The synthesis of disaccharides terminating in D-septanosyl residues using acyclic intermediates

Article abstract of DOI:10.1055/s-1998-3128

A general method for the construction of disaccharides containing D-septanosyl residues from acyclic intermediates has been developed. The synthesis of an analogue of N-acetyl D-lactosamine with a D-galactoseptanosyl unit has also been accomplished with the aim of determining the behaviour of this compound as a substrate for several glycosyltransferases.

Full text of DOI:10.1055/s-1998-3128

March 1998
SYNLETT
307
The Synthesis of Disaccharides Terminating in D-Septanosyl Residues Using Acyclic
Intermediates
c
1
*
Joseph C. M Auliffe and Ole Hindsgaul
Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, Canada
Fax: Int. code +(403) 492 7705; E-mail: Ole.Hindsgaul@ualberta.ca
Received 8 October 1997
9
Abstract: A general method for the construction of disaccharides
containing D-septanosyl residues from acyclic intermediates has been
developed. The synthesis of an analogue of N-acetyl D-lactosamine with
a D-galactoseptanosyl unit has also been accomplished with the aim of
determining the behaviour of this compound as a substrate for several
glycosyltransferases.
In order to test the feasibility of this scheme, the O,S-acetal 1 was
chosen as the model compound (Scheme 2). Following deacetylation
(NaOMe/MeOH), sequential treatment with excess t-butyldiphenylsilyl
chloride (TBDPS-Cl) in pyridine and then Ac O/DMAP gave the 6-O-
silyl ether 2 in high yield (86%). Careful desilylation with excess HF/
pyridine in THF gave the 6-OH compound 3 and was accompanied by
2
10
minimal acetyl group migration. Treatment of this compound with NIS/
1
TfOH in CH Cl at -30°C gave the septanoside 4 as anticipated. The H
2
2
The role of carbohydrates in biochemical processes is eliciting much
NMR spectrum of 4 allowed unambiguous assignment of a seven-
2
attention recently.
Accordingly, the demand for synthetic
membered ring owing to the presence of downfield signals attributed to
carbohydrates and their analogues has grown. The properties of seven-
membered sugars have remained mostly unexplored to date, in contrast
11
H-2, -3, -4 and -5. The signals corresponding to the H-6 protons were
observed at 3.69 and 4.15 ppm with a geminal coupling constant of 14.1
Hz. Long-range coupling between H-4 and one of the H-6 protons (J =
2.4 Hz) was also evident. With this result in hand our attention was
turned to the synthesis of selectively protected intermediates bearing
saccharide aglycones.
3
to five- and six-membered sugars. Aside from the challenge in
constructing such molecules, there is also the potential to derive
information about carbohydrate-protein interaction. This letter describes
the synthesis of disaccharides terminating in D-galacto-, D-gluco- and
D-manno-septanosyl residues. The synthesis of an analogue of N-acetyl
D-lactosamine
(Galβ(1→4)GlcNAc,
LacNAc)
containing
a
D-galactoseptanosyl residue is also presented.
The synthesis of D-hexoseptanosides has not been extended beyond
monosaccharide derivatives of D-galactose and D-glucose.
D-Glucoseptanoses have been obtained either by isopropylidination of
4
D-glucose, ring expansion of methyl 4,6-O-isopropylidene-α-D-
5
6
glucopyranoside or from D-glucose diethyl dithioacetal. The synthesis
of methyl D-galactoseptanoside was also achieved from acyclic
7
intermediates. In general these methods suffer from either low yields or
a lack of applicability to more complex substrates. Elaboration of the
acyclic approach could allow the synthesis of seven-membered sugars
with a range of aglycones.
12
The 1-chloro-1-(ethylthio) compounds 5-7 were synthesized from the
corresponding diethyl dithioacetals by treatment with AcCl/BF Et O
(100:1) at reflux. Glycosylation of the acceptor 8 with 5, promoted by
AgOTf and 2,6-di-t-butyl-4-methyl pyridine (DTBMP) in CH Cl at
3
2
8
2
2
We recently presented a method for the synthesis of D-hexofuranosides
-30°C, gave the O,S-acetal 12 (81%) (Scheme 3). Conversion of this
compound into the 6′-O-TBDPS derivative 13, and then the 6′-OH
compound 14, was accomplished as for the monosaccharide 1.
Likewise, the cyclization of 14 proceeded smoothly to give the
D-galactoseptanoside 15 in excellent yield (89%). The 4-OH acceptor 9
was also glycosylated by 5 to give 16 (56%). In this case however, the
conversion of 16 to the 6′-O-TBDPS derivative 17 was not easily
accomplished, requiring over 24 h to go to completion. Desilylation
gave 18 (65%) which was in turn converted into the septanoside 19 in
from acyclic precursors in which an unprotected O,S-acetal could be
cyclized to a D-furanoside with high stereo- and regioselectivity. The
8
cyclization of differentially protected intermediates clearly presents the
possibility of access to sugars of other ring sizes (Scheme 1). With
regard to seven-membered rings, this strategy involved the synthesis of
an O,S-acetal selectively protected at the primary alcohol. Following
selective deprotection, treatment with a thiophilic promotor would be
expected to result in the formation of a septanoside.
1
good yield (76%). The H NMR spectra of 15 and 19 confirmed the
13
selective formation of the D-galactoseptanosyl residue.
Attention was next turned to derivatives of D-glucose and D-mannose.
The D-gluco donor 6 was coupled to the acceptor 10 with AgOTf
promotion, and the product 20 was elaborated to the D-glucoseptanoside
23 (Scheme 5). Glycosylation of the D-manno acceptor 11 with the
Scheme 1

308
LETTERS
SYNLETT
In both cases, the 6′-OH intermediates 22 and 26 were not isolated but
cyclized directly to the D-septanosides 23 and 27, respectively. This
greatly reduced acetyl migration and hence the presence of by-products
corresponding to other ring-sizes. In contrast to the
1
D-galactoseptanosides, the H NMR spectra of 23 and 27 did not exhibit
13
long range coupling between H-4′ and -6′.
The use of donors prefunctionalised at the primary alcohol was also
examined. Glycosylation of acceptors 8 and 10 with the 1-bromo-1-
14
(ethylthio) donor 28 resulted in average to low yields of the
corresponding O,S-acetals, 16 (65%) and 28 (37%), respectively. In
contrast, the D-mannose derivative 29 was not effective in glycosylating
15
the acceptor 10. The corresponding 1-chloro compound 30 however,
glycosylated 10 to give 25, with virtually the same yield (63%) and
stereoselectivity (4:3) as the pentaacetate donor 7.
Finally, the deprotection of 19 was carried out (NaOMe, MeOH; Pd/C,
H , MeOH, AcOH) yielding the unprotected disaccharide 31 (Scheme
2
16
6). This compound, an analogue of LacNAc, is under evaluation as a
potential substrate for a series of glycosyltransferases.
donor 7 proceeded in acceptable yield (58%), however the product 24
was obtained as a mixture (4:3) of diastereoisomers. This outcome was
in contrast to a previous result in which the treatment of the acceptor 8
8
with 7 gave rise to only one compound. Cyclization of the 6′-OH
intermediate 26 also gave rise to a mixture of D-mannoseptanosides 27.
Interestingly, the ratio of anomers was now determined to be 4:1 in
favor of the α-anomer.
Acknowlegements. This work was supported by the Natural Sciences
and Engineering Research Council of Canada.

March 1998
SYNLETT
309
1
References and Notes
13.
H NMR of D-Septanosyl Residues
1.
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14. Synthesized from the corresponding diethyl dithioacetals upon
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2
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by cyclohexene (1 eq).
1
11.
H NMR Data for 4: δ 2.01-2.16 (4s, 12 H; COMe), 3.39 (s, 3 H;
OMe), 3.69 (ddd, J 2.4 Hz, J 1.5 Hz, J 14.1 Hz, 1 H; H-6),
15. Synthesized by treatment of 29 with AgOAc (2 eq) at –30°C,
followed by HCl in ether.
4,6
5,6
6,6
1
4.15 (dd, J 1.0 Hz, 1 H; H-6), 4.62 (d, J 5.7 Hz, 1 H; H-1),
5,6
1,2
16. 31: Partial H NMR (360 MHz, CD OD): δ = 3.64 (s, 3 H; OMe);
3
4.79 (ddd, J 1.2 Hz, 1 H; H-5), 5.33 (ddd, J 1.5 Hz, 1 H; H-
4,5
3,4
3.65 (m, 1 H; H-2); 4.40 (d, J 8.4 Hz, 1 H; H-1); 4.58 (d, J
6.6 Hz, 1 H; H-1′).
1,2
1′,2′
4), 5.38 (dd, J 9.6 Hz, 1 H; H-3), 5.47 (dd, 1 H; H-2).
2,3
12. a) Wolfrom, M.L.; Weisblat, D.I.; Hanze, A.R. J. Am. Chem. Soc.
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