Expeditious synthesis of enantiopure symmetrical macroheterocycles by ring-closing metathesis of ether and tether-linked 1,2-O- isopropylidenefuranosides

Article abstract of DOI:10.1016/j.carres.2004.12.024

Bis-olefinic symmetrical carbohydrate derivatives were prepared by joining two 1,2-O-isopropylidenefuranose units either through an ether linkage or by a tether of variable size. The ring-closing metathesis (RCM) of these substrates using Grubbs' first-ge

Full text of DOI:10.1016/j.carres.2004.12.024

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 567–578
Expeditious synthesis of enantiopure symmetrical
macroheterocycles by ring-closing metathesis of ether and
tether-linked 1,2-O-isopropylidenefuranosides
Goutam Biswas, Jhimli Sengupta, Madhumita Nath and Anup Bhattacharjya*
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700032, India
Received 27 September 2004; accepted 30 December 2004
Available online 1 February 2005
Abstract—Bis-olefinic symmetrical carbohydrate derivatives were prepared by joining two 1,2-O-isopropylidenefuranose units either
through an ether linkage or by a tether of variable size. The ring-closing metathesis (RCM) of these substrates using GrubbsÕ first-
generation catalyst led to the synthesis of enantiopure symmetrical macroheterocycles containing nine- to twenty-five-membered
rings fused to the 1,2-O-isopropylidenefuranose ring.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Synthesis; Enantiopure; Macroheterocycles; Ring-closing metathesis; Tether-linked 1,2-O-isopropylidenefuranosides
1. Introduction
tion of RCM for the synthesis of such systems.20–22 This
is why the development of strategies for the synthesis of
macrocycles remains an ever-important task for syn-
thetic chemists. Particularly important is the construc-
tion of chiral macrocyclic frameworks from chiral
precursors, because chirality has a profound influence
on the biological activity of drugs and related mole-
cules.23 In this context it was of interest to synthesize
macrocyclic structures having two carbohydrate frag-
ments in the periphery so that these molecules will be
useful for conjugation with other biologically important
molecules through glycosylation leading to biologically
relevant materials such as antibacterial agents. Alterna-
tively, conversion of these carbohydrate-derived macro-
cycles to nucleosides having aforementioned biological
importance is a distinct possibility. Moreover, the result-
ing C2-symmetric molecules will be potentially impor-
tant as precursors for novel chiral ligands in
asymmetric catalysis. We report herein a general
strategy for such symmetrical macroheterocycles from
carbohydrate derivatives by RCM using GrubbsÕ first-
generation catalyst 1.24 We envisioned that RCM using
1 can be applied to A, a bis-olefinic ether-linked pseudo-
disaccharide25 or a tether-linked disaccharide deriva-
tive, leading to the formation of an enantiopure chiral
The emergence of ring-closing metathesis (RCM) as a
tool for constructing various sizes of cyclic compounds
has made phenomenal impact on organic synthesis.1–5
The synthesis of otherwise difficultly accessible cyclic
skeletons, including medium and large ring carbocycles
and heterocycles, has been possible with the use of this
reaction.1–10 Application of RCM and cross metathesis
has also been noteworthy in the carbohydrate area.11–16
Macrocyclic structures are frequently encountered in
naturally occurring compounds. RCM has proved to
be an efficient method for the synthesis of carbohy-
drate-based macrocyclic natural products such as
woodrosin I17 and tricolorin G18 as well as non-carbo-
hydrate macrocyclic compounds.5 The use of macro-
cyclic skeletons as hosts in the recognition of ionic and
neutral molecules is well known.19 Recently the impor-
tance of macrocyclic structures, including nucleosides
as antibacterial agents based on novel targets and as
gene and drug-delivery systems, has led to the applica-
*
Corresponding author. Tel.: +91 33 2472 8697; fax: +91 33 2472
3967; e-mail: anupbh@hotmail.com
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.12.024

568
G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
PCy3
Ru
alkene units. The synthesis of the pseudodisaccharide
Cl
Cl
derivative, bis(3-O-allyl-5-deoxy-1,2-O-isopropylidene-
a-D-xylofuranos-5-yl)ether (5), was achieved by heating
the known31 alcohol 3 with its mesyl derivative 4 in
aqueous sodium hydroxide in the presence of tetrabutyl-
ammonium bromide (Scheme 2). It should be mentioned
that although 5,50-linked pseudodisaccharide derivatives
have been made25 by using the corresponding triflates
instead of the less sensitive mesylates, the present
method utilizing the latter derivatives in aqueous
medium provides an operationally simpler method for
the synthesis of ether-linked pseudodisaccharides.
Ph
PCy3
1
RCM
X
X
A
B
X = O or tether
monosaccharide
Scheme 1. The strategy for the synthesis of chiral symmetrical
macroheterocycles.
The tether-linked symmetrical substrates were pre-
pared by the coupling of two carbohydrate units by
reaction with a bifunctional unit and carrying out fur-
ther transformations to provide the bis-olefinic sub-
strates. The smallest tether used in this work was a
methylene unit, which was introduced by stirring the
carbohydrate derivative in 50% aq sodium hydroxide–
dichloromethane in the presence of tetrabutylammo-
nium bromide, and bis(1,2:5,6-di-O-isopropylidene-a-
D-glucofuranos-3-O-yl)methane (6), bis(3-O-allyl-1,2-
O-isopropylidene-a-D-xylofuranos-5-O-yl)methane (10)
and bis(1,2:5,6-di-O-isopropylidene-3-deoxy-3-C-allyl-
a-D-glucofuranos-3-O-yl)methane (13) were prepared
by applying this procedure (Scheme 3). The RCM sub-
strate bis(5-O-allyl-1,2-O-isopropylidene-a-D-xylofur-
anos-3-O-yl)methane (9) was prepared by phase-
transfer catalyst-mediated allylation32 of 8, which was
obtained from 6 by sequential deprotection to 7, vicinal
diol cleavage with sodium metaperiodate and reduction
with sodium borohydride (Scheme 3). Intermediate 7
was converted to the bis-vinyl derivative, bis(5,6-dide-
oxy-5,6-didehydro-1,2-O-isopropylidene-a-D-xylohexo-
furanos-3-O-yl)methane (11) by treatment with
triphenylphosphine, iodine and imidazole.33
macrocycle B (Scheme 1). Recently the 1,2-O-isopropyl-
idenefuranose scaffold, readily available from the
well-known 1,2:5,6-di-O-isopropylidene-a-D-glucofura-
nose (2) (Scheme 2), has provided the template for a
variety of reactions resulting in the synthesis of diverse
types of enantiomerically pure skeletons.26–28 The use
of this carbohydrate scaffold will enable the future con-
jugation with other molecules via glycosylation at the
anomeric centre. Another advantage of the occurrence
of the O-isopropylidene protected furanoside rings in
the macrocycles B is the future conversion of this ring
system to a nucleoside. As an example, a sequence of
reactions involving removal of the O-isopropylidene
group, acetylation of the resulting diol intermediate
and glycosylation of the diacetate with a base following
well-established procedures has been frequently used to
prepare nucleosides from 1,2-O-isopropylidene pro-
tected furanosides.29,30
2. Results and discussion
The symmetrical substrates required for this work were
prepared from known carbohydrate derivatives. The
general strategy for the synthesis of these substrates
involved the coupling of two carbohydrate units either
by an ether linkage or by a tether. The intermediates
prepared by the former method represent examples of
ether-linked pseudodisaccharide derivatives bearing
The substrates incorporating longer tethers were
prepared according to the process shown in Scheme 4.
Alkylation of the known carbohydrate derivative
14 with 1,3-dibromopropane afforded the propylene
tethered N,N0-di-p-toluenesulfonyl-N,N0-bis(1,2:5,6-di-
O-isopropylidene-3-deoxy-a-D-glucofuranos-3-yl)-1,3-
O
O
Me
Me
OH
O
O
O
Ref. 31
Me
O
O
H
Me
Me
O
HO
O
a
O
O
Me
O
O
O
Me
Me
Me
Me
2
3
b
O
O
O
O
OMs
O
O
5
O
Me
Me
O
4
Scheme 2. Preparation of the pseudodisaccharide substrate 5. Reagents and conditions: (a) CH3SO2Cl, Et3N, CH2Cl2, 25 ꢁC, 2 h, 95%; (b) 50%
aq NaOH, Bu4NBr, 70 ꢁC, 72 h, 71%.

G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
569
readily available 1,3-di(2-bromomethylphenoxy)pro-
pane, in the presence of NaH and then converted to
1,3-bis[2-(5-O-allyl-1,2-O-isopropylidene-a-D-xylofur-
anos-3-O-yl)methylphenoxy]propane (22) by the usual
method (Scheme 4). The vinyl compound 1,3-bis-
[2-(5,6-didehydro-5,6-dideoxy-1,2-O-isopropylidene-a-D-
xylohexofuranos-3-O-yl)methylphenoxy]propane (26)
was prepared by alkylating 5,6-didehydro-5,6-dideoxy-
1,2-O-isopropylidene-a-D-xylohexofuranose (25) with
the aforementioned bis-bromomethylphenoxypropane
(Scheme 4).
Me
O
O
H
Me
O
Me Me
O
H
a
O
2
O
O
O
O
O
6
O
O
Me
Me
Me
Me
b
OH
O
HO
O
HO
HO
H
OH
OH
c
O
O
H
O
The general procedure for carrying out the RCM
reactions involved stirring a 10ꢀ3 M solution of the sub-
strate in CH2Cl2 either at 25 ꢁC or under reflux for 10–
36 h in the presence of 10–50 mol % of the catalyst. The
results of the RCM reactions are presented in Table 1.
Structures of the products are shown in Figure 1.
The RCM of the bis-olefinic 5,50-linked pseudodisac-
charide derivative 5 furnished an inseparable (3:7) mix-
ture of the E and Z isomers of the 13-membered
oxygen heterocycle, (1R,5R,7R,8R,9S,16S,17R,18R)-
(7,8:17,18-diisopropylidenedioxy)-3,6,10,15,19-pentaoxa-
tricyclo[14.3.0.05,9]nonadec-12-ene (27), in 43% yield.
Substantial amount of the starting material was recov-
ered from the reaction, and employment of higher tem-
perature or increased catalyst concentration did not
improve the yield. The occurrence of the (M+H) peak
at m/z 415 in the FAB mass spectrum of the mixture
indicated the formation of the heterocycle 27. The pres-
ence of two geometrical isomers in the mixture was
O
O
O
O
O
8
O
O
O
Me
O
Me
Me
Me
O
7
O
d
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
O
9
Me
Me
Me
Me
O
O
O
O
a
O
O
Me
Me
3
Me
Me
O
O
O
O
10
e
O
O
O
O
7
O
1
O
O
Me
apparent from the H NMR spectrum, which exhibited
O
Me
11
Me
two sets of two-proton multiplets at d 6.02 and 5.82
due to the olefinic protons, as well as from the appear-
ance of two peaks at d 130.67 and 130.62 due to the ole-
finic carbon atoms in the 13C NMR spectrum. The C2-
symmetry of the molecules was indicated by the presence
of single sets of peaks due to the symmetry-related pro-
Me
Me
O
O
H
Me
Me
Me
O
O
Me
Me
O
O
O
a
O
H
H
Me
Me
O
O
1
tons and the carbon atoms in the H and 13C NMR
O
O
O
OH
O
spectra. However, on account of the symmetrical nature
of the isomers, the assignment of stereochemistry to the
olefinic bonds of the respective isomers could not be
made on the basis of NMR spectral data. Although
the formation of nine-membered rings by RCM is
well-known8–10,16 attempts to achieve the RCM of 11
in the presence of GrubbsÕ first-generation catalyst 1
did not result in the formation of any nine-membered
ring product. The starting material was recovered
unchanged along with some intractable materials under
various conditions of solvent, temperature, catalyst
concentration or even after using the GrubbsÕ second-
generation catalyst. The reluctance of the formation of
a nine-membered ring by RCM is not unprecedented,16
O
O
O
12
Me
Me
Me
Me
13
Scheme 3. Synthesis of the methylene acetal-tethered substrates 9–11
and 13. Reagents and conditions: (a) CH2Cl2–50% aq NaOH, Bu4NBr,
25 ꢁC, 48 h, 95% (6), 80% (10), 83% (13); (b) 75% aq AcOH, 25 ꢁC,
12 h, 93%; (c) i. NaIO4, MeOH–H2O, 0–25 ꢁC, 2 h; ii. NaBH4, MeOH,
25 ꢁC, 12 h, 76% two steps; (d) allyl bromide, CH2Cl2–50% aq NaOH,
Bu4NBr, 25 ꢁC, 12 h, 91%; (e) imidazole, I2, Ph3P, toluene, reflux, 5 h,
78% (Ref. 33).
diaminopropane (15), which was converted to the bis-
olefinic substrate N,N0-di-p-toluenesulfonyl-N,N0-bis(5-
O-allyl-1,2-O-isopropylidene-3-deoxy-a-D-xylofuranos-3-
yl)-1,3-diaminopropane (18) following the usual protocol
mentioned earlier for the preparation of 9. A longer
tether was used in 1,3-bis[2-(1,2:5,6-di-O-isopropylid-
ene-a-D-glucofuranos-3-O-yl)methylphenoxy]propane
(19), which was prepared from 2 by alkylation with
Salicylaldehyde was treated with 1,3-dibromopropane in the presence
of K2CO3 in methanol under reflux, and the product was reduced
with NaBH4, followed by treatment with PBr3.

570
G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
O
Me
Me
R
R
O
O
O
O
a
O
O
H
Me
Me
NTs TsN
Me
O
O
O
TsHN
Me
O
Me
Me
Me
14
O
O
15: R =
Me
HO
b
16: R =
c
HO
17: R = CH2OH
18: R = CH2OAllyl
d
O
O
e
Me
Me
Me
O
O
2
O
R
O
Me
O
O
O
R
O
b
O
Me
19: R =
Me
HO
O
20: R =
c
HO
21: R = CH2OH
22 :R = CH2OAllyl
d
O
O
O
O
R2
O
O
e
Me
Me
R1O
O
O
Me
Me
Me
Me
O
HO
HO
O
23: R1 = Bz, R2
=
O
O
O
f
26
24: R1 = Bz, R2 = -CH=CH2
25: R1 = H, R2 = -CH=CH2
g
Scheme 4. Preparation of the tethered substrates 18, 22 and 26. Reagents and conditions: (a) (CH2)3Br2, K2CO3, DMF, 80–120 ꢁC, 8 h, 66%; (b) 75%
aq AcOH, 25 ꢁC, 12 h, 85% (16), 93% (20); (c) i. NaIO4, MeOH–H2O, 0–25 ꢁC, 2 h; ii. NaBH4, MeOH, 25 ꢁC, 12 h, 87% (17), 92% (21) two steps; (d)
allyl bromide, CH2Cl2–50% aq NaOH, Bu4NBr, 25 ꢁC, 12 h, 86% (18), 91% (22); (e) 1,3-di(2-bromomethylphenoxy)propane, NaH, THF, reflux, 8 h,
69% (29), 78% (26); (f) imidazole, I2, Ph3P, toluene, reflux, 5 h, 76% (Ref. 33); (g) LiOH, 50% aq MeOH, 25 ꢁC, 12 h, 90%.
and it is probable that a deleterious steric crowding in
the metathesis activation complex due to the particular
environment adjacent to the reacting olefinic moieties
is responsible for the failure of the reaction. In contrast,
the olefinic sites in 13 are relatively free from such
steric congestion, and the RCM in the presence of 1
afforded the bis-spiro nine-membered heterocycle,
(1R,3R,4R,5R,9R,10R,12R,13R)-(3,4:12,13-di-O-isoprop-
ylidenedioxy)-1,10-bis(1,2-isopropylidenedioxyethyl)-
2,6,8,11-tetraoxadispiro[4.3.4.4]heptadec-15-ene (28), in
85% yield. The mass and NMR spectra of 28 were con-
sistent with the structure, and the Z stereochemistry of
the olefin was assigned on the basis of reported exam-
ples.8–10,16 The pentose substrates 9 and 10 have the
positions of the methylene tethers and olefinic moieties
interchanged. It was found that there was no significant
difference in their behaviour towards RCM using 1, and
the 15-membered oxygen heterocycles, (1S,5S,6R,7R,
9R,18R,20R,21R)-(6,7:20,21-diisopropylidenedioxy)-
2,4,8,11,16,19-hexaoxatricyclo[16.3.0.05,9]heneicos-13-
ene (29) and (1R,7R,9R,10R,11S,18S,19R,20R)-(9,10:
19,20-diisopropylidenedioxy)3,5,8,12,17,21-hexaoxatri-
cyclo[16.3.0.07,11]heneicos-14-ene (30), were obtained as
mixtures of E/Z isomers in 90% and 95% yields from
the respective substrates. Hydrogenation of 29 in the
presence of 10% Pd/C in EtOH led to the formation of
the C2-symmetric molecule, (1S,5S,6R,7R,9R,18R,20R,
21R)-(6,7:20,21-diisopropylidenedioxy)-2,4,8,11,16,19-
hexaoxatricyclo[16.3.0.05,9]heneicosane (34), in 98%
yield. The bis-olefinic amino sugar derivative 18 on

G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
571
Table 1. Ring-closing metathesis (RCM) of symmetrical bis-olefinic carbohydrate derivatives
Substrate
Producta
Yield (%)b
Conditions
Substrate concn
(M · 10ꢀ3
Solvent
Catalyst concn
(mol %)
Temperature
(ꢁC)
Reaction
time (h)
)
5
27 (E:Z = 3:7)c
—
43d
—
85
90
95
78
95
70
6
CH2Cl2
10
25
24
11
13
9
6–7
1
CH2Cl2, benzene, toluene
CH2Cl2
CH2Cl2
10–50
25
10
40–110
Reflux
Reflux
25
24–60
36
10
28e
29 (E:Z = 2.3)c
30 (E:Z = 3:7)c
31e
32 (E:Z = 1:2)c
33e
6
10
18
26
22
6
CH2Cl2
CH2Cl2
10
10
24
36
6
25
Reflux
Reflux
6
CH2Cl2
CH2Cl2
12
15
10
10
1
a Structures are shown in Figure 1.
b Yields are for isolated products.
c The ratio of the E and Z isomers was determined by integration of the 1H NMR peaks of the olefinic protons.
d Yield based on 50% recovered 5.
e Single isomer.
RCM using 1 gave the 17-membered diaza-dioxa hetero-
Me
Me
Me
Me
O
O
O
O
cycle, (1S,7S,8R,9R,11S,20S,22R,23R)-8,9:22,23-diiso-
propylidenedioxy-2,6-bis-(p-toluenesulfonyl)-10,13,18,21-
tetraoxa-2,6-diazatricyclo[18.3.0.07,11]tricos-15-ene (31),
as a single stereoisomer in 78% yield as evident from
the 1H and 13C NMR spectra, which exhibited only
one set of peaks for the olefinic protons and carbon
atoms as well as the anomeric protons and carbon
atoms. Unlike the methylene acetal tethered bis-vinyl
substrate 11, which failed to undergo RCM, 26 having
a similar scaffold incorporating a rather longer tether
gave the 19-membered heterocycle, (2R,3R,3a-
S,20aS,21R,22R,23aR,25aR)-2,3:21,22-diisopropylidene-
dioxy-2,3,3a,20a,21,22,23a,25a-octahydrodibenzo[c,j]di-
furo[2,3-n:3,2-r][1,5,9,13]tetraoxacyclononadeca-5a,14a,
20a,24,25a-pentaene (32), as a mixture of E/Z isomers in
95% yield. The appreciably increased size of the ring in
32 helped in offsetting the unfavourable steric crowding
encountered in the attempted RCM of 11. The synthesis
of a larger ring was demonstrated by the RCM of the
tethered substrate 22, leading to the formation of a
single stereoisomer of the twenty-five-membered oxa-
heterocycle, (2S,3S,3aR,20aR,21S,22S,23aS,31aS)-(2,3:
21,22-diisopropylidenedioxy)-2,3,5,3a,20a,21,22,23a-octa-
hydrodibenzo[c,j]difuro[2,3-c:3,2-r][1,5,9,13,17,21]hexa-
oxacyclopentacosa-7a,14a,20a,27,31a-pentaene (33), in
70% yield. The structure was consistent with the mass
and NMRspectra, which alsoexhibited single setsofpeaks
due to the symmetry-related protons and carbon atoms.
GrubbsÕ first-generation catalyst was used for all the
successful RCM reactions throughout this study, and
both the GrubbsÕ first- and second-generation catalysts
O
O
O
O
O
O
Me
Me
Me
Me
H
H
O
O
O
O
O
O
O
O
Me
O
Me
O
Me
O
Me
27
28
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Me
Me
O
Me
O
Me
O
O
Me
O
Me
O
Me
Me
30
29
O
O
O
O
O
O
O
O
O
Me
NTs TsN
O
O
O
Me
Me
O
O
Me
Me
Me
Me
O
O
O
O
Me
31
32
O
O
O
O
Me
Me
O
O
Me
Me
O
O
O
O
O
O
O
O
33
O
O
Figure 1. Structures of the symmetrical products from the ring-closing
metathesis (RCM) of symmetrical, bis-olefinic carbohydrate deriva-
tives 5, 9–11, 13, 18, 22 and 26.
O
O
O
O
Me
O
O
Me
Me
Me
34

572
G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
failed to bring about the RCM of 11. However, it has
been demonstrated that GrubbsÕ second-generation cat-
alyst improved those RCM reactions that proceeded
sluggishly with the first-generation catalyst.5 So, it is ex-
pected that many of the metathesis reactions described
in this work will furnish better results by switching to
GrubbsÕ second-generation and other RCM catalysts.
The macrocycles described above have multiple
heteroatoms in the ring, and hence some of them may
possess crown ether like properties. In a preliminary study,
the ability of 33 to extract sodium or potassium picrate
(d, J 3.6 Hz, 1H), 5.85 (m, 1H), 5.32–5.22 (m, 2H), 4.58
(d, J 3.6 Hz, 1H), 4.51–4.37 (m, 3H), 4.17–4.11 (m, 1H),
4.00–3.94 (m, 2H), 3.07 (s, 3H), 1.50 (s, 3H), 1.33 (s, 3H).
A mixture of the alcohol 3 (0.39 g, 1.68 mmol), the
mesylate 4 (1.04 g, 3.37 mmol) prepared as described
above, Bu4NBr (0.1 g, 0.33 mmol), 50% aq NaOH
(1.6 mL) was stirred at 70 ꢁC for 72 h. The mixture
was then extracted with CH2Cl2, and the combined or-
ganic layers were washed with water and brine. Removal
of the solvent afforded a syrupy liquid that was chro-
matographed using 1:9 EtOAc–petroleum ether as elu-
from aqueous solutions was explored using the recently
34
ent to give 5 (0.55 g, 71%) as a colourless sticky liquid:
25
D
´
reported method of Mlinaric-Majerski and Kragol.
½aꢁ ꢀ54.0 (c 1.07, CHCl3); IR (Neat): 2932, 1647,
1
However, the experiments indicated that 33 was unable
to extract the above metal salts from aqueous solution
with dichloromethane.
1377 cmꢀ1; H NMR: d 5.91 (d, J 3.9 Hz, 2H), 5.89–
5.79 (m, 2H), 5.28 (dd, J 7.8, 1.5 Hz, 2H), 5.19 (dd, J
10.5, 1.5 Hz, 2H), 4.54 (d, J 3.9 Hz, 2H), 4.43–4.35 (m,
2H), 4.15–4.09 (m, 2H), 4.02–3.95 (m, 2H), 3.89 (d, J
3.1 Hz, 2H), 3.79 (dd, J 10.2, 5.4 Hz, 2H), 3.69 (dd, J
10.1, 6.5 Hz, 2H), 1.49 (s, 6H), 1.31 (s, 6H); 13C
NMR: d 133.8 (CH), 117.3 (CH2), 111.3 (q), 104.8
(CH), 82.2 (CH), 81.4 (CH), 79.0 (CH), 70.8 (CH2),
68.8 (CH2), 26.5 (CH3), 26.0 (CH3); FABMS: m/z 465
(M+Na), 443 (M+H), 427 (MꢀMe); Anal. Calcd for
C22H34O9: C, 59.71; H, 7.74. Found: C, 59.48; H, 7.51.
In conclusion, this work described the preparation of
symmetrical bis-olefinic compounds by tethering two
1,2-O-isopropylidenefuranose units and their RCM pro-
viding an expedient strategy for the synthesis of enantio-
pure symmetrical macroheterocycles. These macrocyclic
compounds are expected to be potentially important due
to their amenability to transformations to other biologi-
cally significant materials.
3.3. General procedure for the synthesis of bis(1,2:5,6-di-
O-isopropylidene-a-D-glucofuranos-3-O-yl)methane (6),
bis(3-O-allyl-1,2-O-isopropylidene-a-D-xylofuranos-5-O-
yl)methane (10) and bis(1,2:5,6-di-O-isopropylidene-3-C-
allyl-a-D-glucofuranos-3-O-yl)methane (13)
3. Experimental
3.1. General
Melting points are uncorrected. Unless otherwise men-
tioned 1H and 13C NMR spectra were recorded in
CDCl3 at 300 and 75 MHz, respectively. Assignments
of CH3, CH2, CH and quaternary (q) carbon atoms in
the 13C NMR spectra were based on DEPT analyses.
Reactions were monitored by thin-layer chromatogra-
phy using E. Merck Silica Gel 60 F254 precoated plates
(No 1.05554). Organic extracts were dried over anhy-
drous sodium sulfate. Unless otherwise mentioned, 60–
120 mesh silica gel was used for column chromatogra-
phy. Solvents were distilled and dried prior to use.
Petroleum ether refers to a fraction boiling between 60
and 80 ꢁC.
The general procedure for the above compounds is illus-
trated by the preparation of 6.
A mixture of 1,2:5,6-di-O-isopropylidene-a-D-glucofu-
ranose (2) (5.0 g, 19.2 mmol), CH2Cl2 (20 mL), 50% aq
NaOH (20 mL) and tetrabutylammonium bromide
(0.62 g, 1.9 mmol) was stirred vigorously at 25 ꢁC for
48 h. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined organic
extracts were washed with water, dried and evaporated
to give an oil, which was chromatographed using 1:10
EtOAc–petroleum ether as eluent to give 6 (4.86 g,
25
D
95%) as a colourless thick liquid: ½aꢁ ꢀ22.7 (c 0.98,
1
CHCl3); IR (KBr): 2986, 2935, 1376 cmꢀ1; H NMR: d
3.2. Bis(3-O-allyl-5-deoxy-1,2-O-isopropylidene-a-D-
xylofuranos-5-yl)ether (5)
5.90 (d, J 3.6 Hz, 2H), 4.86 (s, 2H), 4.55 (d, J 3.6 Hz,
2H), 4.34–4.28 (m, 4H), 4.16 (dd, J 7.2, 2.7 Hz, 2H),
4.10 (dd, J 8.7, 6.0 Hz, 2H) 4.00 (dd, J 8.4, 5.7 Hz,
2H), 1.50 (s, 6H), 1.43 (s, 6H), 1.35 (s, 6H), 1.32 (s,
6H); 13C NMR: d 111.8 (q), 108.9 (q), 105.1 (CH), 92.7
(CH2), 82.9 (CH), 80.9 (CH), 78.7 (CH), 72.4 (CH),
67.0 (CH2), 26.7 (CH3), 26.6 (CH3), 26.1 (CH3), 25.2
(CH3); FABMS: m/z 555 (M+Na); Anal. Calcd for
C25H40O12: C, 56.38; H, 7.57. Found: C, 56.42; H, 7.29.
The above procedure was used to prepare the methyl-
ene acetal derivatives 10 and 13 from 3 and 12,31
respectively.
To a solution of 331 (0.60 g, 2.8 mmol) in CH2Cl2 con-
taining Et3N (0.7 mL) at 0 ꢁC was added dropwise with
stirring CH3SO2Cl (0.2 mL). The mixture was then stir-
red at 25 ꢁC for 2 h. Water at 0 ꢁC was added and the
mixture was stirred for 0.5 h. It was diluted with CH2Cl2
and washed with water, satd aq NaHCO3 solution and fi-
nally water. Removal of the solvent from the organic
layer afforded 4 (0.76 g, 95%) as a pale-yellow oil, which
1
was used without further purification, H NMR: d 5.94

G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
573
3.3.1. Compound 10: Colourless viscous liquid: yield
and the mixture was further stirred for 12 h at
25 ꢁC.The mixture was then acidified with 1:1 AcOH–
H2O and extracted with CH2Cl2. Removal of the sol-
25
D
80%; ½aꢁ ꢀ72.0 (c 0.71, CHCl3); IR (Neat): 3081,
1
1644, 1378 cmꢀ1; H NMR: d 5.92 (d, J 3.6 Hz, 2H),
25
D
5.92–5.79 (m, 2H), 5.28 (d, J 16.5 Hz, 2H), 5.20 (d, J
10.2 Hz, 2H), 4.76 (s, 2H), 4.55 (d, J 3.6 Hz, 2H),
4.40–4.35 (m, 2H), 4.12 (dd, J 12.9, 5.1 Hz, 2H), 3.97
(dd, J 13.8, 5.1 Hz, 2H), 3.89 (d, J 2.7 Hz, 2H), 3.86–
3.74 (m, 4H), 1.49 (s, 6H), 1.32 (s, 6H); 13C NMR: d
133.8 (CH), 117.4 (CH2), 111.5 (q), 105.0 (CH), 96.0
(CH2), 82.2 (CH), 81.6 (CH), 78.9 (CH), 70.8 (CH2),
65.5 (CH2), 26.7 (CH3), 26.2 (CH3); ESIMS (positive
ion): m/z 495 (M+Na); Anal. Calcd for C23H36O10: C,
58.46; H, 7.68. Found: C, 58.42; H, 7.52.
vent afforded 8 (1.51 g, 76%) as a viscous liquid: ½aꢁ
ꢀ110.3 (c 0.60, CHCl3); IR (KBr): 3452, 2985,
1
1379 cmꢀ1; H NMR: d 5.91 (d, J 3.6 Hz, 2H), 4.84 (s,
2H), 4.55 (d, J 3.6 Hz, 2H), 4.35–4.29 (m, 2H), 4.27
(d, J 3.3 Hz, 2H), 3.88 (d, J 6.0 Hz, 4H), 2.68 (br m,
2H), 1.51 (s, 6H), 1.33 (s, 6H); 13C NMR: d 111.9 (q),
104.7 (CH), 91.6 (CH2), 82.5 (CH), 79.9 (CH), 78.7
(CH), 59.2 (CH2), 26.6 (CH3), 26.2 (CH3); FABMS:
m/z 415 (M+Na).
A mixture of the above material (3.30 g, 4.60 mmol) in
CH2Cl2 (50 mL), 50% NaOH solution (40 mL), tetra-
butylammonium bromide (0.15 g, 0.46 mmol) and allyl
bromide (1.16 mL, 13.8 mmol) was vigorously stirred
for 12 h at 25 ꢁC. Water (50 mL) was added, and the
mixture was extracted with CH2Cl2. The combined
organic layer was washed with water and dried, and
3.3.2. Compound 13: Colourless syrupy liquid: yield
25
D
83%; ½aꢁ +98.1 (c 1.19, CHCl3); IR (KBr): 3075,
1
2987, 1375 cmꢀ1; H NMR: d 6.06–5.97 (m, 2H), 5.57
(d, J 3.6 Hz, 2H), 5.16–5.09 (m, 4H), 5.09 (s, 2H), 4.45
(d, J 3.6 Hz, 2H), 4.22 (t, J 6.3 Hz, 2H), 4.13–4.02 (m,
4H), 3.88 (t, J 7.3 Hz, 2H), 2.85 (dd, J 14.4, 8.1 Hz,
2H), 2.60 (dd, J 15.0, 6.6 Hz, 2H), 1.56 (s, 6H), 1.40
(s, 6H), 1.33 (s, 6H), 1.31 (s, 6H); 13C NMR: d 133.1
(CH), 118.4 (CH2), 112.1 (q), 109.2 (q), 103.8 (CH),
89.9 (CH2), 84.4 (q), 82.0 (CH), 81.6 (CH), 72.8 (CH),
67.9 (CH2), 37.7 (CH2), 26.8 (CH3), 26.4 (CH3), 26.3
(CH3), 25.4 (CH3); EIMS: m/z 612 (M), 597 (MꢀCH3);
Anal. Calcd for C31H48O12: C, 60.77; H, 7.90. Found: C,
60.80; H, 7.92.
the solvent was removed under reduced pressure to af-
ford 9 (3.40 g, 91%) as a colourless syrupy liquid: ½aꢁ
25
D
ꢀ24.0 (c 0.77, CHCl3); IR (KBr): 3082, 2985,
1
1375 cmꢀ1; H NMR: d 5.91 (d, J 3.6 Hz, 2H), 5.97–
5.84 (m, 2H), 5.28 (dd, J 17.1, 1.5 Hz, 2H), 5.19 (dd, J
10.2, 1.2 Hz, 2H), 4.78 (s, 2H), 4.56 (d, J 3.6 Hz, 2H),
4.41–4.36 (m, 2H), 4.18 (d, J 3.3 Hz, 2H), 4.08–3.95
(m, 4H), 3.72–3.61 (m, 4H), 1.50 (s, 6H), 1.32 (s, 6H);
13C NMR: d 134.2 (CH), 117.2 (CH2), 111.5 (q), 104.7
(CH), 92.2 (CH2), 82.3 (CH), 78.6 (CH), 78.5 (CH),
72.2 (CH2), 66.9 (CH2), 26.5 (CH3), 26.0 (CH3);
FABMS: m/z 495 (M+Na); Anal. Calcd for
C23H36O10: C, 58.46; H, 7.68. Found: C, 58.32; H, 7.41.
3.4. Bis(5-O-allyl-1,2-O-isopropylidene-a-D-xylofuranos-
3-O-yl)methane (9)
A solution of 6 (4.0 g, 8.84 mmol) in aq AcOH (75% v/v,
20 mL) was stirred for 12 h at 25 ꢁC. The mixture was
then concentrated, and the residue was repeatedly
3.5. Bis(5,6-didehydro-5,6-dideoxy-1,2-O-isopropylidene-
a-D-xylohexofuranos-3-O-yl)methane (11)
coevaporated with toluene (3 · 40 mL) yielding
7
25
(3.16 g, 93%) as a colourless liquid: ½aꢁ ꢀ106.1 (c
To a solution of 7 (0.76 g, 1.40 mmol) in toluene
(10 mL), imidazole (0.80 g, 11.2 mmol) and triphenyl
phosphine (2.93 g, 11.2 mmol) were added, and the mix-
ture was heated under reflux. At the initiation of reflux,
iodine (2.84 g, 11.2 mmol) was added in portions over a
period of 1 h. After completion of addition, reflux was
continued for 5 h. The solution was then cooled and
transferred to a separatory funnel. The organic layer
was separated and washed successively with satd sodium
thiosulfate solution (30 mL), followed by 1 M NaOH
solution (10 mL) and water (3 · 100 mL), respectively.
Removal of the solvent gave a syrupy material that
was chromatographed using 1:13 EtOAc–petroleum
D
1
1.23, CHCl3); IR (KBr): 3434, 1382 cmꢀ1; H NMR: d
5.88 (d, J 3.6 Hz, 2H), 4.90 (s, 2H), 4.57 (br m, 2H),
4.51 (d, J 3.6 Hz, 2H), 4.36 (d, J 2.1 Hz, 2H), 4.11 (dd,
J 9.0, 2.4 Hz, 2H), 3.99 (m, 2H), 3.84 (br d, J 10.1 Hz,
2H), 3.69 (dd, J 11.3, 5.5 Hz, 2H), 3.57 (br m, 2H),
1.50 (s, 6H), 1.31 (s, 6H); 13C NMR: d 111.8 (q), 104.8
(CH), 91.7 (CH2), 82.0 (CH), 79.5 (CH), 78.6 (CH),
68.0 (CH), 63.9 (CH2), 26.4 (CH3), 26.0 (CH3); FABMS:
m/z 475 (M+Na), 453 (M+H).
To a solution of this material (2.30 g, 5.08 mmol) in
MeOH (40 mL) was added dropwise with stirring a
solution of NaIO4 (3.26 g, 15.26 mmol) in water
(10 mL) at 0 ꢁC. Stirring was continued at 25 ꢁC for
2 h. The mixture was filtered, and the filtrate was con-
centrated under reduced pressure. The residue was
extracted with CH2Cl2 and dried, and removal of the
solvent afforded a syrupy material that was dissolved
in methanol (10 mL) and cooled to 0 ꢁC. To this solu-
tion NaBH4 (0.52 g) was added in portions with stirring,
ether as eluent to give 11 (0.52 g, 78%) as a viscous li-
25
D
quid: ½aꢁ ꢀ56.9 (c 1.30, CHCl3); IR (KBr): 3083,
1
2987, 1376 cmꢀ1; H NMR: d 5.94 (d, J 3.6 Hz, 2H),
5.92–5.82 (m, 2H), 5.42 (d, J 17.4 Hz, 2H), 5.30 (d, J
10.5 Hz, 2H), 4.73 (s, 2H), 4.64–4.62 (m, 2H), 4.57 (d,
J 3.6 Hz, 2H), 4.13 (d, J 3.0 Hz, 2H), 1.52 (s, 6H),
1.32 (s, 6H); 13C NMR: d 131.7 (CH), 119.1(CH2),

574
G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
111.5 (q), 104.5 (CH), 92.3 (CH2), 82.8 (CH), 80.9 (CH),
80.4 (CH), 26.5 (CH3), 26.0 (CH3); FABMS: m/z 407
(M+Na), 385 (M+H); Anal. Calcd for C19H28O8: C,
59.36; H, 7.34. Found: C, 59.60; H, 7.13.
J 3.6 Hz, 2H), 4.49 (d, J 3.3 Hz, 2H), 4.35–4.25 (m,
4H), 3.72 (br s, 2H), 3.63 (br m, 2H), 3.26 (m, 2H),
3.04 (m, 2H), 2.46 (s, 6H), 2.08 (m, 2H), 1.49 (s, 6H),
1.25 (s, 6H); 13C NMR: d 144.2 (q), 136.2 (q), 130.1
(CH), 127.1 (CH), 111.6 (q), 104.4 (CH), 83.3 (CH),
79.8 (CH), 64.1 (CH), 59.8 (CH2), 45.1 (CH2), 31.8
(CH2), 26.3 (CH3), 25.9 (CH3), 21.6 (CH3); FABMS:
m/z 750 (M+Na+H).
3.6. N,N0-Di-p-toluenesulfonyl-N,N0-bis(3-deoxy-1,2:5,6-
di-O-isopropylidene-a-D-glucofuranos-3-yl)-1,3-diamino-
propane (15)
Allylation of the above material with allyl bromide
following the procedure described for the conversion
of 8 to 9 yielded 18 (0.29 g, 86%) as a syrupy liquid:
A mixture of 1435 (1.0 g, 2.4 mmol), K2CO3 (0.69 g) and
DMF (5 mL) was heated at 80 ꢁC for 1 h and to it was
added 1,3-dibromopropane (0.25 mL), and the mixture
was stirred at 120 ꢁC for 8 h. It was diluted with water
(30 mL) and extracted with CH2Cl2. The combined or-
ganic layer was washed with water and brine and dried.
Removal of the solvent afforded a syrupy material that
25
½aꢁ ꢀ12.2 (c 0.69, CHCl3); IR (KBr): 2986, 1645,
D
1
1598, 1341 cmꢀ1; H NMR: d 7.72 (d, J 7.4 Hz, 4H),
7.34 (d, J 7.2 Hz, 4H), 5.93 (d, J 3.6 Hz, 2H), 5.88–
5.77 (m, 2H), 5.22 (d, J 17.6 Hz, 2H), 5.17 (d, J
11.3 Hz, 2H), 4.53 (d, J 3.0 Hz, 2H), 4.38–4.31 (m,
4H), 3.88 (m, 4H), 3.44 (dd, J 10.6, 6.8 Hz, 2H), 3.29
(dd, J 10.3, 3.4 Hz, 2H), 3.20 (m, 2H), 3.02 (m, 2H),
2.44 (s, 6H), 2.00 (m, 2H), 1.49 (s, 6H), 1.27 (s,
6H); 13C NMR: 143.8 (q), 136.9 (q), 134.2 (CH),
129.8 (CH), 127.2 (CH), 117.4 (q), 111.3 (CH2), 104.5
(CH), 83.6 (CH), 78.6 (CH), 72.3 (CH2), 67.6 (CH2),
64.5 (CH), 44.9 (CH2), 31.5 (CH2), 26.3 (CH3),
25.8 (CH3), 21.5 (CH3); FABMS: m/z 829 (M+Na),
807 (M+H); Anal. Calcd for C39H54N2O12S2: C,
58.05; H, 6.74; N, 3.47; Found: C, 58.31; H, 6.53; N,
3.68.
was chromatographed using 1:10 EtOAc–petroleum
25
ether as eluent to give 15 (0.66 g, 66%) as a foam: ½aꢁ
D
ꢀ22.4 (c 0.52, CHCl3); IR (KBr): 2987, 2938, 1598,
1
1456, 1379 cmꢀ1; H NMR: d 7.75 (d, J 8.2 Hz, 4H),
7.29 (d, J 8.0 Hz, 4H), 6.02 (d, J 3.5 Hz, 2H), 4.86 (br
s, 2H), 4.13 (br s, 2H), 3.98 (dd, J 9.1, 4.2 Hz, 2H),
3.86 (d, J 4.5 Hz, 4H), 3.66 (br s, 2H), 3.36 (m, 2H),
3.16 (m, 2H), 2.43 (s, 6H), 2.07 (m, 2H), 1.49 (s, 6H),
1.30 (s, 12H), 1.15 (s, 6H); 13C NMR: d 143.6 (q),
137.1 (q), 129.4 (CH), 127.8 (CH), 111.1 (q), 109.5 (q),
105.1 (CH), 84.3 (CH), 80.3 (CH), 71.7 (CH), 67.6
(CH), 65.5 (CH2), 61.3 (CH2), 46.2 (CH2), 26.6 (CH3),
26.3 (CH3), 25.8 (CH3), 25.0 (CH3), 21.5 (CH3);
FABMS: m/z 889 (M+Na), 867 (M+H); Anal. Calcd
for C41H58N2O14S2: C, 56.80; H, 6.74; N, 3.23. Found:
C, 57.06; H, 6.53; N, 3.50.
3.8. 1,3-Bis[2-(1,2:5,6-di-O-isopropylidene-a-D-glucofur-
anos-3-O-yl)methylphenoxy]propane (19)
To a suspension of NaH (0.24 g, 10 mmol) in THF
(50 mL) cooled to 0 ꢁC was added a solution of 2
(2.0 g, 7.7 mmol) with stirring, followed by addition
3.7. N,N0-Di-p-toluenesulfonyl-N,N0-bis(5-O-allyl-3-
deoxy-1,2-O-isopropylidene-a-D-xylofuranos-3-yl)-1,3-
diaminopropane (18)
of
1,3-di(2-bromomethylphenoxy)propane
(1.60 g,
3.85 mmol) at 0 ꢁC. The mixture was then heated under
reflux for 8 h. Excess NaH was destroyed by careful
addition of ice, and the THF was removed under re-
duced pressure. The residue was extracted with
CH2Cl2, washed with H2O and dried. Removal of the
solvent yielded a colourless syrup that was chromato-
The compound 15 (1.04 g, 1.2 mmol) was subjected to
the same procedure as described for the conversion of
25
D
6 to 7 affording 16 (0.88 g, 85%) as a foam: ½aꢁ ꢀ35.7
(c 0.46, CHCl3); IR (KBr): 3495, 2986, 1598,
1
1335 cmꢀ1; H NMR: d 7.75 (d, J 7.5 Hz, 4H), 7.37 (d,
graphed using 1:9 EtOAc–petroleum ether as eluent
25
D
J 7.8 Hz, 4H), 5.89 (d, J 3.5 Hz, 2H), 4.36–4.30 (m,
4H), 4.04 (dd, J 9.0, 3.7 Hz, 2H), 3.84 (br m, 4H),
3.68–3.64 (m, 4H), 3.45–3.42 (m, 2H), 3.33 (m, 2H),
2.46 (s, 6H), 2.44 (m, 2H), 2.17–2.01 (m, 2H), 1.47 (s,
6H), 1.22 (s, 6H); 13C NMR: d 144.4 (q), 135.8 (q),
130.1 (CH), 127.2 (CH), 111.6 (q), 104.7 (CH), 82.5
(CH), 79.8 (CH), 68.5 (CH), 64.5 (CH), 64.3 (CH2),
45.4 (CH2), 32.1 (CH2), 26.2 (CH3), 25.8 (CH3), 21.6
(CH3); FABMS: m/z 809 (M+Na).
yielding 19 (2.5 g, 69%) as a foam: ½aꢁ ꢀ25.2 (c
1.07, CHCl3); IR (KBr): 2983, 2933, 1599, 1377 cmꢀ1
;
1H NMR: d 7.38 (d, J 6.9 Hz, 2H), 7.25 (t, J 7.2 Hz,
2H), 6.95 (t, J 7.2 Hz, 2H), 6.88 (d, J 8.1 Hz, 2H),
5.88 (d, J 3.6 Hz, 2H), 4.73 (d, J 12.6 Hz, 2H), 4.63
(d, J 12.6 Hz, 2H), 4.58 (d, J 3.6 Hz, 2H), 4.40–4.33
(m, 2H), 4.21–4.15 (m, 6H), 4.11–3.98 (m, 6H), 2.32
(m, 2H), 1.49 (s, 6H), 1.41 (s, 6H), 1.34 (s, 6H), 1.29
(s, 6H); 13C NMR: d 155.9 (q), 129.2 (CH), 128.7
(CH), 126.0 (q), 120.4 (CH), 111.5 (q), 110.7 (CH2),
108.7 (q), 105.1 (CH), 82.4 (CH), 81.8 (CH), 81.1
(CH), 72.5 (CH2), 66.6 (2 · CH2), 64.3 (CH), 29.6
(CH2), 26.7 (CH3), 26.6 (CH3), 26.1 (CH3), 25.3
(CH3); FABMS: m/z 795 (M+Na); Anal. Calcd for
The procedure described for the conversion of 7 to 8
was used to convert 16 (0.37 g, 0.47 mmol) to 17
25
D
(0.33 g, 86%) as a foam: ½aꢁ ꢀ29.2 (c 0.63, CHCl3);
1
IR (KBr): 3509, 2985, 1598, 1381 cmꢀ1; H NMR: d
7.73 (d, J 8.2 Hz, 4H), 7.37 (d, J 8.1 Hz, 4H), 5.89 (d,

G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
575
C41H56O14: C, 63.72; H, 7.30. Found: C, 63.57; H,
7.47.
3.10. 5,6-Didehydro-5,6-dideoxy-1,2-O-isopropylidene-a-
D-xylohexofuranose (25)
3-O-Benzoyl-1,2-O-isopropylidene-a-D-glucofuranose
(23)36 was subjected to the procedure used for the con-
version of 7 to 11 leading to the vinyl derivative 24
(76%) as a colourless syrup, which could not be sepa-
rated from traces of triphenyl phosphine and other
unidentified aromatic compounds and was used directly
for the next step: 1H NMR: d 8.02 (d, J 7.3 Hz, 2H), 7.59
(t, J 7.5 Hz, 1H), 7.45 (t, J 7.5 Hz, 2H), 6.04 (d, J 3.6 Hz,
1H), 5.89 (m, 1H), 5.49 (d, J 17.7 Hz, 1H), 5.45 (d, J
2.7 Hz, 1H), 5.28 (d, J 10.5 Hz, 1H), 4.87 (br d, J
3.6 Hz, 1H), 4.69 (d, J 3.6 Hz, 1H), 1.57 (s, 3H),
1.35 (s, 3H). A mixture of 24 (4.13 g, 14.24 mmol), pre-
pared as described above, MeOH (10 mL) and
50% aq LiOH (10 mL) was stirred at 25 ꢁC for 12 h.
The solvent was removed, and the residue was
extracted with ether. The combined organic layer
was washed with water and dried. Removal of the
3.9. 1,3-Bis[2-(5-O-allyl-1,2-O-isopropylidene-a-D-xylo-
furanos-3-O-yl)methylphenoxy]propane (22)
The deprotection of the 19 (2.0 g, 2.59 mmol) using the
procedure described for the conversion of 6 to 7 afforded
25
D
20 (1.66 g, 93%) as a sticky liquid: ½aꢁ ꢀ28.9 (c 1.22,
1
CHCl3); IR (KBr): 3458, 2935, 1379 cmꢀ1; H NMR:
d 7.34–7.28 (m, 4H), 6.99–6.94 (m, 4H), 5.93 (d, J
3.5 Hz, 2H), 4.70 (d, J 11.1 Hz, 2H), 4.66 (d, J 3.6 Hz,
2H), 4.54 (d, J 11.1 Hz, 2H), 4.25–4.10 (m, 8H), 3.93
(br m, 2H), 3.73 (d, J 11.4 Hz, 2H), 3.56 (dd, J 11.4,
5.7 Hz, 2H), 3.36 (br m, 2H), 2.75 (hump, 2H), 2.39–
2.35 (m, 2H), 1.47 (s, 6H), 1.32 (s, 6H); 13C NMR: d
156.5 (q), 130.2 (CH), 129.7 (CH), 125.1 (q), 120.7
(CH), 111.5 (CH), 111.5 (q), 105.1 (CH), 82.0 (CH),
81.7 (CH), 79.5 (CH), 69.6 (CH), 67.6 (CH2), 64.9
(CH2), 64.0 (CH2), 28.8 (CH2), 26.6 (CH3), 26.0
(CH3); FABMS: m/z 715 (M+Na), 693 (M+H).
solvent gave 25 (2.38 g, 90%) a white crystalline solid:
25
D
mp 59–60 ꢁC (EtOAc–petroleum ether); ½aꢁ ꢀ57.6 (c
The tetrahydroxy compound 20 (1.50 g, 2.16 mmol)
was subjected to the procedure for the conversion of 7
to 8 to yield 21 (1.26 g, 92%) as a colourless viscous
0.77, CHCl3); IR (KBr): 3426, 2928, 1381 cmꢀ1
;
1H
NMR: d 5.95 (d, J 3.6 Hz, 1H), 5.95–5.84 (m, 1H),
5.53 (d, J 17.1 Hz, 1H), 5.41 (d, J 10.8 Hz, 1H), 4.72
(br m, 1H), 4.57 (d, J 3.6 Hz, 1H), 4.09 (d, J 2.4 Hz,
1H), 2.08 (s, 1H), 1.51 (s, 3H), 1.32 (s, 3H); 13C
NMR: d 131.1 (CH), 119.4 (CH2), 111.6 (q), 104.5
(CH), 84.8 (CH), 80.8 (CH), 75.6 (CH), 26.6 (CH3),
26.1 (CH3); FABMS: m/z 187 (M+H); Anal. Calcd
for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.25; H,
7.37.
25
liquid: ½aꢁ ꢀ46.2 (c 1.42, CHCl3); IR (KBr): 3489,
D
1
1378 cmꢀ1; H NMR: d 7.32–7.26 (m, 4H), 6.94 (dd, J
14.6, 7.5 Hz, 4H), 5.96 (d, J 3.6 Hz, 2H), 4.71 (d, J
11.7 Hz, 2H), 4.65 (d, J 3.6 Hz, 2H), 4.52 (d, J 11.7 Hz,
2H), 4.26 (dd, J 9.0, 5.1 Hz, 2H), 4.21 (t, J 6.0 Hz, 4H),
4.04 (d, J 3.6 Hz, 2H), 3.88–3.77 (m, 4H), 2.39–2.31
(m, 2H), 2.20 (br m, 2H), 1.48 (s, 6H), 1.32 (s, 6H); 13C
NMR: d 156.5 (q), 129.7 (CH), 129.5 (CH), 125.2 (q),
120.7 (CH), 111.5 (q), 111.2 (CH), 105.1 (CH), 82.8
(CH), 82.3 (CH), 79.8 (CH), 67.3 (CH2), 64.6 (CH2),
60.7 (CH2), 29.0 (CH2), 26.7 (CH3), 26.2 (CH3);
FABMS: m/z 655 (M+Na), 633 (M+H).
3.11. 1,3-Bis[2-(5,6-didehydro-5,6-dideoxy-1,2-O-isopro-
pylidene-a-D-xylohexofuranos-3-O-yl)methylphenoxy]-
propane (26)
Allylation of 21 (3.3 g, 7.11 mmol) by the procedure
described for the conversion of 8 to 9 yielded 22
Alkylation of 25 (0.20 g, 1.08 mmol) with 1,3-di(2-bro-
momethylphenoxy)propane (0.22 g, 0.53 mmol) accord-
ing to the method used for the conversion of 2 to 19
25
D
(3.26 g, 91%) as a syrup: ½aꢁ ꢀ58.3 (c 0.83, CHCl3);
1
IR (Neat): 2983, 1643, 1599, 1377 cmꢀ1; H NMR: d
7.34 (d, J 7.5 Hz, 2H), 7.26 (t, J 7.2 Hz, 2H), 6.95 (t, J
7.2 Hz, 2H), 6.88 (d, J 7.5 Hz, 2H), 5.92 (d, J 3.6 Hz,
2H), 5.94–5.81 (m, 2H), 5.24 (dd, J 17.1, 1.5 Hz, 2H),
5.15 (dd, J 10.5, 1.5 Hz, 2H), 4.70 (d, J 12.6 Hz, 2H),
4.60 (d, J 3.6 Hz, 2H), 4.55 (d, J 12.6 Hz, 2H), 4.40–
4.35 (m, 2H), 4.18 (t, J 6.0 Hz, 4H), 4.07–3.92 (m,
6H), 3.75–3.65 (m, 4H), 2.33–2.29 (m, 2H), 1.48 (s,
6H), 1.29 (s, 6H); 13C NMR: d 155.9 (q), 134.5 (CH2),
128.8 (CH2), 128.7 (CH), 126.0 (q), 120.5 (CH), 117.0
(CH2), 111.5 (q), 110.8 (CH), 105.0 (CH), 82.2 (CH),
82.0 (CH), 79.3 (CH), 72.3 (CH2), 67.5 (CH2), 66.8
(CH2), 64.3 (CH2), 29.3 (CH2), 26.7 (CH3), 26.2
(CH3); FABMS: m/z 735 (M+Na); Anal. Calcd
for C39H52O12: C, 65.71; H, 7.35. Found: C, 65.57; H,
7.63.
gave 26 (0.26 g, 78%) as a colourless viscous liquid:
25
D
½aꢁ ꢀ57.5 (c 0.47, CHCl3); IR (Neat): 3077, 1689,
1
1377 cmꢀ1; H NMR: d 7.33 (d, J 7.5 Hz, 2H), 7.25 (t,
J 7.8 Hz, 2H), 6.94 (t, J 7.5 Hz, 2H), 6.87 (d, J 7.8 Hz,
2H), 6.08–5.96 (m, 2H), 5.94 (d, J 3.6 Hz, 2H), 5.41
(d, J 17.2 Hz, 2H), 5.28 (d, J 9.3 Hz, 2H), 4.69–4.53
(m, 8H), 4.17 (t, J 6.0 Hz, 4H), 3.91 (d, J 3.0 Hz, 2H),
2.32–2.26 (m, 2H), 1.50 (s, 6H), 1.30 (s, 6H); 13C
NMR: d 155.9 (q), 132.2 (CH), 128.70 (CH), 128.66
(CH), 125.9 (q), 120.4 (CH), 118.8 (CH2), 111.2 (q),
110.7 (CH), 104.6 (CH), 83.6 (CH), 82.7 (CH), 81.5
(CH), 66.9 (CH2), 64.2 (CH2), 29.1 (CH2), 26.6 (CH3),
26.0 (CH3); MS (positive ion ESI): m/z 647 (M+Na);
Anal. Calcd for C35H44O10: C, 67.29; H, 7.10. Found:
C, 67.30; H, 7.07.

576
G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
3.12. General procedure for the ring-closing metathesis
1374 cmꢀ1; single isomer; 1H NMR: d 5.78–5.76 (m,
2H), 5.68 (d, J 3.3 Hz, 2H), 5.33 (s, 2H), 4.51 (d, J
3.0 Hz, 2H), 4.22 (dd, J 12.3, 6.0 Hz, 2H), 4.09 (m,
4H), 3.93 (dd, J 8.1, 6.3 Hz, 2H), 2.41 (m, 4H), 1.55
(s, 6H), 1.43 (s, 6H), 1.36 (s, 6H), 1.33 (s, 6H); 13C
NMR: d 127.8 (CH), 113.0 (q), 109.2 (q), 103.2 (CH2),
89.9 (CH2), 84.8 (q), 82.9 (CH), 82.4 (CH), 73.5 (CH),
67.4 (CH2), 30.3 (CH2), 27.0 (CH3), 26.6 (CH3), 26.5
(CH3), 25.5 (CH3); MS (positive ion ESI) m/z 607
(M+Na); Anal. Calcd for C29H44O12: C, 59.58; H,
7.59. Found: C, 59.70; H, 7.42.
The general procedure for the above compounds is illus-
trated by the RCM of 9.
3.12.1.
(1S,5S,6R,7R,9R,18R,20R,21R)-(6,7:20,21-
Diisopropylidenedioxy)-2,4,8,11,16,19-hexaoxatricyclo-
[16.3.0.05,9]heneicos-13-ene (29). To a solution of 9
(0.10 g, 0.21 mmol) in degassed CH2Cl2 (30 mL), 1
(0.018 g, 10 mol %) was added and refluxed for 10 h in
an Ar atmosphere. The solvent was evaporated, and
the residue was chromatographed using 1:9 EtOAc–
petroleum ether as eluent to yield 29 (0.084 g, 90%) as
a foam: IR (KBr): 1648, 1377 cmꢀ1; 1H NMR (2:3-mix-
ture of E, Z isomers): d 5.93 (d, J 3.6 Hz, 1.2H), 5.90 (d,
J 3.9 Hz, 0.8H), 5.85 (m, 0.8H), 5.78 (m, 1.2H), 4.81 (s,
0.8H), 4.79 (s, 1.2H), 4.46 (d, J 3.6 Hz, 0.8H), 4.45 (d, J
3.9 Hz, 1.2H), 4.41–4.36 (m, 2.4H), 4.31 (dd, J 12.3,
1.8 Hz, 1.6H), 4.20 (d, J 3.0 Hz, 0.8H), 4.17–4.03 (m,
2.4H), 3.95–3.89 (m, 0.8H), 3.87 (dd, J 10.5, 3.6 Hz,
1.2H), 3.80 (dd, J 10.5, 5.7 Hz, 0.8H), 3.67 (dd, J 10.5,
6.0 Hz, 0.8H), 3.46 (dd, J 10.5, 6.3 Hz, 1.2H), 1.50 (s,
2.4H), 1.41 (s, 3.6H), 1.31 (s, 6H); 13C NMR (2:3-mix-
ture of E, Z isomers): d 132.5 (CH), 129.9 (CH), 111.9
(q), 105.0 (CH), 94.3 (CH2), 92.3 (CH2), 82.8 (CH),
82.6 (CH), 82.1 (CH), 80.1 (CH), 79.3 (CH), 78.7
(CH), 70.5 (CH2), 67.1 (CH2), 66.4 (CH2), 65.6 (CH2),
26.7 (CH3), 26.3 (CH3), 26.2 (CH3); MS (EI) m/z 444
(M); Anal. Calcd for C21H32O10: C, 56.75; H, 7.26.
Found: C, 56.48; H, 7.43.
3.12.4. (1R,7R,9R,10R,11S,18S,19R,20R)-(9,10:19,20-
Diisopropylidenedioxy)3,5,8,12,17,21-hexaoxatricyclo-
[16.3.0.07,11]heneicos-14-ene (30). Pale-yellow viscous
;
liquid: yield 95%; IR (KBr): 2986, 1614 cmꢀ1 1H
NMR (3:7-mixture of E, Z isomers): d 5.92 (d, J
3.6 Hz, 1.4H), 5.87–5.83 (m, 2.6H), 4.78 (s, 0.6H), 4.73
(s, 1.4H), 4.56 (d, J 3.6 Hz, 2H), 4.36–4.28 (m, 4H),
4.09–3.98 (m, 2H), 3.95 (d, J 2.7 Hz, 0.6H), 3.92 (d, J
3.0 Hz, 1.4H), 3.80–3.74 (m, 2H), 3.55 (dd, J 9.0,
4.5 Hz, 0.6H), 3.42 (dd, J 9.0, 6.0 Hz, 1.4H), 1.49 (s,
6H), 1.32 (s, 6H); 13C NMR (3:7-mixture of E, Z iso-
mers): d 130.9 (CH), 130.0 (CH), 111.6 (q), 104.9
(CH), 104.5 (CH), 97.2 (CH2), 94.9 (CH2), 83.0 (CH),
82.7 (CH), 82.5 (CH), 81.0 (CH), 78.7 (CH), 78.5
(CH), 70.3 (CH2), 66.1 (CH2), 64.8 (CH2), 64.3 (CH2),
26.6 (CH3), 26.2 (CH3); ESIMS (positive ion): m/z 467
(M+Na); Anal. Calcd for C21H32O10: C, 56.75; H,
7.26. Found: C, 56.82; H, 7.32.
3.12.2.
(1R,5R,7R,8R,9S,16S,17R,18R)-(7,8:17,18-
3.12.5. (1S,7S,8R,9R,11S,20S,22R,23R)-8,9:22,23-
Diisopropylidenedioxy-2,6-bis-(p-toluenesulfonyl)-10,13,
Diisopropylidenedioxy)-3,6,10,15,19-pentaoxatricyclo-
[14.3.0.05,9]nonadec-12-ene (27). Colourless syrup:
yield 43% based on 50% recovered starting material,
IR (KBr): 1635, 1378 cmꢀ1; H NMR (3:7-mixture of
18,21-tetraoxa-2,6-diazatricyclo[18.3.0.07,11]tricos-15-ene
(31). Pale-yellow needles: mp 198–200 ꢁC (CHCl3-
25
1
petroleum ether); yield 78%, single isomer; ½aꢁ ꢀ30.3
D
E, Z isomers): d 6.02 (br t, J 3.0 Hz, 1.4H), 5.90 (d, J
3.9 Hz, 0.6H), 5.89 (d, J 3.9 Hz, 1.4H), 5.82 (br t, J
3.9 Hz, 0.6H), 4.57 (d, J 3.9 Hz, 0.6H), 4.54 (d, J
3.6 Hz, 1.4H), 4.43–4.32 (m, 2H), 4.26 (d, J 13.8,
2.9 Hz, 1.4H), 4.13 (dd, J 11.7, 3.6 Hz, 0.6H), 4.04 (d,
J 3.6 Hz, 0.6H), 4.01 (d, J 3.3 Hz, 1.4H), 3.90–3.74 (m,
4H), 3.70–3.62 (m, 2H), 1.49 (s, 6H), 1.32 (s, 6H); 13C
NMR (3:7-mixture of E, Z isomers): d 130.67 (CH),
130.62 (CH), 111.9 (q), 111.8 (q), 83.7 (CH), 83.5
(CH), 81.0 (CH), 77.7 (CH), 77.1 (CH), 69.2 (CH2),
67.0 (CH2), 66.2 (CH2), 65.9 (CH2), 26.9 (CH3), 26.8
(CH3), 26.4 (CH3), 26.2 (CH3); FABMS: m/z 415
(M+H); Anal. Calcd for C20H30O9: C, 57.96; H, 7.30.
Found: C, 58.09; H, 7.42.
(c 0.92, CHCl3); IR (KBr): 2988, 2937, 1597, 1380,
1
1340 cmꢀ1; H NMR: d 7.73 (d, J 8.2 Hz, 4H), 7.36 (d,
J 8.1 Hz, 4H), 5.96 (d, J 3.6 Hz, 2H), 5.80 (br s, 2H),
4.42–4.40 (m, 2H), 4.30–4.25 (m, 6H), 3.83–3.79 (m,
2H), 3.69 (dd, J 10.5, 8.2 Hz, 2H), 3.41 (dd, J 10.5,
2.2 Hz, 2H), 3.20–3.10 (m, 2H), 2.87–2.77 (m, 2H), 2.45
(s, 6H), 2.24 (m, 2H), 1.48 (s, 6H), 1.21 (s, 6H); 13C
NMR: d 144.0 (q), 135.9 (q), 130.9 (CH), 129.9 (CH),
127.5 (CH), 111.2 (q), 104.7 (CH), 82.5 (CH), 79.1
(CH), 71.0 (CH2), 67.1 (CH2), 64.7 (CH), 44.7 (CH2),
33.3 (CH2), 26.4 (CH3), 25.9 (CH3), 21.5 (CH3); FABMS:
m/z 779 (M+H); Anal. Calcd for C37H50N2O12S2: C,
57.05; H, 6.47; N, 3.60. Found: C, 56.97; H, 6.28; N, 3.32.
3.12.6.
(2R,3R,3aS,20aS,21R,22R,23aR,25aR)-
3.12.3. (1R,3R,4R,5R,9R,10R,12R,13R)-(3,4:12,13-Diiso-
propylidenedioxy)-1,10-bis(1,2-isopropylidenedioxyethyl)-
2,3:21,22-Diisopropylidenedioxy-2,3,3a,20a,21,22,23a,25a-
octahydrodibenzo[c,j]difuro[2,3-n:3,2-r][1,5,9,13]tetraoxa-
cyclononadeca-5a,14a,20a,24,25a-pentaene (32). Colour-
less, sticky liquid: yield 95%; IR (KBr): 2983, 1689,
2,6,8,11-tetraoxadispiro[4.3.4.4]heptadec-15-ene
Colourless, viscous liquid: yield 85%, single isomer
(28).
25
D
½aꢁ
+109.1 (c 0.77, CHCl3); IR (Neat): 2935,
1378 cmꢀ1 1H NMR (1:2-mixture of E, Z isomers):
;

G. Biswas et al. / Carbohydrate Research 340 (2005) 567–578
577
7.39–7.26 (m, 4H), 7.01–6.87 (m, 4H), 6.12 (d, J 4.5 Hz,
1.33H), 5.93 (d, J 4.5 Hz, 0.67H), 5.88–5.85 (m, 2H),
4.99 (m, 2H), 4.69–4.48 (m, 6H), 4.19–4.15 (m, 4H),
3.90 (d, J 2.4 Hz, 1.33H), 3.73 (d, J 2.4 Hz, 0.67H),
2.41–2.37 (m, 1.33H), 2.26–2.22 (m, 0.67H), 1.47 (s,
6H), 1.31 (s, 6H); 13C NMR: d 157.4, 155.6, 131.1,
129.6, 128.6, 128.5, 127.3, 126.0, 121.1, 120.7, 112.5,
112.3, 111.4, 104.9, 86.2, 83.7, 83.5, 83.2, 81.2, 76.4,
68.9, 68.3, 65.8, 65.6, 29.5, 29.0, 26.4, 26.2; ESIMS (posi-
tive ion): m/z 619 (M+Na); Anal. Calcd for C33H40O10: C,
66.43; H, 6.76. Found: C, 66.60; H, 6.47.
Thanks are due to Mr. S. Chowdhury for general assis-
tance. The help of Dr. R. Mukhopadhyay, Dr. A.
Banerjee and Mr. K. Sarkar for NMR and mass spectral
analyses is acknowledged.
References
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21,22-Diisopropylidenedioxy)-2,3,5,3a,20a,21,22,23a-octa-
hydrodibenzo[c,j]difuro[2,3-c:3,2-r][1,5,9,13,17,21]hexa-
oxacyclopentacosa-7a,14a,20a,27,31a-pentaene
Yellowish-white viscous liquid: yield 70%, single isomer;
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25
½aꢁ ꢀ32.5 (c 0.73, CHCl3); IR (KBr): 2929, 1377 cmꢀ1
;
D
1H NMR: d 7.25–7.35 (m, 4H), 6.89–6.98 (m, 4H), 5.91
(d, J 3.6 Hz, 2H), 5.57 (br m, 2H), 4.67 (d, J 12.3 Hz,
2H), 4.61 (d, J 3.6 Hz, 2H), 4.54 (d, J 12.3 Hz, 2H),
4.31 (m, 2H), 4.18 (m, 4H), 3.96 (d, J 2.7 Hz, 2H),
3.89 (d, J 10.2, 5.7 Hz, 2H), 3.76 (d, J 10.2 Hz, 2H),
3.64–3.54 (m, 4H), 2.33 (m, 2H) 1.49 (s, 6H), 1.32 (s,
6H); 13C NMR: d 156.2, 129.5, 129.3, 129.0, 126.4,
120.7, 111.7, 111.3, 104.9, 83.0, 81.8, 78.9, 71.1, 67.7,
66.5, 64.8, 29.2 26.8, 26.3; ESIMS (positive ion) m/z
707 (M+Na); Anal. Calcd for C37H48O12: C, 64.90; H,
7.07. Found: C, 65.00; H, 7.07.
14. Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43,
295–298.
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Diisopropylidenedioxy)-2,4,8,11,16,19-hexaoxatricy-
clo[16.3.0.05,9]heneicosane (34)
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A mixture 29 (0.20 g, 0.45 mmol) and Pd–C (10%)
(0.020 g) in EtOH (20 mL) was stirred under hydrogen
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ether as eluent to give 34 (0.20 g, 98%) as a colourless
25
D
thick liquid, ½aꢁ ꢀ108.4 (c 0.75, CHCl3); IR (Neat):
1378 cmꢀ1
;
1H NMR: d 5.87 (d, J 3.6 Hz, 2H), 4.85
(s, 2H), 4.53 (d, J 3.6 Hz, 2H), 4.35–4.31 (m, 2H),
4.26 (d, J 2.4 Hz, 2H), 3.83 (t, J 9.6 Hz, 2H), 3.59–
3.52 (m, 6H), 1.78 (br m, 2H), 1.60 (br m, 2H), 1.51
(s, 6H), 1.32 (s, 6H); 13C NMR: d 111.8 (q), 104.5
(CH), 91.2 (CH2), 82.4 (CH), 78.8 (CH), 78.2 (CH),
71.2 (CH2), 66.0 (CH2), 26.7 (CH3), 26.2 (CH3), 25.8
(CH2); ESIMS (positive ion): m/z 469 (M+Na); Anal.
Calcd for C21H34O10: C, 56.49; H, 7.68. Found: C,
56.69; H, 7.47.
´
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24. (a) The formation of symmetrical chiral macrocycles as
side products through dimerization has been reported.
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