Synthesis of densely functionalised C-glycosides by a tandem oxy Michael addition-Wittig olefination pathway

Article abstract of DOI:10.1016/j.carres.2009.12.014

Wittig olefination of 5,6-dideoxy-5,6-anhydro-6-nitro-d-glucofuranose (5) triggered a concomitant cyclisation via oxy Michael addition of the C2-hydroxyl group resulting in the formation of C-vinyl glycosides with Z-olefinic geometry.

Full text of DOI:10.1016/j.carres.2009.12.014

Carbohydrate Research 345 (2010) 457–461
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of densely functionalised C-glycosides by a tandem oxy Michael
addition–Wittig olefination pathway
R. Senthil Kumar a, K. Karthikeyan a, B. V. N. Phani Kumar b, D. Muralidharan a, P. T. Perumal a,
*
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
b Chemical Physics Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Wittig olefination of 5,6-dideoxy-5,6-anhydro-6-nitro-D-glucofuranose (5) triggered a concomitant cycli-
Received 21 September 2009
Received in revised form 19 November 2009
Accepted 14 December 2009
Available online 16 December 2009
sation via oxy Michael addition of the C2-hydroxyl group resulting in the formation of C-vinyl glycosides
with Z-olefinic geometry.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Tandem cyclisation
C-Vinyl glycosides
Oxy Michael addition
Wittig olefination
1. Introduction
organometallic reagents to epoxides derived from carbohydrates
30
has been reported in two instances. Wipf and co-workers
re-
The vital role played by carbohydrates in various biological pro-
cesses is evident from the recent advances made in glycobiology.1–6
Because carbohydrates occur as constituents of various glycoproteins
and glycolipids the developmentof carbohydrate-based drugs will be
of much use in the treatment of various diseases such as obesity and
diabetes.7 However, the task remains elusive mainly because of the
hydrolytic lability of O-linked carbohydrates, the glycosides, towards
enzyme and chemicals. However, replacement of the anomeric oxy-
gen with a carbon substituent confers the C-glycoside molecules’
tremendous stability towards enzymes and chemicals with minimal
loss or enhancement in biological activity with respect to the parent
O-glycosides.8–13 This is mainly attributed to the nearly similar con-
formation of the O- and C-glycosides in the solution state.14,15 C-Gly-
cosides are also found in number of natural products such as the
antibiotics vineomycin,16 elfamycin, aurodox and efrotomycin.17 As
a consequence, a number of strategies have been developed for the
syntheses of C-glycosides by various research groups.18–27
ported the addition of alkenyl zirconocenes to glycal epoxides
and Haudrechy and co-workers31 reported the addition of metal
acetylides to carbohydrate-derived epoxides. Wittig olefination,
the most sought after reaction in olefin synthesis, has been used
in the synthesis of C-vinyl glycosides. Wittig olefination has been
carried out both at the C-1 of a formyl furanose32–34 and at the ano-
meric carbon of a suitably modified furanose.35,36 The latter ap-
proach is a simple and straightforward method especially when
ring closure happens in one-pot. However the process occurs by
oxy Michael addition on the newly formed olefin by C-4 alkoxide
and hence the olefin is saturated and therefore the end product
is C-alkyl glycoside and not C-alkenyl glycoside.
2. Results and discussion
2.1. Synthesis of C-glycosides
C-Vinyl glycosides form a unique class of C-glycosides that as-
sumes importance on account of their unsaturation, which is fur-
ther amenable to a myriad of chemical reactions. However, only
a handful of reports on their synthesis exist in the literature. For
example, Taylor and co-workers28,29 developed two approaches
We envisioned that by installing a powerful Michael acceptor
moiety in the substrate we could drive the cyclisation to the other
side and thereby retain the newly formed olefinic moiety. To this
end, we wanted to prepare the chiral diene (6) and to selectively
cyclise it using appropriate base taking advantage of the difference
in Michael acceptor power of the nitrovinyl and carbethoxy vinyl
groups. Thus, our synthesis began with the preparation of the
for the stereoselective synthesis of either
a or b-C-vinyl glycosides
from a common chiron derived from -glucose. The addition of
D
1,2-O-isopropylidene-5,6-dideoxy-5,6-dehydro-6-nitro-D-glucofu-
ranose (4) from the known aldehyde37 (2) using modified reaction
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
conditions38,39 (Scheme 1).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.12.014

458
R. Senthil Kumar et al. / Carbohydrate Research 345 (2010) 457–461
O
O
O2N
O
O
OHC
RO
O
ref 37
O
CH3NO2
O
O
HO
NaOMe, MeOH
O
O
O
HO
RO
3a,b
2a, R = Bn,
2b, R = Et.
1
MsCl, TEA
DCM, O-25ºC
H
O2N
O
O
O
RO
4a,b
Scheme 1. Synthesis of nitrovinyl glucofuranose.
Table 1
The 1,2-O-isopropylidine group was removed with TFA–H2O
and the anomeric mixture of hemiacetals, after coevaporation of
TFA with toluene, was heated at reflux with the phosphorane in
acetonitrile for the appropriate time to obtain the diene (6)
(Scheme 2). However, the proton NMR spectrum of the isolated
product did not conform to the expected diene structure. Only
two olefinic protons were observed instead of four. In addition,
D2O exchange experiments confirmed the presence of single hy-
droxy group. These two facts together with the nature of splitting
pattern of the individual protons led us to arrive at the cyclic struc-
ture, the C-vinyl glycoside 7a for the product. Thus, indeed a fortit-
utious reaction had occurred towards our synthetic endeavour as
our synthetic scheme was shortened by one step. Having obtained
this potential compound, we next varied the reaction conditions in
order to increase the yield of 7a from its initial modest yield. Sol-
vent screening with THF, Et2O, toluene and DCM instead of aceto-
nitrile did not show any significant improvement on the yield
(Table 1, entries 1–3). Additives such as LiBr and LiCl also did not
have any substantial effect on the reaction (Table 1, entries 3 and
7). On the other hand, the use of bases such as Et3N and K2CO3
for prolonged reaction times and reflux conditions led to a de-
crease of product spot intensity as detected by TLC, with the for-
mation of a mixture of more polar compounds40 (Table 1, entry
8). However, increasing the stoichiometry of the phosphorane from
1.2 to 2.5 equiv significantly increased the yield to nearly 75% over
two steps. A further increase in the phosphorane did not show any
improvement. To elucidate the generality of this methodology
various other phosphoranes were reacted under this optimised
Entry
Product
Solvent
Ylide (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7a
7a
7a
CH3CN
THF
THF
Et2O
Toluene
DCM
CH3CN
CH3CN
CH3CN
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.5
10
10
10
10
10
10
10
24
4
45
42
40b
30
20
35
48c
Traced
75
a
b
c
Isolated yield after column chromatography.
LiCl 0.5 equiv was added.
LiBr 0.5 equiv was added.
d
NEt3 or K2CO3 0.5 equiv was added.
conditions and in all cases, the reaction followed a similar path
and resulted in the corresponding C-vinyl furanoside (Table 2).
Replacement of bulkier 3-O-benzyl group with ethyl group in the
substrate did not show any marked difference with regard to either
yield or stereochemical outcome of the reaction (Table 2, entry 7).
A tentative mechanism to account for the formation of the C-
glycoside is given in Scheme 3. Thus, it is likely that the Wittig re-
agent deprotonates41 the hydroxyl protons of the hemiacetal and
triggers the tandem cyclisation by oxy Michael addition. This is
further supported by the above observation that increasing the
stoichiometry of the Wittig reagent increases the yield.
OH OH
OR'
O2N
OR
O
H
O2N
O
6
'
O2N
O
TFA/H2O
Ph3P=CHCOOR
OH
OH
O
_____________
CH3CN, reflux
O
RO
RO
4a,b
5a,b
O
O2N
COOR'
HO
OR
7a-g
Scheme 2. Wittig olefination of nitrovinyl glucofuranose

R. Senthil Kumar et al. / Carbohydrate Research 345 (2010) 457–461
459
Table 2
Synthesis of C-vinyl furanoside
Entry
R
R0
Product 7
Time (h)
Yielda (%)
2.0%
H
5.8%
B
A
1
2
3
4
5
6
7
Bn
Bn
Bn
Bn
Bn
Bn
Et
Et
7a
7b
7c
7d
7e
7f
4.0
5.0
5.0
4.5
5.0
9.0
9.5
75
68
65
70
75
68
65
iPr
tBu
nBu
Bn
10.0%
9.0%
H
H
H
H
H
H
1
H
H
1
H
O2N
O
O
H
4
H
7.6%
4
O2N
2
nOct
nOct
H
H
2
H
3
H
3
CO Et
OBn
7g
2
HO
CO Et
OBn
2
HO
a
Isolated yield after column chromatography.
3.0%
Figure 1. NOE studies of the C-vinyl glycoside 7a.
2.2. Stereochemical assignment of C-glycosides
furanosides. Further, these C-glycosides, due to the presence of
these synthetic handles, would serve as versatile intermediates in
various chiron approach-based synthesis of natural and unnatural
products.
The relative stereochemistry of the product was established by
NOE studies and coupling constant values (Fig. 1). A coupling con-
stant value of 11.5 Hz between the vinylic protons indicated Z-
geometry at olefinic carbons. The
a-anomeric configuration and
the cis relationship of C1–H and C2–H (furanoside numbering) pro-
tons are clearly indicated by the presence of an NOE (9%) and the
coupling constant values. Similar compounds have been reported
earlier.28,29 Also the presence of an NOE between C3–H and C4–H
(7.6%) shows the cis relationship of these protons and the absence
of an NOE interaction between C1–H and C4–H clearly indicates
the trans relationship between the C1 and C4 substituents. This
is further confirmed by the irradiation of C2–H which showed an
NOE of 10% with C1–H and only 3% with C3–H thereby indicating
the trans relationship between protons C2–H and C3–H. Finally,
the structure was unambiguously confirmed by single crystal X-
ray diffraction of the benzyl ester derivative (7e,42 Fig. 2). It is also
evident from the above observation that epimerisation about C4
3. Experimental
3.1. General methods
Melting points were determined in capillary tubes and are
uncorrected. IR spectra were taken as neat for liquid compound
and as KBr pellets for solids on a Perkin–Elmer Spectrometer
RXI FT-IR. 1H NMR (500 and 400 MHz) and 13C NMR (125 and
100 MHz) spectra were recorded in CDCl3 with TMS as an inter-
nal standard on a JEOL or Bruker Spectrometer. HRMS were
recorded on a JEOL JMS600 and Q-TOF Mass spectrometer. Spe-
cific rotation was recorded on a RUDOLPH AUTOPOL II, Automatic
Polarimeter.
and C2 (1,2:5,6-di-O-isoproylidene-D-glucofuranose numbering)
had taken place under the basic nature of Wittig reaction condi-
tion. This is clear from the fact that C1–H and C2–H are syn in
the product whereas they are anti (C2–H and C3–H of D-glucofura-
nose) in the reactant. Similarly the hydrogens on C2 and C3 are anti
in the product and are syn in the starting compound (C3–H and
3.2. Experimental procedure for (3aR,5R,6S,6aR)-6-(benzyloxy)-
2,2-dimethyl-5-((E)-2-nitrovinyl)tetrahydrofuro[2,3-d][1,3]diox-
ole 4a
To a solution of aldehyde 2a (1.30 g, 4.67 mmol) in dry CH3OH
(10 mL) was added nitromethane (2.91 g, 47.7 mmol) followed by
NaOCH3 (0.302 g, 5.60 mmol) and stirred for 1.5 h. The pH of the
mixture was brought to 2 by the addition of glacial HOAc and
the solvent was evaporated under reduced pressure. The residue
was dissolved in CH2Cl2 and was given brine wash, dried (Na2SO4)
and concentrated under reduced pressure. Column chromatogra-
phy of the obtained residue gave the C-5 epimeric mixture of nitro
alcohols 3a as viscous oil. To a stirred solution of 3a (1.33 g,
3.93 mmol) of nitro alcohol dissolved in dry dichloromethane
(10 mL) at 0 °C was added methanesulfonyl chloride (0.97 mL,
12.60 mmol) followed by triethylamine (2.35 mL, 16.94 mmol)
and stirred further for 45 min. After completion, the reaction mix-
ture was diluted with dichloromethane and was given a bicarbon-
ate wash, dried with Na2SO4, filtered and concentrated under
reduced pressure. Column chromatography 0.8:9.2 (EtOAc–petro-
leum ether) of the residue gave 1.15 g (92%) of the compound 4a
as yellow oil. A similar procedure with 2b gives compound 4b.
C4–H of D-glucofuranose).
2.3. Conclusions
In summary, we report a novel tandem Michael–Wittig reaction
sequence for the synthesis of C-vinyl furanosides. Though the
above sequence has the literature precedence in C-glycoside syn-
thesis, the end products of such reactions were C-alkyl glycosides
and not C-alkenyl glycosides. This is essentially because the formed
olefin is consumed in situ in the subsequent Michael addition.
However, in our case, due to the presence of powerful Michael
acceptor moiety in the substrate, the oxy Michael addition pre-
cedes Wittig olefination and hence the newly formed olefin is in-
tact in the product. Because the obtained C-glycosides has dense
functionalities viz. acidic methylene, nitro group, conjugated ester
and partially protected hydroxyl groups in stereochemically pure
form, the reported reaction sequence constitutes a powerful meth-
od for the stereoselective synthesis of functionalised C-vinyl
O
O
O
CHO
OBn
O
O2N
O2N
O2N
H
Ph3P CHCOOEt
COOEt
HO
OBn
HO
BnO
OH
(excess)
7a
5a
8
Scheme 3. Tentative mechanism for the formation of C-vinyl glycoside.

460
R. Senthil Kumar et al. / Carbohydrate Research 345 (2010) 457–461
Figure 2. ORTEP diagram of compound 7e.
3.2.1. (3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-((E)-2-nit-
rovinyl)tetrahydrofuro[2,3-d][1,3]dioxole 4a
3.3.1. (Z)-Ethyl 3-((2R,3R,4S,5R)-3-(benzyloxy)-4-hydroxy-5-
(nitromethyl)tetrahydrofuran-2-yl)acrylate 7a
Viscous oil; IR (neat): 2981, 1660, 1524, 1347, 1218 cmꢀ1
;
Yield: 0.115 g (75%); viscous oil; IR (neat): 3463, 2910, 1712,
Rf = 0.31 (20% EtOAc–petroleum ether); [
a
]
ꢀ76.0 (c 1.0, CHCl3);
1553, 1372 cmꢀ1; Rf = 0.23 (30% EtOAc–petroleum ether); [
a]
D
D
1H NMR (500 MHz, CDCl3): d 1.33 (s, 3H, isopropylidene-CH3),
1.48 (s, 3H, isopropylidene-CH3), 4.04 (d, J = 3.1 Hz,1H, H-3), 4.45
(d, J = 12.2 Hz, 1H, OCHHPh), 4.63–4.67 (m, 2H, H-2, OCHHPh),
4.88–4.90 (m, 1H, H-4), 5.99 (d, J = 3.8 Hz, 1H, H-1), 7.16 (dd,
J = 13.7, 3.8 Hz, 1H, CH@CHNO2) 7.18–7.25 (m, 3H, CH@CHNO2,
Ar-H), 7.29–7.36 (m, 3H, Ar–H); 13C NMR (125 MHz, CDCl3): d
26.3, 26.9, 72.3, 77.1, 82.4, 82.5, 105.2, 112.5, 128.0, 128.5, 128.8,
136.1, 136.7, 141.0; HRMS: Found 344.1107 C16H19NO6Na
[M+Na]+ calcd 344.1110.
+206.0 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.25 (t,
J = 7.6 Hz, 3H, OCH2CH3), 3.22 (br s, exchanges with D2O, 1H,
OH), 4.08 (q, J = 7.6 Hz, 2H, OCH2CH3), 4.24 (d, J = 3.1 Hz, 1H, H-
2), 4.43 (br s, becomes doublet on D2O exchange, 1H, H-3), 4.52
(ABq, J = 11.5 Hz,
Dm = 46 Hz, 2H, OCH2Ph), 4.59–4.66 (m, 2H,
CH2NO2), 4.88–4.91 (m, 1H, H-4), 5.65–5.67 (m, 1H, H-1), 5.91
(dd, J = 11.5, 1.5 Hz, 1H, CH@CH–COOEt), 6.39 (dd, J = 11.5,
6.9 Hz, 1H, CH@CH–COOEt), 7.23–7.31 (m, 5H, Ar–H); 13C NMR
(125 MHz, CDCl3): d 14.2, 60.7, 72.6, 74.7, 74.9, 77.6, 78.6, 86.0,
120.9, 127.8, 128.0, 128.5, 137.6, 147.1, 166.3; HRMS: Found
352.1376; C17H21NO7 [M+H]+ calcd 351.1318.
3.2.2. (3aR,5R,6S,6aR)-6-Ethoxy-2,2-dimethyl-5-((E)-2-nitro-
vinyl)tetrahydrofuro[2,3-d][1,3]dioxole 4b
Viscous oil; IR (neat): 2981, 1660, 1528, 1354, 1376, 1214 cmꢀ1
;
3.3.2. (Z)-Isopropyl 3-((2R,3R,4S,5R)-3-(benzyloxy)-4-hydroxy-
5-(nitromethyl) tetrahydrofuran-2-yl)acrylate 7b
Rf = 0.30 (20% EtOAc–petroleum ether); [
a
]
ꢀ65.8 (c 3.5, CHCl3);
D
1H NMR (400 MHz, CDCl3): d 1.16 (t, J = 6.8 Hz, 3H, OCH2CH3),
1.34 (s, 3H, isopropylidene-CH3), 1.50 (s, 3H, isopropylidene-CH3),
3.42–3.45 (m, 1H, OCHHCH3), 3.59–3.67 (m, 1H, OCHHCH3), 3.97
(d, J = 3.2 Hz, 1H, H-3), 4.62 (d, J = 4.0 Hz, 1H, H-2), 4.93 (d,
J = 3.2 Hz, 1H, H-4), 5.97 (d, J = 4.0 Hz, 1H, H-1), 7.24 (br s, 2H);
13C NMR (100 MHz, CDCl3): d 16.3, 27.5, 28.2, 67.7, 78.4, 84.3,
84.9, 106.4, 113.6, 137.1, 142.4.; HRMS: Found: 282.0947
C11H17NO6Na [M+Na]+ calcd 282.0954.
Yield: 0.116 g (68%); viscous oil; IR neat: 3464, 2981, 1710,
1555 cmꢀ1; Rf = 0.24 (30% EtOAc–petroleum ether); [
a] +303.5 (c
D
0.6, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.22 (d, J = 6.1 Hz, 3H, iso-
propyl-CH3), 1.25 (d, J = 6.9 Hz, 3H, isopropyl-CH3), 2.58 (br s, 1H,
OH), 4.25 (d, J = 3.8 Hz, 1H, H-2), 4.43 (br s, 1H, H-3), 4.53 (ABq,
J = 12.2 Hz, Dm = 28.8 Hz, 2H, OCH2Ph), 4.59–4.67 (m, 2H, CH2NO2),
4.87–4.90 (m, 1H, H-4), 4.95 (septet, J = 6.1 Hz, 1H, CH(CH3)2),
5.65–5.67 (m, 1H, H-1), 5.88 (dd, J = 12.2, 1.5 Hz, 1H, CH@CH–
COOiPr), 6.36 (dd, J = 11.5, 6.9 Hz, 1H, CH@CH–COOiPr), 7.24 (d,
J = 7.6 Hz, 1H, Ar–H), 7.27–7.33 (m, 4H, Ar–H); 13C NMR
(125 MHz, CDCl3): d 21.8, 21.9, 68.2, 72.7, 74.4, 75.2, 77.5, 78.5,
86.1, 121.5, 127.7, 128.1, 128.5, 137.5, 146.5, 165.6; HRMS: Found
388.1379; C18H23NO7Na [M+Na]+ calcd 388.1372.
3.3. Representative procedure for C-glycosides 7a–g
To the nitro compound 4a 0.142 g (0.44 mmol) was added TFA–
H2O (3 mL, 3:2) at room temperature and stirred for 3 h. After com-
pletion, the TFA was coevaporated with toluene and the sticky mass
of hemiacetals was directly used in the next step. A solution of car-
bethoxymethylene triphenylphosphorane (0.326 g, 0.96 mmol) in
dry acetonitrile was added to the solution of hemiacetal in dry ace-
tonitrile (2 mL), and the mixture was stirred in an oil bath at 85 °C
for 4.0 h. After completion of the reaction, the solvent was evapo-
rated under reduced pressure and the residue was dissolved in
EtOAc, given a water wash, dried (Na2SO4) filtered and concentrated
under reduced pressure. Column chromatography 2:8 (EtOAc–
petroleum ether) of the crude compound yielded 7a as a colourless
viscous oil 0.115 g (75%).
3.3.3. (Z)-tert-Butyl 3-((2R,3R,4S,5R)-3-(benzyloxy)-4-hydroxy-
5-(nitromethyl) tetrahydrofuran-2-yl)acrylate 7c
Yield: 0.108 g (65%); viscous oil; IR (neat): 3458, 2880, 1709,
1558, 1369 cmꢀ1; Rf = 0.31 (30% EtOAc–petroleum ether); [
a]
D
+172.2 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.44 (s, 9H,
C(CH3)3), 2.72 (d, J = 4.5 Hz, 1H, OH), 4.23 (d, J = 3.8 Hz, 1H, H-2),
4.43 (br s, 1H, H-3), 4.53 (ABq,, J = 11.5 Hz,
Dm = 26.6 Hz, 2H,
OCH2Ph), 4.62–4.68 (m, 2H, CH2NO2), 4.87–4.92 (m, 1H, H-4),
5.64–5.66 (m, 1H, H-1), 5.84 (dd, J = 11.5, 1.5 Hz, 1H, CH@CH–
COOC(CH3)3), 6.29 (dd, J = 12.2, 6.9 Hz, 1H, CH@CH–COOC(CH3)3),

R. Senthil Kumar et al. / Carbohydrate Research 345 (2010) 457–461
461
7.24–7.33 (m, 5H, Ar–H); 13C NMR (125 MHz, CDCl3): d 28.2, 72.7,
74.5, 75.1, 77.5, 78.4, 81.1, 86.0, 123.0, 127.7, 128.1, 128.6, 137.6,
145.2, 165.5; HRMS: Found: 380.1603 C19H25NO7 [M+H]+ calc
379.1631.
J = 12.0, 7.2 Hz, 1H, CH@CH–COOn-Oct); 13C NMR (100 MHz,
CDCl3): d 13.9, 15.1, 22.5, 25.9, 28.5, 29.11, 29.16, 31.7, 64.6,
66.4, 74.1, 75.3, 77.2, 78.3, 86.5, 120.7, 146.5, 166.0; HRMS: Found:
374.2184 C18H32NO7 [M+H]+ calcd 374.2179.
3.3.4. (Z)-Butyl 3-((2R,3R,4S,5R)-3-(benzyloxy)-4-hydroxy-5-
(nitromethyl)tetrahydrofuran-2-yl)acrylate 7d
Acknowledgement
Yield: 0.117 g (70%); viscous oil; IR (neat): 3460, 2894, 1715,
The authors R.S.K and K.K are thankful to the Council of Scien-
tific and Industrial Research, New Delhi, India, for research
fellowships.
1551, 1375 cmꢀ1; Rf = 0.27 (30% EtOAc–petroleum ether); [
a]
D
+136.7 (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3): d 0.92 (t,
J = 7.6 Hz, 3H, CH2CH3), 1.29–1.44 (m, 2H, CH2CH3), 1.50–1.62 (m,
2H, CH2CH2CH3), 2.52 (br s, 1H, OH), 4.05 (t, J = 5.3 Hz, 2H,
CH2CH2CH2CH3), 4.25 (d, J = 3.8 Hz, 1H, H-2), 4.42 (br s, 1H, H-3),
Supplementary data
4.52 (ABq, J = 12.2 Hz,
Dm = 29.6 Hz, 2H, OCH2Ph), 4.59–4.67 (m,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2009.12.014.
2H, CH2NO2), 4.87–4.90 (m, 1H, H-4), 5.65–5.66 (m, 1H, H-1),
5.92 (dd, J = 11.5, 1.5 Hz, 1H, CH@CH–COOn-But), 6.37 (dd,
J = 11.5, 4.2 Hz, 1H, CH@CH–COOn-But), 7.23–7.33 (m, 5H, Ar–H);
13C NMR (125 MHz, CDCl3): d 13.8, 19.2, 30.7, 64.5, 72.8, 74.4,
75.2, 77.5, 78.6, 86.1, 120.9, 127.8, 128.1, 128.5, 137.5, 146.8;
166.2; HRMS: Found: 380.1648 C19H25NO7 [M+H]+ calcd
379.1631.
References
1. Dwek, R. A. Chem. Rev. 1996, 96, 683–792.
2. Dwek, R. A.; Butters, T. D. Chem. Rev. 2002, 102, 283–284.
3. Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A. Science 2001, 291,
2370–2376.
4. Fraser Reid, B.; Tatsuta, K.; Thiem, J. Glycoscience: Chemistry and Chemical
Biology; Springer: Heidelberg, Germany, 2001.
5. Varki, A. Glycobiology 1993, 3, 97–130.
6. Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620–9621.
7. Wong, C.-H. Carbohydrate Based Drug Discovery; Wiley-VCH: Weinheim,
Germany, 2003.
8. Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913–9959.
9. Pellissier, H. Tetrahedron 2005, 61, 2947–2993.
10. Schmieg, J.; Yang, G.; Franck, R. W.; Tsuji, M. O. J. Exp. Med. 2003, 198, 1631–
1641.
11. Taylor, E. A.; Clinch, K.; Kelly, P. M.; Li, L.; Evans, G. B.; Tyler, P. C.; Schramn, V.
L. J. Am. Chem. Soc. 2007, 129, 6984–6985.
12. Levy, W.; Chang, D. The Chemistry of C-Glycosyl Compounds; Elsevier:
Cambridge, UK, 1995.
3.3.5. (Z)-Benzyl 3-((2R,3R,4S,5R)-3-(benzyloxy)-4-hydroxy-5-
(nitromethyl) tetrahydrofuran-2-yl)acrylate 7e
Yield: 0.136 g (75%); white solid mp 97–99 °C; IR (neat): 3462,
2920, 1713, 1551, 1369 cmꢀ1; Rf = 0.28 (30% EtOAc–petroleum
ether); [
2.52 (br s, 1H, OH), 4.20 (d, J = 3.8 Hz, 1H, H-2), 4.39 (br s, 1H, H-
3), 4.46 (ABq, J = 12.2 Hz, = 39 Hz, 2H, OCH2Ph), 4.58–4.66 (m,
a]
+158.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d
D
D
m
2H, CH2NO2), 4.87–4.90 (m, 1H, H-4), 5.08 (s, 2H, COOCH2Ph),
5.64–5.66 (m, 1H, H-1), 5.97 (dd, J = 11.5, 1.5 Hz, 1H, CH@CH–
COOCH2Ph), 6.42 (dd, J = 11.5, 6.9 Hz, 1H, CH@CH–COOCH2Ph),
7.21 (d, J = 6.9 Hz, 2H, Ar–H), 7.22 –7.36 (m, 8H, Ar–H); 13C NMR
(125 MHz, CDCl3): d 66.5, 72.7, 74.4, 75.0, 77.5, 78.6, 85.9, 120.6,
127.8, 128.1, 128.4, 128.5, 128.6, 128.7, 135.7, 137.5, 147.7,
165.8; HRMS: Found: 414.1481 C22H23NO7 [M+H]+ calcd
413.1474.
13. Yuasa, H.; Hashimoto, H. Rev. Heteroat. Chem. 1998, 19, 35–65.
14. Wei, A.; Boy, K. M.; Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9432–9436.
15. Espinosa, J.-F.; Canada, F. J.; Asensio, J. L.; Martin-Pastor, M.; Dietrich, H.;
Martin-Lomas, M.; Schmidt, R. R.; Jimenez-Barbero, J. J. Am. Chem. Soc. 1996,
118, 10862–10871.
16. Omura, S.; Tanaka, H.; Oiwa, R.; Awaya, J.; Masuma, R.; Tanaka, K. J. Antibiot.
1977, 30, 908–916.
17. Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691–1694.
18. Crisostomo, F. R. P.; Carrillo, R.; Martin, T.; Garcia-Tellado, F.; Martin, V. J. Org.
Chem. 2005, 70, 10099–10101.
19. Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett. 2007, 9, 1121–1124.
20. Masson, G.; Compain, P.; Martin, O. R. Org. Lett. 2000, 2, 2971–2974.
21. Moreno, B.; Quehen, C.; Rose-Helene, M.; Leclerc, E.; Quirion, J.-C. Org. Lett.
2007, 9, 2477–2480.
3.3.6. (Z)-Octyl 3-((2R,3R,4S,5R)-3-(benzyloxy)-4-hydroxy-5-(ni-
tromethyl)tetrahydrofuran-2-yl)acrylate 7f
Yield: 0.137 g (68%); semi solid; IR (neat): 3461, 2922, 1712,
1553, 1376 cmꢀ1; Rf = 0.38 (30% EtOAc–petroleum ether); [
a]
D
+114.3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.88 (t,
J = 6.8 Hz, 3H, n-Oct), 1.27 (br s, 10H, n-Oct), 1.61 (br s, 2H, n-
Oct), 2.30 (s, 1H, OH), 4.06 (t, J = 6.0 Hz, 2H, n-Oct), 4.27 (d,
J = 3.6 Hz, 1H, H-2), 4.43 (br s, 1H, H-3), 4.54 (ABq, J = 12.0 Hz,
22. Liu, Y.; Gallagher, T. Org. Lett. 2004, 6, 2445.
23. Parrish, J. D.; Little, R. D. Org. Lett. 2002, 4, 1439–1442.
24. Schweizer, F.; Inazu, T. Org. Lett. 2001, 3, 4115–4118.
25. Terauchi, M.; Abe, H.; Matsuda, A.; Shuto, S. Org. Lett. 2004, 6, 3751–3754.
26. Leonelli, F.; Capuzzi, M.; Calcagno, V.; Passacantilli, P.; Piancatelli, G. Eur. J. Org.
Chem. 2005, 13, 2671–2676.
Dm = 24.2 Hz, 2H, OCH2Ph), 4.60–4.70 (m, 2H, CH2NO2), 4.88–4.92
27. Chjara, J. L.; Sesmilo, E. Angew. Chem., Int. Ed. 2002, 41, 3242–3246.
28. Jeanmart, S.; Taylor, R. J. K. Tetrahedron Lett. 2005, 46, 9043–9048.
29. McAllister, G.; Paterson, D. E.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2003, 42,
1387–1391.
30. Wipf, P.; Pierce, J. G.; Zhuang, N. Org. Lett. 2005, 7, 483–485.
31. Guillarme, S.; Ple, K.; Haudrechy, A. J. Org. Chem. 2006, 71, 1015–1017.
32. Rothman, J. H. J. Org. Chem. 2007, 72, 3945–3948.
33. Dondoni, A.; Zuurmond, H. M.; Boscarato, A. J. Org. Chem. 1997, 62, 8114–8124.
34. Kozlowski, J. S.; Marzabadi, C. H.; Rath, N. P.; Spilling, C. D. Carbohydr. Res. 1997,
300, 301–313.
(m, 1H, H-4), 5.66–5.69 (m, 1H, H-1), 5.93 (dd, J = 12.0, 1.6 Hz,
1H, CH@CH–COOn-Oct), 6.38 (dd, J = 11.6, 6.8 Hz, 1H, CH@CH–
COOn-Oct), 7.24–7.33 (m, 5H, Ar–H); 13C NMR (100 MHz, CDCl3):
d 14.0, 22.6, 25.9, 28.5, 29.1, 29.2, 31.8, 64.7, 72.7, 74.1, 75.1,
77.2, 78.4, 85.9, 120.9, 127.6, 127.9, 128.4, 137.3, 146.6, 165.9;
HRMS: Found: 458.2143 C23H33NO7Na [M+Na]+ calcd 458.2155.
3.3.7. (Z)-Octyl 3-((2R,3R,4S,5R)-3-ethoxy-4-hydroxy-5-(nitrom-
ethyl)tetrahydrofuran-2-yl)acrylate 7g
35. Ohrui, H.; Jones, G. H.; Moffatt, G. J.; Maddox, M. L.; Christensen, A. T.; Byram, S.
K. J. Am. Chem. Soc. 1975, 97, 4602–4613.
Yield: 0.106 g (65%); viscous oil; IR (neat): 3461, 2929, 1716,
36. Egron, D.; Durand, T.; Roland, A.; Vidal, J.-P.; Rossi, J.-C. Synlett 1999, 435–437.
37. Wolform, M. L.; Hanessian, S. J. Org. Chem. 1962, 27, 1800–1804.
38. Iida, T.; Funabashi, M.; Yoshimura, J. Bull. Chem. Soc. Jpn. 1973, 46, 3203.
39. Torii, S.; Inokuchi, T.; Oi, R.; Kondo, K.; Kobayashi, T. J. Org. Chem. 1986, 51, 254.
40. In addition to epimerisation base also promotes retro Michael reaction: Zou,
W.; Wu, A.-T.; Bhasin, M.; Sandbhor, M.; Wu, S.-H. J. Org. Chem. 2007, 72, 2686–
2689.
41. Johnson, W. Ylide Chemistry; Academic Press: New York, NY, 1966.
42. Crystallographic data of the structure of compound 7e have been deposited
with the Cambridge Crystallographic Data centre as supplementary publication
no. CCDC-675835.
1554, 1417, 1384 cmꢀ1; Rf = 0.37 (30% EtOAc–petroleum ether);
[a]
+161.4 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.88 (t,
D
J = 7.2 Hz, 3H, n-Oct), 1.12 (t, J = 6.8 Hz, 3H, OCH2CH3), 1.27–1.37
(br s, 10H, n-Oct), 1.65 (quintet, J = 6.4 Hz, 2H, n-Oct), 2.35 (br s,
1H, OH), 3.42–3.49 (m, 1H, OCHHCH3), 3.54–3.61 (m, 1H,
OCHHCH3), 4.09–4.14 (m, 3H, H-2), 4.42 (br s, 1H, H-3), 4.60–
4.71 (m, 2H, CH2NO2), 4.83–4.87 (m, 1H, H-4), 5.63–5.66 (m, 1H,
H-1), 5.92 (dd, J = 12.0, 2.0 Hz, 1H, CH@CH–COOn-Oct), 6.32 (dd,