Joined use of oxazolidinone and desymmetric amino protection: a new strategy for protection of glucosamine

Article abstract of DOI:10.1016/j.tetlet.2010.02.021

Joined use of N-benzyl oxazolidinone and N-benzyl-N-benzyloxycarbonyl (N-BnCbz) desymmetric amino-protecting function is reported. The new synthetic approach enables the facile preparation of type 1 and type 2 LacNAc disaccharides in satisfactory yields. One-pot deprotection of N-BnCbz and O-benzyl ether is achieved by hydrogenolysis under mild conditions.

Full text of DOI:10.1016/j.tetlet.2010.02.021

Tetrahedron Letters 51 (2010) 1910–1913
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Joined use of oxazolidinone and desymmetric amino protection: a new
strategy for protection of glucosamine
*
Shih-Che Lin, Chin-Sheng Chao, Chiu-Ching Chang, Kwok-Kong T. Mong
Department of Applied Chemistry, National Chiao Tung University, 1001, Ta-Hsueh Road, Hsinchu 300, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Joined use of N-benzyl oxazolidinone and N-benzyl-N-benzyloxycarbonyl (N-BnCbz) desymmetric
amino-protecting function is reported. The new synthetic approach enables the facile preparation of type
1 and type 2 LacNAc disaccharides in satisfactory yields. One-pot deprotection of N-BnCbz and O-benzyl
ether is achieved by hydrogenolysis under mild conditions.
Received 25 December 2009
Revised 3 February 2010
Accepted 5 February 2010
Available online 8 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
A number of naturally occurring glycoconjugates contain N-
acetyl glucosamines that glycosylate at C-3 and C-4 positions.1
Typical examples are the Lewis blood group antigens, which con-
tain either Gal-b(1?3)-GlcNAc (type 1 LacNAc) or Gal-b(1?4)-Glc-
NAc (type 2 LacNAc) backbone.2 Some of these blood group
antigens such as Lewis Y antigen have been proven to be specific
tumor markers for cancer diseases; thus, they are attractive targets
for various biomedical investigations.3 To sustain these research
activities, the supply of pure oligosaccharide samples and their
conjugates is crucial. One of the important factors in oligosaccha-
ride synthesis is the effective formation of glycosidic bonds. How-
ever, due to steric hindrance and hydrogen-bonding interaction,
the C-3 and C-4 hydroxyl functions in N-acetyl glucosamine are
weakly nucleophilic, and therefore glycosylations of these hydro-
xyl functions are often problematic.4,5 To solve these problems, dif-
ferent amino-protecting groups have been designed, which include
N-phthaloyl (N-Phth),6 N-tetrachlorophthaloyl (N-TCPhth),7 N-
dithiasuccinoyl (N-Dts),8 N-trichloroethoxycarbonyl (N-Troc),9 N-
trichloroacetyl (N-TCA),10 N-trifluoroacetyl (N-TFA),11 N,N-diacetyl
(N-Ac2),12 N-p-nitrobenzyloxy-carbonyl (N-PNZ),13 N-dimethyl-
phosphoryl (N-DMP),14 and others.15 In routine practice, the amino
function of glucosamine is often masked with a protecting function
in the early stage of synthesis. After a series of protecting group
manipulations and glycosylations, this amino-protecting group
has to be removed in the final stage. This standard strategy de-
mands the use of a robust protecting function to survive different
conditions, but such a function has to be taken off in the end.
Therefore, it is not easy to design a single protecting function
embracing both features. A point in case is the use of N-Phth pro-
tection, which is stable to different reaction conditions,5 but its re-
moval is non-trivial.15,16
In 2001, Kerns and co-workers reported using N-unprotected
oxazolidinone for the protection of C-3 hydroxyl and C-2 amino
functions in glucosamine.17 This function was later elaborated to
N-acetyl18–22 and N-benzyl oxazolidinone derivatives.23–25 The pri-
mary goal of using oxazolidinone function is to search for a good a-
directing glucosamine donor.17 Subsequent studies reveal some
degree of inconsistency in the stereochemical preference of gly-
cosylations.22,25,26 We speculated that other than stereochemical
preference, the unique feature of N-benzyl oxazolidinone may im-
part additional utilities (Fig. 1).
Our rationale is grounded on the following facts. Firstly, the
‘tied-up’ C-3 hydroxyl and C-2 amino functions reduce the steric
hindrance at C-4 position and therefore should facilitate its glyco-
sylation.21 Secondly, the oxazolidinone protection has been shown
to decrease the reactivity of the anomeric-leaving function,22,27
which paves the way for the reactivity-based glycosylation.28
Thirdly, the hydrolytic opening of oxazolidinone and reprotection
of amine function lead to the formation of desymmetric amino-
protected glucosamine, which to the best of our knowledge has
rarely been studied in the literature.9b In the light of the discussion
above, this study reports a useful strategy for the protection of glu-
cosamine capitalizing the N-benzyl oxazolidinone and its derived
desymmetric N-benzyl-N-benzyloxycarbonyl (N-BnCbz) functions.
unreactive thio-function
reactive thio-function
STol
O
STol
P'O
O
P'O
"PO
H/P"O
NBn
O
NBn
R
O
OH
unhindered
C-4 acceptor site
C-3 acceptor site
* Corresponding author. Tel.: +886 3 5712121x56585; fax: +886 3 5723764.
E-mail address: tmong@mail.nctu.edu.tw (K.-K.T. Mong).
Figure 1. N-Benzyl oxazolidinone-protected glucosamine and its derived disubsti-
tuted-desymmetric amino-protected glucosamine.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.021

S.-C. Lin et al. / Tetrahedron Letters 51 (2010) 1910–1913
1911
In the beginning, 2-Troc-2-deoxy thioglucopyranoside 1 pre-
pared from glucosamine28 was converted to 4,6-O-benzylidene-
OBn
O
OBn
O
t-BuOK, DMF, rt,
75%
BnO
BnO
HO
STol
2N-benzyl-2,3-N,O-carbonyl-2-deoxy thioglucopyranoside
3 via
O
STol
NHBn
benzylidene acetal intermediate 2 (Scheme 1).25 However, the
reductiveringopening of benzylideneacetal 3 required considerable
experimentation (Table 1). Previous efforts using either sodium cya-
noborohydride–hydrogen chloride (NaBH3CN/HCl)29 or triethylsi-
NBn
7
O
6
HO(CH2)6Cl 9, NIS,
cat. TMSOTf, 4A MS
CH2Cl2, -65 oC,
OBn
O
CbzCl, NaHCO3,
MeOH, rt
lane–boron trifluoride etherate (Et3SiH/BF3ÁEt2O)30 led to b?
a
BnO
HO
STol
anomerization. This undesirable reaction is attributable to the coor-
dination of BF3 to ring oxygen atom that promotes the endocyclic
cleavage of C1–O5 linkage.24,31 After some investigations, using tri-
ethylsilane–trifluoroacetic acid (Et3SiH/TFA) at low reaction tem-
N(Cbz)Bn
82%
8
88%
OBn
OBn
PdCl2, Et3SiH,
Et3N, CH2Cl2, rt
perature was found to be effective for the reduction of b?
a
O
O
BnO
BnO
anomerization.32 To our delight, N-benzyl-2,3-N,O-carbonyl-pro-
tected b-thioglucopyranoside 4b was formed exclusively in high
80% yield at À20 °C (Table 1, entry 3). However, anomerization of
OR
OR
HO
HO
N(Cbz)Bn
NHBn
45%
10, R = (CH2)6Cl
11, R = (CH2)6Cl
4b to
a-anomer 4a and trace amount of complete deacetalation
Scheme 2. Synthesis of desymmetric (N-BnCbz)-protected glucosamine acceptor 10.
product 5 were observed at higher reaction temperatures (Table 1,
entries 1 and 2). Noted that the use of the literature procedure re-
sulted in a 1:6 a
/b-anomeric mixture (Table 1, entry 4).24 The b-ano-
Further support of their structures could be obtained by high tem-
perature NMR spectroscopy, as demonstrated for glycoside 10 (ca
VT-NMR from rt to 100 °C in deuterated DMSO solvent).37 The
broadening of resonance signal is due to the presence of the Cbz
carbamate function because such a broadening phenomenon had
gone for glucosamine glycoside 11, in which the Cbz function
was removed.
With glucosamine acceptors 4b and 10 in hand, the stage was
ready to study their glycosylations with known thioglycosides
12–16 (Table 2).38 Glycosylations of 4b with thiogalactopyranoside
meric configuration of 4b was supported by the 13C chemical shift at
86.7 ppm and 1JCH coupling constant of 161 Hz.33
After the preparation of glucosamine acceptor 4b, this study
proceeded to synthesize a desymmetric amino-protected glucosa-
mine acceptor (Scheme 2). In this regard, N-benzyl oxazolidinone-
protected glucosamine thioglycoside 625 was treated with t-BuOK
to produce benzylamine derivative 7,25 which was chemoselective-
ly converted to desymmetric N-benzyl-N-benzyloxycarbonyl (N-
BnCbz)-protected glucosamine thioglycoside 8.34 Subsequent gly-
cosylation of aglycon acceptor 9 with thioglycoside 8 using N-iodo-
succinimide (NIS) and trimethylsilyl trifluoromethanesulfonate
(TMSOTf) as promoters furnished glucosamine glycoside 10.35
Noted that the assignment of 1H NMR spectra of 8 and 10 was dif-
ficult due to the peak broadening of the resonance signals.36 None-
theless, their preliminary identifications were evidenced by HRMS.
12 and thiofucopyranoside 13 produced Gal-
charide 17 and Fuc- (1?4)-GlcNAc disaccharide 18 as the single
anomers (Table 2, entries 1 and 2). Intriguingly, the thiotolyl func-
tion in thioglycoside 18 underwent b? anomerization forming an
inseparable 1:3.5 /b-anomeric mixture. Though this anomeriza-
a(1?4)-GlcNAc disac-
a
a
a
tion can be explained by C1–O5 endocyclic bond cleavage as de-
scribed before,31 it is unclear why the same anomerization did
not occur in the glycosylation of 12. Due to the deactivation of oxa-
zolidinone function, self-condensation of 4b did not occur under
the present reaction conditions.22,27 Glycosylations of 4b with thio-
glycosides 14 and 15 furnished type 2 LacNAc disaccharides 19 and
20 in high yields (Table 2, entries 3 and 4). For glycosylations of
C6H5CH(OMe)2,
OH
O
cat.TsOH,
CH3CN, rt
Ph
O
O
HO
O
STol
NHTroc
STol
NHTroc
HO
HO
1
92%
2
BnBr,
Et3SiH, CF3CO2H
NaH,DMF,
0 oC-rt
O
O
Ph
OBn
4A MS, CH2Cl2, T oC,
O
OBn
O
STol
O
O
BnO
NBn
OR
BnO
O
OBn
OR
yield% (refer Table 1)
80%
O
O
N(Cbz)Bn
O
BnO
BnO
3
N(Cbz)Bn
O
OBn
21 R = (CH2)6Cl
or
OBn
O
OBz
OBn
OH
O
OBn
BnO
22 R = (CH2)6Cl
O
HO
HO
HO
STol
O
O
STol
O
NBn
NBn
NBn
OAc
O
STol
O
O
O
1. Pd(OH)2, H2,
AcO
4b
4a
5
OR
NHAc
O
4:1:5 AcOH/H2O/EtOAc for 21;
4:1:2 AcOH/H2O/EtOAc for 22
60 oC, overnight,
Scheme 1. Synthesis of glucosamine acceptor 4b.
O
OAc
OAc
From 21,
24 R = (CH2)6Cl, 50%
AcO
or
2. Ac2O, pyr., rt
Table 1
Reaction conditions and results of reductive benzylidene ring opening of thioglyco-
side 3
OAc
O
Entry
Acid (equiv)
Et3SiH (equiv)
T (°C)
Yield (%) of 4a
a:b
AcO
OAc
OR
NHAc
O
O
1
2
3
4
TFA (6)
TFA (6)
TFA (6)
BF3 (2)
5
5
5
25
0
35
57
80
65
1:1
AcO
AcO
1:10
b only
1:6b
OBz
À20
From 22,
25 R = (CH2)6Cl, 58%
12
À20
a
Total yield of 4a and 4b after chromatography purification.
The method was referred to Ref. 23.
b
Scheme 3. Deprotection of disaccharides 21 and 22.

1912
S.-C. Lin et al. / Tetrahedron Letters 51 (2010) 1910–1913
Table 2
Glycosylation studies of glucosamine acceptors 4b and 10
NIS, cat. TMSOTf,
4A MS, CH2Cl2, T oC
thioglycoside donor
glucosamine acceptor
disaccharide
+
12, 13, 14, 15 or 16;
4b or 10
17, 18, 19, 20,
21, 22, or 23
Entry
Thioglycoside donor
Glucosamine acceptor
T (°C)
À70
Disaccharide product
Yield (%)
OLev
O
BnO
BnO
OLev
BnO
OBn
O
O
BnO
O
STol
BnO
1
4b
70
STol
O
OBn
12
NBn
O
17
BnO
OBn
O
STol
OBn
OBn
O
OBn
O
OBn
BnO
O
13
2
4b
À60
85
O
STol
NBn
O
18 (α:β = 1:3.5)
OBn
OBn
BnO
BnO
BnO
OBn
O
O
O
STol
OLev
O
BnO
STol
O
3
4
5
6
4b
4b
10
10
À65
À70
À70
À65
65
80
93
80
OLev
14
15
NBn
O
19
OBn
OBn
BnO
BnO
BnO
OBn
O
O
O
STol
O
O
BnO
STol
OBz
OBz
NBn
O
20
OBn
O
BnO
OR
O
13
15
N(Cbz)Bn
O
OBn
OBn
R= (CH ) Cl 21
BnO
2
6
OBn
O
BnO
OBn
OR
O
O
BnO
N(Cbz)Bn
OBz
R =(CH2)6Cl
BnO
22
OBn
OBn
BnO
AllO
O
O
BnO
OBn
STol
OR
O
O
BnO
AllO
N(Cbz)Bn
OBz
7
10
À65
73
16
OBz
R =(CH2)6Cl
23
glucosamine acceptor 10, thioglycoside donors 13, 15, and 16 were
employed. All the glycosylations furnished the expected disaccha-
ride products 21–23 in high (73–93%) yields (Table 2, entries 5–7).
For NMR spectroscopy of disaccharides 21–23, the phenomenon of
resonance peak broadening was also observed.
methods for selected disaccharide products. As the deprotection
methods for oxazolidinone have already been developed,23 this
study focused on the deprotection of desymmetric amino protec-
tion of Fuc-a(1?3)-GlcNAc glycoside 21 and type 1 LacNAc glyco-
side 22 (Scheme 3). An advantage of using N-Cbz protection in
glucosamine is that it can be removed along with the benzyl ether
and benzylamine functions during Pd-catalyzed hydrogenolysis.39
After studying the glycosylation properties of glucosamine
acceptors 4b and 10, we next explored appropriate deprotection

S.-C. Lin et al. / Tetrahedron Letters 51 (2010) 1910–1913
1913
1995, 405–415; (c) Jensen, K. J.; Hansen, P. R.; Venugopal, D.; Barany, G. J. Am.
Chem. Soc. 1996, 118, 3148–3155.
9. (a) Ellervik, U.; Magnusson, G. Carbohydr. Res. 1996, 280, 251–260; (b)
Dullenkopf, W.; Castro-Palomino, J. C.; Manzoni, L.; Schmidt, R. R. Carbohydr.
Res. 1996, 296, 135–147.
10. Blatter, G.; Beau, J.-M.; Jacquinet, J.-C. Carbohydr. Res. 1994, 260, 189–202.
11. Reckendorf, W. M. Z.; Wassiliadou-Micheli, N. Chem. Ber. 1970, 103, 1792–
1796.
In our hands, the optimization of reaction conditions was required.
Ultimately, Pd(OH)2 was found to be the most effective catalyst for
the deprotection of N-BnCbz and O-Bn in 21 and 22
(Scheme 3).23,40,41 Both hydrogenolysis reactions were performed
in AcOH/H2O/EtOAc solvent mixtures under 1 atm H2 at 60 °C.
For NMR characterization, the resulting debenzylated products
12. Castro-Palomino, J. C.; Schmidt, R. R. Tetrahedron Lett. 1995, 36, 6871–6874.
13. Qian, X.; Hindsgaul, O. Chem. Commun. 1997, 1059–1060.
14. Yang, Y.; Yu, B. Tetrahedron Lett. 2007, 48, 4557–4560.
15. Bongat, A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342, 374–406. and
references cited therein.
16. Ye, X.-S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410–2431.
17. Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123, 9461–9462.
18. Boysen, M.; Gemma, E.; Lahmann, M.; Oscarson, S. Chem. Commun. 2005, 3044–
3046.
were further acetylated to produce the peracetyl Fuc-a(1?3)-Glc-
NAc glycoside 24 and type 1 LacNAc glycoside 25.
In summary, this study reports a versatile amino protection
strategy for glucosamine by the joined use of N-benzyl oxazolidi-
none and desymmetric N-BnCbz function. The scope of investiga-
tion includes the installation, deprotection, and application of
these protecting functions. As glucosamine constitutes the key
component in different oligosaccharide structures, the results of
this study should be found useful for their preparation.
19. Geng, Y.; Zhang, L.-H.; Ye, X.-S. Chem. Commun. 2008, 597–599.
20. Olsson, J. D. M.; Eriksson, L.; Lahmann, M.; Oscarson, S. J. Org. Chem. 2008, 73,
7181–7188.
21. Crich, D.; Vinod, A. U. J. Org. Chem. 2005, 70, 1291–1296.
22. Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70, 4195–4198.
23. Manabe, S.; Ishii, K.; Ito, Y. J. Org. Chem. 2007, 72, 6107–6115.
24. Manabe, S.; Ishii, K.; Ito, Y. J. Am. Chem. Soc. 2006, 128, 10666–10667.
25. Geng, Y.; Zhang, L.-H.; Ye, X.-S. Tetrahedron 2008, 64, 4949–4958.
26. Litjens, R. E. J. N.; van den Bos, L. J.; Codée, J. D. C.; Overkleeft, H. S.; van der
Marel, G. A. Carbohydr. Res. 2007, 342, 419–429.
Acknowledgments
We express our thanks to the National Science Council for
financial support of this work (Grant No. NSC 97-2113-M-009 -
007) and Mr. Tsung-Yi Chen for MS analysis.
27. The decreased reactivity was also illustrated in 2,3-cyclic carbonate protection:
Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201–4203.
28. Mong, T. K.-K.; Huang, C.-Y.; Wong, C.-H. J. Org. Chem. 2003, 68, 2135–2142.
29. Garegg, P. J. Pure Appl. Chem. 1984, 56, 845–858.
Supplementary data
30. Rolf, D.; Gray, G. R. J. Am. Chem. Soc. 1982, 104, 3539–3541.
31. Manabe, S.; Ishii, K.; Hashizume, D.; Koshino, H.; Ito, Y. Chem. Eur. J. 2009, 15,
6894–6901.
32. DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett. 1995, 36, 669–
672.
33. Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293–297.
34. (a) Bergmann, M.; Zervas, L. Ber. Dtsch. Chem. Ges. 1932, 65, 1192–2101; (b)
Mane, R. S.; Kumar, K. S. A.; Dhavale, D. D. J. Org. Chem. 2008, 73, 3284–3287.
35. Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31,
1331–1334.
36. Lafont, D.; Boullanger, P. J. Cabohydr. Chem. 1992, 11, 567–586.
37. VT-NMR of 10 was referred to Supplementary data.
38. Synthesis of 12: (a) Chao, C.-S.; Li, C.-W.; Chen, M.-C.; Chang, S.-S.; Mong, K.-K.
T. Chem. Eur. J. 2009, 15, 10972–10982; synthesis of 13: (b) Mong, K.-K. T.;
Wong, C.-H. Angew. Chem., Int. Ed. 2002, 41, 4087–4090; (c) Synthesis of 14 and
15 was referred to Ref. 27.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.021.
References and notes
1. (a) Dwek, R. A. Chem. Rev. 1996, 96, 683–720; (b) Vestweber, D.; Blanks, J. E.
Physiol. Rev. 1999, 79, 181–213; (c) Strous, G. J.; Dekker, J. Crit. Rev. Biochem.
Mol. Biol. 1992, 27, 57–92; (d) Mannori, G.; Crottet, P.; Cecconi, O.; Hanasaki, K.;
Aruffo, A.; Nelson, R. M.; Varki, A.; Bevilacqua, M. P. Cancer Res. 1995, 55, 4425–
4431.
2. Matkins, W. M. Science 1966, 152, 172–181.
3. Baldus, S. E.; Mönig, S. P.; Zirbes, T. K.; Thakran, J.; Köthe, D.; Köppel, M.;
Hanisch, F. G.; Thiele, J.; Schneider, P. M.; Hölscher, A. H.; Dienes, H. P. Histol.
Histopathol. 2006, 21, 503–510.
4. Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819–6825.
5. Liao, L.; Auzanneau, F.-I. J. Org. Chem. 2005, 70, 6265–6273.
6. (a) Lemieux, R. U.; Takeda, T.; Chung, B. Y. ACS Symp. Ser. 1976, 39, 90–115; (b)
Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203–218.
7. Debenham, J. S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Am. Chem. Soc. 1995,
117, 3302–3303.
´
39. Kocienski, P. J. Amino Protecting Group. In Protecting Groups, 3rd ed.; Georg
Thieme: Germany, 2004. pp 487–657.
40. Argouarch, G.; Gilson, C. L.; Stones, G.; Sherrington, D. C. Tetrahedron Lett. 2002,
43, 3795–3798.
41. Marwood, R. D.; Correa, V.; Taylor, C. W.; Potter, B. V. L. Tetrahedron: Asymmetry
2000, 11, 397–403.
8. (a) Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99, 7363–7365; (b)
Meinjohanns, E.; Meldal, M.; Paulsen, H.; Bock, K. J. Chem. Soc., Perkin Trans. 1