Concise synthesis of zanamivir and its C4-thiocarbamido derivatives utilizing a [3+2]-cycloadduct derived from d-glucono-δ-lactone

Article abstract of DOI:10.1016/j.tet.2012.01.011

A concise synthesis of zanamivir (GG167, 1) has been accomplished utilizing the adduct of a highly diastereoselective 1,3-dipolar cycloaddition between methyl acrylate and the nitrone derived from d-glucono-δ-lactone. Azide-free introduction of C4 nitrogen functionality and one-pot selective O-acetylation followed by straightforward generation of dihydropyran moiety are two advantages in this synthesis. Using the established methodology and common intermediate, two representative C4-thiocarbamido derivatives of zanamivir were also synthesized.

Full text of DOI:10.1016/j.tet.2012.01.011

Tetrahedron 68 (2012) 2041e2044
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concise synthesis of zanamivir and its C4-thiocarbamido derivatives utilizing
a [3þ2]-cycloadduct derived from
Xue-Bin Zhu, Meng Wang, Shaozhong Wang, Zhu-Jun Yao
D
-glucono-
d
-lactone
*
State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, Institute of Chemical Biology and Drug Innovation,
School of Chemistry and Chemical Engineering, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of zanamivir (GG167, 1) has been accomplished utilizing the adduct of a highly di-
Received 6 December 2011
Received in revised form 28 December 2011
Accepted 6 January 2012
astereoselective 1,3-dipolar cycloaddition between methyl acrylate and the nitrone derived from
D-
glucono- -lactone. Azide-free introduction of C4 nitrogen functionality and one-pot selective O-acety-
d
lation followed by straightforward generation of dihydropyran moiety are two advantages in this syn-
thesis. Using the established methodology and common intermediate, two representative C4-
thiocarbamido derivatives of zanamivir were also synthesized.
Available online 13 January 2012
Keywords:
Zanamivir
Ó 2012 Elsevier Ltd. All rights reserved.
Sialic acid derivative
D
-Glucono-d-lactone
1,3-Dipolar cycloaddition
Diastereoselective synthesis
1. Introduction
(4) has been commonly used as the starting material.3,4 Besides
these literature approaches through various intermediates derived
Zanamivir (GG167, relenza, 1) is a famous inhibitor of influenza
neuraminidase (NA), and it has been marketed for the treatment of
influenza (Fig. 1).1,2 In most commercial syntheses of zanamivir and
other sialic acid analogues, the natural nine-carbon sugar Neu5Ac
from Neu5Ac, we developed an alternative route using
-lactone (2) as the economic starting material in 2004.5 More re-
cently, we also accomplished a diastereoselective synthesis of 4-
amido-N5-acetyl-4-deoxyneuraminic acid (5) from
-glucono-
D-glucono-
d
D
d-
lactone (2), utilizing a highly diastereoselective 1,3-dipolar cyclo-
addition (Scheme 1).6 These works provide more economic op-
portunities to access diverse derivatives of 4-amido-N5-acetyl-4-
deoxyneuraminic acid with various modifications at the C4 func-
tionality, which is believed to play key roles in the mechanisms of
viral diseases.
Because 4-amido-N5-acetyl-4-deoxyneuraminic acid (5) and
zanamivir (1) share close structural similarity in the skeleton, in
principle, the intermediate 7 previously used in our synthesis of 56
would be also applicable for the synthesis of zanamivir and its
analogues (Scheme 1). Therefore, as an extension of our previous
work, we further explored the synthesis of zanamivir (1) and its C4-
amido derivatives starting from the enantiopure [2þ3]-cycloadduct
7. In this article, we wish to report our newly established short
synthesis of zanamivir and its two representative C4-
thiocarbamido derivatives.
Fig. 1. Zanamivir (1) and other representative sialic acid derivatives.
2. Results and discussion
Following our previous work, the
prepared from the adduct 8 in two steps (OeN cleavage by
a-keto ester 9 could be easily
* Corresponding author. Tel./fax: þ86 25 8359 3732; e-mail addresses: yaoz@
nju.edu.edu, yaoz@mail.sioc.ac.cn (Z.-J. Yao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.011

2042
X.-B. Zhu et al. / Tetrahedron 68 (2012) 2041e2044
Scheme 2. Short synthesis of zanamivir (1).
Scheme 1. Our previous study on the synthesis of 4-amido-N5-acetyl-4-
deoxyneuraminic acid (5).
hydrogenolysis and alcohol oxidation).5,6 However, further
transformations to N4-Boc-N5-acetyl-4-deoxyneuraminic acid
methyl ester 10 were found to be more problematic in our at-
tempts (Fig. 2). The use of alternative protecting groups not only
increased the steps, but also made it difficult to achieve a rea-
sonable yield of product. Quite a number of conditions were tried
next selective acetylation of all hydroxyl groups in the presence of
a free amino functionality. In this practically challenging opera-
€
tion, a proper Bronsted acid was essentially needed to temporarily
mask the free C4 amino group (as the ammonium) during the
acetylation. Proper conditions were then screened for the selective
O-acetylation of the highly polar amino-sugar derivative 11.12 After
many times of failed experiments under various acidic conditions,
we found that treatment of 11 with Ac2O in the presence of
3e5 equiv of concd H2SO4 afforded a mixture of 12 and 13. This
initial result encouraged us to finely adjust the quantity of concd
H2SO4 in Ac2O. To our delight, when concd H2SO4 was increased to
10% in acetic anhydride by volume,13 cyclic enol ether 124b,14 was
detected as the single product in 50% isolated yield over two steps.
Following the known procedure,4a transformation of intermediate
12 to zanamivir was concisely achieved in modest yield by in-
troduction of the guanidine group with 1H-pyrazole-1-
carboxamidine hydrochloride and hydrolysis with 10% NaOH.
Using our newly established procedure, intermediate 12
could be prepared and accumulated conveniently. Because only
the free amino group is exposed, compound 12 can serve as
a very useful intermediate for potential diverse modifications at
and failed in converting the
a-keto ester 9 into the cyclized
precursor 10 by selective hydrolysis of the two acetonides, in-
cluding Dowex 50W-X8 in MeOH,7 Amberlyst-15 in MeOH,8 cat.
PPTs in MeOH, 80% aq AcOH,9 BF3$OEt2 in DCM,10 cat. BiBr3 in
MeCN11 and 40% aq HF in MeCN.5 The middle acetonide was
found much more stable than the N-Boc functionality under the
above acidic conditions.
its C4 amino functionality. With such
a consideration, 12
was employed to react with isothiocyanates 1415 and 17,16 in
parallel, affording the corresponding thiocarbamides 15 and 18
smoothly. Both products were further converted to the zanami-
vir derivatives 16 and 19 after basic hydrolysis, respectively
(Scheme 3).17
Fig. 2. Attempted conversion of
deoxyneuraminic acid methyl ester 10.
a-keto ester
9
into N4-Boc-N5-acetyl-4-
3. Conclusion
In summary, we have accomplished a new straightforward and
concise synthesis of zanamivir from the cheap material
D-glucono-
To avoid the above mentioned problems in manipulating pro-
tecting groups, we decided to take a direct but more challenging
approach to remove all the protecting groups at first (Scheme 2).
Hydrolysis followed by in situ cyclization of 11 was completed in
1 N methanolic HCl solution within half hour, without affecting
the methyl ester. It is noteworthy here that the N-acetyl group
could also be removed when treatment with higher concentration
of HCl or for a longer reaction time. The crude moisture-sensitive
hydrochloric acid salt 11 was then immediately subjected to the
d
-lactone. An azide-free protocol was adopted to introduce the C4
amino group, and a one-pot procedure was studied, optimized, and
successfully applied as the key operation to the direct synthesis of
the advanced intermediate 12 from amino-sugar substrate 11 by
acid-assisted selective O-acetylation and in situ generation of
dihydrofuran functionality. Two representative C4-thiocarbamido
zanamivir derivatives 16 and 19 were also conveniently synthe-
sized using the common intermediate 12 with the newly estab-
lished procedures.

X.-B. Zhu et al. / Tetrahedron 68 (2012) 2041e2044
2043
(ESI, m/z): 431.67 (MþH)þ; ESI-HRMS calcd for C18H26N2O10Na
[MþNa]þ 453.1485, found 453.1483.
4.1.2. 5-Acetamido-2,6-anhydro-4-guanidino-3,4,5-trideoxy-
D-glyc-
ero- -galacto-non-2-enonic acid (zanamivir, 1). To a solution of
D
amine 12 (300 mg, 0.7 mmol) and 1H-pyrazole-1-carboxamidine
(310 mg, 2.1 mmol) in anhydrous DMF (2 mL) was added N,N-dii-
sopropylethylamine (0.36 mL, 2.1 mmol). The mixture was stirred
at room temperature for 96 h. During this period, two additional
batches of 1H-pyrazole-1-carboxamidine hydrochloride (103 mg,
0.7 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.7 mmol) in
DMF (0.5 mL) were added at 48 h and 72 h, respectively. Methanol
(15 mL), water (6 mL), and 10% NaOH solution (2 mL) were added,
and the mixture was stirred for additional 12 h. Acetic acid was
then added until pH 7.5. The solvent was removed by concentration
under reduced pressure at 40 ꢀC. The residue was filtered, and the
filtrate was applied to a column of Dowex 50WX8-200 (Hþ) resin
and washed with water until neutralization. The column was then
eluted with 1.5 N aqueous ammonium hydroxide, and the com-
bined fractions were concentrated. The residue was recrystallized
by isopropanol/water (3:1) to afforded zanamivir as a white solid
a 20
(120 mg, 52%). Mp 252e254 C; ½ ꢂD þ40.5 (c 1.0, H2O); 1H NMR
ꢀ
(300 MHz, D2O):
d
5.61 (d, J¼2.1 Hz, 1H), 4.44 (dd, J¼2.1, 9.3 Hz, 1H),
4.37 (dd, J¼1.2, 10.8 Hz, 1H), 4.21 (t, J¼9.6 Hz, 1H), 3.92e3.98 (m,
1H), 3.88 (dd, J¼3.7, 12 Hz, 1H), 3.61e3.67 (m, 2H), 2.02 (s, 3H); 13C
NMR (75 MHz, D2O):
d 175.5, 170.3, 158.1, 150.4, 105.0, 76.5, 70.9,
69.2, 64.2, 52.2, 48.9, 23.1; Anal. Calcd for C12H20N4O7$1.17H2O:
C, 40.78, H, 6.37, N, 15.85; found: C, 40.62, H, 6.37, N, 15.57; MS (ESI,
m/z): 333.00 [MþH]þ; ESI-HRMS calcd for C12H20N4O7Na [MþNa]þ
355.1230, found 355.1234.
Scheme 3. Synthesis of zanamivir C4-thiocarbamides 15 and 18.
4. Experimental section
4.1.3. 5-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-[N0-(2-
thiophenemethyl)thiourea]-3,4,5-trideoxy-D-glycero-D-galacto-non-
4.1. General methods
2-enonic acid methyl ester (15). To a solution of 12 (200 mg,
0.46 mmol) in anhydrous DCM (3 mL) was added dropwise iso-
thiocyanate 14 (142 mg, 0.92 mmol) in anhydrous DCM (3 mL). The
mixture was stirred at room temperature overnight, and then
concentrated and purified by silica gel column chromatography
(dichloromethane/methanol¼25:1) to afford 15 (217 mg, 80%) as
All reactions were conducted using oven-dried glassware. Sol-
vents were obtained from commercial suppliers and used without
further distillation unless stated. IR spectra were recorded on an FT-
IR instrument. 1H NMR spectra were recorded at 300, 400 or
500 MHz, and 13C NMR spectra were recorded at corresponding
instruments, and assigned in parts per million (
points were measured with the samples after column chromatog-
raphy (without recrystallization) and uncorrected.
a white solid. Mp 180e182 ꢀC; ½a D20
þ60.7 (c 1.0, CHCl3); IR (KBr):
ꢂ
d
). All melting
nmax 3318, 3056, 2951, 1739, 1658, 1548, 1438, 1371, 1221, 1131, 1043,
745, 600 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d 7.65 (br, 1H), 7.10 (dd,
J¼1.2, 4.8 Hz, 1H), 6.92e6.96 (m, 3H), 6.20 (d, J¼10.2 Hz, 1H), 5.95
(d, J¼2.4 Hz, 1H), 5.68e5.74 (m, 1H), 5.47e5.49 (m, 1H), 5.20e5.25
(m, 1H), 4.86e4.90 (m, 1H), 4.60 (dd, J¼2.4, 12.6 Hz, 1H), 4.34 (dd,
J¼2.1, 9.9 Hz, 1H), 4.10e4.16 (m, 1H), 3.97e4.07 (m, 1H), 2.04e2.06
4.1.1. 5-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-amino-3,4,5-
trideoxy-D-glycero-D-galacto-non-2-enonic acid methyl ester (12). A
suspension of ester 9 (500 mg, 0.99 mmol) in cooled methanolic
HCl solution (1 N, 0 ꢀC) was stirred for 0.5 h and then allowed to
warm to room temperature. The solvent was removed under re-
duced pressure. The residue was dried in vacuo to afford 11
(360 mg) as a white solid, which was used in the next step without
further purification. MS (ESI, m/z): 323.33 [MþH]þ.
(m, 9H), 1.68 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 183.4, 172.7, 170.6,
170.2, 169.8, 161.2, 150.0, 140.2, 126.8, 126.0, 125.2, 110.8, 76.6, 71.0,
67.5, 61.8, 53.0, 52.4, 48.6, 43.5, 22.9, 20.8, 20.7, 20.6; Anal. Calcd for
C24H31N3O10S2: C, 49.22, H, 5.34, N, 7.17; found: C, 49.21, H, 5.41, N,
7.27; MS (ESI, m/z): 586.00 [MþH]þ; ESI-HRMS calcd for
C24H31N3O10S2Na [MþNa]þ 608.1349, found 608.1332.
To a solution of 11 (360 mg) in acetic anhydride (2 mL) in an ice
bath was added slowly concd sulfuric acid (0.2 mL). The solution
was then warmed to room temperature and stirred for 12 h.
Methanol (5 mL) was added and the mixture was neutralized by
adding aqueous ammonia to pH 10. After extraction with DCM
(3ꢁ20 mL), the combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (dichloromethane/
methanol/triethylamine¼20:1:0.2) to afford 12 (215 mg, 50% in two
4.1.4. 5-Acetamido-2,6-anhydro-4-[N0-(2-thiophenemethyl)thio-
urea]-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (16). A
solution of ester 15 (200 mg, 0.34 mmol) in MeOH (5 mL) and
aqueous NaOH (1 N, 5 mL) was stirred at room temperature for
3 h. The mixture was neutralized with Dowex 50WX8 (Hþ) resin
to pH 6, filtered and concentrated. The residue was purified by
silica gel column chromatography (dichloromethane/meth-
anol¼5:1) to afford 16 (117 mg, 77%) as a white solid. Mp
steps).4b,14 Mp 152e154 ꢀC; ½a 2D0
ꢂ
þ33.7 (c 1.0, MeOH); IR (KBr): nmax
>200 ꢀC; ½a 2D0
ꢂ
þ38.7 (c 1.0, MeOH); IR (KBr): nmax 3272, 2931,
3313, 3073, 2360, 1743, 1654, 1547, 1438, 1371, 1252, 1215, 1132,
1598, 1454, 1374, 1280, 757 cmꢃ1 1H NMR (300 MHz, CD3OD):
;
1043, 944, 852, 706, 597 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d
6.14 (br
d
7.29 (m, 1H), 7.12e7.13 (m, 1H), 6.95 (m, 1H), 5.59 (d, J¼15.9 Hz,
m, 1H), 5.49 (m, 1H), 5.29 (m, 1H), 4.60e4.63 (m, 1H), 4.38e4.43
(m, 2H), 4.08e4.15 (m, 2H), 3.78 (s, 3H), 1.99e2.04 (m, 12H); MS
1H), 4.70e4.88 (m, 2H), 3.84e3.85 (m, 1H), 3.76e3.81 (m, 2H),
3.47e3.49 (m, 1H), 3.32e3.33 (m, 3H), 2.03 (s, 3H); 13C NMR

2044
X.-B. Zhu et al. / Tetrahedron 68 (2012) 2041e2044
(75 MHz, D2O):
d
183.2, 174.7, 149.2, 127.6, 127.0, 126.3, 123.9, 72.2,
MS (ESI, m/z): 491.58 [MꢃH]ꢃ; ESI-HRMS calcd for C17H22N3O7S2
[MꢃH]ꢃ 491.1600, found 491.1614.
71.1, 71.0, 67.8, 62.6, 59.9, 55.7, 48.4, 42.5, 22.0; MS (ESI, m/z):
444.58 [MꢃH]ꢃ; ESI-HRMS calcd for C17H22N3O7S2 [MꢃH]ꢃ
444.0899, found 444.0916.
Acknowledgements
4.1.5. 5-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-4-[N0-(1H-indole-
3-ethyl)thiourea]-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic
Financial supports from NSFC (No. 21032002), MOST 973 Pro-
gram (No. 2010CB833200) and the Fundamental Research Funds for
the Central Universities (No. 1082020502) are greatly appreciated.
acid methyl ester (18). To a solution of 12 (200 mg, 0.46 mmol) in
anhydrous DCM (3 mL) was added isothiocyanate 17 (186 mg,
0.92 mmol) in anhydrous DCM (3 mL) dropwise. The mixture was
stirred at room temperature overnight, and then concentrated
and purified by silica gel column chromatography (dichloro-
methane/methanol¼25:1) to afford 18 (241 mg, 82%) as a white
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.011.
solid. Mp 176e179 ꢀC; ½a D20
ꢂ
þ69.2 (c 1.0, CHCl3); IR (KBr): nmax
3317, 2924, 1720, 1640, 1545, 1282, 747 cmꢃ1
;
1H NMR (300 MHz,
References and notes
CDCl3):
d
8.46 (br, 1H), 7.54 (d, J¼7.8 Hz, 1H), 7.34 (d, J¼8.1 Hz,
1H), 7.18 (t, J¼4.5 Hz, 1H), 7.08 (t, J¼4.5 Hz, 1H), 6.87 (br, 1H), 6.22
(br, 1H), 5.81 (br, 1H), 5.43 (dd, J¼2.4, 5.4 Hz, 1H), 5.22e5.28 (m,
1H), 4.62 (dd, J¼2.7, 12.3 Hz, 1H), 4.21e4.27 (m, 1H), 4.10e4.20 (m,
1H), 3.95 (br, 1H), 3.80 (s, 3H), 3.76e3.80 (m, 2H), 2.97 (t, J¼6 Hz,
1. (a) Kiefel, M. J.; von Itzstein, M. Prog. Med. Chem. 1999, 36, 1e28; (b) von Itz-
stein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Phan, T. V.;
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2H), 2.05 (s, 9H), 1.78 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 183.8,
172.6, 170.7, 170.2, 169.9, 161.5, 144.7, 136.2, 126.8, 122.5, 122.1,
119.4, 118.4, 112.4, 111.4, 110.9, 76.6, 71.0, 67.6, 62.0, 52.8, 52.5,
48.5, 44.9, 24.9, 22.9, 20.8, 20.7, 20.7; Anal. Calcd for
C29H36N4O10S: C, 55.05, H, 5.74, N, 8.86; found: C, 55.01, H, 5.78,
N, 8.78; MS (ESI, m/z): 633.08 [MþH]þ, 655.08 [MþNa]þ; ESI-
HRMS calcd for C29H36N4O10SNa [MþNa]þ 655.2050, found
655.2052.
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4.1.6. 5-Acetamido-2,6-anhydro-4-[N0-(1H-indole-3-ethyl)thiourea]-
3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (19). A solu-
tion of ester 18 (200 mg, 0.32 mmol) in MeOH (5 mL) and aqueous
NaOH (1 N, 5 mL) was stirred at room temperature for 3 h. The
mixture was then neutralized with Dowex 50WX8 (Hþ) resin to
pH 6, filtered and concentrated. The residue was purified by silica
gel column chromatography (dichloromethane/methanol¼4:1) to
afford 19 (107 mg, 69%) as a white solid. Mp >200 ꢀC; ½a D20
þ31.5
ꢂ
(c 0.8, MeOH); IR (KBr): nmax 3233, 2917, 1612, 1451, 1370, 1268,
1135, 1035, 747 cmꢃ1 1H NMR (300 MHz, DMSO-d6):
; d 10.84 (s,
13. Kok, G. B.; Campbell, M.; Mackey, B.; von Itzstein, M. J. Chem. Soc., Perkin Trans. 1
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3.93e4.06 (m, 2H), 3.63e3.70 (m, 4H), 3.35e3.44 (m, 2H), 2.91
(t, J¼7.5 Hz, 2H), 1.90 (s, 3H); 13C NMR (75 MHz, DMSO-d6):
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d
172.0, 163.8, 145.1, 136.6, 127.6, 127.4, 123.2, 121.3, 118.8, 118.6,
112.0, 111.7, 110.3, 77.4, 69.8, 68.8, 63.9, 52.4, 47.5, 44.8, 25.1, 23.0;