, 369–374;
(b) Pougny, J.-R.; Nassr, M. A. M.; Sinaÿ, P. J. Chem. Soc., Chem. Commun. 1981,
375–376.
8. Persky, R.; Albeck, A. J. Org. Chem. 2000, 65, 5632–5638.
9. Martin, O. R.; Saavedra, O. M.; Xie, F.; Liu, L.; Picasso, S.; Vogel, P.; Kizu, H.;
Asano, N. Bioorg. Med. Chem. 2001, 9, 1269–1278.
4. (a) Cribiú, R.; Cumpstey, I. Chem. Commun. (Cambridge) 2008, 1246–1248; (b)
Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290; (c) Sharma, G. V. M.;
Chander, A. S.; Krishnudu, K.; Krishna, P. R. Tretahedron Lett. 1998, 39, 6957–
6960; (d) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1996, 52, 12091–12110;
10. Battelli, E.; D’Andrea, P.; Mascanzoni, S.; Passacantilli, P.; Piancatelli, G.
Carbohydr. Res. 1998, 306, 221–230.