Application of novel, N-DTPM protected D-glucosamine building blocks in oligosaccharide synthesis

Article abstract of DOI:10.1016/S0040-4039(01)00367-7

A study of glycosylation reactions was performed, using novel N-DTPM protected glucosamine donors 1-3 and acceptors 4-9 ranging from achiral primary alcohols to various alcohols within the D-GlcNAc-, D-Gal- and D-Glu-series. The results show high yielding reactions with good β-selectivities.

Full text of DOI:10.1016/S0040-4039(01)00367-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3133–3136
Application of novel, N-DTPM protected
D
-glucosamine building
blocks in oligosaccharide synthesis
Latika Singh and Joachim Seifert*
Alchemia Pty Ltd., 3 Hi-Tech Court, Brisbane Technology Park, Eight Mile Plains, Qld 4113, Australia
Received 8 January 2001; revised 19 February 2001; accepted 28 February 2001
Abstract—A study of glycosylation reactions was performed, using novel N-DTPM protected glucosamine donors 1–3 and
acceptors 4–9 ranging from achiral primary alcohols to various alcohols within the
D-GlcNAc-, D-Gal- and D-Glu-series. The
results show high yielding reactions with good b-selectivities. © 2001 Elsevier Science Ltd. All rights reserved.
2-Amino-2-deoxy-glycopyranosides are ubiquitous and
important constituents of glycoproteins, glycolipids and
proteoglycans. The carbohydrate moieties therein are
involved in important biological processes including
cancer metastasis, inflammation and other cellular
recognition phenomena.1 The syntheses of these biolog-
ically active structures requires orthogonal protecting
groups which are both efficient and cost effective.
Within the framework of a project on the syntheses of
complex oligosaccharides, the novel (1,3-dimethyl-2,4,6
(1H,3H,5H)-trioxopyrimidin-5-ylidene) methyl protect-
ing group (‘DTPM’ group, Scheme 1) was developed.
This amino protecting group was designed as a cheap
and efficient amino protecting group orthogonal to the
most common reaction conditions encountered in car-
bohydrate chemistry (i.e. acylation/deacylation, alkyla-
tion, silylation/desilylation, hydrogenolysis, reductive
arylidene cleavage, oxidative aryl ether cleavage and
Lewis acid promoted reactions).2
Herein we present a systematic study exploring the
stereochemical course in N-DTPM assisted glycosyla-
tions using the glucosamine building blocks 1–3 as
glycosyl donors3 and compounds 4–9 as acceptors4 of
varying reactivities (Scheme 1). The products obtained
from glycosylations of the acceptors 4–8 with the
donors 1–3 are shown in Scheme 2 and the results are
shown in Table 1 (vide infra).
From our studies, a general pattern of reactivities and
selectivities emerges. Thiomethyl glycoside
1 and
trichloroacetimidate 3 are the donors of choice for high
yielding reactions with N-DTPM protected building
blocks. Even though the N-DTPM is apparently non-
OH
Me
Me
OAc
O
OH
O
O
O
BnO
BnO
AcO
OH
Ph
O
AcO
X
X
BnO
OMe
O
NH
O
5
4
6
1
2
3
β - SMe
O
Me Me
α - Br
CH3
OBn
H
OH
OBz
O
N
O
O
O
HO
BnO
α - O-(C=NH)CCl3
O
OBn
OMe
HO
HO
O
O
N
CH3
N3
N3
BzO
OMe
DTPM
7
8
9
Scheme 1. N-DTPM protected D
-glucosamine building blocks 1–33 served as glycosyl donors during the glycosylation studies; the
alcohols 4–94 were used, representing glycosyl acceptors of various reactivities.
Keywords: amino sugars; glycosidation; vinylogous amide.
* Corresponding author. Tel.: +61 7 3340 0200; fax: +61 7 3340 0222; e-mail: jseifert@alchemia.com.au
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00367-7

3134
L. Singh, J. Seifert / Tetrahedron Letters 42 (2001) 3133–3136
OBn
O
OAc
O
BnO
DTPMNH
O
Ph
O
AcO
AcO
AcO
O
O
OMe
8
O
AcO
AcO
7
OAc
O
O
OBn
N3
N3
AcO
AcO
DTPMNH
X
14α/β
13α/β
(Entries 17-19)
(Entries 14-16)
DTPMHN
6
5
1- 3
OAc
OAc
DTPMHN
O
OAc
OAc
DTPMHN
OAc
O
4
O
OAc
O
Me
Me
OAc
O
O
O
O
O
12α/β
AcO
BnO
BnO
11α/β (Entries 4-10)
AcO
O
(Entries 11-13)
O
BnO
OMe
DTPMHN
O
10α/β
(Entries 1-3)
Me Me
Scheme 2. Glycosylation reactions of N-DTPM protected
from achiral primary alcohols to various alcohols within the
D
-glucosamine derivatives 1–3 with several glycosyl acceptors ranging
-GlcNAc-, -Gal- and -Glu-series.
D
D
D
Table 1. Glycosylation reactions of N-DTPM protected
D-glucosamine derivatives 1–3 with alcohols 4–8
Entry
Donor
Acceptor
Promotora
Solvent (temperature, °C)
Product (yield, %)
a/b-Ratiob
1
2
3
4
5
6
7
8
1
2
3
1
1
1
2
3
3
3
1
2
3
1
2
3
1
2
3
4
4
4
5
5
5
5
5
5
5
6
6
6
7
7
7
8
8
8
DMTST
AgOTf
CH2Cl2 (0)
CH3CN (0)
CH2Cl2 (0)
CH2Cl2 (0)
CH3CN (0)
CH3CN (0)
CH3CN (0)
CH2Cl2 (0)
Et2O (0)
Et2O (−78)
CH2Cl2 (0)
CH3CN (0)
CH2Cl2 (0)
CH2Cl2 (0)
CH3CN (0)
CH2Cl2 (0)
CH2Cl2 (0)
CH3CN (0)
CH2Cl2 (0)
10 (95)
10 (95)
10 (98)
11 (90)
11 (82)
11 (94)
11 (80)
11 (88)
11 (79)
11 (77)
12 (95)
12 (37)
12 (97)
13 (84)
13 (54)
13 (53)
14 (86)
14 (83)
14 (80)
1/5
1.2/1
1/5
1/8.2
1/4.2
1/4.7
1/4.2
1/2.3
1/1
TMSOTf
DMTST
DMTST
NIS/TfOH
AgOTf
TMSOTf
TMSOTf
TMSOTf
DMTST
AgOTf
TMSOTf
DMTST
AgOTf
TMSOTf
DMTST
AgOTf
9
10
11
12
13
14
15
16
17
18
19
1.3/1
1/8
1/6
1/2
1/3.5
1/1.2
1/1
1/1.3
1/2.1
1/4.2
TMSOTf
8
a The following equivalents of activating reagents were added: (i) DMTST5 (5 equiv.); (ii) NIS (1.7 equiv.)/TfOH7 (0.17 equiv.); (iii) AgOTf (1.5
9
equiv.); (iv) TMSOTf (0.2 equiv.).
b Selected 1H NMR data is shown in Ref. 10.
neighbouring group participating in origin, good b-
selectivities were obtained with the thioglycoside 1 and
DMTST5 as promoter, especially with primary alcohol
acceptors (entries 1, 4 and 11). Despite recent reports in
the literature,6 NIS/TfOH7 as promoter for 1 was much
less efficient than DMTST and only the entries in
Tables 1 and 2 gave satisfactory results.
With the trichloroacetimidate 3, reactions were fast and
generally not as b selective. Because a-linked -GlcNAc
moieties are constituents of biologically relevant pro-
teoglycans (i.e. heparan sulfate, heparin), we tried to
achieve a-selectivity in these glycosylation reactions.
The reduced b-selectivity of 3 encouraged us to change
the reaction conditions towards a-selectivity. Unfortu-
D
Table 2. Glycosylations on diol 9 using the N-DTPM protected
D
-glucosamine derivatives 1–3
Entry
Donor
Promotera
Solvent (temperature, °C)
Productsa (yield, %)
15a
15b
16
17
1
2
3
4
5
1
1
1
2
3
DMTST
DMTST
NIS/TfOH
AgOTf
CH2Cl2 (0)
14
15
21
13
16
51
25
25
60
72
33
11
19
10
8
nd
nd
24
10
nd
CH2Cl2 (−40)
CH2Cl2/CH3CN 1/1 (−40)
Et2O (−40)
TMSOTf
CH2Cl2(40)
a See footnote a, Table 1, nd=not determined.

L. Singh, J. Seifert / Tetrahedron Letters 42 (2001) 3133–3136
3135
(Entries 1-5)
1 - 3
15 α/β + 16 + 17
OAc
9
+
OAc
O
O
OAc
O
AcO
AcO
AcO
AcO
OH
O
O
OBz
O
OBz
O
O
OBz
O
AcO
AcO
DTPMHN
DTPMHN
O
DTPMHN
O
AcO
AcO
AcO
DTPMHN
HO
BzO
BzO
BzO
OMe
OMe
OMe
17
16
15α/β
Scheme 3. Reaction of diol 9 with glycosyl donors 1–3; other stereoisomers as shown were not isolated.
resulted in significantly more (1“4) glycosylation
product 16 than at −40°C. At this lower temperature,
the regioselectivity could be improved and trichloroace-
timidate 3 furnished the 3-O-glycosylated disaccharides
15a/b in excellent yield and regioselectivity (entry 5,
88%, 15a/b:16ꢀ11:1). Surprisingly, thioglycoside 1 was
inferior to the bromide 2 under these conditions. Fur-
thermore, when 1 was activated by NIS/TfOH (entry
3), no regio- and stereoselective preference was achieved
and nearly statistical product distribution was obtained,
including overglycosylation to trisaccharide 17.
nately, the shift to lower temperatures and ether as the
solvent (entries 9 and 10) gave only moderate a-
selectivities.
In contrast to building blocks 1 and 3, the reactivity
and selectivity of bromide 2 in glycosylation reactions
does not follow a general pattern and is strongly depen-
dent on the acceptor substrate. Broadly, it is less
stereoselective than the DMTST promotion of thiogly-
coside 1 and more b-selective than the trichloroacetimi-
date 3.
In summary we have shown that the novel N-DTPM
group can be used efficiently in carbohydrate chemistry.
The best results were obtained with thioglycoside 1 and
Entries 14–19 show glycosylation reactions of the sec-
ondary 3-OH and 4-OH groups of acceptors within the
D
-glucosamine series. Despite the large steric bulk of
trichloroacetimidate 3 of N-DTPM protected D-glucos-
the N-DTPM protecting group, glycosylations of the
3-OH group of compound 8 (entries 17–19) proceeded
rapidly and in high yields. In contrast to other results,
trichloroacetimidate 3 displayed the best b-selectivity in
glycosylation reactions with 8.4d Next, attention
focussed on glycosylations with glycosyl acceptor 7,4c
leading to chitobiose derivatives 13a/b, representing a
partial structure of N-glycans (entries 14–16). Unlike
the reactions on acceptor 8, the chitobiose formation
was slower and required prolonged reaction times. Only
the DMTST promoted reaction of thioglycoside 1
(entry 14) furnished compound 13a/b in high yield and
b-selectivity. The best result of chitobiose formation
was achieved with the N-acetyl analogue of 7. Its
reaction with thioglycoside 1 under NIS/TfOH promo-
tion gave b-selectively the corresponding chitobiose
derivative in 72% yield. Analogues of acceptors 7 and 8
bearing the N-phthaloyl group as amino protection
were also studied. Due to the large steric demand of
both N-protecting groups, these reactions proceeded
very slowly and in low yields. Therefore, we believe that
amine. Furthermore, thioglycoside 1 exhibits good b-
selectivities when activated by DMTST. Currently we
are investigating the utility of N-DTPM protection in
oligosaccharide synthesis including a-stereoselective
linkage of D-galactosamine with serine/threonine, which
represents a common motif of biologically important
O-glycan structures.
Acknowledgements
We thank Dr. Laurent Bornaghi and Mr. Stephen
Taylor for providing us with the acceptor 5 and the
precursor to building block 1, respectively. We are
grateful to Mr. Hoan The Vu for the ESI-MS measure-
ments.
References
N-phthaloyl protected
D-glucosamine acceptors are
mismatched substrates for N-DTPM protected
cosamine donors 1–3.
D-glu-
1. (a) Varki, A. Glycobiology 1993, 3, 97–130; (b) Dwek, R.
Chem. Rev. 1996, 96, 683–720.
2. (a) Toth, I.; Dekany, G.; Kellam, B. Int. Pat. Appl.
PCT/AU 98/00808; (b) Dekany, G.; Bornaghi, L.; Papa-
georgiou, J.; Taylor, S. Tetrahedron Lett. 2001, 42, 3129–
3132.
After examining selectively deblocked alcohols as
acceptors, we next investigated whether regioselective
glycosylations could be achieved with N-DTPM pro-
tected
D
D
-glucosamine donors 1–3. For this purpose, the
3. (a) For thiomethylglycoside 1 see Ref. 2; (b) Glycosyl
-galacto configured diol 94e was chosen. The products
bromide 2 was prepared from
D-glucosamine in three
steps: (i) DTPM–NMe2,2 MeOH (80%); (ii) Ac2O/pyri-
dine (97%); (iii) HBr/HOAc, CH2Cl2, 0°C (91%); (c)
obtained from the glycosylations are shown in Scheme
3 and the results are compiled in Table 2. Compound 9
was expected to be glycosylated at the more reactive
equatorial 3-hydroxy group. Glycosylations at 0°C
Trichloroacetimidate 3 was prepared from
D-glucosamine
in four steps: (i) DTPM–NMe2,2 MeOH (80%); (ii) Ac2O/

3136
L. Singh, J. Seifert / Tetrahedron Letters 42 (2001) 3133–3136
pyridine (97%); (iii) piperidine, THF, 0°C (91%); (iv)
Cl3CCN, K2CO3, CH2Cl2, 0°C (92%).
steps); (e) Compound 9: Buskas, Th.; Konradsson, P. J.
Carbohydr. Chem. 2000, 19, 25–51; (f) Guenther, W.; Kunz,
H. Carbohydr. Res. 1992, 228, 217–241.
4. (a) Compounds 4 and 6 were purchased from Sigma/
Aldrich; (b) Compound 5: Liptak, A.; Jodal, J.; Nanasi, P.
Carbohydr. Res. 1975, 44, 1–11; (c) Compound 7 was
prepared from ethyl-4-O-acetyl-3,6-di-O-benzyl-2-deoxy-
5. Andersson, F.; Fu¨gedi, P.; Garegg, P. J.; Nashed, M.
Tetrahedron Lett. 1986, 27, 3919–3922.
6. Xe, X. S.; Wong, C. H. J. Org. Chem. 2000, 65, 2410–2431.
7. Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331–1334.
2-phthalimido-1-thio-b-D
-glucopyranoside4f in three steps:
(i) BnOH, NIS, TfOH, CH3CN, −40°C (85%); (ii)
H2NCH2CH2NH2, n-BuOH, 100°C; Tf–N3, DMAP,
CH3CN (85%, two steps); (d) Compound 8 was prepared
from ethyl-3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-pht-
8. Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
9. (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25,
212–235; (b) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr.
Chem. Biochem. 1994, 50, 21–123.
halimido-b-D
-glucopyranoside4f in three steps: (i) MeOH,
1
NIS, TfOH, CH3CN, −40°C (85%); (ii) H2NCH2CH2-
NH2, n-BuOH, 100°C; Tf–N3, DMAP, CH3CN (83%, two
10. For selected H NMR data (500 MHz, CDCl3), see Table
3.
Table 3.
Compound
l [NH (JNH,2)]
l [H
6
-C=(JNH,H-Cꢀ)]
l [H-11 (J1,2)]
l [H-12 (J1,2)]
l (NMe)
10a
10b
11a
11b
12a
12b
13a
13b
14a
14b
15a
15b
16
10.13 (9.7 Hz)
10.11 (9.3 Hz)
10.35 (9.6 Hz)
10.17 (9.3 Hz)
10.22 (9.8 Hz)
10.22 (9.8 Hz)
10.04 (9.9 Hz)
10.02 (9.4 Hz)
10.20 (10.0 Hz)
10.35 (9.3 Hz)
10.18 (9.9 Hz)
10.05 (8.5 Hz)
10.25 (8.9 Hz)
10.37 (9.6 Hz),
9.98 (7.6 Hz)
8.04 (13.4 Hz)
8.09 (13.2 Hz)
8.07 (13.9 Hz)
8.16 (13.3 Hz)
8.10 (13.1 Hz)
8.10 (13.1 Hz)
8.10 (13.7 Hz)
7.99 (13.2 Hz)
7.90 (13.7 Hz)
8.21 (13.4 Hz)
8.31 (13.7 Hz)
8.02 (13.7 Hz)
8.10 (14.0 Hz)
8.29 (13.5 Hz),
7.79 (13.5 Hz)
5.02 (3.6 Hz)
4.41 (8.0 Hz)
4.59 (3.3 Hz)
4.57 (3.3 Hz)
5.51 (5.0 Hz)
5.37 (5.0 Hz)
4.43 (8.0 Hz)
4.26 (8.2 Hz)
4.33 (8.0 Hz)
4.42 (7.8 Hz)
5.11 (3.6 Hz)
5.04 (3.7 Hz)
5.04 (3.7 Hz)
5.03 (3.7 Hz)
3.23, 3.21
3.22, 3.19
3.20, 3.14
3.20, 3.13
3.31, 3.27
3.30, 3.26
3.25, 3.23
3.32
3.21, 3.18
3.32, 3.27
3.17, 3.02
3.16, 3.01
3.31, 3.19
3.21, 3.11,
3.05, 2.90
5.13 (3.6 Hz)
4.18 (8.0 Hz)
5.05 (3.7 Hz)
4.62 (8.1 Hz)
5.78 (3.9 Hz)
4.28 (8.5 Hz)
5.34 (3.7 Hz)
4.73 (8.3 Hz)
5.19 (3.6 Hz)
4.80 (8.0 Hz)
4.96 (8.2 Hz)
5.10 (7.5 Hz),
4.70 (8.1 Hz)
17
.
.