Facile synthesis of d-lividosamine

Article abstract of DOI:10.1016/j.carres.2009.11.019

A simple, four-step synthesis of d-lividosamine starting from N-acetyl-d-glucosamine via a furanosyl oxazoline intermediate is described.

Full text of DOI:10.1016/j.carres.2009.11.019

Carbohydrate Research 345 (2010) 315–317
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Facile synthesis of D-lividosamine
*
Zhi-Lai Zhan, Feng-Xia Ren, Yi-Min Zhao
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, 100850 Beijing, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, four-step synthesis of
D-lividosamine starting from N-acetyl-D-glucosamine via a furanosyl
Received 24 September 2009
Received in revised form 12 November 2009
Accepted 13 November 2009
Available online 20 November 2009
oxazoline intermediate is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
D-Lividosamine
Synthesis
Oxazoline
Deoxygenation
D
-Lividosamine (2-amino-2,3-dideoxy-
D
-glucose) is a naturally
3-hydroxyl group into an epoxide,12,13 ketone8 or glycal,14–16 and
even from non-carbohydrate sources.17,18 The existing methods
commonly involve procedures that have limitations due to low
product yields, complexity of product mixtures, and difficulties
associated with obtaining the starting compounds.
Barton and McCombie demonstrated that secondary alcohols
can be deoxygenated by reduction of their thiocarbonyl deriva-
tives. For example, reduction of thiocarbonyl derivatives of
secondary alcohols with tri-n-butylstannane provided the corre-
sponding deoxy products in good yields.19 This approach proceeds
through a free radical pathway and is generally suitable for steri-
cally hindered polyfunctional compounds.9 Rasmussen et al. syn-
occurring 2-aminosugar, first found by Mori et al. as a part of the
aminoglycoside antibiotics lividomycin-A and lividomycin-B,
which were isolated from Streptomyces lividus.1
D-Lividosamine oc-
curs also in the structure of 30-deoxykanamycin C, an antibiotic
from a mutant of Streptomyces cremeus,2 and as a key intermediate
in the synthesis of the carbapenem antibiotic thienamycin.3 Be-
cause D-lividosamine can be used as a building block in biologically
interesting synthetic or semi-synthetic glycosides, especially ami-
noglycoside antibiotics, in which a 3-deoxy-sugar moiety may
diminish the sensitivity to enzymatic deactivation, a number of
methods have been developed for the synthesis of
or its derivatives.
The challenge commonly met in deoxygenation of secondary hy-
droxyl groups in carbohydrate chemistry has interested chemists in
the synthesis of this compound. Most of the syntheses methods be-
D-lividosamine
thesized several deoxy-sugars including
procedure, but the synthesis of -lividosamine needed several
steps to form a partially protected pyranose intermediate and the
total yield of
-lividosamine was relatively low.20
A facile approach for preparing -lividosamine was developed
recently in our laboratory, from 2-methyl-(1,2-dideoxy-5,6-O-iso-
propylidene- -glucofurano)-[2,1-d]-2-oxazoline (2), a furanosyl
oxazoline intermediate previously used in the synthesis of 2-acet-
amido-2-deoxy-mannose21 and 2-acetamido-2-deoxy-b-
-gluco-
pyranosides.22
-Lividosamine was synthesized in four steps from
D-lividosamine by this
D
D
gin with
D-glucosamine. The 3-hydroxyl group of a suitably pro-
D
tected -glucosamine derivative is converted to a leaving group
D
such as a halogen4 or thiolate,5–7 which is reductively removed by
catalytic hydrogenation or other reduction conditions to afford the
desired 3-deoxy product. Deoxygenation procedures of this kind
are normally inefficient because SN2 processes are hindered at the
secondary carbons of carbohydrates both sterically and through
dipolar effects.8 In addition, rearrangements and eliminations will
occur when carbocations are intermediates.9 Radical-type reactions
a-D
D
D
commercially accessible N-acetyl-D-glucosamine in an overall yield
of about 50% (Scheme 1).
N-Acetyl-D-glucosamine was converted into 2 in dry acetone at
used in the synthesisof
D
-lividosamineinvolved oftenharsh reaction
reflux using anhydrous FeCl3 as the catalyst. The crude product 2
could be used directly in the next step without purification.22
Treatment of 2 with thionocarbonyl-1,10-diimidazole (TCDI) in
THF at reflux afforded 3 in 89% yield after chromatography on silica
gel. The reduction of 3 with tributyltin hydride in the presence of
2,20-azobisisobutyronitrile (AIBN) gave 4 (86%). The best result
conditions such as intense UV radiation,3 Li–EtNH2,10 and Na–NH3.11
Other methods have also been developed through transforming the
* Corresponding author. Tel.: +86 10 66931648; fax: +86 10 68211656.
E-mail address: zhaoym@nic.bmi.ac.cn (Y.-M. Zhao).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.11.019

316
Z.-L. Zhan et al. / Carbohydrate Research 345 (2010) 315–317
O
O
tetrahydrofuran (200 mL). The reaction mixture was heated to gen-
O
O
tle reflux under an N2 atmosphere until TLC analysis (CHCl3–
CH3OH 10:1) confirmed the disappearance of the starting material
(2 h). After cooling, the solution was concentrated in vacuo and the
product was isolated by flash chromatography (EtOAc–CHCl3 4:1)
O
N
O
N
N
a
b
HO
D-GlcNAc
N
O
to give 3 as white needles (6.5 g, 89%) mp 124–126 °C. ½a D20
ꢁ
O
S
O
ꢂ65.3 (c 0.67, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.29, 1.40
(2 ꢀ 3H, s, CMe2), 2.10 (3H, d, J = 1.2 Hz, N@C–Me), 4.00 (1H, dd,
J = 3.2, 8.8 Hz, H-4), 4.10 (1H, dd, J = 4.0, 8.8 Hz, H-6a), 4.16 (1H,
dd, J = 5.8, 8.8 Hz, H-6b), 4.28 (1H, m, H-5), 4.75 (1H, dd, J = 1.2,
5.2 Hz, H-2), 5.87 (1H, d, J = 3.2 Hz, H-3), 6.16 (1H, d, J = 5.2 Hz,
H-1), 7.08 (1H, d, J = 0.8), 7.63 (1H, s), 8.35 (1H, s). 13C NMR
(100 MHz, CDCl3): d 14.21, 24.94, 26.93, 67.37, 72.27, 75.92,
80.19, 84.23, 106.52, 109.97, 117.94, 130.99, 136.57, 168.12,
182.05. ESI-MS m/z: [M+H]+ 354.0, [M+Na]+ 375.8, [M+Cl]ꢂ 388.1.
HRESI-MS m/z calcd for C15H19N3O5S [M+H]+ 354.1118, found:
354.1095.
2
3
O
O
OH
O
O
d
c
HO
OH
NH2HCl
O
1
4
N
Scheme 1. Reagents and conditions: (a) acetone, FeCl3, reflux, 20 min; (b) TCDI,
THF, reflux, 1 h; (c) Bu3SnH, AIBN, toluene, reflux, 2 h; (d) 2 N HCl, reflux, 2 h.
was achieved when a mixture of 3 and AIBN dissolved in toluene
was slowly added to toluene solution of tributyltin hydride at
reflux under a N2 atmosphere.
1.4. 2-Methyl-(1,2,3-trideoxy-5,6-O-isopropylidene–
glucofurano)-[2,1-d]-2-oxazoline (4)
D-
The deprotection of compound 4 was carried out in 2 N HCl at re-
flux. After concentrating the reaction mixture under reduced pres-
Compound 3 (6.0 g, 17 mmol) and AIBN (2.52 g, 15.3 mmol)
were dissolved in dry toluene (100 mL). Under a gentle flow of
N2, the solution was added dropwise into a refluxing solution of
tri-n-butylstannane (14.8 g, 51 mmol) in toluene (100 mL) over
1 h. The mixture was heated reflux for a further 1 h until TLC anal-
ysis confirmed the disappearance of the starting material. After
cooling, the solvent was removed under reduced pressure and
the product was purified by flash chromatography (CHCl3–CH3OH
sure, crude
the syrup in hot methanol followed by the addition of acetone,
idosamine precipitated as white solid in 80% yield. At this stage, the
product possessed dominantly the configuration as indicated by
D
-lividosamine was obtained as syrup. By dissolving
D-liv-
a
the presence of one anomeric signal at d 5.12 (d, 1H, J = 3.2 Hz) in
the 1H NMR spectrum. When the product was further purified by
recrystallization from MeOH–acetone, it was converted into a mix-
20:1) to give 4 (3.32 g, 86%) as a yellow oil. ½a D20
ꢂ5.7 (c 0.11,
ꢁ
CHCI3); 1H NMR (400 MHz, CDCl3): d 1.36, 1.44 (2 ꢀ 3H, s, CMe2),
1.94 (1H, m, H-3a), 2.03 (3H, d, J = 1.6 Hz, N@C–Me), 2.25 (1H,
dd, J = 4.4, 12.8 Hz, H-3b), 3.83 (1H, m, H-6a), 3.89 (1H, m, H-4),
4.11 (2H, m, H-5, H-6a), 4.62 (1H, t, J = 5.6, 6.0 Hz, H-2), 6.06 (1H,
d, J = 5.2 Hz, H-1). 13C NMR (100 MHz, CDCl3): d 12.25, 23.30,
24.63, 32.72, 65.20, 69.27, 74.76, 77.00, 105.44, 107.87, 163.55.
ESI-MS m/z: [M+H]+ 228.0. HRESI-MS m/z calcd for C11H17NO4
[M+H]+ 228.1230, found 228.1237.
ture of
a and b isomers in a ratio of about 4:1. Another anomeric sig-
nalappeared inthe1HNMRspectrumof therecrystallizedproductat
d 4.16 (d, 1H, J = 8 Hz), indicating the presence of the b-anomer.
1. Experimental
1.1. General methods
Melting points were determined with a RD-2 type Melting Point
Instrument (Tianjin Tianguang Optical Instrument Co., Ltd) and are
uncorrected. Optical rotations were measured at 20 °C with a Per-
kin–Elmer 343 polarimeter. NMR spectra were obtained with a
JNM-ECA-400 (Japan) spectrometer (400 MHz for 1H NMR and
100 MHz for 13C NMR). ESI-MS spectra were obtained with an
API3000 spectrometer (Applied Biosystems, USA), HRESI-MS spectra
were obtained with a Agilent 6520 Q-TOF spectrometer. Column
chromatography was performed on silica gel (Qingdao Haiyang
Chemical Industry Co., Ltd), which was used without pretreatment.
Toluene and THF were freshly distilled from sodium wire.
1.5. 2-Amino-2,3-dideoxy-D-glucose hydrochloride (1)
Compound 4 (3 g, 13 mmol) was dissolved in 2 N HCl (60 mL),
heated at reflux for 2 h and then treated with activated charcoal.
After filtration of the charcoal, the solution was concentrated in va-
cuo. The syrupy residue was dissolved in hot CH3OH and the product
was obtained as a white precipitate by the addition of acetone
(2.15 g, 80%). The product was identified as the a-anomer of D-livi-
dosamine,whilethe1HNMRspectrumshownonlyasingleanomeric
signal at d 5.12 ppm. Recrystallization from CH3OH–acetone gave
needles, which were a mixture of
a and b isomers in a 4:1 ratio as re-
vealed by 1H NMR analysis. Mp 163–164 °C. ½a 2D0
ꢁ
+44.3 (c 0.33, H2O);
1.2. 2-Methyl-(1,2-dideoxy-5,6-O-isopropylidene–
D-
lit.:5
½
a 2D5
ꢁ
+73.3?43.9 (c 1.05, H2O); lit.:6
½ ꢁ
a 2D3
+13 (c 0.7, H2O). 1H
glucofurano)-[2,1-d]-2-oxazoline (2)21
NMR (400 MHz, (CD3)2SO): d 1.68 (1H, q, J = 12 Hz, H-3a), 2.00 (1H,
m, H-3b), 3.16 (1H, m, H-2), 3.37 (1H, ddd, J = 4.8 Hz, H-4), 3.49
(2H, m, H-5, H-6a), 3.61 (1H, dd, J = 1.6, 11.2 Hz, H-6b), 4.35 (1H, s,
1H NMR (400 MHz, (CD3)2SO): d 1.26, 1.30 (2 ꢀ 3H, s, CMe2),
1.92 (3H, d, J = 0.8 Hz, N@C–Me), 3.63 (1H, dd, J = 2.8, 6.4 Hz, H-
4), 3.82 (1H, dd, J = 5.6, 8.4 Hz, H-6a), 3.97 (1H, dd, J = 6.4, 8.4 Hz,
H-6b), 4.02 (1H, t, J = 3.2 Hz, 4 Hz, H-5), 4.25 (2H, m, H-2, H-3),
5.46 (1H, d, J = 4.8 Hz, OH), 6.13 (1H, d, J = 4.8 Hz, H-1). ESI-MS
m/z: [M+H]+ 244.3, [M+Na]+ 266.2.
C6–OH), 5.14 (1H, s, C4–OH), 5.12 (1H, d, J = 3.2 Hz, H-1 fora-isomer),
7.15 (1H, d, J = 3.6 Hz, C1–OH), 8.11 (3H, s, C2–NH2HCl). 13C NMR
(100 MHz, (CD3)2SO): d 31.11, 48.35, 60.61, 63.45, 73.10, 87.50.
ESI-MS m/z: [M+H]+ 164.2, [M+Na]+ 186.1, [M+Cl]ꢂ 198.1. HRESI-
MS m/z calcd for C6H13NO4 [M+H]+ 164.0917, found 164.0891.
1.3. 2-Methyl-(1,2-dideoxy-3-O-(methylthio)thiocarbonyl-5,6-
O-isopropylidene–D-glucofurano)-[2,1-d]-2-oxazoline (3)
Acknowledgments
We thank the Ministry of Science and Technology of the
People’s Republic of China for financial support through the
Under a gentle flow of N2, solid TCDI (7.2 g, 40 mmol) was
added to a solution of the oxazoline 2 (5.0 g, 20 mmol) in dry

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Supplementary data
Supplementary data associated with this article can be found, in
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