Practical synthesis of building blocks for oligosaccharides containing the β-d-Galp-(1→3)-β-d-Glc p NAc motif

Article abstract of DOI:10.1055/s-0033-1340620

An efficient, new pathway for the synthesis of the title sequence has been developed. The sequence has been obtained as a glycosyl donor, β-d-Galp-(1→3)-β-d-GlcpNAc-1-SEt, or equipped with a linker (spacer) suitable for conjugation to other molecules, β-d-Galp-(1→3)- β-d-GlcpNAc-1-(OCH₂CH₂)₃N₃. Both disaccharides have been obtained in crystalline condition for the first time and fully characterized. The existing synthesis of the intermediate disaccharide glycosyl donor was improved by conducting the silver triflate mediated glycosylation under base-deficient conditions in the presence of 1,1,3,3-tetramethylurea and in the absence of molecular sieves. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340620

748▌
PRACTICAL SYNTHETIC PROCEDURES
practical synthetic procedures
Practical Synthesis of Building Blocks for Oligosaccharides Containing the
β-D-Galp-(1→3)-β-D-GlcpNAc Motif
Disaccharide Building Blocks
Sameh E. Soliman,a,b Pavol Kováč*b
a
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt
b
NIDDK, LBC, National Institutes of Health, Bethesda, MD 20892-0815, USA
Fax +1(301)4805703; E-mail: kpn@helix.nih.gov
PSP
Received: 29.11.2013; Accepted: 19.12.2013
No268
Abstract: An efficient, new pathway for the synthesis of the title sequence has been developed. The sequence has been obtained as a gly-
cosyl donor, β-D-Galp-(1→3)-β-D-GlcpNAc-1-SEt, or equipped with a linker (spacer) suitable for conjugation to other molecules, β-D-
Galp-(1→3)-β-D-GlcpNAc-1-(OCH2CH2)3N3. Both disaccharides have been obtained in crystalline condition for the first time and fully
characterized. The existing synthesis of the intermediate disaccharide glycosyl donor was improved by conducting the silver triflate medi-
ated glycosylation under base-deficient conditions in the presence of 1,1,3,3-tetramethylurea and in the absence of molecular sieves.
Key words: carbohydrates, oligosaccharides, synthetic methods, thioglycosides, protecting groups
OAc
O
AcO
AcO
AcO
Ph
O
Br
Ph
O
OAc
O
AcO
AcO
O
O
O
O
O
3
SEt
NHCOCCl3
SEt
c
HO
83%
b
NHCOCCl3
pathway 1
2
91%
OAc
4
a
OAc
O
~90%
Ph
O
OAc
O
N3
AcO
AcO
O
O
O
O
AcO
AcO
SEt
3
NHCOCCl3
NHCOCCl3
OAc
1
c
6
95%
b
90%
pathway 2
OAc
N3
Ph
O
N3
O
O
AcO
AcO
O
O
O
a
AcO
AcO
OAc
O
3
HO
3
NHCOCCl3
NHCOCCl3
93%
7
8
AcO
Br
3
Scheme 1 Reagents and conditions: (a) (1) NaOMe, MeOH, r.t., (2) PhCH(OMe)2, CSA, MeCN; (b) AgOTf, 1,1,3,3-tetramethylurea, CH2Cl2;
(c) 8-azido-3,6-dioxaoctan-1-ol (5), NIS, AgOTf, 4 Å MS, CH2Cl2.
Derivatives of common sugars that are ‘standard building Introducing a linker (spacer) to this building block allows
blocks’ in chemical oligosaccharide synthesis are of con- conjugation to other molecules (e.g., proteins). Also, both
tinuing interest in this laboratory. The thioglycoside β-D- the thioglycoside and its linker-equipped counterpart can
Galp-(1→3)-β-D-GlcpNAc-1-SEt represents a motif pres- act as intermediates for the preparation of several up-
ent in human milk oligosaccharides (e.g., Lacto-N-biose, stream di-, tri-, and tetrasaccharide fragments of the O-an-
Lacto-N-tetraose and its sialylated/fucosylated deriva- tigen of Vibrio cholerae O139.5,6
tives), and in carbohydrate moieties of glycoproteins and
We describe herein two efficient synthetic pathways
glycolipids1–4 (e.g., Type I glycans, Lewis a, Sialyl Lewis
(Scheme 1) for the total synthesis of 8-azido-3,6-dioxaoc-
a, and Lewis b antigens).
tyl 4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-ace-
tyl-β-D-galactopyranosyl)-2-trichloroacetamido-β-D-
glucopyranoside (6) starting from the known ethyl 3,4,6-
SYNTHESIS 2014, 46, 0748–0751
Advanced online publication: 30.01.2014
DOI: 10.1055/s-0033-1340620; Art ID: SS-2013-M0770-PSP
© Georg Thieme Verlag Stuttgart · New York
tri-O-acetyl-2-deoxy-1-thio-2-trichloroacetamido-β-D-
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
glucopyranoside (1).7 The 2-deoxy-2-trichloroacetamido

PRACTICAL SYNTHETIC PROCEDURES
Disaccharide Building Blocks
749
group is a powerful stereocontrolling auxiliary in the syn- The 1H NMR spectrum of 6 showed two doublets for an-
thesis of 1,2-trans-linked 2-aminosugar-containing oligo- omeric protons at δ 4.74 (J1,2 = 8.0 Hz) and 5.12 (J1,2 = 8.3
saccharides.8
Hz) assigned by a COSY experiment to H-1 of the β-D-ga-
lactose and β-D-glucose moieties, respectively. Both the
1H and 13C NMR spectra confirmed the presence of the
linker signals, and 2D spectroscopy permitted the com-
plete nuclei–signal assignments.
Pathway 1
Thioglycoside 17 was O-deacetylated (Zemplén) and the
formed triol was treated with benzaldehyde dimethyl ace-
tal in acetonitrile in the presence of 10-camphorsulfonic
acid (CSA) to give the crystalline 4,6-O-benzylidene ace-
tal 2 in ~90% yield.7
Pathway 2
Experimental evidence from a large number of complex
oligosaccharide syntheses dictates that, whenever possi-
ble, it is advantageous to run glycosylations with small-
size glycosyl donors, compared to running this type of re-
action with larger size glycosyl donors. Therefore, an al-
ternative strategy for the construction of the target
disaccharide 6 was explored.
Disaccharide 4 has been originally prepared by Sherman
and co-workers7 within their study of glycosylation with
N-trichloroacetyl-protected D-glucosamine derivatives.
According to the original protocol,7 2,3,4,6-tetra-O-ace-
tyl-α-D-galactopyranosyl bromide (3)9 was condensed in
dichloromethane with ethyl 4,6-O-benzylidene-2-deoxy-
1-thio-2-trichloroacetamido-β-D-glucopyranoside (2), in Glycosidation of N-trichloroacetyl-D-glucosaminyl thio-
the presence of 4 Å molecular sieves using silver triflate glycoside donor 17 with the linker molecule 8-azido-3,6-
as promoter and sym-collidine (0.5 equiv relative to 3) as dioxaoctan-1-ol (5)5 gave exclusively the corresponding
acid scavenger. Formation of byproducts was observed, β-glycoside 7 in virtually theoretical yield. The anomeric
including cleavage of the acid-labile benzylidene group. configuration followed from the 1H NMR data (δ 4.91, d,
The highest yield of the desired disaccharide obtained un- J1,2 = 8.5 Hz for H-1).
der these conditions was 60%. As an alternative, the same
authors used the corresponding imidate as the glycosyl
Deacetylation of 7, followed by 4,6-benzylidination, fur-
nished the new spacer-equipped monosaccharide acceptor
donor, which resulted in improved yield (70%). A higher
1
8 in excellent yield (93%). The H NMR spectrum of 8
yield of compound 4 (~90%)10 from the same synthons
showed a doublet at δ 3.09 (J = 3.4 Hz), which showed
correlation with the signal for H-3 (δ 4.24) and disap-
was obtained in this laboratory by using a larger relative
amount of base during the glycosylation step; however,
peared after exchange with deuterium oxide, and was
when we repeated the same protocol at a few later occa-
therefore assigned to 3-OH.
sions using different batches of molecular sieves, we ob-
Using our revised protocol for the preparation of 4, cou-
pling of the glycosyl bromide 3 with the N-trichloroace-
tyl-D-glucosamine derivative 8 at low temperature, with
served that the yields were inconsistent. We hypothesized
that the basicity of molecular sieves from different
batches/suppliers was not identical, which made it virtual-
silver triflate as promoter in the presence of 1,1,3,3-tetra-
ly impossible to rationalize the optimum amount of base
methylurea and, again, in the absence of molecular sieves,
to be used.
afforded the crystalline β-linked disaccharide 6 in 90%
To ensure isomerization of the plausible orthoester inter-
yield.
mediate,11,12 the reaction had to be conducted under base-
The two routes gave the target disaccharide 6, which is a
versatile intermediate in complex oligosaccharide synthe-
deficient conditions, while the acidity during the reaction
had to be low, to keep the acid-labile benzylidene group
sis, in 68% and 80% overall yield, respectively, showing
intact. Our revised protocol, which we have followed suc-
the advantage of pathway 2 over pathway 1.
cessfully on a multigram scale, has consistently afforded
disaccharide 4 in ~90% yield. It employs 1,1,3,3-tetra-
methylurea as base11 and does not require the use of mo-
lecular sieves.
Optical rotations were measured at ambient temperature for solu-
tions in CHCl3 with a Perkin-Elmer model 341 automatic polarim-
eter. Melting points were measured on a Kofler hot-stage apparatus.
Thin-layer chromatography (TLC) was performed on silica gel 60
The β-configuration of the interglycosidic linkage follows
1
from the H NMR spectrum (δ 4.76, d, J1,2 = 7.9 Hz, H-
1II). Formation of the α-isomer was not observed. In addi-
tion, the 13C NMR spectrum showed the two anomeric
carbons at δ 83.1 (C-1I) and 99.3 (C-1II), and an additional
signal at δ 101.3 corresponding to the benzylidene carbon
(PhCH).
coated glass slides. Column chromatography was performed by elu-
tion from prepacked (Varian, Inc.) columns of silica gel with an
Isolera flash chromatograph (Biotage) connected to an external
evaporative light scattering detector (Varian, Inc., model 380-LC).
NMR spectra were measured at 600 MHz (1H) and 150 MHz (13C)
with a Bruker Avance spectrometer. Assignments of NMR signals
were made using homonuclear and heteronuclear two-dimensional
correlation spectroscopy, run with the software supplied with the
spectrometers. For the reporting of assignments of NMR signals,
nuclei associated with the spacer are denoted with a prime; sugar
residues are serially numbered, beginning with the one bearing the
aglycone, and are identified by a Roman numeral superscript in list-
ings of signal assignments. Liquid chromatography–electrospray
ionization mass spectrometry (ESIMS) was performed with a
Hewlett-Packard 1100 MSD spectrometer. Crystalline acetobromo-
Treatment of the thioglycoside disaccharide 4 in dichloro-
methane at low temperature with 8-azido-3,6-dioxaoctan-
1-ol (5),5 in the presence of N-iodosuccinimide and a cat-
alytic amount of silver triflate gave the spacer-equipped
disaccharide 6 in 83% yield, after chromatography. The
compound was now obtained crystalline for the first time.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 748–751

750
S. E. Soliman, P. Kováč
PRACTICAL SYNTHETIC PROCEDURES
α-D-galactose (3) was purchased from Sigma-Aldrich.13 Solutions
in organic solvents were dried with anhydrous Na2SO4, and concen-
trated at 40 °C/2 kPa.
HRMS (ESI): m/z [M + Na]+ calcd for C20H29Cl3N4O11Na:
629.0791; found: 629.0791.
Anal. Calcd for C20H29Cl3N4O11: C, 39.52; H, 4.81; N, 9.22. Found:
C, 39.67; H, 4.88; N, 9.34.
Ethyl 4,6-O-Benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl)-1-thio-2-trichloroacetamido-β-D-glucopy-
ranoside (4)
8-Azido-3,6-dioxaoctyl 4,6-O-Benzylidene-2-deoxy-2-trichloro-
acetamido-β-D-glucopyranoside (8)
A solution of acetobromo-α-D-galactose13 (3; 307.5 mg, 0.75 mmol)
in anhydrous CH2Cl2 (1.5 mL) was added, at –30 °C in one portion,
to a mixture of glycosyl acceptor 27 (228.4 mg, 0.5 mmol), 1,1,3,3-
tetramethylurea (119.6 μL, 0.95 mmol), and powdered AgOTf
(218.4 mg, 0.85 mmol) in anhydrous CH2Cl2 (5 mL). The cooling
was removed and, with continued stirring, the mixture was allowed
to warm to r.t. (~1 h), when TLC (toluene–acetone, 8:1) indicated
that all acceptor had been consumed. Et3N (0.5 mL) was added, and
the mixture was diluted with CH2Cl2 (5 mL) and filtered through a
Celite® pad. The filtrate was washed successively with 0.5 M aq
HCl (20 mL), aq NaHCO3 (20 mL), and brine (20 mL), then dried.
After concentration, chromatography (toluene–acetone, 15:1) gave
the desired disaccharide 4; yield: 358 mg (91%).
Acetate 7 (11.37 g, 18.7 mmol) was treated with 1 M methanolic
NaOMe (3.0 mL) in MeOH (300 mL) overnight. The mixture was
neutralized with Amberlite IR-120, filtered, concentrated, and dried
in vacuo to give the expected intermediate triol, which was used
without further purification.
1H NMR (600 MHz, acetone-d6 + D2O): δ = 4.72 (d, J1,2 = 8.2 Hz,
1 H, H-1), 3.91–3.88 (m, 1 H, H-1′a), 3.84 (dd, J = 2.5, 11.8 Hz, 1
H, H-6b), 3.76–3.72 (m, 1 H, H-3), 3.70–3.57 (m, 11 H, H-1′b, H-2′,
H-3′, H-4′, H-5′, H-2, H-6a), 3.41–3.38 (m, 3 H, H-4, H-6′), 3.33–
3.30 (m, 1 H, H-5).
13C NMR (150 MHz, acetone-d6 + D2O): δ = 162.7 (NCOCCl3),
101.6 (C-1), 93.9 (CCl3), 77.4 (C-5), 74.6 (C-3), 72.1 (C-4), 71.1,
71.0, 70.9, 70.5 (4 CH2), 69.2 (C-1′), 62.4 (C-6), 58.6 (C-2), 51.2
(C-6′).
Mp 203.5–204.0 °C (i-PrOH).
[α]D –20 (c 1.0, CHCl3) [Lit.7 [α]D –28 (c 2.0, CH2Cl2)].
HRMS (ESI): m/z [M + NH4]+ calcd for C14H27Cl3N5O8: 498.0925;
found: 498.0932.
1H NMR (600 MHz, CDCl3): δ = 7.49–7.37 (m, 5 H, Ph), 7.01 (d,
J = 7.9 Hz, 1 H, NH), 5.56 (s, 1 H, PhCH), 5.32 (dd, J3,4 = 2.7 Hz,
J4,5 = 0.8 Hz, 1 H, H-4II), 5.19 (dd, J1,2 = 7.9 Hz, J2,3 = 10.4 Hz, 1 H,
H-2II), 5.10 (d, J1,2 = 10.4 Hz, 1 H, H-1I), 4.92 (dd, J2,3 = 10.4 Hz,
A solution of the foregoing triol in MeCN (150 mL) was treated
with benzaldehyde dimethyl acetal (5.1 mL, 33.7 mmol) and CSA
(82 mg) for 2 h at r.t. The reaction was quenched with Et3N
(5.0 mL) and concentrated. Chromatography (CHCl3–acetone, 9:1
→ 5:1) afforded 8; yield: 9.9 g (93% over two steps).
J
3,4 = 3.4 Hz, 1 H, H-3II), 4.76 (d, J1,2 = 7.9 Hz, 1 H, H-1II), 4.48 (t,
J = 9.5 Hz, 1 H, H-3I), 4.36 (dd, J = 4.9, 10.6 Hz, 1 H, H-6Ia), 4.11
(dd, J = 6.9, 11.3 Hz, 1 H, H-6II ), 4.01 (dd, J = 6.5, 11.3 Hz, 1 H,
H-6II ), 3.82–3.73 (m, 3 H, H-6Iba, H-4I, H-5II), 3.67 (m, 1 H, H-2I),
b
[α]D –35.6 (c 1.0, CHCl3).
3.57 (m, 1 H, H-5I), 2.74 (m, 2 H, SCH2), 2.12, 2.03, 1.95, 1.89 (4
1H NMR (600 MHz, CDCl3): δ = 7.50–7.36 (m, 5 H, Ph), 7.24 (d,
J = 7.2 Hz, 1 H, NH), 5.55 (s, 1 H, PhCH), 4.98 (d, J1,2 = 8.4 Hz, 1
H, H-1), 4.35 (dd, J = 4.9, 10.5 Hz, 1 H, H-6b), 4.24 (br ddd, J = 3.4,
9.1, 9.9 Hz, 1 H, H-3), 3.95–3.92 (m, 1 H, H-1′a), 3.84–3.78 (m, 2
H, H-6a, H-1′b), 3.72–3.61 (m, 9 H, H-2′, H-3′, H-4′, H-5′, H-2),
3.57 (t, J = 9.2 Hz, 1 H, H-4), 3.53–3.49 (m, 1 H, H-5), 3.41 (t,
J = 5.0 Hz, 2 H, H-6′), 3.09 (d, J = 3.4 Hz, 1 H, D2O exchange, OH).
13C NMR (150 MHz, CDCl3): δ = 162.7 (NCOCCl3), 136.9 (ipso
Ph), 129.3, 128.3, 126.1 (Ph), 101.9 (PhCH), 100.4 (C-1), 92.4
(CCl3), 81.5 (C-4), 70.8, 70.6 (2 CH2), 70.5 (C-3), 70.4, 70.0 (2
CH2), 68.7 (C-1′), 68.5 (C-6), 66.2 (C-5), 59.3 (C-2), 50.6 (C-6′).
s, 12 H, 4 COCH3), 1.28 (t, J = 7.4 Hz, 3 H, SCH2CH3).
13C NMR (150 MHz, CDCl3): δ = 170.3–169.6 (4 OCOCH3), 161.5
(NCOCCl3), 136.9 (ipso Ph), 129.3, 128.3, 126.1 (Ph), 101.3
(PhCH), 99.3 (C-1II), 92.3 (CCl3), 83.1 (C-1I), 78.7 (C-4I), 77.1 (C-
3I), 70.9 (C-3II), 70.7 (C-5I), 70.6 (C-5II), 68.8 (C-2II), 68.5 (C-6I),
66.8 (C-4II), 61.3 (C-6II), 57.5 (C-2I), 24.9 (SCH2), 20.7–20.5 (4
OCOCH3), 15.1 (SCH2CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C31H38Cl3NO14NaS:
808.0971; found: 808.0971.
Anal. Calcd for C31H38Cl3NO14S: C, 47.31; H, 4.87; Cl, 13.51; N,
1.78; S, 4.07. Found: C, 47.23; H, 4.82; Cl, 13.66; N, 1.84; S, 3.88.
HRMS (ESI): m/z [M + NH4]+ calcd for C21H31Cl3N5O8: 586.1238;
found: 586.1241.
8-Azido-3,6-dioxaoctyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloro-
acetamido-β-D-glucopyranoside (7)
Anal. Calcd for C21H27Cl3N4O8: C, 44.26; H, 4.78; N, 9.83. Found:
C, 44.26; H, 4.68; N, 9.75.
A mixture of thioglycoside 17 (5 g, 10.1 mmol), 8-azido-3,6-dioxa-
octan-1-ol5 (5; 2.5 g, 14.1 mmol), and 4-Å MS (2.5 g) in anhydrous
CH2Cl2 (40 mL) was stirred for 30 min under nitrogen. The mixture
was cooled to –20 °C and NIS (3.4 g, 15.2 mmol) followed by pow-
dered AgOTf (1.3 g, 5.1 mmol) were added with stirring. After 1 h,
the mixture was treated with Et3N (3.0 mL), filtered through
Celite®, and the filtrate was concentrated. Chromatography (tolu-
ene–acetone, 19:1 → 6:1) gave the spacer-equipped monosaccha-
ride 7; yield: 5.9 g (95%).
8-Azido-3,6-dioxaoctyl 4,6-O-Benzylidene-2-deoxy-3-O-
(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2-trichloroacet-
amido-β-D-glucopyranoside (6)
Pathway 1
A mixture of thioglycoside disaccharide 4 (787 mg, 1.0 mmol), 8-
azido-3,6-dioxaoctan-1-ol5 (5; 262 mg, 1.5 mmol), and 4-Å MS (0.5
g) in anhydrous CH2Cl2 (10 mL) was stirred for 30 min under nitro-
gen. The mixture was cooled to –15 °C and NIS (337 mg, 1.5 mmol)
followed by powdered AgOTf (128 mg, 0.5 mmol) were added with
stirring. After 1 h, the mixture was treated with Et3N (1.0 mL), fil-
tered through Celite®, and the filtrate was concentrated. Chroma-
tography (hexane–acetone, 2:1) gave the spacer-equipped
disaccharide 6; yield: 751 mg (83%).
[α]D –11.9 (c 1.0, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 7.01 (d, J = 8.9 Hz, 1 H, NH), 5.29
(dd, J = 9.3, 10.6 Hz, 1 H, H-3), 5.12 (t, J = 9.6 Hz, 1 H, H-4), 4.91
(d, J1,2 = 8.5 Hz, 1 H, H-1), 4.29 (dd, J = 4.7, 12.3 Hz, 1 H, H-6b),
4.16 (dd, J = 2.4, 12.3 Hz, 1 H, H-6a), 4.03 (dt, J1,2 = J2,NH ~8.5 Hz,
J2,3 = 10.6 Hz, 1 H, H-2), 3.91–3.84 (m, 2 H, H-1′), 3.78–3.62 (m, 9
Mp 124.0–124.5 °C (i-PrOH).
[α]D –15.1 (c 1.8, CHCl3).
H, H-2′, H-3′, H-4′, H-5′, H-5), 3.48 (t, J = 5.0 Hz, 2 H, H-6′), 2.10,
2.03, 2.02 (3 s, 9 H, 3 COCH3).
13C NMR (150 MHz, CDCl3): δ = 170.7–169.4 (3 OCOCH3), 162.0
(NCOCCl3), 100.9 (C-1), 92.4 (CCl3), 72.2 (C-3), 72.0 (C-5), 71.2
(CH2), 70.6, 70.3, 69.9 (3 CH2), 68.4 (C-4), 68.3 (C-1′), 62.1 (C-6),
56.0 (C-2), 50.6 (C-6′), 20.8, 20.6, 20.5 (3 OCOCH3).
1H NMR (600 MHz, CDCl3): δ = 7.50–7.37 (m, 5 H, Ph), 7.10 (d,
J = 7.5 Hz, 1 H, NH), 5.55 (s, 1 H, PhCH), 5.31 (dd, J3,4 = 3.4 Hz,
J
4,5 = 0.6 Hz, 1 H, H-4II), 5.19 (dd, J1,2 = 8.0 Hz, J2,3 = 10.4 Hz, 1 H,
H-2II), 5.12 (d, J1,2 = 8.3 Hz, 1 H, H-1I), 4.91 (dd, J2,3 = 10.4 Hz,
Synthesis 2014, 46, 748–751
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Disaccharide Building Blocks
751
J3,4 = 3.5 Hz, 1 H, H-3II), 4.74 (d, J1,2 = 8.0 Hz, 1 H, H-1II), 4.55 (t,
J = 9.6 Hz, 1 H, H-3I), 4.35 (dd, J = 4.9, 10.5 Hz, 1 H, H-6Ia), 4.11
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
(dd, J = 7.1, 11.2 Hz, 1 H, H-6II ), 3.98 (dd, J = 6.5, 11.2 Hz, 1 H,
a
H-6II ), 3.95–3.92 (m, 1 H, H-1′a), 3.83–3.77 (m, 2 H, H-6Ib, H-1′b),
b
3.74–3.70 (m, 2 H, H-4I, H-5II), 3.68–3.61 (m, 8 H, H-2′, H-3′, H-
4′, H-5′), 3.55–3.50 (m, 2 H, H-2I, H-5I), 3.41 (t, J = 5.0 Hz, 2 H, H-
6′), 2.11, 2.01, 1.95, 1.90 (4 s, 12 H, 4 COCH3).
References
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(7) Sherman, A. A.; Yudina, O. N.; Mironov, Y. V.; Sukhova,
E. V.; Shashkov, A. S.; Menshov, V. M.; Nifantiev, N. E.
Carbohydr. Res. 2001, 336, 13.
13C NMR (150 MHz, CDCl3): δ = 170.3–169.5 (4 OCOCH3), 161.9
(NCOCCl3), 136.9 (ipso Ph), 129.3, 128.3, 126.1 (Ph), 101.4
(PhCH), 99.6 (C-1I), 99.5 (C-1II), 92.5 (CCl3), 79.0 (C-4I), 76.0 (C-
3I), 71.0 (C-3II), 70.7 (2 C, 2 CH2), 70.6 (C-5II), 70.5 (CH2), 70.0
(CH2), 68.9 (C-2II), 68.8 (C-1′), 68.6 (C-6I), 66.8 (C-4II), 66.2 (C-
5I), 61.2 (C-6II), 58.7 (C-2I), 50.6 (C-6′), 20.7–20.5 (4 OCOCH3).
HRMS (ESI): m/z [M + Na]+ calcd for C35H45Cl3N4O17Na:
921.1737; found: 921.1739.
Anal. Calcd for C35H45Cl3N4O17: C, 46.70; H, 5.04; N, 6.22. Found:
C, 46.88; H, 5.06; N, 6.21.
Pathway 2
A solution of acetobromo-α-D-galactose13 (3; 1.4 g, 3.4 mmol) in
anhydrous CH2Cl2 (8 mL) was added, at –30 °C in one portion, to a
mixture of glycosyl acceptor 8 (1.1 g, 1.89 mmol), 1,1,3,3-tetra-
methylurea (520 μL, 4.37 mmol), and powdered AgOTf (971 mg,
3.78 mmol) in anhydrous CH2Cl2 (20 mL). The cooling was re-
moved and, with continued stirring, the mixture was allowed to
warm to r.t. (~1 h), when TLC (hexane–acetone, 3:2) indicated that
all acceptor had been consumed. Et3N (0.5 mL) was added, and the
mixture was diluted with CH2Cl2 (10 mL) and filtered through a
Celite® pad. The filtrate was washed successively with 0.5 M aq
HCl (50 mL), aq NaHCO3 (50 mL), and brine (50 mL), then dried.
After concentration, chromatography (hexane–acetone, 2:1) gave
the desired disaccharide 6; yield: 1.53 g (90%).
(8) Vibert, A.; Lopin-Bon, C.; Jacquinet, J.-C. Tetrahedron Lett.
2010, 51, 1867.
(9) Schroeder, L. R.; Counts, K. M.; Haigh, F. C. Carbohydr.
Res. 1974, 37, 368.
(10) Hou, S.; Kováč, P. Carbohydr. Res. 2011, 346, 1394.
(11) Banoub, J.; Bundle, D. R. Can. J. Chem. 1979, 57, 2091.
(12) Garegg, P. J.; Norberg, T. Acta Chem. Scand., Ser. B 1979,
33, 116.
(13) Freshly crystallized and thoroughly dried. Amorphous
material or crystalline material that had been stored for a
longer time may be partially hydrolyzed and contain a small
amount of HBr. Introducing such material into the reaction
mixture may, eventually, change the acidity of the reaction
mixture, resulting in (partial) cleavage of the benzylidene
group.
Acknowledgment
This research was supported by the Intramural Research Program of
the NIH, NIDDK.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 748–751