Unusual synthesis of carbohydrate sec-sec ether-linked pseudodisaccharides

Article abstract of DOI:10.1016/j.carres.2008.01.013

In this paper, we describe the synthesis of sec-sec ether-linked pseudodisaccharides by the coupling of various secondary carbohydrate alcohols with di-O-isopropylidene allose 3-O-triflate. Reactions proceeded with inversion of configuration to give the 3-substituted di-O-isopropylidene glucose derivatives. The crystal structure of a sec-sec ether-linked pseudodisaccharide is reported.

Full text of DOI:10.1016/j.carres.2008.01.013

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 2094–2100
Unusual synthesis of carbohydrate sec–sec ether-linked
pseudodisaccharides
Tashfeen Akhtar,a Lars Erikssonb and Ian Cumpsteya,*
aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
bDivision of Structural Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
Received 30 September 2007; received in revised form 11 January 2008; accepted 11 January 2008
Available online 18 January 2008
Presented at Eurocarb 14th Lubeck, Germany, September 2007
¨
Abstract—In this paper, we describe the synthesis of sec–sec ether-linked pseudodisaccharides by the coupling of various secondary
carbohydrate alcohols with di-O-isopropylidene allose 3-O-triflate. Reactions proceeded with inversion of configuration to give the
3-substituted di-O-isopropylidene glucose derivatives. The crystal structure of a sec–sec ether-linked pseudodisaccharide is reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Ether-linked pseudodisaccharides; Glycomimetics; Sugar triflates
1. Introduction
O
OH
OH
O
O
OH
HO
HO
HO
O
HO
R2N
O
The great significance of diverse carbohydrate structures
in nature means that unusual modifications have a cer-
tain inherent interest as potentially biologically active
molecules. One such class of structures is tail-to-tail
ether-linked pseudodisaccharides, and recently several
articles on the synthesis of such (6–6) tail-to-tail-linked
structures (Chart 1a) have been published.1–3 This
followed the isolation of the hypoglycaemic, Coyolosa,
which was reported to have such a structure,4 although
now, as a result of these studies, it appears that this
reported structure is incorrect. Ether-linked pseudodi-
saccharides are not altogether unknown in nature
though, and an exotoxin from Bacillus thuringiensis
containing a primary–secondary Glc-(4–5)-Rib ether-
linked pseudodisaccharide substructure was isolated5
and subsequently synthesised6 30 years ago by Sorm
and co-workers (Chart 1b). A few other reports of
synthetic primary–primary and primary–sec ether-
linked pseudodisaccharides also exist.7–9
HO
O
OH
HO
HO
OR'
HO
OH
O
OBn
O
TfO
OBn
1
Chart 1. (a) A (6–6) ether-linked pseudodisaccharide synthesised by
Haines; (b) ether-linked pseudodisaccharide portion of Thuringiensin,
the B. thuringiensis exotoxin; (c) triflate 1 used for sec–sec ether
synthesis by Paulsen.
sec–sec Ethers are much more challenging to synthe-
sise than primary–sec or primary–primary ethers, as a
Williamson-type synthesis necessarily requires an SN2
reaction at a secondary carbon centre.10 Substitution is
often disfavoured with respect to the alternative E2
pathway that gives an alkene product. In a carbohydrate
context, Paulsen and co-workers have reported the
synthesis of various sec–sec ethers based on the
coupling of saturated and unsaturated carbasugar C-1
alcohols with a secondary carbohydrate triflate 1
*
Corresponding author. Tel.: +46 8 674 7263; e-mail: cumpstey@
organ.su.se
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.01.013

T. Akhtar et al. / Carbohydrate Research 343 (2008) 2094–2100
2095
O
O
O
O
O
O
O
O
O
NsHN
BnO
O
O
a or b or c
O
O
O
O
O
O
BnO
O
O
BnO
O
OMe
TfO
O
O
2
O
3
O
O
O
O
4
O
5
Scheme 1. Reagents and conditions: (a) 2, NaH, DMF, rt; 4, 48%; (b) NaH, DMF, rt; 4, 52%; 5, 8%; (c) NaOH, DMF, rt; 4, 51%; 5, 14%.
(Chart 1c).11,12 Kovac and co-workers have seen ether-
linked pseudodisaccharides as by-products in their tin
acetal b-mannoside-forming alkylations; a sec–sec Glc-
O2II
(2–4)-Glc ether was formed as the major product when
O2I
the synthesis of glucosides was attempted using the same
O1I
method.13,14
C2II
O1II
C2I
C3I
C1II
C1I
C3II
C4II
O4II
O4I
O3I
C4I
C5I
2. Results and discussion
C5II
O5I
As part of our research program on the synthesis of
non-glycosidically linked carbohydrate analogues,15 we
were attempting the synthesis of a (3–6) amine-linked
pseudodisaccharide. Treatment of the sulfonamide 216
and triflate 317 with sodium hydride in DMF resulted
in the formation of a new product (Scheme 1). The
sulfonamide 2 was recovered completely unreacted.
The 1H NMR spectra of the new compound showed sig-
nals consistent with two di-O-isopropylidene-protected
sugar moieties, i.e., eight methyl singlets between 1.3
and 1.6 ppm; doublets for two anomeric protons at
5.79 and 5.87 ppm; the signal for H-2 at 4.70 ppm was
a doublet (J1,2 3.5 Hz), with no coupling to H-3, consis-
tent with a gluco configuration; the other H-2 signal at
4.64 ppm was a triplet (J 4.2 Hz) as expected for an allo
configuration. The mass spectrum showed a peak at
m/z 525, consistent with [M+Na]+ for M = 502. This
data is consistent with a gluco-allo (3–3) ether-linked
structure 4, formed in 48% yield based on dimerisation
of the triflate 3.
We were also able to obtain crystals of 4 and to solve
the X-ray structure, giving an unambiguous structural
proof (Fig. 1).
We repeated the reaction in the absence of the sulfon-
amide. Triflate 3 was treated with sodium hydride in
DMF. Once again, the unsymmetrical ether-linked
disaccharide 4 was formed as the major product
(52%), but now we isolated a minor amount of a second
product. In its 1H and 13C NMR spectra, this compound
only showed signals equivalent to a gluco configured
C6II
O6II
O5II
C6I
O6I
Figure 1. X-ray structure of 4 as thermal ellipsoids drawn at 50%
probability and showing crystallographic atom numbering scheme.
Selected dihedral angles (°): C3II–O3I–C3I–C4I, ꢀ166.2; C3II–O3I–
C3I–C2I, +78.3; C3I–O3I–C3II–C2II, ꢀ99.7; C3I–O3I–C3II–C4II,
I
I
II
˚
+149.7. Bond angle (°): C3 –O3 –C3 , +114.3. Bond lengths (A):
O3I–C3I, 1.412; O3I–C3II, 1.434.
diisopropylidene protected monosaccharide, with H-2
appearing as a doublet at 4.65 ppm (J1,2 3.6 Hz). How-
ever, its mass spectrum showed a peak at m/z 525, and
thus it was assigned the C2-symmetric dimeric structure
5 (i.e., with double inversion), formed in 8% yield.
The formation of these species may be explained by the
partial hydrolysis of the triflate by trace hydroxide.
Attack on the triflate sulfur would give the allo alcohol-
ate (7ꢀH+), which could then attack a second triflate 3
by SN2 reaction with inversion to give the unsymmetrical
dimer 4. Alternatively, SN2 attack by hydroxide at C-3 of
the carbohydrate with inversion would give the gluco
alcohol 8, which could then be deprotonated and attack
a second triflate to give the C2-symmetric dimer 5. Even
though we tried to carry out the reaction under anhy-
drous conditions, the formation of both of these prod-
ucts was always seen. Carrying out the reaction with
sodium hydroxide rather than sodium hydride resulted
in the formation of the same products (4, 51%; 5, 14%).
In no case was any elimination product seen. Indeed,
it has been shown previously that this triflate 3 is not
prone to 1,2-elimination, even under strongly basic
conditions.18 Schmidt and co-workers have also carried
3
The J2,3 1H–1H coupling constant is much smaller in gluco
configured 1,2:5,6-di-O-isopropylidene derivatives than their C-3
epimers. For example, compare 1H NMR data for allo 7 and gluco 8
alcohols. 7: 4.60 (1H, dd, J1,2 3.9 Hz, J2,3 4.9 Hz, H-2), 5.80 (1H, d,
H-1); 8: 4.53 (1H, d, J1,2 3.7 Hz, H-2), 5.94 (1H, d, H-1).

2096
T. Akhtar et al. / Carbohydrate Research 343 (2008) 2094–2100
plicities are quoted as singlet (s), doublet (d), doublet of
OBn
O
OH
O
OH
O
Ph
O
Ph
+
O
Ph
O
O
O
doublets (dd), triplet (t), apparent triplet (at) or appar-
ent triplet of doublets (atd). Carbon nuclear magnetic
resonance (13C) spectra were recorded on Bruker
Avance II 400 (100 MHz) or 500 (125 MHz) spectrome-
ters and multiplicities assigned using DEPT. Spectra
were assigned using COSY and HSQC experiments.
All chemical shifts are quoted on the d-scale in parts
per million (ppm). Residual solvent signals were used
as an internal reference. Low- and high-resolution
(HRMS) electrospray (ESI) mass spectra were recorded
using a Bruker Microtof instrument. Optical rota-
tions were measured on a Perkin–Elmer 241 polarimeter
with a path length of 1 dm; concentrations are given in
g/100 mL. Thin-layer chromatography (TLC) was car-
ried out on Merck Kieselgel sheets, pre-coated with
60F254 Silica. Plates were visualised with UV light and
developed using 10% sulfuric acid, or an ammonium
molybdate (10% w/v) and cerium(IV) sulfate (2% w/v)
solution in 10% sulfuric acid. Flash column chromato-
graphy was carried out on silica gel (35–70 lm, Grace).
DMF was distilled or bought anhydrous from Aldrich;
no difference between these qualities was seen. Reactions
performed under an atmosphere of nitrogen were main-
tained by an inflated balloon.
O
a
HO
BnO
HO
OMe
11 OMe
OMe
10
OBn
OBn
O
Ph
O
Ph
O
O
O
O
b, c
HO
OH OMe
OMe
10
9
Scheme 2. Reagents and conditions: (a) BnBr, Bu4NHSO4, DCM,
NaOH, H2O, 45 °C; 10, 62%; 11 20%; (b) PDC, 4 A, DCM, 87%; (c)
NaBH4, THF, MeOH, ꢀ30 °C; 9, 52%; 10, 20%.
˚
out SN2 reactions on triflate 3 and other secondary car-
bohydrate triflates (1 and 4-epi-3), but using the anion of
carbohydrate hemiacetals to give glycoside products.19
This prompted us to investigate the addition of external
alcohols that could act as nucleophiles in potential SN2
reactions.
Some secondary carbohydrate alcohols were synthes-
ised by slightly modified procedures: 1020 and 1120 were
formed from the monobenzylidene diol using Garegg’s
phase transfer conditions21 in 62% and 20% yields,
respectively. Compound 10 was then oxidised (87%)
and the resulting ketone reduced22 to give 923 (52%)
and 10 (20%), which were easily separable by column
chromatography (Scheme 2).
3.2. Synthesis of alcohols
Secondary carbohydrate alcohols 7–11 and carbasugar
alcohol 1224 were treated with allo triflate 3 and NaH in
DMF, and ether-linked pseudodisaccharides 4,5,13–16
were formed as the major product in all cases, although
small amounts of the unsymmetrical 4 and symmetrical 5
dimers were often seen, especially when a large excess of
triflate 3 was used (see Table 1). 1H NMR coupling con-
stants indicated that the furanose rings (labelled II in
4,13–16) all had the gluco configuration. The fact that
the only product detected derived from the alcohols 9–
12 (i.e., in all cases where it was possible to distinguish)
was the ether-linked pseudodisaccharide with inversion
of configuration at C-3 of the triflate 3 is consistent with
a straightforward SN2 reaction mechanism.
In conclusion, we have discovered that allo triflate 3
behaves as a good electrophile for SN2 reactions with
secondary alkoxide nucleophiles, including furanoses,
axial and equatorial pyranose hydroxyls and a carba-
sugar, under standard alkylation conditions, and have
applied this to the synthesis of various sec–sec carbo-
hydrate ether-linked pseudodisaccharides.
Synthesis of 10 and 11: Methyl 4,6-O-benzylidene-a-D-
mannopyranoside (5.11 g, 18.1 mmol) was dissolved in
DCM (150 mL) and Bu4NHSO4 (1.23 g, 3.62 mmol)
and benzyl bromide (3.78 mL, 31.8 mmol) were added.
Sodium hydroxide (1.25 g) was dissolved in water
(15 mL) and the solution added. The reaction mixture
was heated to 45 °C. After 20 h, TLC (3:1 pentane–
EtOAc) showed formation of major (Rf 0.8) and minor
(Rf 0.4) products and little starting material (Rf 0.1)
remaining. Dichloromethane (250 mL) was added, and
the mixture washed with water (200 mL). The aqueous
phase was re-extracted with DCM. The combined
organic extracts were dried (Na2SO4), filtered and con-
centrated under diminished pressure. The residue was
purified by flash column chromatography (6:1?3:1 pen-
tane–EtOAc) to give 10 (4.21 g, 62%) and 9 (1.32 g,
20%). Starting diol (0.58 g, 11%) was also recovered.
Synthesis of 9: Alcohol 10 (1.0 g, 2.69 mmol) was dis-
˚
solved in DCM (25 mL) and 4 A molecular sieves (6.5 g)
and pyridinium dichromate (5.05 g, 13.4 mmol) were
added. The reaction mixture was stirred at rt. Further
PDC (1.0 g, 2.66 mmol) was added after 14 h, and again
after a further 5 h. After a further 1 h, TLC (4:1 pen-
tane–EtOAc) showed complete consumption of starting
material (Rf 0.6) and formation of a major product (Rf
0.8). The reaction mixture was loaded directly onto a sil-
ica column and eluted with 25:1 DCM-ether to give the
ketone (864 mg, 87%).
3. Experimental
3.1. General methods
1H NMR spectra were recorded on Bruker Avance II
400 (400 MHz), or 500 (500 MHz) spectrometers; multi-

T. Akhtar et al. / Carbohydrate Research 343 (2008) 2094–2100
Table 1. Etherification reactions; all reactions carried out with NaH in DMF
2097
Entry
Alcohol (1 equiv)
Equiv triflate 3
Product
Yielda (%)
O
II
O
O
O
O
O
O
O
O
1
1.5
89b
O
O
O
O
O
HO
HO
O
7 17
O
O
I
O
4
O
O
O
O
O
63b
O
O
2
1.5
O
O
O
O
O
8
O
O
5
OBn
O
Ph
O
O
I
O
OBn
O
Ph
O
O
O
O
OMe
3
3.3
78
OH OMe
O
O
O
9
II
13
OBn
Ph
O
I
O
O
O
OBn
O
Ph
Ph
O
O
O
O
4
5
2.5
2.0
95
64
OMe
HO
O
O
O
14
OMe
10
II
O
II
O
O
OH
O
O
O
O
O
BnO
O
Ph
O
O
O
11 OMe
I
BnO
OMe
15
O
BnO
BnO
BnO
O
OH
O
II
6
2.0
BnO
BnO
BnO
34
OBn
O
12 24
O
OBn
I
O
16
a Isolated yields based on alcohols.
b It is possible that small quantities of 4 and 5 derived solely from triflate 3 artificially inflate the yields in these cases. For entry 1, 0.28 equiv triflate 3
was recovered. For entry 2, 0.05 equiv triflate 3 was recovered, along with pseudodisaccharide 5 accounting for 0.33 equiv triflate 3.
The ketone (860 mg, 2.32 mmol) was dissolved in THF
(23 mL) and MeOH (3 mL) and cooled to ꢀ30 °C under
N2. Sodium borohydride (133 mg, 3.5 mmol) was added.
Further NaBH4 (10 mg, 0.26 mmol) was added, and after
a further 45 min, TLC (3:1 pentane–EtOAc) showed
complete conversion into major (Rf 0.3) and minor (Rf
0.5) products, and the absence of ketone (Rf 0.6). The
reaction mixture was poured into a mixture of NH4Cl
(saturated aqueous) and extracted with EtOAc. The
organic extracts were dried (Na2SO4), filtered and con-
centrated under diminished pressure. The residue was
purified by flash column chromatography (6:1 pentane–
EtOAc) to give 10 (174 mg, 20%) and 9 (450 mg, 52%).
3.3. General procedure for the synthesis of
pseudodisaccharides
Alcohol (0.05–0.78 mmol) 7–12 and allose triflate 3 (1.5–
2.0 equiv) were dissolved in DMF (2.0 mL) at room
temperature under nitrogen. NaH (2.0 equiv) was added

2098
T. Akhtar et al. / Carbohydrate Research 343 (2008) 2094–2100
and the mixture stirred at room temperature. The reac-
tion mixture turned brown within 10 min. Further tri-
flate 3 was added if necessary. After TLC showed the
formation of a major product (30 min–4 h 30 min), the
reaction mixture was poured into brine (50 mL),
extracted with ether (2 ꢁ 75 mL), dried (MgSO4) and
concentrated under diminished pressure. The crude
product was purified by flash column chromatography.
H-3II, H-4II, H-5I), 4.26 (1H, d, J1,2 3.6 Hz, H-2II),
I
4.29 (1H, dd, J5,6 5.2 Hz, H-60 ), 4.50 (1H, aq, J
0
6.1 Hz, H-5II), 4.57, 4.72 (1H, ABq, JAB 12.0 Hz,
PhCH2), 4.68 (1H, s, H-1I), 5.54 (1H, s, PhCH), 5.80
(1H, d, H-1II), 7.26–7.41 (8H, m, Ar-H), 7.46–7.49
(2H, m, Ar-H). 13C NMR (100.6 MHz, CDCl3): d
25.2, 26.5, 26.7, 27.0 (4 ꢁ q, 2 ꢁ C(CH3)2), 55.2 (q,
OCH3), 58.4 (d, C-5I), 66.7 (t, C-6II), 69.4 (t, C-6I),
72.9 (t, PhCH2), 73.0 (d, C-5II), 73.5, 76.3 (2 ꢁ d, C-3I,
C-4I) 77.0 (d, C-2I), 81.5, 82.5 (2 ꢁ d, C-3II, C-4II),
82.7 (d, C-2II), 99.7 (d, C-1I), 102.4 (d, PhCH), 105.3
(d, C-1II), 108.7, 111.7 (2 ꢁ s, C(CH3)2), 126.3, 128.1,
128.3, 128.4, 128.7, 129.1 (6 ꢁ d, Ar-CH) 137.3, 137.8
(2 ꢁ s Ar-C); ESIMS: m/z 637 (100%, [M+Na]+); HRE-
SIMS (m/z): calcd for C33H42O11Na: 637.2619. Found
637.2626.
3.4. 3-O-(1,2:5,6-Di-O-isopropylidene-3-deoxy-a-D-allo-
furanos-3-yl)-1,2:5,6-di-O-isopropylidene-a-D-glucofura-
nose (4)
24
Rf 0.3 (3:1 pentane–EtOAc ); ½aꢂD +50.1 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3): d 1.32, 1.33, 1.35, 1.36,
1.41, 1.44, 1.49, 1.54 (24H, 8 ꢁ s, 4 ꢁ C(CH3)2), 3.89
(1H, dd, J2,3 4.7 Hz, J3,4 8.4 Hz, H-3I), 3.92–4.11 (7H,
I
II
m, H-4I, H-6I, H-60 , H-3II, H-4II, H-6II, H-60 ), 4.28
(1H, dat, J 4.0 Hz, J 6.8 Hz, H-5I), 4.37 (1H, dat, J
5.9 Hz, J 7.5 Hz, H-5II), 4.64 (1H, at, J 4.2 Hz, H-2I),
4.70 (1H, d, J1,2 3.5 Hz, H-2II), 5.79 (1H, d, J1,2
3.9 Hz, H-1I), 5.87 (1H, d, H-1II). 13C NMR
(100.6 MHz, CDCl3): d 25.4, 25.4, 26.4, 26.4, 26.8,
27.0, 27.0, 27.0 (8 ꢁ q, 4 ꢁ C(CH3)2), 65.2, 67.6 (2 ꢁ t,
C-6I, C-6II), 72.4 (d, C-5II), 75.4 (d, C-5I), 77.9 (d,
C-2I), 78.6, 80.3, 81.4, 82.5 (4 ꢁ d, C-4II, C-3II, C-4I,
C-3I), 83.5 (d, C-2II), 104.4 (d, C-1I), 105.4 (C-1II),
109.2, 109.7, 111.9, 113.1 (4 ꢁ s, 4 ꢁ C(CH3)2); ESIMS:
m/z 525 (100%, [M+Na]+); HRESIMS (m/z): calcd for
C24H38O11Na: 525.2306. Found 525.2339.
3.7. 3-O-(Methyl 4,6-O-benzylidene-2-O-benzyl-3-deoxy-
a-D-mannopyranosid-3-yl)-1,2:5,6-di-O-isopropylidene-a-
D-glucofuranose (14)
23
Rf 0.6 (3:1 pentane–EtOAc); ½aꢂ ꢀ4.9 (c 1, CHCl3); 1H
D
NMR (400 MHz, CDCl3): d 1.17, 1.21, 1.40, 1.47 (12H,
4 ꢁ s, 2 ꢁ C(CH3)2), 3.37 (3H, s, OCH3), 3.77 (1H, dat,
J5,6 4.6 Hz, J 10.2 Hz, H-5I), 3.85 (1H, dd, J1,2 1.7 Hz,
0
J2,3 3.2 Hz, H-2I), 3.86 (1H, at, J 10.2 Hz, H-6I), 3.96
(1H, dd, J5,6 5.3 Hz, J6,6 8.6 Hz, H-6II), 3.98 (1H, dd,
0
J3,4 3.2 Hz, J4,5 10.1 Hz, H-4II), 4.02 (1H, dd, J3,4
II
8.8 Hz, H-3I), 4.07 (1H, dd, J5,6 6.0 Hz, H-60 ), 4.10
0
(1H, dd, J4,5 10.1 Hz, H-4I), 4.15 (1H, d, J2,3 3.0 Hz,
H-3II), 4.23–4.28 (2H, m, H-5II, H-60 ), 4.64 (1H, d,
I
3.5. Bis(1,2:5,6-di-O-isopropylidene-3-deoxy-a-D-gluco-
furanos-3-yl) ether (5)
J1,2 1.6 Hz, H-1I), 4.71, 4.83 (1H, ABq JAB 12.0 Hz,
PhCH2), 4.82 (1H, d, J1,2 3.6 Hz, H-2II), 5.62 (1H, s,
PhCH), 5.75 (1H, d, H-1II), 7.25–7.40 (8H, m, Ar-H),
7.49–7.53 (2H, m, Ar-H). 13C NMR (100.6 MHz,
CDCl3): d 25.4, 26.0, 26.9, 27.0 (4 ꢁ q, 2 ꢁ C(CH3)2),
55.0 (q, OCH3), 64.4 (d, C-5I), 68.0 (t, C-6II), 68.9 (t,
C-6I), 72.4 (d, C-5II), 73.8 (t, PhCH2), 77.3 (d, C-2I)
77.8 (d, C-4II), 78.2 (d, C-4I), 81.6 (d, C-3I), 83.5 (d,
C-2II), 83.6 (d, C-3II), 100.7 (d, C-1I), 101.6 (d, PhCH),
105.4 (d, C-1II), 109.3, 111.7 (2 ꢁ s, 2 ꢁ C(CH3)2),
126.0, 127.9, 128.1, 128.5, 129.0 (5 ꢁ d, Ar-CH), 137.6,
138.3 (2 ꢁ s, Ar-C); ESIMS: m/z 637 (100%,
[M+Na]+); HRESIMS (m/z): calcd for C33H42O11Na:
637.2619. Found 637.2588.
24
Rf 0.6 (3:1 pentane–EtOAc); ½aꢂ ꢀ49.7 (c 1, CHCl3); 1H
D
NMR (400 MHz, CDCl3): d 1.29, 1.32, 1.40, 1.48 (24H,
0
4 ꢁ s, 8 ꢁ CH3), 3.92 (2H, dd, J5,6 5.6 Hz, J6,6 8.6 Hz,
H-6), 4.04–4.09 (6H, m, H-3, H-4, H-60), 4.15 (2H,
atd, J 5.8 Hz, J4,5 7.8 Hz, H-5), 4.65 (2H, d, J1,2
3.6 Hz, H-2), 5.81 (2H, d, H-1). 13C NMR
(100.6 MHz, CDCl3):
d
25.5, 26.3, 26.9, (3 ꢁ q,
4 ꢁ C(CH3)2), 67.8 (t, C-6), 72.4 (d, C-5), 81.1, 81.3
(2 ꢁ d, C-3, C-4), 82.3 (d, C-2), 105.7 (d, C-1), 109.1,
112.1 (2 ꢁ s, 2 ꢁ C(CH3)2); ESIMS: m/z 525 (100%,
[M+Na]+); HRESIMS (m/z): calcd for C24H38O11Na:
525.2306. Found 525.2314.
3.8. 3-O-(Methyl 4,6-O-benzylidene-3-O-benzyl-2-deoxy-
a-D-mannopyranosid-2-yl)-1,2:5,6-di-O-isopropylidene-a-
D-glucofuranose (15)
3.6. 3-O-(Methyl 4,6-O-benzylidene-2-O-benzyl-3-deoxy-
a-D-altropyranosid-3-yl)-1,2:5,6-di-O-isopropylidene-a-
D-glucofuranose (13)
24
Rf 0.5 (3:1 pentane–EtOAc); ½aꢂ ꢀ19.0 (c 1, CHCl3); 1H
D
24
Rf 0.4 (3:1 pentane–EtOAc); ½aꢂ +28.8 (c 1, CHCl3); 1H
NMR (400 MHz, CDCl3): d 1.17, 1.35, 1.42, 1.46 (12H,
4 ꢁ s, 2 ꢁ C(CH3)2), 3.35 (3H, s, OCH3), 3.77 (1H, dat,
D
NMR (400 MHz, CDCl3): d 1.23, 1.29, 1.40, 1.45 (12H,
4 ꢁ s, 4 ꢁ CH3), 3.37 (3H, s, OCH3), 3.58 (1H, d, J2,3
2.6 Hz, H-2I), 3.76 (1H, at, J 10.1 Hz, H-6I), 3.96–4.08
J5,6 4.1 Hz, J 9.6 Hz, H-5I), 3.82 (1H, at, J 9.9 Hz,
0
H-6I), 3.86 (1H, dd, J1,2 1.5 Hz, J2,3 3.2 Hz, H-2I), 3.91
(1H, dd, J3,4 9.8 Hz, H-3I), 3.97 (1H, dd, J5,6 6.2 Hz,
II
(4H, m, H-3I, H-4I, H-6II, H-60 ), 4.15–4.24 (3H, m,

T. Akhtar et al. / Carbohydrate Research 343 (2008) 2094–2100
2099
J6,6 8.4 Hz, H-6II), 4.03 (1H, at, J 9.3 Hz, H-4I), 4.04
done at different / to cover at least half of the Ewald
sphere.
0
(1H, d, J3,4 3.0 Hz, H-3II), 4.09 (1H, dd, J4,5 7.8 Hz,
II
H-4II), 4.15 (1H, dd, J5,6 6.1 Hz, H-60 ), 4.23–4.31
0
I
(2H, m, H-60 , H-5II), 4.70, 4.91 (1H, ABq, JAB
3.11. Structure solution and refinement
11.7 Hz, PhCH2), 4.78 (1H, d, J1,2 1.5 Hz, H-1I), 4.81
(1H, d, J1,2 3.7 Hz, H-2II), 5.62 (1H, s, PhCH), 5.83
(1H, d, H-1II), 7.24–7.39 (8H, m, Ar-H), 7.48–7.50
(2H, m, Ar-H). 13C NMR (100.6 MHz, CDCl3): d
25.6, 26.3, 26.9, 27.0 (4 ꢁ q, 2 ꢁ C(CH3)2), 55.0 (q,
OCH3), 63.9 (d, C-5I), 67.8 (t, C-6II), 69.0 (t, C-6I),
72.9 (d, C-5II), 73.7 (t, PhCH2), 75.7 (d, C-3I), 79.6 (d,
C-4I), 80.2 (d, C-2I), 81.4 (d, C-4II), 83.5 (d, C-2II),
85.4 (C-3II), 100.6 (d, C-1I), 101.6 (d, PhCH), 105.6 (d,
C-1II), 109.1, 111.7 (2 ꢁ s, 2 ꢁ C(CH3)2), 126.2, 127.7,
127.7, 128.3, 128.5, 129.0 (6 ꢁ d, Ar-CH), 137.7, 138.6
(2 ꢁ s, Ar-C); ESIMS: m/z 637 (100%, [M+Na]+);
HRESIMS (m/z): calcd for C33H42O11Na: 637.2619.
Found 637.2641.
The structures were solved by direct methods using
SHELXS 97 giving electron density maps where most of
the non-hydrogen atoms could be resolved. The rest of
the non-hydrogen atoms were located from different elec-
tron density maps and the structure model was refined
with full matrix least square calculations on F2 using
the program SHELXL 97. All non-hydrogen atoms were
refined with anisotropic displacement parameters and
the hydrogens, which were placed at geometrically calcu-
lated positions and let to ride on the atoms they were
bonded to, were given isotropic displacement parameters
calculated as n ꢃ Ueq. for the non-hydrogen atoms with
n = 1.5 for methyl hydrogens (–CH3) and n = 1.2 for
methylenic (–CH2–) and methinic (CH) hydrogens.
The ring O4I–C1I–C2I–C3I–C4I can be described by
3.9. 3-O-(2,3,4,6-Tetra-O-benzyl-5a-carba-b-D-glucopyr-
anosyl)-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (16)
˚
the Cremer–Pople parameters: Q(2) = 0.395(3) A and
/(2) = 301.2(4)° and the ring O4II–C1II–C2II–C3II–C4II
23
1
˚
Rf 0.9 (3:1 pentane–EtOAc); ½aꢂD +9.3 (c 1, CHCl3); H
NMR (400 MHz, CDCl3): d 1.16, 1.33, 1.41, 1.44 (12H,
4 ꢁ s, 2 ꢁ C(CH3)2), 1.39 (1H, m, H-5aI), 1.66 (1H, m,
can be described by the parameters Q(2) = 0.327(3) A
and /(2) = 300.5(4)°. Both sugar rings can be described
with the T furanose pucker descriptor.
H-5I), 2.15 (1H, dat, J 4.0 Hz, J5a,5a 13.6 Hz, H-5a0),
0
3.37 (1H, at, J 9.0 Hz, H-2I or H-3I), 3.43–3.54 (4H, m,
H-1I, H-4I, H-6I, H-2I or H-3I), 3.57 (1H, dd, J5,6
0
Acknowledgements
II
5.3 Hz, J6,6 8.9 Hz, H-60), 3.95–3.98 (2H, m, H-3 ,
0
II
H-6II), 4.08 (1H, dd, J5,6 6.2 Hz, J6,6 8.4 Hz, H-60 ),
4.14 (1H, dd, J3,4 3.2 Hz, J4,5 7.0 Hz, H-4II), 4.29 (1H,
aq, J 6.4 Hz, H-5II), 4.45 (2H, s, PhCH2), 4.51 (1H, d,
J 10.8 Hz, PhCHH0), 4.57 (1H, d, J1,2 3.8 Hz, H-2II),
4.72 (1H, d, J 11.2 Hz, PhCHH0), 4.84–4.92 (4H, m,
PhCH2, 2 ꢁ PhCHH0), 5.60 (1H, d, H-1II), 7.18–7.34
(20H, m, Ar-H); 13C NMR (100.6 MHz, CDCl3): d
25.6, 26.0, 26.8, 26.9 (4 ꢁ q, 2 ꢁ C(CH3)2), 30.0 (t,
C-5a), 39.0 (d, C-5), 67.3 (t, C-6II), 70.1 (t, C-6I), 72.9
(d, C-5II), 73.4, 75.4, 75.7, 75.9 (4 ꢁ t, 4 ꢁ PhCH2),
79.9, 80.9, 81.0, 81.4, 82.9, 85.0, 86.6 (7 ꢁ d, C-1I, C-2I,
C-3I, C-4I, C-2II, C-3II, C-4II), 105.5 (d, C-5II), 108.9,
111.6 (2 ꢁ s, 2 ꢁ C(CH3)2), 127.4, 127.7, 127.7, 127.8,
127.8, 127.9, 128.2, 128.5, 128.5, 128.6 (10 ꢁ d, Ar-CH),
138.5, 138.6, 138.8 (3 ꢁ s, 4 ꢁ Ar-C); ESIMS: m/z 803
(100%, [M + Na]+), 819 (7%, [M+K]+); HRESIMS (m/
z): calcd for C47H56O10Na: 803.3766. Found 803.3741.
0
0
The authors would like to thank the Swedish Research
˚
Council (Vetenskapsradet) and Carl Tryggers Stiftelse
fo¨r Vetenskaplig Forskning for financial support. T.A.
is grateful to the Higher Education Commission of Paki-
stan for a fellowship under the international research
support initiative program.
Supplementary data
Complete crystallographic data for the structural analy-
sis have been deposited with the Cambridge Crystallo-
graphic Data Centre, CCDC no. 662554. Copies of
this information may be obtained free of charge from
the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK. (fax: +44-
1223-336033, e-mail: deposit@ccdc.cam.ac.uk or via:
www.ccdc.cam.ac.uk). Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.carres.2008.01.013.
3.10. Data collection and measurement
Single crystal X-ray diffraction patterns were recorded
with an Oxford Diffraction Xcalibur-II kappa diffrac-
tometer equipped with an Enhance-III closed tube
References
˚
Mo-radiation source (k = 0.71073 A) X-ray source.
The sample–detector distance was 50 mm and standard
data collection routines delivered with the diffractometer
was used for the data collection. Several x scans were
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