Stereoselective synthesis of a C-glycosylic compound (a "methyl C-glycoside") through a regioselective free-radical ring-opening reaction. A single-crystal X-ray structure determination

Article abstract of DOI:10.1016/S0008-6215(02)00137-4

Readily available 3,4,6-tri-O-acetyl-D-glucal was converted to 2,6-anhydro-5,7-O-benzylidene-1,3,4-trideoxy-D-arabino-hept-3-enitol, a methyl C-glycosylic compound. Cyclopropanation of 4,6-O-benzylidene-D-glucal, followed by tributylstannyl radical-mediated regioselective ring opening of the 1,2-cyclopropano sugar led to a 2,6-anhydro-1-deoxyheptose, (a "methyl C-β-D-glycoside"). The stereochemistry of the 1,2-cyclopropano sugar and the "methyl C-glycoside" were confirmed by single-crystal X-ray diffraction studies.

Full text of DOI:10.1016/S0008-6215(02)00137-4

Carbohydrate Research 337 (2002) 1523–1527
www.elsevier.com/locate/carres
Stereoselective synthesis of a C-glycosylic compound (a ‘‘methyl
C-glycoside’’) through a regioselective free-radical ring-opening
reaction. A single-crystal X-ray structure determination
Bhagavathy Shanmugasundaram,a Babu Varghese,b Kalpattu K. Balasubramaniana,*
aDepartment of Chemistry, Indian Institute of Technology, Madras, Chennai 600 036, India
bRegional Sophisticated Instrumentation Centre, Indian Institute of Technology, Madras, Chennai 600 036, India
Received 7 February 2002; accepted 8 June 2002
Abstract
Readily available 3,4,6-tri-O-acetyl-
enitol, a methyl C-glycosylic compound. Cyclopropanation of 4,6-O-benzylidene-
diated regioselective ring opening of the 1,2-cyclopropano sugar led to
-glycoside’’). The stereochemistry of the 1,2-cyclopropano sugar and the ‘‘methyl C-glycoside’’ were confirmed by
D
-glucal was converted to 2,6-anhydro-5,7-O-benzylidene-1,3,4-trideoxy-
-glucal, followed by tributylstannyl radical-me-
2,6-anhydro-1-deoxyheptose, (a ‘‘methyl
D-arabino-hept-3-
D
a
C-b-D
single-crystal X-ray diffraction studies. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: C-Glycoside; 1,2-Cyclopropanated sugar; Radical ring opening; Single-crystal X-ray diffraction
C-Glycosylic compounds, frequently referred to as
‘‘C-glycosides’’, are a class of compounds that continue
to receive attention in carbohydrate and synthetic or-
ganic chemistry. Some of the total syntheses of biologi-
cally important macromolecules have been achieved
using C-glycosides as chiral building blocks.1 Hence,
efficient and stereocontrolled methods for the synthesis
of C-glycosides and obtaining chiral templates for more
complex synthetic targets constitute major challenges in
this area.2
Our laboratory has earlier reported the synthesis of
unsaturated aryl C-glycosides and other aryl C-deoxy-
glycosides.3 An ongoing research project in this area in
our laboratory is the development of new methodology
for the synthesis of alkyl C-glycosides. Because of the
attendant problems in regio- and stereoselectivity (ob-
served especially at the anomeric centre of sugars),
free-radical reactions have been increasingly employed
in organic synthesis.4 Unsaturated sugars, in particular
3,4,6-tri-O-acetyl-D-glucal, have found widespread use
as carbohydrate synthons.5
Cyclopropanation of appropriately protected glycals
paves the way for the introduction of alkyl groups at
either C-1 or C-2 of the pyranose ring. Several method-
ologies have been employed in the last decade for
stereocontrolled cyclopropanation in carbohydrates.6
Although several reactions are known for solvolytic7
and electrophilic ring opening,8 there are only a few
reports on the free-radical ring-opening of cyclo-
propanated sugars.9
Herein, we report a different approach for synthesis
of a C-b-D-glycoside via tri-(n-butyl)stannyl radical-
mediated ring opening of a 1,5-anhydro-1,2-cyclo-
propylcarbinyl-2-deoxyhexitol system.10 3,4,6-Tri-O-
acetyl-
-glucal11 (2) using benzaldehyde dimethylacetal.
Diastereoselective cyclopropanation of 2 was carried
D
-glucal (1) was converted to 4,6-O-benzylidene-
D
out using the Simmons–Smith reaction to furnish 1,5-
anhydro-4,6-O-benzylidene-2-deoxy-1,2-C-methylene-
1
D
-glycero-
D
-talo-hexitol (3) (Scheme 1). Although H
* Corresponding author. Tel.: +91-44-2451106; fax: +91-
44-2452462
E-mail address: kkbalu@hotmail.com (K.K. Balasubrama-
nian).
NMR spectral data showed the presence of the cyclo-
propane ring, the stereochemistry at the bicyclic ring
junction still required confirmation.
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00137-4

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B. Shanmugasundaram et al. / Carbohydrate Research 337 (2002) 1523–1527
Table 1
The resulting cyclopropylcarbinol 3 was converted to
1,5-anhydro-4,6-O-benzylidene-2-deoxy-1,2-C-methyl-
ene-3-O-xanthyl- -glycero- -talo-hexitol (4) (Scheme
2) whose NMR spectrum revealed unexpected results.
The H-3 [(C-11 as depicted in the ORTEP diagram (Fig.
1)] of 4 at l 6.16 appeared as a triplet (J2,3=J3,4 11.5
Hz), thus providing no information as to the configura-
tion at C-1 and C-3. Proof for the stereochemistry of
the xanthate derivative 4 was obtained by single-crystal
X-ray diffraction study (Fig. 1).
Summary of crystal data and data collection parameters for
1,5-anhydro-4,6-O-benzylidine-2-deoxy-1,2-C-methylene-3-O-
xanthyl-
D
D
D
-glycero-
D
-talo-hexitol (4) and for 2,5-anhydro-5,7-
-arabino-hex-3-enitol (5)
O-benzylidene-1,3,4-dideoxy-b-
D
Chemical formula
C16H18O4S2
(4)
C14H16O3 (5)
Formula weight
Crystal system
Space group
338.42
monoclinic
P21
232.27
monoclinic
P21
The observed stereoselectivity in 4, based on the
X-ray diffraction analysis, is consistent with an oxygen-
directed (allylic 3-OH) Simmons–Smith cyclopropana-
tion, while cyclopropanation of 3,4,6-tri-O-benzyl-
Temperature (K)
293(2)
1.54160
293 (2)
1.54180
,
Wavelength (A)
Lattice parameters
,
a (A)
6.4107(9)
13.991(3)
9.2746(2)
95.92(2)
827.43(19)
2
9.437(3)
5.5107(10)
23.852(3)
90.110(16)
1240.5(5)
4
,
b (A)
D
-glucal using dichlorocarbene is reported to lead to a
,
c (A)
product with opposite stereochemistry.12 A summary of
the crystallographic data is provided in Table 1, and the
selected atomic parameters are shown in Tables 2 and 3.
Free-radical ring-opening reaction of 4 using the
standard Barton radical deoxygenation conditions with
i (°)
3
,
V (A )
Z
Dcalcd (mg m−3
)
1.358
3.047
1.244
0.703
Absorption coefficient
(mm−1
F(000)
v (mm−1
)
356
3.047
496
0.703
)
Index ranges
05h57,
05k516,
−115l511
0.25×0.1
×0.075
1628
1489
220
1
05h510,
05k56,
−285l528
0.3×0.15×0.15
Crystal size (mm)
Scheme 1. Conditions: (a) (i) Na2CO3, MeOH, (ii) Ph-
CH(OMe)2, p-TsOH, DMF; (b) Zn–Cu, CH2I2, Et2O (45%
overall).
Measured data
Unique data
Parameters
Restraints
2758
2437
308
1
R (all data)
wR2
Goodness-of-fit
Mean and maximum
shift/esd
0.0451
0.1230
1.063
0.0614
0.1704
1.136
0.002–0.000
0.002–0.000
Maximum and minimum 0.253, −0.461 0.355, −0.269
Scheme 2. Conditions: (a) NaH, CS2, MeI, THF, 90% (b)
Bu3SnH, AIBN, toluene, reflux, 80%.
difference electron
−3
,
density (e A
)
Bu3SnH afforded exclusively the 2,6-anhydro-5,7-O-
benzylidene-1,3,4-trideoxy-b- -arabino-hept-3-enitol
(5). NMR (1H, NOE and COSY) spectral studies estab-
lished the anomeric configuration as b-
D
D
.
As expected the free-radical ring opening of 4
stereospecifically afforded the b anomer of the C-glu-
coside 5 with no trace of the seven-membered (i.e., the
cyclopropane ring-opened) product.† We have estab-
lished also the stereochemistry of 5 by X-ray crystallo-
graphic analysis. Crystallographically 5 shows two
nonequivalent molecules in the asymmetric unit. How-
ever, stereochemically both the molecules are found to
Fig. 1. ORTEP diagram of 1,5-anhydro-4,6-O-benzylidine-2-
† Ref. 10 reports both the ring opened and ring expanded
products in the ratio of 3:2, respectively, in the case of a
4,5-cyclopropanated sugar.
deoxy-1,2-C-methylene-3-O-xanthyl-
(4).
D-glycero-D-talo-hexitol

B. Shanmugasundaram et al. / Carbohydrate Research 337 (2002) 1523–1527
1525
Table 3
Atomic coordinates (×104) and equivalent isotropic displace-
be identical, hence only one of the molecule is repre-
sented in the ORTEP diagram (Fig. 2).
The present study provides a potential route for the
stereoselective synthesis of C-glycosides. Research is
underway to extend this approach to the stereoselective
synthesis of other C-glycosides.
2
3
,
ment parameters (A ×10 ) for 2,5-anhydro-5,7-O-benzyli-
dene-1,3,4-dideoxy-b-D-arabino-hex-3-enitol (5)
x
y
z
Ueq
O(1%)
O(2%)
O(3%)
C(1%)
C(2%)
C(3%)
C(4%)
C(5%)
C(6%)
C(7%)
C(8%)
C(9%)
C(10%)
C(11%)
C(12%)
C(13%)
C(14%)
O(1)
O(2)
O(3)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
3674(3)
5777(3)
7285(3)
2326(5)
2196(6)
3286(5)
4647(4)
4795(4)
6205(4)
1203(5)
7092(4)
8229(4)
9062(5)
10086(6)
10279(6)
9450(6)
8460(5)
−1326(3)
789(3)
2295(3)
−2680(4)
−2782(5)
−1739(4)
−350(4)
−189(4)
1220(4)
−3819(5)
2116(4)
3254(4)
4070(5)
5115(5)
5324(5)
4514(5)
3476(5)
10243(7)
6837(6)
9386(6)
10347(12)
8486(12)
6984(10)
7256(9)
4537(1)
3545(1)
4048(1)
4247(2)
3813(2)
3649(2)
3928(2)
4164(2)
4446(2)
4662(2)
3821(2)
3399(2)
3414(2)
3009(3)
2589(2)
2567(2)
2962(2)
459(1)
59(1)
56(1)
56(1)
68(1)
78(2)
63(1)
52(1)
50(1)
57(1)
93(2)
51(1)
52(1)
68(1)
83(2)
75(2)
74(2)
64(1)
54(1)
48(1)
48(1)
60(1)
63(1)
60(1)
47(1)
43(1)
51(1)
96(2)
43(1)
45(1)
60(1)
72(1)
73(2)
73(2)
59(1)
1. Experimental
General procedure.—IR spectra were determined as
their solutions in CCl4 using a SHIMADZU IR 470
model instrument. 1H and 13C NMR spectra were
recorded on a JOEL-GSX 400 spectrometer with
CDCl3 as solvent and Me4Si as internal standard. Elec-
tron-impact mass spectra (EIMS) were obtained with a
SHIMADZU-QP 5000 instrument.
9821(8)
10038(10)
10073(17)
7071(9)
6589(9)
1,5-Anhydro-4,6-O-benzylidene-2-deoxy-1,2-C-methyl-
ene-D-glycero-D-talo-hexitol (3).—To a stirred suspen-
4434(11)
4103(11)
5660(11)
7735(12)
8136(10)
−1373(6)
2053(5)
−533(6)
−1458(10)
430(10)
1860(10)
1633(8)
−913(8)
−1129(9)
−1272(18)
1867(7)
sion of zinc dust (420 mg, 4.4 mmol) and CuCl (135
mg, 1 mmol) in dry ether (3 mL) was added CH2I2 (0.12
mL, 1.5 mmol), followed by acetyl chloride (20 mL).
Then a solution of 4,6-O-benzylidene-D-glucal (350 mg,
1.5 mmol) in ether (5mL) was added, and the mixture
was heated under reflux. After 5 min CH2I2 (0.12 mL,
1.5 mmol) was again added, and heating was continued
for 45 min. The reaction mixture was diluted with ether
1461(1)
950(1)
754(2)
1193(2)
1356(2)
1069(2)
845(1)
Table 2
Atomic coordinates (×104) and equivalent isotropic displace-
2
3
551(2)
310(2)
,
ment parameters (A ×10 ) for 1,5-anhydro-4,6-O-ben-
zylidine-2-deoxy-1,2-C-methylene-3-O-xanthyl-
o-hexitol (4)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
D
-glycero-D-tal
1187(1)
1603(2)
1577(2)
1980(2)
2402(2)
2441(2)
2041(2)
2319(8)
4399(10)
4798(10)
3254(12)
1153(13)
694(10)
x
y
z
Ueq
S(1)
−147(2)
4762(1)
4067(1)
5105(2)
4505(2)
6998(3)
4832(2)
3473(5)
2668(6)
1861(6)
1855(5)
2660(4)
3458(3)
4339(3)
5975(4)
6197(3)
5348(3)
5515(3)
6512(3)
7257(4)
6876(5)
4593(3)
3712(5)
2999(1)
1720(2)
−3616(4)
−1691(3)
−2313(4)
277(3)
−2347(6)
−2350(8)
−3080(8)
−3837(8)
−3858(6)
−3116(4)
−3128(4)
−3664(5)
−2172(5)
−1628(4)
−88(4)
69(1)
77(1)
63(1)
44(1)
67(1)
49(1)
71(2)
96(2)
91(2)
85(2)
64(1)
48(1)
47(1)
66(1)
51(1)
41(1)
43(1)
53(1)
62(1)
77(2)
47(1)
99(2)
S(2)
−4385(2)
3044(6)
O(1)
O(2)
O(3)
O(4)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
1372(4)
−122(6)
−1850(4)
5208(8)
6426(11)
5727(12)
3783(12)
2524(9)
3198(7)
1891(7)
1903(10)
1243(7)
119(6)
−270(6)
−1028(7)
−873(9)
−2973(9)
−1955(6)
−4343(13)
162(5)
−1003(6)
−728(8)
1662(4)
3553(8)
Fig. 2. ORTEP diagram of 2,5-anhydro-5,7-O-benzylidene-
1,3,4-dideoxy-b- -arabino-hex-3-enitol (5).
D

1526
B. Shanmugasundaram et al. / Carbohydrate Research 337 (2002) 1523–1527
and washed with 5% NaOH, followed by water.
Column chromatography of the crude product using
3:2 EtOAc–hexane yielded 285 mg (75%); mp 133–
135 °C; [h]3D0 −82.7° (c 0.719, CH2Cl2); IR cm−1):
3600, 3008, 2928, 2896, 1452, 1379, 1286, 1091, 1030,
(d, 1 H, H-4), 4.2–4.3 (m, 1 H, H-6a, 6b), 5.4 (s, 1 H,
benzylidene H), 5.59 (d, 1 H, H-2), 5.83 (d, 1 H, H-3),
7.25–7.38 (m, 5 H, Phꢀ); 13C NMR: l 21.90, 70.01,
71.81, 72.66, 75.90, 97.00, 102.40, 127.08, 127.20,
128.60, 129.20, 133.14, 138.6; EIMS: Anal. Calcd for
C14H16O3, 232.11; Found: m/z 232 [M], 188, 149, 126,
105, 83, 77, 55, 43.
1
966, 872, 598; H NMR: l 0.77–0.85 (m, 2 H, H-7),
1.34 (dd, 1 H, H-2), 2.77 (bs, 1 H, OH), 3.25–3.5 (m, 3
H, H-4, 5, 1), 3.7 (m, 1 H, H-3), 4.22 (m, 2 H, H-6a,
6b), 5.39 (s, 1 H, benzylidene H), 7.2–7.4 (m, 5 H, Ph);
13C NMR: l 11.9, 17.61, 54.5, 67.94, 68.53, 68.59,
82.08, 96.19, 101.58, 128.30, 128.20, 129.08, 137.34;
EIMS: Anal. Calcd for C14H16O4, 248.27; Found: m/z
247 [M−1], 149, 107, 91, 77, 55.
X-ray crystallography.—Well-grown single crystals
of appropriate size were selected for structure determi-
nation. The cell dimensions were obtained by the
method of short vectors, followed by least-squares
refinement of the 25 reflections collected through search
routine. The intensity data were collected at room
temperature on an Enraf–Nonius CAD4 diffractome-
ter. The data were corrected for Lorentz and polarisa-
tion effects, and an absorption correction was applied
on the basis of „-scans. The structures were solved by
direct methods (SHELXS97),13 and full matrix least-
squares refinement was carried out using the program,
SHELX-97.14 Hydrogen atom positions were fixed on
geometrically calculated positions (after verifying these
positions through a difference Fourier map) and were
allowed to ride on their respective carrier atoms. The
thermal parameters of the nonhydrogen atoms were
anisotropically refined. The final convergence was
achieved with R=0.0451 and 0.0614, respectively, for 4
and 5.
1,5-Anhydro-4,6-O-benzylidene-2-deoxy-1,2-C-methyl-
ene-3-O-xanthyl-D-glycero-D-talo-hexitol (4).—It is im-
portant to note that the reaction has to be conducted
under a perfectly dry argon atmosphere for good yields.
To a solution of 3 (200 mg, 0.8 mmol) in dry THF (10
mL) was added NaH (60 mg, 50% oil dispersion, 1.2
mmol) under dry argon atmosphere, and the mixture
was stirred at rt for 1 h. CS2 (0.14 mL, 2.4 mmol) and
a catalytic amount of imidazole (10 mg) was then
added, and stirring was continued for 30 min, followed
by the addition of MeI (0.1 mL, 2 mmol). After 30 min
the reaction was quenched with MeOH. The solvents
were evaporated under vacuum, and the reaction mix-
ture was worked up by extracting with CH2Cl2.
Column chromatography of the crude product using
4:1 EtOAc–hexane yielded 245 mg (90%) of 4. Recrys-
tallization of the product using 1:9 EtOAc–CCl4 gave
single crystals: mp 147–149 °C; [h]3D0 −180.5° (c 0.886,
CH2Cl2); IR (cm−1): 3024, 2992, 2944, 2880, 1452,
2. Supplementary material
The full crystallographic details of compounds 4 and
5 have been deposited (deposition numbers: 191424 and
191425) with Cambridge Crystallographic Data Centre.
These data can be obtained, on request from The
Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; (fax: +44-1223-336033; e-mail: deposit@
ccdc.cam.ac.uk; www: http://www.ccdc.cam.ac.uk).
1
1408, 1376, 1235, 1203, 1129, 1049, 915, 694; H NMR:
l 0.90 (m, 2 H, H-7), 2.00 (m, 1 H, H-2), 2.5 (s, 3 H,
ꢀSMe3), 3.2–3.9 (m, 3 H, H-5, 6a, 6b), 4.3 (bs, 1 H,
H-4), 5.5 (s, 1 H, benzylidene H), 6.16 (t, 1 H, H-3,
J
2,3=J3,4 11.5 Hz), 7.2–7.4 (m, 5 H, Phꢀ); 13C NMR: l
12.49, 15.12, 19.18, 55.69, 68/6, 76.36, 77.63, 78.76,
79.92, 101.36, 126.13, 128.17, 129.03, 137.04; EIMS:
Anal. Calcd for C14H18O4S2, 338.06; Found: m/z 338,
277, 231, 125, 107, 91, 81, 67.
Acknowledgements
2,6-Anhydro-5,7-O-benzylidene-1,3,4-trideoxy-D-ara-
bino-hept-3-enitol (5).—About 0.6 mmol of 4 in dry
toluene (10 mL) was heated to reflux under a dry
nitrogen atmosphere. To this was added dropwise a
mixture of Bu3SnH (209 mg, 0.72 mmol) and a catalytic
amount of AIBN in dry toluene, and the mixture was
refluxed for 1 h, with monitoring by TLC. The toluene
in the reaction mixture was evaporated in vacuum, and
the crude product was chromatographed (silica gel
column) using 7:3 EtOAc–hexane to yield 5 in about
80% yield. Recrystallization was done in dry MeOH
gave single crystals: mp 114–116 °C; [h]2D9 +99.4° (c
0.767, CH2Cl2); IR (cm−1): 3040, 2976, 2944, 2864,
The authors thank Dr K. Vijayakumaran for useful
discussions and CSIR, New Delhi for funding.
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