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
Article history:
Received 25 December 2009 Revised 3 February 2010 Accepted 5 February 2010 Available online 8 February 2010
a b s t r a c t
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.
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 LacGal-b(1?4)-Glc-NAc) 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.3To 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.4,5To 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),10N-trifluoroacetyl (N-TFA),11N,N-diacetyl
(N-Ac2),12 N-p-nitrobenzyloxy-carbonyl (N-PNZ),13
N-dimethyl-phosphoryl (N-DMP),14and others.15In 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,5but 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.17This function was later elaborated to
N-acetyl18–22and N-benzyl oxazolidinone derivatives.23–25The
pri-mary goal of using oxazolidinone function is to search for a good
a
-directing glucosamine donor.17 Subsequent studies reveal somedegree of inconsistency in the stereochemical preference of gly-cosylations.22,25,26We 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.21Secondly, 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.9bIn 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.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.02.021
*Corresponding author. Tel.: +886 3 5712121x56585; fax: +886 3 5723764. E-mail address:[email protected](K.-K.T. Mong).
O H/P"O P'O O NBn STol O O "PO P'O OH NBn STol R unreactive thio-function unhindered C-4 acceptor site reactive thio-function C-3 acceptor site
Figure 1. N-Benzyl oxazolidinone-protected glucosamine and its derived disubsti-tuted-desymmetric amino-protected glucosamine.
Tetrahedron Letters 51 (2010) 1910–1913
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Tetrahedron Letters
In the beginning, 2-Troc-2-deoxy thioglucopyranoside 1 pre-pared from glucosamine28 was converted to
4,6-O-benzylidene-2N-benzyl-2,3-N,O-carbonyl-2-deoxy thioglucopyranoside 3 via benzylidene acetal intermediate 2 (Scheme 1).25 However, the
reductive ring opening of benzylidene acetal 3 required considerable experimentation (Table 1). Previous efforts using either sodium cya-noborohydride–hydrogen chloride (NaBH3CN/HCl)29or
triethylsi-lane–boron trifluoride etherate (Et3SiH/BF3Et2O)30 led to b?
a
anomerization. This undesirable reaction is attributable to the coor-dination of BF3to ring oxygen atom that promotes the endocyclic
cleavage of C1–O5 linkage.24,31After some investigations, using
tri-ethylsilane–trifluoroacetic acid (Et3SiH/TFA) at low reaction
tem-perature was found to be effective for the reduction of b?
a
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 20 °C (Table 1, entry 3). However, anomerization of 4b to
a
-anomer 4a and trace amount of complete deacetalation 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 1:6a
/b-anomeric mixture (Table 1, entry 4).24Theb-ano-meric configuration of 4b was supported by the13C chemical shift at
86.7 ppm and1J
CHcoupling 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 625was treated with t-BuOK to produce benzylamine derivative 7,25which was
chemoselective-ly converted to desymmetric N-benzyl-N-benzyloxycarbonyl (N-BnCbz)-protected glucosamine thioglycoside 8.34Subsequent 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 of1H 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.
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).38Glycosylations of 4b with thiogalactopyranoside
12 and thiofucopyranoside 13 produced Gal-
a
(1?4)-GlcNAc disac-charide 17 and Fuc-a
(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?a
anomerization forming an inseparable 1:3.5a
/b-anomeric mixture. Though this anomeriza-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.22,27Glycosylations 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 ofO NBn STol O O Ph O O 2 1 C6H5CH(OMe)2, cat.TsOH, CH3CN, rt 92% O NHTroc STol OH HO HO BnBr, NaH,DMF, 0 oC-rt 80% O NHTroc STol O O Ph HO 3 O HO O OBn NBn STol O Et3SiH, CF3CO2H 4A MS, CH2Cl2, T oC,
yield% (refer Table 1)
4b O OBn HO O NBn O STol 4a O NBn STol OH HO O O 5 Scheme 1. Synthesis of glucosamine acceptor 4b.
Table 1
Reaction conditions and results of reductive benzylidene ring opening of thioglyco-side 3
Entry Acid (equiv) Et3SiH (equiv) T (°C) Yield (%) of 4a a:b
1 TFA (6) 5 25 35 1:1
2 TFA (6) 5 0 57 1:10
3 TFA (6) 5 20 80 bonly
4 BF3(2) 12 20 65 1:6b
a
Total yield of 4a and 4b after chromatography purification.
b
The method was referred to Ref.23.
O NHBn STol OBn BnO HO 6 O N(Cbz)Bn STol OBn BnO HO CbzCl, NaHCO3, MeOH, rt 82% O NBn STol OBn BnO O O 7 t-BuOK, DMF, rt, 75% O N(Cbz)Bn OR OBn BnO HO 10, R = (CH2)6Cl HO(CH2)6Cl 9, NIS, cat. TMSOTf, 4A MS CH2Cl2, -65 oC, 88% O NHBn OR OBn BnO HO 11, R = (CH2)6Cl PdCl2, Et3SiH, Et3N, CH2Cl2, rt 45% 8
Scheme 2. Synthesis of desymmetric (N-BnCbz)-protected glucosamine acceptor 10.
O N(Cbz)Bn OR OBn BnO O O OBz OBn BnO BnO 22 R = (CH2)6Cl 1. Pd(OH)2, H2,
4:1:5 AcOH/H2O/EtOAc for 21;
4:1:2 AcOH/H2O/EtOAc for 22
60 oC, overnight, 2. Ac2O, pyr., rt O NHAc OR OAc AcO O O OBz OAc AcO AcO O OR N(Cbz)Bn OBn BnO O 21 R = (CH2)6Cl O BnOOBn OBn or O OR NHAc OAc AcO O From 21, 24 R = (CH2)6Cl, 50% O AcOOAc OAc or From 22, 25 R = (CH2)6Cl, 58% Scheme 3. Deprotection of disaccharides 21 and 22.
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.
After studying the glycosylation properties of glucosamine acceptors 4b and 10, we next explored appropriate deprotection
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.39Table 2
Glycosylation studies of glucosamine acceptors 4b and 10
disaccharide thioglycoside donor 17, 18, 19, 20, 21, 22, or 23 4b or 10 glucosamine acceptor
NIS, cat. TMSOTf, 4A MS, CH2Cl2,ToC 12, 13, 14, 15 or 16;
+
Entry Thioglycoside donor Glucosamine acceptor T (°C) Disaccharide product Yield (%)
1 O STol OBn OLev BnO BnO
12
4b 70 O BnO OLev BnO BnO O STol OBn O O NBn O17
70 2 O BnOOBn OBnSTol13
4b 60 O BnOOBn OBn O STol OBn O O NBn O18 (
α:β = 1:3.5)
85 3 O STol OLev OBn BnO BnO14
4b 65 O OLev OBn BnO BnO O STol OBn O O NBn O19
65 4 O STol OBz OBn BnO BnO15
4b 70 O O Bz OBn BnO BnO O OBn O O NBn O STol20
80 5 13 10 70 O OR N(Cbz)Bn OBn BnO O R = (CH2)6Cl O BnOOBn OBn21
93 6 15 10 65 R = (CH2)6Cl O OR N(Cbz)Bn OBn BnO O O OBz OBn BnO BnO22
80 7 O STol OBz OBn BnO AllO16
10 65 O OR N(Cbz)Bn OBn BnO O O OBz OBn BnO AllO R = (CH2)6Cl23
73 1912 S.-C. Lin et al. / Tetrahedron Letters 51 (2010) 1910–1913In our hands, the optimization of reaction conditions was required. Ultimately, Pd(OH)2was found to be the most effective catalyst for
the deprotection of N-BnCbz and O-Bn in 21 and 22 (Scheme 3).23,40,41Both hydrogenolysis reactions were performed
in AcOH/H2O/EtOAc solvent mixtures under 1 atm H2 at 60 °C.
For NMR characterization, the resulting debenzylated products were further acetylated to produce the peracetyl Fuc-
a
(1?3)-Glc-NAc glycoside 24 and type 1 Lac(1?3)-Glc-NAc 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 installainvestiga-tion, deprotecinvestiga-tion, and applicainvestiga-tion 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.
Acknowledgments
We express our thanks to the National Science Council for financial support of this work (Grant No. NSC 972113M009 -007) and Mr. Tsung-Yi Chen for MS analysis.
Supplementary data
Supplementary dataassociated with this article can be found, in the online version, atdoi:10.1016/j.tetlet.2010.02.021.
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