Synthesis of an L-quinovose-containing disaccharide

Article abstract of DOI:10.1016/S0008-6215(00)00316-5

The synthesis of a versatile L-rhamnose monosaccharide synthon is described. This synthon is used in the synthesis of a disaccharide containing the rare sugar, 6-deoxy-L-glucose, linked to the 3-C-hydroxymethyl group of methyl 2,3-O-isopropylidene 3-C-(hydroxymethyl)-β-D-erythrofuranoside.

Full text of DOI:10.1016/S0008-6215(00)00316-5

www.elsevier.nl/locate/carres
Carbohydrate Research 330 (2001) 517–521
Note
Synthesis of an -quinovose-containing disaccharide
L
Jamie R. Rich1, Robert S. McGavin1, Kerry B. Reimer*
Department of Chemistry, Uni6ersity of Northern British Columbia, 3333 Uni6ersity Way, Prince George,
BC, Canada V2N 4Z9
Received 30 October 2000; accepted 28 November 2000
Abstract
The synthesis of a versatile
of a disaccharide containing the rare sugar, 6-deoxy-
2,3-O-isopropylidene 3-C-(hydroxymethyl)-b- -erythrofuranoside. © 2001 Elsevier Science Ltd. All rights reserved.
L
-rhamnose monosaccharide synthon is described. This synthon is used in the synthesis
L
-glucose, linked to the 3-C-hydroxymethyl group of methyl
D
Keywords: -Quinovose; 6-Deoxy- -glucose; Rhamnosyl ulose; Apiose; 3-C-(hydroxymethyl)-b- -erythrofuranose
L
L
D
Rhamnogalacturonan II is a complex
oligosaccharide containing many unusual
structural elements and rare monosacchar-
ides.1,2 One of the more complex structural
elements is a fully substituted rhamnose
monosaccharide, b-linked to 3-C-(hydroxy-
elaboration into highly branched oligosacchar-
ides. Efficient synthesis of this b-linked rham-
nose disaccharide is very difficult, and we have
tried various approaches to this problem. One
approach we tried was the use of the ulosyl
thioglycoside 7 as a glycosyl donor3 together
with the alcohol 84 in dichloromethane. The
resulting ulosyl disaccharide was then re-
duced, using sodium borohydride, to give the
2%-hydroxy disaccharide. The glycosylation re-
action gave predominantly the unwanted a-
linked product, which upon reduction of the
carbonyl group at C-2%, gave the disaccharide
methyl)-b-
D
-erythrofuranose (b- -apiose) (see
D
Fig. 1), which is part of a side-chain structure
of rhamnogalacturonan II. We have recently
been directing our efforts at synthesizing this
disaccharide, suitably protected for further
9 with an -gluco configuration.
L
In separate experiments, the glycosylation
reaction was also carried out using diethyl
ether as the solvent; in addition, various re-
ducing agents were used (sodium borohydride,
L-selectride, LS-selectride and N-selectride).
Similar results were obtained in all cases, with
the major product having the a-gluco configu-
ration, and about 10% of the reaction mixture
contained a 1:1 mixture of co-eluting products
that were determined to be the disaccharides
Fig. 1. Partial structure of one of the branched side chains
found within the structure of rhamnogalacturonan II.
* Corresponding author. Tel.: +1-250-9606675; fax: +1-
250-9605545.
E-mail address: reimerk@unbc.ca (K.B. Reimer).
1 Present address: Department of Chemistry, University of
Alberta, Edmonton, Alberta, Canada T6G 2G2.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00316-5

518
J.R. Rich et al. / Carbohydrate Research 330 (2001) 517–521
Scheme 1. (a) CH3C(OMe)3, PTSA, in DMF; (b) allyl bromide, NaH, in DMF; (c) 80% aq HOAc; (d) BzCl in pyridine; (e)
HCl–MeOH; (f) pyridinium chlorochromate, CH2Cl2; (g) (i) triflic acid, N-iodosuccinimide in CH2Cl2 (ii) NaBH4 in CH2Cl2–
MeOH.
having the b-gluco and b-rhamno configura-
tions. These results indicate that under the
conditions that were used, the a-glycosidic
bond was preferentially formed. We are con-
tinuing to work on this particular glycosyla-
tion, varying the nature of the rhamnosyl
donor, in order to efficiently prepare the b-
rhamnosyl linkage.
allyl bromide in DMF to give 3. Opening of
the orthoester was achieved by treatment with
80% aq acetic acid to give the 2-O-acetyl
derivative 4. The free hydroxyl group of 4 was
then benzoylated to give 5. Compound 5 is a
highly versatile synthon with hydroxyl groups
at the 2-, 3- and 4-positions protected such
that it allows for a variety of deprotection
senarios following glycosylation. In addition,
compound 5 can be prepared with a minimum
of chromatography allowing for relatively
easy scale-up (Scheme 1).
Although the desired b-rhamno linkage was
not formed, this result is interesting in that
it provides a route to introducing the
rare monosaccharide 6-deoxy-
L
-glucose ( -
L
quinovose) into an oligosaccharide synthesis
(we were able to find only one reference in
Removal of the acetyl group of 5 was
achieved using methanolic HCl to give 6.8 The
1H NMR spectrum of 6 showed that the signal
for H-2 of the rhamnosyl residue had shifted
to 4.28 ppm, from 5.45 ppm for compound 5,
consistent with deacetylation of the 2-position.
The resulting alcohol 6 was oxidized using
pyridinium chlorochromate9 to give the ulosyl
the literature to naturally occurring
L
-
quinovose).5 Situations where this would be
useful are structural studies of oligosacchar-
ides where structural modifications are intro-
duced in order to elucidate the biological
function of oligosaccharides. a-
could serve as a useful substitute for a-
cose or a- -rhamnose.
L
-Quinovose
1
L
-fu-
derivative 7. The H NMR spectrum for 7
L
showed the loss of the signal for H-2 and the
collapse of the signal for H-1 to a singlet, and
the 13C NMR showed a signal at 194.5 ppm
that was attributed to the carbonyl carbon at
C-2. These data are consistent with the oxida-
tion of 6 to 7.
Although we have previously cited the use
of 5 in the literature,6 its preparation was not
published; in this work we wish to report the
details of the synthesis of this useful synthon.
Compound 5 was prepared in a series of reac-
tions using the ethyl thioglycoside 17 as a
starting material. The orthoester of ethyl thio-
glycoside 1 was formed by treatment with
trimethyl orthoacetate in N,N-dimethylfor-
mamide (DMF) and a catalytic amount of
p-toluenesulfonic acid. The 4-hydroxyl group
of the resulting orthoester 2 was then pro-
tected with an allyl group by treatment with
Disaccharide 9 was synthesized by reaction
of 7 with 84 in dichloromethane using N-iodo-
succinimide as a glycosylation promoter, with
a catalytic amount of triflic acid. The un-
purified product of this reaction was reduced
using sodium borohydride to give 9 as the
main product. The 1H NMR signal for H-3% of
9 had a J3%,2% coupling constant of about 9.5

J.R. Rich et al. / Carbohydrate Research 330 (2001) 517–521
519
Hz consistent with an equatorial orientation
of the hydroxyl at C-2%, indicating that the
non-reducing monosaccharide had the gluco
3 was dissolved in 80% aq AcOH (100 mL)
and stirred at rt for 30 min. The solution was
then evaporated to dryness, and the residue
was co-evaporated with EtOH (3×25 mL) to
remove traces of AcOH. The resulting syrup 4
was then dissolved in pyridine (40 mL), and
BzCl (4.15 mL, 35.8 mmol) was added. After
30 min the mixture was filtered through Celite,
and the filtrate was evaporated to dryness.
The syrupy residue was dissolved in CH2Cl2
and washed successively with satd aq
NaHCO3 and water. The organic phase was
dried and evaporated to dryness to give 5 as a
syrup. Crystallization from hexane gave pure
5 (2.455 g, 49.80%). The mother liquor was
then purified by chromatography using silica
gel (6:1 hexane–ethyl acetate) giving an addi-
tional sample of 5 (0.987 g, 20.0%); total yield
69.8%: mp 92.5–92.7 °C; [h]2D5 −77.2° (c 1.06,
13
configuration. The one-bond C–1H coupling
constant (1J13
) for C-1%, measured from a
–1
C
H
1H-detected C–1H correlation spectrum of 9,
was found to be 172.8 Hz, a value characteris-
tic of a-glycosidic linkages.10
13
1. Experimental
General methods.—1H and 13C NMR spec-
tra were compiled with a Bruker AMX 300
spectrometer. All samples used CDCl3 as a
solvent with tetramethylsilane as an internal
reference. Optical rotations were measured on
an Autopol III polarimeter. Thin-layer chro-
matography (TLC) utilized Silica Gel-60 F254
(E. Merck), with detection by UV light and by
charring with 5% sulfuric acid in EtOH.
Medium-pressure column chromatography
was performed with silica gel (E. Merck, 230–
400 mesh).
1
CHCl3); H NMR (300.13 MHz, CDCl3): l
8.00 (m, 2 H, aromatic), 7.58 (m, 1 H, aro-
matic), 7.45 (m, 2 H, aromatic), 5.80 (m, 1 H,
OCH2CHꢀCH2), 5.48–5.43 (m, 2 H, H-2 and
H-3), 5.22 (d, 1 H, J1,2 1.0 Hz, H-1), 5.07–5.21
(m, 2 H, OCH2CHꢀCH2), 4.22 (dq, 1 H, J5,4
9.3 Hz, H-5), 4.16 (m, 2 H, OCH2CHꢀCH2),
3.58 (m, 1 H, H-4), 2.65 (m, 2 H, SCH2CH3),
2.12 (s, 3 H, OCOCH3) 1.39 (d, 3 H, J6,5 6.2
Hz, H3-6), 1.31 (t, 3 H, J 7.5 Hz, SCH2CH3);
13C NMR (75.03 MHz, CDCl3): l 170.1 (CꢀO
acetate), 165.4 (CꢀO benzoate), 134.7
(CH2CHꢀCH2), 133.4 (para aromatic), 130.1
(ipso aromatic), 129.8 (ortho aromatic), 128.7
(meta aromatic), 117.4 (CH2CHꢀCH2), 82.2
(C-1), 79.1 (C-4), 74.1 (CH2CHꢀCH2), 72.6,
72.5 (C-2,3), 68.6 (C-5), 25.7 (SCH2CH3), 21.1
(OCOCH3), 18.1 (C-6), 15.1 (SCH2CH3).
Anal. Calcd for C20H26O6S: C, 60.89; H, 6.64.
Found: C, 60.87; H, 6.64.
Ethyl 2-O-acetyl-4-O-allyl-3-O-benzoyl-1-
thio-h-
L
-rhamnopyranoside (5).—A sample of
ethyl-1-thio-a-
L
-rhamnopyranoside (1)7 (2.602
g, 12.50 mmol) was dissolved in N,N-
dimethylformamide (52 mL) containing
trimethyl orthoacetate (2.70 mL, 21.2 mmol).
p-Toluenesulfonic acid (52 mg, 0.27 mmol)
was added, and the mixture was placed under
partial vacuum on a rotatory evaporator and
heated to 50 °C. After 15 min triethylamine
(0.40 mL) was added, and the solution was
concentrated to a syrup. The syrup was dis-
solved in CH2Cl2 and washed with satd aq
NaHCO3 and water. The organic phase was
dried and concentrated to give crude 2 as a
syrup. The sample of crude 2 was dissolved in
N,N-dimethylformamide (50 mL) and cooled
to 0 °C under nitrogen, followed by the addi-
tion of NaH (2.11 g, 0.0703 mol, 80% disper-
sion in oil). After 15 min allyl bromide (4.60
mL, 52.8 mmol) was added. After 10 min the
reaction was complete, and excess NaH was
quenched by the addition of MeOH. The reac-
tion mixture was evaporated to a syrup, which
was then dissolved in CH2Cl2 and washed
with water. The organic phase was dried and
concentrated to give crude 3 as a syrup. Crude
Ethyl
rhamnopyranoside (6).—A sample of ethyl 2-
O-acetyl-4-O-allyl-3-O-benzoyl-1-thio-a-
4-O-allyl-3-O-benzoyl-1-thio-h- -
L
L
-
rhamnopyranoside (5) (4.080 g, 10.34 mmol)
was dissolved in 45 mL of methanolic HCl
(prepared by dissolving 35 mL of acetyl chlo-
ride in 65 mL of MeOH). The solution was
left stirring at rt for 8 h and then neutralized
by adding solid NaHCO3. The solution was
filtered and evaporated to dryness. The
residue was taken up in CH2Cl2 and washed
with H2O. The organic layer was dried over

520
J.R. Rich et al. / Carbohydrate Research 330 (2001) 517–521
H3-6), 1.34 (t, 3 H, J 7.5 Hz, SCH2CH3); 13C
NMR (75.03 MHz, CDCl3): l 194.5 (CꢀO,
Na2SO4, and the filtrate was evaporated to
dryness. The crude syrup was purified by
chromatography using silica gel (4:1 hexane–
ethyl acetate) to give 6 (2.63 g, 72.2%); [h]D25
C-2),
165.7
(CꢀO
benzoate),
134.2
(CH2CHꢀCH2), 133.7 (para aromatic), 130.1
(ortho aromatic), 129.6 (ipso aromatic), 128.7
(meta aromatic), 118.1 (CH2CHꢀCH2), 85.8
(C-1), 82.5 (C-4), 78.4 (C-3), 74.0
(CH2CHꢀCH2), 69.0 (C-5), 26.3 (SCH2CH3),
17.8 (C-6), 15.2 (SCH2CH3). Anal. Calcd for
C18H22O5S: C, 61.69; H, 6.33; S, 9.15. Found:
C, 61.73; H, 6.42; S, 8.78.
1
−119° (c 0.789, CHCl3); H NMR (300.13
MHz, CDCl3): l 8.11 (m, 2 H, aromatic), 7.59
(m, 1 H, aromatic), 7.46 (m, 2 H, aromatic),
5.79 (m, 1 H, OCH2CHꢀCH2), 5.36 (dd, 1 H,
J3,4 9.0, J3,2 3.0 Hz, H-3), 5.24 (d, 1 H, J1,2 1.8
Hz, H-1), 5.17, 5.07 (2m,
2
H,
OCH2CHꢀCH2), 4.28 (br. m, H-2), 4.21 (dq, 1
H, J5,4 9.2 Hz, H-5), 4.15 (m, 1 H,
OCH2CHꢀCH2), 3.63 (dd, J3,4 +J4,5 19.5 Hz,
H-4), 2.73–2.54 (m, 2 H, SCH2CH3), 2.47 (br.
s, 1 H, 2-OH), 1.37 (d, 3 H, J6,5 6.3 Hz, H3-6),
1.30 (t, 3 H, J 7.5 Hz, SCH2CH3); 13C NMR
(75.03 MHz, CDCl3): l 165.6 (CꢀO benzoate),
134.7 (CH2CHꢀCH2), 133.5 (para aromatic),
130.0 (ipso aromatic), 129.9 (ortho aromatic),
128.7 (meta aromatic), 117.5 (CH2CHꢀCH2),
84.1 (C-1), 78.9 (C-4), 75.2 (C-2), 74.1
(CH2CHꢀCH2), 71.4 (C-3), 68.4 (C-5), 25.3
(SCH2CH3), 18.1 (C-6), 15.1 (SCH2CH3).
Anal. Calcd for C18H24O5S: C, 61.34; H, 6.86;
S, 9.10. Found: C, 61.31; H, 7.02; S, 8.73.
Methyl 4-O-allyl-3-O-benzoyl-h-
pyranosyl-(1“31)-2,3-O-isopropylidene-3-C-
(hydroxymethyl)-h- -erythrofuranoside (9).—
A sample of ethyl 4-O-allyl-3-benzoyl-1-thio-
-rhamnopyranosid-2-ulose (7) (0.138 g,
L
-quino6o-
D
a-
L
0.394 mmol) was dissolved in CH2Cl2 (3.0
mL) followed by the addition of N-iodosuc-
cinimide (0.0920 g, 0.409 mmol) and crushed 3
,
A molecular sieves. To this solution a sample
of methyl 2,3-O-isopropylidene-3-C-(hydrox-
ymethyl)-a-
-erythrofuranoside (8)4 (0.0389 g,
D
0.190 mmol) in CH2Cl2 (3.0 mL) was added,
followed by the addition of triflic acid (15 mL
of 10% triflic acid in diethyl ether). The reac-
tion mixture was stirred at rt under an atmo-
sphere of N2. After 45 min triethylamine was
added until the dark-colored solution turned
yellow. The reaction mixture was filtered, and
the filtrate was washed successively with satd
aq NaHCO3 and 10% Na2S2O3. The organic
layer was dried over Na2SO4, filtered and
evaporated to dryness. The syrupy residue was
taken up in 1:1 MeOH–CH2Cl2 (3.0 mL) and
NaBH4 (71 mg, 1.9 mmol) was added. After
10 min the reaction mixture was washed with
aq HCl (1.0 M), dried over Na2SO4, and
evaporated to dryness. The syrupy residue was
purified by chromatography using 4:1 hex-
ane–ethyl acetate as eluant. Compound 9 was
obtained as a syrup (0.0425 g, 45.3%); [h]D25
Ethyl 4-O-allyl-3-benzoyl-1-thio-h-
nopyranosid-2-ulose (7).—A sample of ethyl 4-
O-allyl-3-O-benzoyl-1-thio-a- -rhamnopy-
L
-rham-
L
ranoside (6) (0.8926 g, 2.533 mmol) was dis-
solved in CH2Cl2 (40.0 mL). Pyridinium
chlorochromate (1.703 g, 7.899 mmol) was
added to this solution, and the mixture was
refluxed for 2.5 h. The reaction mixture was
cooled and concentrated to a volume of about
10 mL. Silica gel (approx. 10 g) was added to
the dark concentrate, and the mixture was
placed on a rotary evaporator and evaporated
to dryness. The silica gel mixture was loaded
onto a silica gel column, and the mixture was
purified by chromatography using 4:1 hex-
ane–ethyl acetate as eluant. Compound 7 was
obtained as a syrup (0.552 g, 62.2%); [h]D25
1
−108° (c 1.32, CHCl3); H NMR (300.13
1
−223° (c 2.34, CHCl3); H NMR (300.13
MHz, CDCl3): l 8.09 (m, 2 H, aromatic), 7.58
(m, 1 H, aromatic), 7.46 (m, 2 H, aromatic),
5.73 (m, 1 H, OCH2CHꢀCH2), 5.41 (dd, 1 H,
J3%,2%+J3%,4% 18.9 Hz, H-3%), 5.11, 5.04 (2m, 2 H,
OCH2CHꢀCH2), 4.96 (s, 1 H, H-1), 4.91 (d, 1
H, J1%,2% 3.7 Hz, H-1%), 4.46 (s, 1 H, H-2),
4.11–4.07 (m, 2 H, OCH2CHꢀCH2), 4.07, 3.96
(2d, 2 H, J4a,4b 9.7 Hz, H-4a, H-4b), 4.01, 3.57
(2d, 2 H, J5a,5b 9.7 Hz, H-5a, H-5b), 3.84 (dq, 1
MHz, CDCl3): l 8.11 (m, 2 H, aromatic), 7.62
(m, 1 H, aromatic), 7.48 (m, 2 H, aromatic),
5.89–5.75 (m, 2 H, OCH2CHꢀCH2, H-3), 5.33
(s,
1
H, H-1), 5.26–5.11 (m,
2
H,
OCH2CHꢀCH2), 4.48 (dq, 1 H, J5,4 9.5 Hz,
H-5), 4.28–4.12 (m, 2 H, OCH2CHꢀCH2),
3.61 (dd, J3,4 +J4,5 19.2 Hz, H-4), 2.84–2.65
(m, 2 H, SCH2CH3), 1.44 (d, 3 H, J6,5 6.2 Hz,

J.R. Rich et al. / Carbohydrate Research 330 (2001) 517–521
521
financial support of this work.
H, J5%,4% 9.7 Hz, H-5%), 3.67 (br. m, 1 H, H-2%),
3.43 (s, 3 H, OCH3), 3.21 (dd, 1 H, J4%,3%+J4%,5%
18.6 Hz, H-4%), 1.50, 1.38 (2s, 6 H, C(CH3)2),
1.33 (d, 3 H, J6%,5% 6.2 Hz, H3-6%); 13C NMR
(75.03 MHz, CDCl3): l 166.4 (CꢀO benzoate),
134.5 (CH2CHꢀCH2), 133.2 (para aromatic),
130.4 (ipso aromatic), 129.9 (ortho aromatic),
128.6 (meta aromatic), 117.7 (CH2CHꢀCH2),
References
1. Whitcombe, A. J.; O’Neill, M. A.; Steffan, W.; Alber-
sheim, P.; Darvill, A. G. Carbohdyr. Res. 1995, 271,
15–29.
2. Vidal, S.; Doco, T.; Williams, P.; Pellerin, P.; York, W.
S.; O’Neill, M. A.; Glushka, J.; Darvill, A. G.; Alber-
sheim, P. Carbohdyr. Res. 2000, 326, 277–294.
3. Lichtenthaler, F. W.; Kla¨res, U.; Lergenmu¨ller, M.;
Schwidetzky, S. Synthesis 1992, 179–184.
4. Nachman, F. J.; Ho¨nel, M.; Williams, T. M.; Halaska, R.
C.; Mosher, H. S. J. Org. Chem. 1986, 51, 4802–4806.
5. Pathirana, C.; Jensen, P. R.; Dwight, R.; Fenical, W. J.
Org. Chem. 1992, 57, 740–742.
6. Rich, J. R.; McGavin, R. S.; Gardner, R.; Reimer, K. B.
Tetrahedron: Asymmetry 1999, 10, 17–20.
7. Auzanneau, F.-I.; Bundle, D. R. Carbohydr. Res. 1991,
212, 13–24.
113.5 (C(CH3)2), 108.2 (1J13
172.1 C-1),
–1
C
100.3 (1J13
172.8 C-1%), 90.H1 (C-2), 87.9
–1
C
(C-3), 81.4 H (C-4%), 76.3 (C-3%), 74.1
(CH2CHꢀCH2, C-4), 72.0 (C-2), 69.6 (C-5),
67.6 (C-5%), 54.8 (OCH3), 27.6, 25.5
(C(CH3)2), 18.0 (C-6%). Anal. Calcd for
C25H34O10: C, 60.72; H, 6.93. Found: C, 60.43;
H, 7.09.
8. Byramova, N. E.; Ovchinnikov, M. V.; Backinowsky, L.
V.; Kochetkov, N. K. Carbohydr. Res. 1983, 124, C8–
C11.
9. Piancatelli, G.; Scettri, A.; Dauria, M. Synthesis 1982,
245–258.
10. Bock, K.; Pedersen, C. J. Chem Soc., Perkin Trans. 2
1974, 293–297.
Acknowledgements
We wish to thank the Natural Sciences and
Engineering Research Council of Canada for
.