N-thiodiglycoloyl derivatives of glucosamine as glycosyl donors

Article abstract of DOI:10.1016/S0040-4039(99)02136-X

N-Thiodiglycoloyl (TDG) protection of O-acetylated glucosamine could be readily carried out with thiodiglycolic anhydride and then treatment with acetic anhydride in pyridine. Ensuing reaction with hydrazinium acetate and then base-catalyzed activation with trichlorocetonitrile afforded N-TDG protected glucosamine donor 3. Glycosylation of acceptors 8 and 5 in dichloromethane with TMSOTf as the catalyst gave β-glycosides 6 and 9 in high yields. For TDG cleavage MeONa/MeOH treatment followed by radical desulfurization with Bu₃SnH/AIBN and reacetylation with Ac₂O/pyridine was employed, thus giving N-acetyl glucosamine containing compounds 7 and 10 in a convenient, high-yielding procedure. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02136-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 629–632
N-Thiodiglycoloyl derivatives of glucosamine as glycosyl
donors1
Julio C. Castro-Palomino and Richard R. Schmidt ∗
Fakultät für Chemie, Universität Konstanz, M725, D-78457 Konstanz, Germany
Received 11 October 1999; accepted 15 November 1999
Abstract
N-Thiodiglycoloyl (TDG) protection of O-acetylated glucosamine could be readily carried out with thiodi-
glycolic anhydride and then treatment with acetic anhydride in pyridine. Ensuing reaction with hydrazinium
acetate and then base-catalyzed activation with trichlorocetonitrile afforded N-TDG protected glucosamine donor
3. Glycosylation of acceptors 8 and 5 in dichloromethane with TMSOTf as the catalyst gave β-glycosides 6 and 9 in
high yields. For TDG cleavage MeONa/MeOH treatment followed by radical desulfurization with Bu3SnH/AIBN
and reacetylation with Ac2O/pyridine was employed, thus giving N-acetyl glucosamine containing compounds 7
and 10 in a convenient, high-yielding procedure. © 2000 Elsevier Science Ltd. All rights reserved.
Glucosamine frequently occurs as a constituent of glycoconjugates;2 generally, the glucosamine
moiety is N-acetylated and found in β-glycosidic linkage. Glycoside bond-formation with donors derived
from N-acetylglucosamine (GlcNAc) leads to 1,3-oxazolinium intermediates,3 which exhibit only weak
glycosyl donor properties. Therefore, various alternatives have been investigated having, for instance,
a phthaloyl,2,3 tetrachlorophthaloyl,4,5 dithiasuccinyl,6 trichloroethoxycarbonyl7,8 or dimethylmaleoyl
group9 in the 2-position, thus supporting, via neighbouring group participation, the formation of the
β-anomer. Due to the strong electron withdrawing character of the N-substituents, these glucosamine
derivatives exhibit increased glycosyl donor properties. However, the intermediate generation of free
amino groups in all the above-mentioned methodologies is quite frequently disadvantageous.10 There-
fore, methods retaining the N-acetyl functionality in the activated species are of great interest.11 Recently,
we proposed the use of N,N-diacetyl derivatives of amino sugars12 as a convenient solution to this
problem. These kinds of compounds are readily available and give β-linked glycosides with reactive
acceptors in very high yields. Removal of one of the N-acetyl groups can be performed under very mild
conditions (MeONa, MeOH), thus leading directly to the desired N-acetyl glycosides; even the selective
cleavage of one of the N-acetyl groups can be performed in the presence of O-acetyl protective groups.
Therefore, this method seemed to be an ideal solution. However, for less reactive glycosyl acceptors
transacetylation from donor to acceptor was observed to some extent.12
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02136-X
tetl 16064

630
It was rationalized that this undesirable side reaction could be overcome by a corresponding cyclic
N,N-diacyl amino protective group, thus requiring a readily removable auxiliary group Y which would
enable liberation of the N,N-diacetyl group (Scheme 1). The deprotection conditions could then be
maintained as mild as with the N,N-diacetyl compounds. Therefore, we turned our attention to the N-
thiodiglycoloyl (TDG) residue as a nitrogen protecting group (Scheme 1, Y=S).
Scheme 1.
In analogy to other imido derivatives of glucosamine, the corresponding cyclic imide A should afford,
via anchimeric assistance by one of the carbonyl groups as shown in B, only β-glycosides C. The
resulting glycosides could then be transformed by radical reductive desulfurization13 into the known
N,N-diacetyl compounds D which, as discussed, readily affords target molecules E.
In our first attempts, we tried to protect the free glucosamine utilizing Lemieux’s classic procedure.3 At
first one equivalent of NaOMe in MeOH is added to the glucosamine hydrochloride in order to liberate
the free amine, and then one equivalent of commercially available thiodiglycolic anhydride is quickly
added so as to avoid decomposition of the amino sugar. As expected in this case, for the six-membered
ring formation the ring closure reaction did not proceed as smoothly as for the phthalimido ring closure
(five-membered ring formation).3 Hence, heating of the amide intermediate with acetic anhydride at 60°C
in pyridine for 6 h was required, and the N-TDG-protected glucosamine was obtained as an α/β mixture
in 35% overall yield.
Looking for alternatives, we found that addition of one equivalent of the thiodiglycolic anhydride to
the known O-acetylated amine 114 in pyridine, followed by acetic anhydride addition and heating at
60°C for 6 h, led to the N-TDG-protected glucosamine 2 in 70% yield as pure β-anomer (Scheme 2).
Regioselective removal of the anomeric O-acetyl group with hydrazinium acetate15 in DMF and further
addition of CCl3CN in the presence of DBU afforded the desired donor 3 in high overall yield.
Scheme 2.

631
For the glycosylation with trichloroacetimidate 3 the reactive 6-O-unprotected galactose derivative 416
was chosen as acceptor because GlcNAcβ(1–6)Gal linkages occur frequently in nature. Glycosylation
of 3 with the known acceptor 4,16 using TMSOTf as a catalyst afforded, as expected, only the β-
linked disaccharide 5 in a very high yield (93%) (Scheme 3). Encouraged by this excellent result, we
concentrated our attention to the deprotection of the TDG group.
Scheme 3.
Thus, reaction of disaccharide 5 with Bu3SnH/AIBN in toluene at 110°C resulted in complete
succinoyl protected disaccharide. Obviously, a novel highly efficient intramolecular C–C bond formation
between the two radicals led to the formation of the cyclic product with extrusion of (tri-n-butyl) tin
sulfur compounds. To avoid this undesired intramolecular reaction, first cleavage of the cyclic imide
structure was accomplished with MeONa/MeOH. Treatment of the residue with Bu3SnH in THF led to
direct generation of the acetamido group, and subsequent acetylation with Ac2O/Py afforded the desired
disaccharide 712 in 89% yield.
Because GlcNAcβ(1–3)Galβ(1–4)Glc trisaccharides also occur frequently in nature, known 3,4 O-
unprotected lactose 810 was investigated as acceptor (Scheme 4). Reaction of trichloroacetimidate 3 with
8 under similar conditions as described for 5 afforded the expected trisaccharide 9 as a single product.
The NMR data support the structural assignments.17 The deprotection was performed under the same
conditions as described for 5, affording the known N-monoacetyl trisaccharide 1012 in 87% overall yield.
Scheme 4.

632
In conclusion, TDG-protected trichloroacetimidate from glucosamine was readily available and it
gave, along with the investigated acceptors, excellent glycosylation yields. The deprotection sequence
was mild, and afforded the naturally occurring acetamido sugars in high overall yields.
References
1. This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
2. (a) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123; (b) Garg, H. G.; Vondem Brunch, K.;
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9. Aly, M. R. E.; Castro-Palomino, J. C.; Ibrahim, E. I.; El-Ashry, E. H.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 2305–2316.
10. Greilich, U. Diss. Universität Konstanz; Castro-Palomino, J. C. unpublished results.
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12. Castro-Palomino, J. C.; Schmidt, R. R. Tetrahedron Lett. 1995, 36, 6871–6874.
13. Van Rheenan, V.; Cha, D. A.; Hartley, W. M. Organic Synthesis Coll. 1988, 6, 342–344.
14. Bergmann, M.; Zervas, L. Ber. Dtsch. Ges. 1931, 64, 975–981.
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17. Values of [α]D were measured at 20°C and 1H NMR spectra were recorded in CDCl3 at 250 MHz. Compound 2: [α]D +11
(c 0.7, CHCl3). 1H NMR (250 MHz, CDCl3); δ=1.91–2.39 (4 s, 12H, 4Ac), 3.50 (m, 4H, 2CH2S), 3.85 (m, 1H, 5-H), 4.11
(m, 1H, 6-H), 4.32 (m, 1H, 60-H), 5.03 (dd, 1H, J1,2=J2,3=9.5 Hz, 2-H), 5.18 (dd, 1H, J3,4=J4,5=9.5 Hz, 4-H), 5.81 (dd, 1H,
J2,3=J3,4=9.5 Hz, 3-H), 6.51 (d, 1H, J1,2=9.5 Hz, 1-H). Compound 3: [α]D +14.5 (c 1, CDCl3). 1H NMR (250 MHz, CDCl3):
δ=1.91–2.39 (4 s, 12H, 4Ac), 3.54 (m, 4H, 2CH2S), 3.88 (m, 1H, 5-H), 4.28 (m, 2H, 6-H, 60-H), 5.15 (dd, 1H, J1,2=J2,3=9.5
Hz, 2-H), 5.22 (dd, 1H, J3,4=J4,5=9.5 Hz, 4-H), 5.83 (dd, 1H, J2,3=J3,4=9.5 Hz, 3-H), 6.82 (d, 1H, J1,2=9.5 Hz, 1-H), 8.21 (s,
1
1H, NH). Compound 5: [α]D +6 (c 1, CHCl3). H NMR (250 MHz, CDCl3): δ=2.01–2.39 (3s, 9H, 3OAc), 3.60 (m, 4H,
2CH2S), 3.90 (m, 4H, H-5a, H-2a, H-5b, H-6b), 4.02 (m, 3H, H-60b, H-3a, H-6a), 4.12 (dd, J3,4=J4,5<1 Hz, H-4a), 4.30
(m, 1H, H-60a), 4.50–4.85 (m, H, 3CH2Ph, H-1a), 5.05 (dd, 1H, J1,2=1.5, J2,3=9.8 Hz, H-2b), 5.20 (dd, 1H, J3,4=J4,5=9.8
Hz, H-4b), 5.55 (dd, 1H, J2,3=J3,4=9.8 Hz, H-3b), 5.90 (d, 1H, J1,2=9.5 Hz, H-1b), 7.35–7.75 (m, 20H, Ar). Compound 6:
[α]D +15 (c 1, CHCl3). 1H NMR (250 MHz, CDCl3): δ=2.01–2.39 (3s, 9H, 3OAc), 3.05 (m, 4H, 2CH2), 3.90–4.00 (m, 4H,
H-5a, H-2a, H-5b, H-6b), 4.10 (m, 3H, H-60b, H-3a, H-6a), 4.15 (dd, J3,4=J4,5<1 Hz, H-4a), 4.28 (m, 1H, H-60 a), 4.50–4.85
(m, 7H, 3CH2Ph, H-1a), 5.10 (dd, 1H, J1,2=1.5, J2,3=9.8 Hz, H-2b), 5.22 (dd, 1H, J3,4=J4,5=9.8 Hz, H-4b), 5.56 (dd, 1H,
J2,3=J3,4=9.8 Hz, H-3b), 5.84 (d, 1H, J1,2=9.5 Hz, H-1b), 7.35–7.75 (m, 20H, Ar). Compound 9: [α]D −38 (c 1, CDCl3). 1H
NMR (250 MHz, CDCl3): δ=1.90–2.28 (3s, 9H, 3OAc), 3.60 (m, 4H, 2CH2S), 3.71–4.32 (m, 12H, H-2a, H-3a, H-4a, H-5a,
H-6a, H-6b, H-60a, H-60b, H-2b, H-5b, CH2Ph), 4.51–4.82 (m, 7H, 3CH2Ph, H-1a), 5.12 (dd, 1H, J3,4=J4,5=9.8 Hz, H-4),
5.22 (d, 1H, J1,2=10.2 Hz, H-1b), 5.65 (d, 1H, J2,3=10.3, J3,4=9.8 Hz, H-3), 7.15–7.45 (m, 20H, 5Ar).