Synthesis of oseltamivir and tamiphosphor from N-acetyl-d-glucosamine

Article abstract of DOI:10.1039/c3ob41622d

Using N-acetyl-d-glucosamine as a starting material, the anti-influenza drugs oseltamivir and tamiphosphor were synthesized via a pivotal intermediate of aldehyde 8. An intramolecular Horner-Wadsworth-Emmons reaction was utilized to construct the highly f

Full text of DOI:10.1039/c3ob41622d

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Synthesis of Oseltamivir and Tamiphosphor from NꢀAcetylꢀDꢀglucosamine
ab
a
ChihꢀAn Chen and JimꢀMin Fang*
a
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan. E-mail:
jmfang@ntu.edu.tw; Fax: (8862) 23637812; Tel: (8862) 33661663
b
The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
1
13
31
†
Electronic supplementary information (ESI) available: H, C, P and 2D NMR spectra.
See DOI:
1

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Abstract
Using NꢀacetylꢀDꢀglucosamine as a starting material, the antiꢀinfluenza drugs oseltamivir
and tamiphosphor were synthesized via a pivotal intermediate of aldehyde 8. An
intramolecular Horner–Wadsworth–Emmons reaction was utilized to construct the highly
functionalized cyclohexene ring. The existing Nꢀacetyl group was transformed into an azido
group for the subsequent aziridination, followed by implantation of a 3ꢀpentoxy group in the
desired stereochemistry.
2

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Introduction
Influenza has been a longꢀstanding health threat to human. In addition to season’s
influenza epidemics, emergence of new influenza strains may become global pandemics and
claims enormous number of lives as that occurred in Spanish flu (H1N1, 1918), Asian flu
(H2N2, 1957), Hong Kong flu (H3N2, 1968), bird flu (H5N1, 2003), swine flu (H1N1, 2009),
and the recent flu transmission from avian to human (H7N9, 2013). Influenza virus is a
1
negativeꢀsense singleꢀstrain RNA virus of the Orthomyxoviridae family. There are 8 pieces
of segmented RNA in influenza virus for production of 11 proteins, among which
hemagglutinin (HA), neuraminidase (NA) and M2 channel proteins are located on the surface
2, 3
of virus. Use of amantadine and rimantadine in treatment of influenza infection is limited
4–6
due to the high drug resistance of these M2 channel blockers. At present, the most effective
7–10
11, 12
antiꢀinfluenza drugs are NA inhibitors
including zanamivir,
oseltamivir (1 in Figure
13, 14
15, 16
17, 18
®
1),
peramivir
and laninamivir
. Tamiflu , the phosphate salt of oseltamivir, is
currently the most popular orally available drug for influenza treatment. However,
oseltamivirꢀresistant viruses have emerged over the years due to the extensive use of
oselt Oa ms ei lvt ai rm i ni vi nr fl ius e nc zoa n tvh eer rt ae pd y.by endogenous esterase to the active carboxylate, which
19–21
with three arginine residues (Arg118, Arg292 and Arg371) in the active site of NA.
We
3

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2
2, 23
have previously found that tamiphosphor
(2 in Figure 1), designed by replacement of the
carboxylate group in oseltamivir with a phosphonate group, showed better NA inhibition,
presumably due to the stronger electrostatic interactions of the phosphonate group with the
three arginine residues in the active site of influenza NA. The cellꢀbased assays and mouse
23
tests further indicate that tamiphosphor is a potent antiꢀinfluenza agent to improve the
survival rate of mice challenged by lethal doses of avian (H5N1) and human (H1N1)
viruses including the oseltamivirꢀresistant strain.
The current industrial synthesis of oseltamivir is originally designed by Kim and
24
coworkers in Gilead, and then developed by the research teams in Roche using naturally
2
5, 26
occurring shikimic acid as a starting material.
This industrial process was further
2
7, 28
by Karpf and coworkers.
To cope with the potential need of large quantity of oseltamivir
during influenza pandemics, chemists have also devised various methods for the synthesis of
2
9, 30
oseltamivir without using shikimic acid.
In contrast, only a few methods are reported for
22, 31–33
the synthesis of tamiphosphor.
Carbohydrates are abundant and inexpensive natural
source of chiral molecules suitable for construction of the scaffold of highly functionalized
cyclohexene ring in oseltamivir and tamiphosphor. For example, the total synthesis of
3
4
35
36, 37
38
oseltamivir has been achieved by using
Dꢀglucose,
D
ꢀglucal,
Dꢀmannose,
Dꢀmannitol,
4

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3
9
and Dꢀribose as the starting materials, and we have utilized Dꢀxylose as a starting material
22
the synthesis of both oseltamivir and tamiphosphor. In a different approach to tamiphosphor,
3
2
33
Streicher’s group and Gunasekera have converted the carboxylic acid group in oseltamivir
derivatives to iodine and bromine atoms by Hunsdiecker–Barton halodecarboxylation, and
3
1, 40
subsequently carried out the palladiumꢀcatalyzed phosphonylation
to furnish
tamiphosphor.
back side attack
at allylic position
OH
H
E
O
E
3
AcN
5
H
AcHN
LG
N-nucleophile
NH
2
A
1
2
3
E = CO Et, Oseltamivir
E = PO(OH)
E = PO(OEt)
2
2
, Tamiphosphor
2
LG = leaving group
O
PO(OEt)
E
2
AcHN
E
AcHN
HO
R
R
4
HO
R
OH
HWE
OH
B
C
E
H
OH
5
(
2
EtO) OP
O
R
5
R
OH
NHAc
O
4
HO
R
HO R
OH
R
R
NHAc
HO
D
D-GlcNAc
Figure 1 Retrosynthetic analysis of oseltamivir (1) and tamiphosphor (2)
We report herein the syntheses of oseltamivir and tamiphosphor using
DꢀGlcNAc as a
starting material (Figure 1). Our retrosynthetic analysis shows that aziridine A can be a good
5

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candidate for implantation of pentanꢀ3ꢀol and amino groups in the desired stereochemistry at
the 3ꢀ and 5ꢀpositions, respectively. Intermediate B having three substituents in allꢀtrans
configuration on the cyclohexene core structure can be constructed by an intramolecular
4
1
Horner–Wadsworth–Emmons (HWE) reaction of compound C, which can exist as a
furanoside tautomer D. Thus, DꢀGlcNAc appears to be an appropriate chiralꢀpool precursor
for the synthesis of oseltamivir and tamiphosphor. This approach is evolved from an idea
using the existing acetamido group of
DꢀGlcNAc to construct aziridine A in the desired
stereochemistry, and to avoid extra steps for introduction of acetamido group in our previous
2
2
synthesis using Dꢀxylose. Thus, the syntheses of oseltamivir and tamiphosphor are expected
to be accomplished in a straightforward manner with reduced synthetic steps.
Results and discussion
Scheme 1 shows a synthesis of oseltamivir from DꢀGlcNAc. The reaction of DꢀGlcNAc
4
2
2 3
with acetone in the presence of Et O:BF gave oxazolidine 4. This reaction was considered
to proceed with an initial acetalization of the terminal 5,6ꢀdiol to form a furanose derivative,
which was then promoted by Lewis acid to give an oxonium ion intermediate E for the
intramolecular reaction with the adjacent acetamide group. Compound 4 was treated with
6

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43
BnBr under basic condition to give the benzyl ether 5. Treatment of 5 with benzyl alcohol in
the presence of a TFA catalyst afforded the βꢀanomer of benzyl furanoside 6 as the exclusive
product in 80% yield. After deacetalization, the NOESY spectrum of diol product 7 showed
the correlation of βꢀanomeric proton (Hꢀ1) with the adjacent acetamido proton (AcNH). Diol
7
4
was subjected to an oxidative cleavage by NaIO to give aldehyde 8, which underwent
4 3
Knoevenagel condensation with triethyl phosphonoacetate in the presence of TiCl and Et N
44, 45
to give compound 9.
Such Knoevenagel condensation could not be realized in
4
conventional conditions using piperidine/HOAc, NH OAc or NaH, presumably due to the low
nucleophilicity of the anion of triethyl phosphonoacetate. Compound 9 contained the Eꢀ and
1
1
Zꢀisomers in a ratio of 1:1. As shown in H– H COSY spectrum, the Eꢀisomer having Hꢀ5 on
H
the same side of phosphonate group occurred at δ 7.67 with a relatively small coupling
constant (JH–P = 14.5 Hz), whereas the Zꢀisomer having Hꢀ5 on the opposite side of
45
H
phosphonate group appeared at δ 7.23 with a large coupling constant (JH–P = 46.0 Hz).
Catalytic hydrogenation of 9 rendered a simultaneous debenzylation and saturation of the
2
C=C bond to provide a lactol (structure D in Scheme 1, E = CO Et), which readily
tautomerized in basic conditions to form an aldehyde intermediate for intramolecular HWE
4
1
reaction, giving the product of cyclohexꢀ1ꢀenecarboxylate 10. As the scaffold of
7

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polysubstituted cyclohexene ring was constructed, elaboration of substituents by
functionalꢀgroup transformations was executed. The acetamido group in 10 was first
hydrolyzed in refluxing HCl–EtOH solution (1 M), and the intermediate product of amine
46
4
was subsequently treated with imidazoleꢀ1ꢀsulfonyl azide in the presence of CuSO and
2 3
K CO to give an azide 11 in 81% yield. Diol 11 was smoothly converted to the dimesylated
2
derivative 12, which has been transformed into aziridine A (LG = MsO and E = CO Et) for
28, 47
the synthesis of (–)ꢀoseltamivir.
We thus accomplished a formal synthesis of oseltamivir
from DꢀGlcNAc.
8

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O
O
OH
+
H
O
O
a
O
O
b
O
HO
HO
H
O
H
O
OH
NHAc
D-GlcNAc
HO
N
HO
H
4
N
H
E
O
O
HO
HO
H
O
c
O
d
O
H
O
O
OBn
OBn
O
H
H
H
BnO
N
BnO
NHAc
EtO2C
BnO
NHAc
5
6
7
H
H
5
O
e
O
OBn
f
O
g, h
OBn
(
EtO)2OP
H
H
BnO
NHAc
BnO
NHAc
8
9 (Z/E = 1:1)
O
O
AcHN
HO
N3
i, j
OEt
k
OEt
HO
OH
OH
10
11
O
O
N3
MsO
ref 28, 47
O
OEt
OEt
AcHN
OMs
NH2
12
1
Scheme 1 Synthesis of (–)ꢀOseltamivir from
DꢀGlcNAc. Reagents and conditions: (a)
o
3 2
BF ꢁEt O, acetone, reflux, 20 min; 59%; (b) BnBr, NaH, DMF, 0 C to rt, 2 h; 91%; (c) cat.
TFA, BnOH, rt, 12 h; 80%; (d) 70% HOAc–H
2
4 2
O, rt, 12 h; 95%; (e) NaIO , acetone, H O, 0
o
o
2
C, 3 h, 96%; (f) EtO CCH
2
PO(OEt)
2
, TiCl
4
, NEt
3
, THF, 0 C, 1 h; 76%; (g) Pd/C, H
2
, EtOH,
o
rt, 24 h; (h) NaH, THF, 0 C, 1 h; 62% yield of 10 (from 9); (i) HCl–EtOH (1 M), reflux, 12 h;
2 3 4 2
(j) imidazoleꢀ1ꢀsulfonyl azide, K CO , CuSO ꢁ5H O, EtOH, rt, 2 h; 81% yield of 11 (from
o
1
0); (k) MsCl, NEt
3
, EtOAc, 0 C, 2 h; 85%.
During this study, we have encountered several unexpected hurdles. In the beginning, we
9

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planned to introduce triethyl phosphonoacetate moiety via the substitution reaction of
mesylate 15 (Figure 2). Thus, compound 13 was subjected to an oxidative cleavage with
4 4
NaIO , followed by reduction with NaBH , to give 14. The selective monoꢀmesylation of the
primary hydroxyl group in 14 was accomplished by using a stoichiometric amount of MsCl at
o
0
3
C in the presence of Et N to provide mesylate 15. However, several attempts to substitute
the mesyl group of 15 with the anion of triethyl phosphonoacetate in THF solution failed,
41
N
even in the presence of 15ꢀcrownꢀ5. Under such conditions, an intramolecular S 2 reaction
by the adjacent 3ꢀOH group might occur to give an oxetane product, of which structure was
1
inferred from the H NMR and MS spectra of the crude reaction mixture. Alternatively, the
mesylate 17 and its triflate analog with the 3ꢀOH protected as benzyl ether were prepared
from alcohol 16. However, the nucleophilic substitution reactions with triethyl
phosphonoacetate also failed in various reaction conditions (in THF or DMF solution with or
o
22, 48
without 15ꢀcrownꢀ5, 25–70 C, 12–24 h).
Our initial plan was to take advantage of the existing acetamido group to transform
DꢀGlcNAc into aziridine A for an azideꢀfree synthesis of oseltamivir. Thus, diol 10 was
activated as the dimesylate derivative 18, and treated with base (e.g., NaH, LDA, KHMDS
and DMAP) in attempt to render the intramolecular substitution reactions to generate the
10

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47, 49
Nꢀacetylaziridine product. Instead, we obtained ethyl 3ꢀacetamidobenzoate (19)
in such
basic conditions due to elimination of two MsOH molecules from 18. Alternatively,
dimesylate 23 having tꢀBocNH substituent at the Cꢀ3 position was prepared from compound 9
2
via a fiveꢀstep sequence: (i) treatment of 9 with Boc O to give 20, (ii) Michaelꢀtype reduction
4
of 20 with NaBH to give 21, (iii) debenzylation of 21 by catalytic hydrogenation to give a
lactol, (iv) intramolecular HWE reaction of the lactol to afford cyclohexeneꢀ1ꢀcarboxylate 22,
and (v) dimesylation with excess MsCl to give 23. After removal of the tꢀBoc group from 23,
3
the amine intermediate in THF solution was treated with Et N in order to form the desired
aziridine product. Again, only ethyl 3ꢀacetamidobenzoate (19) was obtained by elimination
reactions. It was interesting to note that an unexpected product of cyclic carbamate 24 was
2
obtained when the reaction was performed in aqueous media (e.g., EtOH–H O or
3 2 3 3
CH CN–H O solution) with excess NaHCO instead of Et N.
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HO
HO
HO
MsO
O
OBn
O
O
OBn
OBn
H
H
3
H
HO
NHAc
NHAc
HO
NHAc
HO
13
14
15
O
HO
O
MsO
AcHN
MsO
OBn
O
3
OEt
OBn
H
H
BnO
NHAc
BnO
NHAc
OMs
16
17
18
EtO2C
H
O
O
AcHN
OBn
Ac
(
EtO)2OP
OEt
H
BnO
N
Boc
19
2
0
(
EtO)2OP
H
O
BocHN
O
OEt
OBn
EtO2C
H
HO
BnO
NHBoc
OH
22
2
1
O
O
H
H
H
N
BocHN
MsO
OEt
OEt
3
O
O
OMs
OMs
2
3
2
4
(EtO)2OP
(
EtO)2OP
H
O
O
(EtO)2OP
(EtO)2OP
OEt
NHBoc
O
H
H
O
N
HO
H
H
HO
35
36
Figure 2 Chemical structures of side products 13–24, 35 and 36.
For the synthesis of tamiphosphor, aldehyde 8 was reacted with tetraethyl
4 3
methylenediphosphonate in the presence of TiCl and Et N to give the condensation product
4
4, 45
25 (Scheme 2).
By a procedure similar to that for cyclohexeneꢀ1ꢀcarboxylate 10,
diphosphonate 25 was subjected to catalytic hydrogenation, followed by treatment with NaH
to furnish the intramolecular HWE reaction, giving cyclohexeneꢀ1ꢀphosphonate 28a.
12

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However, this transformation also yielded an unidentified side product, which could not be
separated from 28a. Attempts to improve the HWE reaction by using different bases (e.g.,
2 3 3 2
K CO , NaOEt and Et N/MgBr ) in various conditions failed to give a clean cyclization
2
product 28a. Alternatively, we treated 25 with Boc O in the presence of DMAP to give the
2 3
derivative 26. Because saponification of 26 with K CO in EtOH often caused undesired
4
double bond migration, we thus utilized NaBH reduction to remove the acetyl group, giving
27 by concurrent saturation of the C=C double bond in aqueous EtOH solution. In an attempt
to remove benzyl groups by catalytic hydrogenation in EtOH solution, we unexpectedly
obtained appreciable amounts of ethyl glycoside 35 and cyclic carbamate 36 (Figure 2) in
addition to the desired lactol product. Fortunately, the catalytic hydrogenation was
successfully conducted in THF solution to remove both benzyl groups. Thus, the subsequent
intramolecular HWE reaction was carried out to give a pure cyclization product 28b (53%
yield from 27) after chromatography on a silica gel column. The tꢀBoc group in 28b was
removed by TFA, and azide 29 was prepared by reaction with imidazoleꢀ1ꢀsulfonyl azide.
Compound 29 was subjected to mesylations with excess MsCl, and the dimesylated product
3
30 was treated with a freshly distilled (EtO) P in anhydrous toluene solution to give a
28
3
phosphoryl aziridine 31. If the purchased (EtO) P reagent was used without prior distillation,
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50
the reaction with azide 30 would afford a phosphonamide product. Attempt to convert 30 by
4
7
3
using Staudinger reaction with Ph P to an unprotected aziridine product failed. The
phosphoryl aziridine 31 was selectively attacked at the allylic position by pentanꢀ3ꢀol in the
3 2 2 4
presence of BF ꢁEt O to furnish phosphonamide 32, which was heated in H SO –EtOH
solution (3 M) under reflux for 4 h to give the corresponding amine product. The NOESY
spectrum of 32 supported the correlation of Hꢀ3 with NH on the same face. The amino group
N
was subjected to acetylation, and the product 33 underwent an S 2 reaction with sodium azide
to replace the mesyloxy group at the Cꢀ5 position, giving compound 34. Reduction of the
azido group, followed by treatment with trimethylsilyl bromide, culminated in the synthesis
22
of (–)ꢀtamiphosphor.
14

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(
EtO)2OP
H
O
H
O
O
a
OBn
Ac
c
OBn
(EtO) OP
2
H
H
BnO
N
BnO
NHAc
Y
8
25 Y = H
6 Y = Boc
b
2
O
(
(
EtO)2OP
EtO)2OP
RHN
HO
P
OEt
d, e
O
OBn
OEt
H
BnO
NHBoc
OH
27
2
8a R = Ac
2
8b R = Boc
O
O
P
N3
P
OEt
OEt
N3
OEt
OEt
f, g
h
HO
MsO
OH
OMs
2
9
3
0
O
H
H
O
P
O
P
P
OEt
OEt
O
H
i
j
nOe
OEt
OEt
N
3
EtO
H
EtO
N
P
OMs
EtO
EtO
OMs
O
3
1
32
O
P
O
P
O
OEt
OEt
O
OEt
OEt
k
l
AcHN
AcHN
OMs
N3
3
3
34
O
O
P
OR
OR
m
AcHN
n
NH2
3
2
R = Et
R = H
Scheme 2 Synthesis of (–)ꢀtamiphosphor from
DꢀGlcNAc. Reagents and conditions: (a)
o
H
2
C[PO(OEt)
2
2
] , TiCl
4
, NEt
3
, 0 C, 1 h; (b) Boc
2
O, DMAP, reflux, 3 h; 32% yield of 26 (from
o
aldehyde 8); (c) NaBH
4
, EtOH, H
2
O, 0 C to rt, 12 h; quantitative; (d) Pd/C, H
2
, THF, rt, 24 h;
o
(
e) NaH, THF, 0 C, 1 h; 53% of 28b from 27; (f) for 28a, HCl–EtOH (1 M), reflux, 12 h; for
2 2 2 3 4 2
28b, TFA, CH Cl , rt, 2 h; (g) imidazoleꢀ1ꢀsulfonyl azide, K CO , CuSO ꢁ5H O, EtOH, rt, 2
o
3 3
h; 58% yield of 29 (from 28b); (h) MsCl, NEt , EtOAc, 0 C, 2 h; 84%; (i) P(OEt) ,
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3 2
anhydrous toluene, reflux, 1 h; 77%; (j) BF ꢁEt O, 3ꢀpentanol, rt, 16 h; 87%; (k)
o
o
H
2
SO
4
–EtOH (3 M), 70 C, 4 h; then pyridine, Ac
2
O, 0 C, 15 min; 80%; (l) NaN
3
, DMF, 100
o
2 3
C, 2 h; 85%; (m) H , Lindlar catalyst, EtOH, rt, 16 h; 85%; (n) TMSBr, CHCl , rt, 24 h;
85%.
Conclusion
Even though the syntheses of oseltamivir and tamiphosphor from DꢀGlcNAc were not as
straightforward as shown in our initial plan (Figure 1), we have finally overcome hurdles to
complete the target syntheses. The intramolecular HWE reaction was applied to construct the
scaffold of polysubstituted cyclohexenes. It was not reliable to introduce phosphonoacetate
and diphosphorylmethyl moieties by the substitution reactions of triflate or mesylate
compounds (e.g., 15). The better resolution was to perform Knoevenagel reactions of
4
aldehyde 8 followed by Michaelꢀtype reduction with NaBH . In the previous routes to
22
34
oseltamivir and tamiphosphor from
Dꢀxylose or Dꢀglucose , extra steps are needed to
introduce acetamido group and to invert some chiral centers. We thought that
DꢀGlcNAc
might be a better starting material because its absolute configuration is preset to manipulate
the required stereochemistry in oseltamivir and tamiphosphor. Unfortunately, our experiments
16

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revealed that the devised direct aziridination of dimesylated compounds (e.g., 18 and 23) with
2
the adjacent NHAc, NHBoc or NH groups could not be realized as our anticipation for
azideꢀfree synthesis. In the long run, we still needed to prepare the dimesylated compounds 12
and 30 with an adjacent azido group for the subsequent aziridination. The problems and
resolutions encountered in our study may be learned when one will design new methods for
the synthesis of oseltamivir and tamiphosphor bearing the highly functionalized cyclohexene
ring.
Experimental
General
All the reagents and solvents were reagent grade and were used without further
purification unless otherwise specified. All solvents were anhydrous grade unless indicated
2 2 2
otherwise. CH Cl was distilled from CaH . All nonꢀaqueous reactions were carried out in
ovenꢀdried glassware under a slight positive pressure of argon unless otherwise noted.
Reactions were magnetically stirred and monitored by thinꢀlayer chromatography on silica gel
using aqueous pꢀanisaldehyde and phosphomolybdic acid as visualizing agents. Silica gel
(0.040–0.063 mm particle sizes) and reversedꢀphase RPꢀ18 (0.040–0.063 mm particle sizes)
17

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were used for column chromatography. Flash chromatography was performed on silica gel of
o
6
0–200 ꢂm particle size. Molecular sieves were activated under high vacuum at 220 C over 6
h.
Melting points were recorded in open capillaries and are not corrected. Optical rotations
–1
2
–1
D
were measured on digital polarimeter; [α] values are given in units of 10 deg cm g .
Nuclear magnetic resonance (NMR) spectra were obtained on 400 MHz spectrometer.
H C
Chemical shifts (δ) are given in parts per million (ppm) relative to δ 7.24 / δ 77.0 (central
3 3 H 2 2 H C 3 H
line of t) for CHCl /CDCl , δ 4.80 for H O/D O, δ 3.31 / δ 48.2 for CD OD, or δ 2.49 /
C 6
δ 39.5 for DMSOꢀd . The splitting patterns are reported as s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), dd (double of doublets) and br (broad). Coupling constants (J) are
given in Hz. Distortionless enhancement polarization transfer (DEPT) spectra were taken to
determine the types of carbon signals. The ESI–MS experiments were conducted on a
highꢀresolution mass spectrometer.
2
ꢀMethylꢀ(1,2ꢀdideoxyꢀ5,6ꢀOꢀisopropylideneꢀ[2,1ꢀd]ꢀ2ꢀoxazoline) (4). Compounds 4
4
2
was prepared from DꢀGlcNAc according to the previously reported method. To a suspension
of 2ꢀacetamidoꢀ2ꢀdeoxyꢀDꢀglucopyranose (GlcNAc, 21.0 g, 95 mmol) in anhydrous acetone
18

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3 2
(300 mL) was added BF ꢁEt O (37.8 mL, 285 mmol). The mixture was stirred at reflux for 20
min under an atmosphere of nitrogen, cooled in an iceꢀbath, and treated with triethylamine
(140 mL). The mixture was added into a cold solution of sodium carbonate (60 g) in water
(400 mL) with stirring. Acetone, triethylamine and some water were removed by rotary
o
evaporation while the temperature of water bath was kept below 40 C. The residue was
extracted with Et O (300 mL × 4). The combined extracts were dried (MgSO ) and
2
4
o
concentrated by rotary evaporation while the temperature of water bath was kept below 40 C
5 3
to give compound 4 (13.7 g, 59% yield). C11H17NO ; brownish syrup; TLC (CHCl /MeOH,
25
1
0:1) R = 0.4; [α]
–28.7 (c 4.2, EtOAc); IR vmax (neat) 3377, 2987, 1666 (C=N), 1383,
D
f
–1 1
1
3
211, 1068, 918 cm . H NMR (CDCl , 400 MHz) δ 6.11 (1 H, d, J = 4.8 Hz), 4.37 (1 H, d, J
=
4.8 Hz), 4.31–4.25 (2 H, m), 4.07 (1 H, dd, J = 8.4, 6.4 Hz), 3.96 (1 H, dd, J = 8.8, 4.8 Hz),
13
3
3
.68 (1 H, dd, J = 7.6, 2.0 Hz), 1.97 (3 H, s), 1.36 (3H , s), 1.29 (3 H, s); C NMR (CDCl ,
100 MHz) δ 167.2, 109.4, 107.2, 81.8, 78.2, 74.3, 72.7, 67.3, 26.8, 25.1, 14.1; HRMS (ESI)
+
calcd for C11
H
18NO
5
: 244.1185, found: m/z 244.1185 [M + H] .
2
ꢀMethylꢀ(1,2ꢀdideoxyꢀ3ꢀOꢀbenzylꢀ5,6ꢀOꢀisopropylideneꢀ[2,1ꢀd]ꢀ2ꢀoxazoline)
(5).
43
Compound 5 was prepared according to the previously reported method. NaH (840 mg, 20.9
19

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mmol; 60% dispersion in oil) was washed with hexane (2 ×) under an atmosphere of nitrogen,
then compound 4 (3.38 g, 13.9 mmol) in anhydrous DMF (30 mL) was added dropwise at 0
o
o
C. After 10 min, BnBr (1.83 mL, 15.3 mmol) was added dropwise into the suspension at 0 C.
The iceꢀbath was removed, and the mixture was stirred for 2 h at room temperature to give a
pale yellow clear solution. MeOH was added to quench excess NaH, and the mixture was
2 2
concentrated under reduced pressure. The residue was extracted with CH Cl and water, dried
4
(MgSO ), filtered, and concentrated to give compound 5, which was used in the next step
without further purification. An analytical sample of 5 (4.22 g, 91%) was obtained by
3
chromatography on a silica gel column (packed in EtOAc/hexane (1:3) containing 10% NEt )
3 5
with elution of EtOAc/hexane (1:1) containing 3% NEt . C18H23NO ; pale yellow syrup; TLC
2
4
(
EtOAc/hexane, 2:1) R = 0.5, [α] –32.7 (c 4.0, EtOAc); IR vmax (neat) 2986, 1669 (C=N),
f
D
–
1 1
1
381, 1210, 1071 cm ; H NMR (CDCl , 400 MHz) δ 7.34–7.26 (5 H, m), 6.10 (1 H, d, J =
3
5.2 Hz), 4.70 (1 H, d, J = 12.0 Hz), 4.63 (1 H, d, J = 11.6 Hz), 4.50 (1 H, d, J = 4.8 Hz), 4.35
(1 H, dd, J = 12.4, 6.0 Hz), 4.10–4.06 (2 H, m), 4.00 (1 H, dd, J = 8.4, 5.6 Hz), 3.82 (1 H, dd,
13
3
J = 6.8, 2.4 Hz), 2.00 (3 H, s), 1.39 (3 H, s), 1.35 (3 H, s); C NMR (CDCl , 100 MHz) δ
167.1, 137.8, 128.6 (2 ×), 128.0, 127.9 (2 ×), 109.2, 107. 2, 81.8, 81.7, 75.6, 72.8, 72.3, 67.2,
5
26.9, 25.5, 14.3; HRMS (ESI) calcd for C18H24NO : 334.1654, found: m/z 334.1660 [M +
20

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+
H] .
2
ꢀAcetamidoꢀ1,3ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ5,6ꢀOꢀisopropylideneꢀβꢀDꢀglucofuranose (6).
Oxazolidine 5 (4.22 g, 12.67 mmol) was dissolved in BnOH (16 mL), and a catalytic amount
of TFA (56 ꢃL) was added. The mixture was stirred for 12 h at room temperature until
disappearance of the starting material based on TLC analysis. The mixture was subjected to
silica column chromatography (EtOAc/hexane, 1:3) to remove excess BnOH, and then eluted
6
with EtOAc/hexane (1:1) to give the desired product 6 (4.46 g, 80%). C25H31NO ; pale yellow
o
25
solid, mp 145.2–146.8 C; TLC (EtOAc/hexane, 2:1) R = 0.4; [α] –90.1 (c 4.7, EtOAc); IR
f
D
–
1 1
v
5
1
max (neat) 1651, 1548, 1371, 1067 cm ; H NMR (CDCl
3
, 400 MHz) δ 7.38–7.26 (10 H, m),
.88 (1 H, d, J = 7.2 Hz, NH), 5.04 (1 H, s, anomeric), 4.87–4.81 (2 H, m), 4.62 (1 H, d, J =
2.0 Hz), 4.55–4.50 (2 H, m), 4.44–4.37 (2 H, m), 4.12 (1 H, dd, J = 8.4, 5.6 Hz), 4.06 (1 H,
13
dd, J = 8.4, 6.4 Hz), 3.99 (1 H, d, J = 5.2 Hz), 1.97 (3 H, s), 1.47 (3 H, s), 1.38 (3 H, s); C
NMR (CDCl , 100 MHz) δ 169.9, 138.2, 137.5, 128.5 (2 ×), 128.4 (2 ×), 128.0 (2 ×), 127.8 (2
3
×), 127.6 (2 ×), 108.7, 105.9, 82.9, 81.8, 74.5, 71.7, 69.6, 66.7, 60.0, 26.8, 25.4, 23.3; HRMS
–
(ESI) calcd for C25
H30NO
6
: 440.2073, found: m/z 440.2064 [M – H] .
21

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2
ꢀAcetamidoꢀ1,3ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀβꢀDꢀglucofuranose (7). Compound 6 (7.5 g, 17
mmol) was dissolved in 70% aqueous HOAc (80 mL), and stirred for 12 h at room
temperature. After disappearance of the starting material based on TLC analysis, the mixture
was added to saturated NaHCO3(aq) cooled in an iceꢀbath. The mixture was extracted with
2 2 2 4
CH Cl and H O, dried (MgSO ), filtered, and concentrated to give diol 7 (6.45 g, 95%),
6
which was used in the next step without further purification. C22H27NO ; pale yellow syrup;
25
TLC (CHCl
3
/MeOH, 10:1) R
f
= 0.3; [α]
D
–118.4 (c 4.6, EtOAc); IR vmax (neat) 3399, 3283,
–1
1
1
651, 1550, 1372, 1044 cm ; H NMR (CDCl , 400 MHz) δ 7.38–7.29 (10 H, m), 6.95 (1 H,
3
d, J = 7.6 Hz, NH), 5.05 (1 H, s, anomeric), 4.92 (1 H, d, J = 11.6 Hz), 4.75 (1 H, d, J = 11.6
Hz), 4.64 (1 H, d, J = 7.6 Hz, 2ꢀCH), 4.60 (1 H, d, J = 12.0 Hz), 4.48 (1 H, d, J = 12.0 Hz),
4
3
1
1
.34 (1 H, dd, J = 8.8, 6.0 Hz, 4ꢀCH), 4.14–4.08 (2 H, m), 3.83 (1 H, d, J = 11.2 Hz, 6ꢀCH),
.75 (1 H, d, J = 10.8 Hz, 6'ꢀCH), 3.44 (1 H, d, J = 4.0 Hz, 5ꢀOH), 3.39 (1 H, br s, 6ꢀOH),
13
.96 (3 H, s); C NMR (CDCl , 100 MHz) δ 170.4, 137.5, 137.4, 128.6 (2 ×), 128.4 (2 ×),
3
28.0, 127.9 (2 ×), 127.8, 127.7 (2 ×), 106.0, 82.8, 80.1, 71.7, 70.7, 69.3, 63.9, 59.3, 22.9;
–
HRMS (ESI) calcd for C22
H26NO
6
: 400.1760, found: m/z 400.1768 [M – H] .
2
ꢀAcetamidoꢀ5ꢀoxoꢀ1,3ꢀdiꢀOꢀbenzylꢀ2,5ꢀdeoxyꢀβꢀDꢀxylofuranose (8). Diol 7 (6.45 g,
22

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4
16.1 mmol) was dissolved in acetone (200 mL), then NaIO (5.17 g, 24.1 mmol) in water (40
o
o
mL) was added at 0 C. The mixture was stirred for 3 h at 0 C to give a white suspension.
2
Acetone was removed by rotary evaporation. The residue was extracted with Et O and water,
4
dried (MgSO ), filtered, and concentrated to give aldehyde 8 (5.73 g, 96%), which was used
5 3
in the next step without further purification. C21H23NO ; colorless syrup; TLC (CHCl /MeOH,
25
1
0:1) R = 0.4; [α]
–121 (c 9.6 , EtOAc); IR vmax (neat) 3281, 1734, 1655, 1547, 1373,
D
f
–
1 1
1
120 cm ; H NMR (CDCl , 400 MHz) δ 9.64 (1 H, s), 7.37–7.27 (10 H, m), 6.20 (1 H, br,
3
NH), 5.20 (1 H, s, anomeric), 4.96 (1 H, d, J = 12.0 Hz), 4.83 (1 H, d, J = 12.0 Hz), 4.65–4.57
1
3
(
4 H, m), 4.33 (1 H, d, J = 7.2 Hz), 1.95 (3 H, s); C NMR (CDCl , 100 MHz) δ 199.8, 170.1,
3
1
8
3
37.4, 137.1, 128.6 (2 ×), 128.5 (2 ×), 128.0 (2 ×), 127.95, 127.9, 127.8 (2 ×), 106.6, 85.6,
5
4.6, 72.1, 69.5, 59.8, 23.1; HRMS (ESI) calcd for C21H22NO : 368.1498, found: m/z
–
68.1498 [M – H] .
Ethyl
2ꢀacetamidoꢀ1,3ꢀdiꢀOꢀbenzylꢀ2,5,6ꢀtrideoxyꢀ6ꢀdiethoxyphosphorylꢀβꢀDꢀxyloꢀheptꢀ5ꢀeneꢀf
uranuronate (9). Aldehyde 8 (356 mg, 0.96 mmol) was dissolved in anhydrous THF (20 mL)
o
at 0 C, and TiCl
4
(1 M in CH
2
2
Cl , 1.06 mL) was added dropwise. The mixture was stirred for
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o
5
min at 0 C, and a solution of triethyl phosphonoacetate (238 mg, 1.06 mmol) and
triethylamine (585 mg, 5.8 mmol) in anhydrous THF (5 mL) was added dropwise. The
o
resulting brownish red suspension was stirred for 1 h at 0 C, diluted with Et
2
O (80 mL), and
2
quenched with 1 M HCl(aq) (10 mL). The mixture was extracted with Et O and 1 M HCl(aq),
4
dried (MgSO ), filtered, and concentrated to give pale yellow syrup. Purification by silica gel
2 2
column chromatography (EtOAc/hexane gradients, 1:1 to 3:1, then CH Cl /MeOH, 15:1)
9
gave the alkene product 9 as a mixture of Z/E isomers (1:1, 421 mg, 76%). C29H38NO P;
3 f
colorless syrup, TLC (CHCl /MeOH, 10:1) R = 0.5; IR vmax (neat) 1724, 1656, 1550, 1453,
–1 1
1
239, 1025 cm ; H NMR (CDCl , 400 MHz) δ 7.67 (0.5 H, dd, J = 46.0, 8.0 Hz, vinyl H of
3
Zꢀisomer), 7.34–7.19 (10.5 H, m), 6.24 (0.5 H, d, J = 7.6 Hz, NH), 5.99–5.95 (0.5 H, m), 5.90
(0.5 H, d, J = 7.6 Hz, NH), 5.58–5.54 (0.5 H, m), 5.06 (0.5 H, s, anomeric), 5.05 (0.5 H, s,
anomeric), 4.86–4.76 (2 H, m), 4.61–4.43 (3 H, m), 4.25–4.07 (4 H, m), 4.03–3.85 (3 H, m),
1
3
1
.95 (1.5 H, s), 1.93 (1.5 H, s), 1.31–1.09 (9 H, m); C NMR (CDCl
3
, 100 MHz) δ
2
2
2
1
70.2/170.0, 164.6 (d, J C–P = 15.3 Hz)/164.3 (d, J C–P = 14.5 Hz), 161.1 (d, J C–P = 6.4
2
1
Hz)/159.6 (d, J
= 5.9 Hz), 138.2/137.7, 138.0/137.4, 128.6–127.5 (10 ×), 124.7 (d, J
=
C–P
C–P
1
3
1
82.0 Hz)/124.2 (d, J C–P = 183.3 Hz), 107.2/106.3, 85.4/84.7, 80.8 (d, J C–P = 18.0 Hz)/79.4
3
(d, J
= 4.8 Hz), 72.2/71.9, 69.3, 63.1–62.9 (2 ×), 61.7/61.6, 59.8/59.7, 23.3/23.2,
C–P
24

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31
1
6.5–16.3 (2 ×), 14.3/14.2; P NMR (CDCl
3
, 162 MHz) δ 12.70/11.07; HRMS (ESI) calcd
–
9
for C29H37NO P: 574.2206, found: m/z 574.2203 [M – H] .
Ethyl
(3S,4R,5R)ꢀ3ꢀacetamidoꢀ4,5ꢀdihydroxycyclohexꢀ1ꢀeneꢀ1ꢀcarboxylate
(10).
Compound 9 (2.31 g, 4.02 mmol) was treated with Pd/C (300 mg) in EtOH (50 mL) at room
temperature for 24 h under an atmosphere of hydrogen. After disappearance of the starting
material based on TLC analysis, the mixture was filtered through a pad of Celite. The filtrate
was concentrated by rotary evaporation to give the desired lactol (1.55 g) as colorless syrup.
NaH (177 mg, 4.42 mmol; 60% dispersion in oil) was washed with hexane (2 ×) under an
atmosphere of nitrogen, and then the aboveꢀprepared lactol (1.55 g) in anhydrous THF (40
o
o
mL) was added dropwise at 0 C. The mixture was stirred for 1 h at 0 C, and quenched with
4 2
NH Cl(aq). THF and H O were removed by rotary evaporation. The residue was purified by
silica gel column chromatography (CH
2
Cl
2
/MeOH, 15:1 to 10:1) to give the product 10 (603
o
mg, 62%). C11
H17NO
5
; white solid, mp 183.6–184.3 C; TLC (CHCl
3
/MeOH, 5:1) R
f
= 0.4;
21
[
α] +58.0 (c 2.2, MeOH); IR vmax (KBr) 3478, 3391, 3302, 2977, 2925, 1709, 1634, 1549,
D
–1 1
1
3
376, 1329, 1278, 1231 cm ; H NMR (CD OD, 400 MHz) δ 6.56 (1 H, s), 4.50 (1 H, br s),
4.20 (2 H, br d, J = 6.4 Hz), 3.77 (1 H, br s), 3.52 (1 H, br s), 2.79 (1 H, br d, J = 17.2 Hz),
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1
3
2
1
2
3
.22 (1 H, br s), 2.02 (3 H, s), 1.29 (3 H, br s); C NMR (CD OD, 100 MHz) δ 173.4, 167.5,
5
38.4, 130.1, 75.3, 70.7, 61.9, 54.0, 32.9, 22.7, 14.5; HRMS (ESI) calcd for C11H16NO :
–
42.1028, found: m/z 242.1030 [M – H] .
Ethyl (3S,4R,5R)ꢀ3ꢀazidoꢀ4,5ꢀdihydroxycyclohexꢀ1ꢀeneꢀ1ꢀcarboxylate (11). Compound
0 (210 mg, 0.87 mmol) was dissolved in EtOH (99.5%, 6.7 mL), and 12 M HCl (0.7 mL)
1
was added. The mixture was stirred at reflux for 12 h under an atmosphere of nitrogen. After
disappearance of the starting material based on TLC analysis, the mixture was concentrated
by rotary evaporation to give an amine product (174 mg).
4 2
A mixture of the aboveꢀprepared amine product (174 mg), CuSO ꢁ5H O (22 mg, 0.09
2
mmol) and K CO
3
(360 mg, 2.61 mmol) in EtOH (4 mL) was treated with
imidazoleꢀ1ꢀsulfonyl azide (300 mg, 1.74 mmol) in EtOH (1 mL). The mixture was stirred for
2
h at room temperature. After disappearance of the amine starting material based on TLC
4
analysis, the mixture was neutralized with NH Cl(aq), and concentrated by rotary evaporation.
2 2 2 4
The residue was extracted with CH Cl and H O, dried (MgSO ), filtered, and concentrated to
give an azide product 11 (160 mg, 81% yield from acetamide 10), which was used in the next
9 13 3 4 f
step without further purification. C H N O ; pale yellow syrup, TLC (EtOAc/hexane, 1:1) R
26

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1
9
=
0.3; [α]
D
3
+6.4 (c 2.2, EtOAc); IR vmax (neat) 3415, 2100 (N ), 1714, 1654, 1248, 1098,
–
1 1
1
4
2
1
067 cm ; H NMR (CDCl , 400 MHz) δ 6.59 (1 H, t, J = 2.4 Hz), 4.18 (2 H, q, J = 7.2 Hz),
3
.09–4.06 (1 H, m), 3.79–3.73 (1 H, m), 3.57 (1 H, m), 2.87 (1 H, dd, J = 18.0, 5.2 Hz),
13
.27–2.18 (1 H, m), 1.26 (3 H, t, J = 7.2 Hz); C NMR (CDCl , 100 MHz) δ 165.9, 134.1,
3
27 6 8
30.8, 75.9, 69.7, 63.7, 61.5, 32.3, 14.3; HRMS (ESI) calcd for C18H N O : 455.1890, found:
+
m/z 455.1886 [2M + H] .
Ethyl
(3S,4R,5R)ꢀ3ꢀazidoꢀ4,5ꢀdi(methanesulfonyloxy)cyclohexꢀ1ꢀeneꢀ1ꢀcarboxylate
28, 47
(12).
Diol 11 (59 mg, 0.26 mmol) and methanesulfonyl chloride (89 mg, 0.78 mmol) were
o
dissolved in anhydrous EtOAc (5 mL) at 0 C. NEt
3
(108 ꢃL, 0.78 mmol) was added dropwise
o
o
2
at 0 C. The mixture was stirred for 2 h at 0 C. H O was added to quench the excess
methanesulfonyl chloride. The mixture was extracted with EtOAc and 1 M HCl(aq). The
4
organic layer was washed with saturated NaHCO3(aq), dried (MgSO ), filtered, concentrated,
and purified by silica gel column chromatography (EtOAc/hexane gradients, 1:2 to 1:1) to
17 3 8 2
give the dimesylated product 12 (85 mg, 85 %). C11H N O S ; colorless syrup; TLC
1
(
EtOAc/hexane, 1:1) R
f
= 0.4; H NMR (CDCl
3
, 400 MHz) δ 6.70 (1 H, s), 4.88–4.82 (1 H,
m), 4.74–4.70 (1 H, m), 4.32–4.30 (1 H, m), 4.20 (2 H, q, J = 7.2 Hz), 3.17 (3 H, s),
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13
3
.14–3.07 (1 H, m), 3.11 (3 H, s), 2.67–2.59 (1 H, m), 1.27 (3 H, t, J = 7.2 Hz); C NMR
(
CDCl , 100 MHz) δ 164.3, 132.1, 130.5, 79.2, 74.0, 61.9, 61.3, 39.6, 39.2, 31.3, 14.3; HRMS
3
+
(ESI) calcd for C11
H
17
N
3
O
8
NaS
2
: 406.0355, found: m/z 406.0359 [M + Na] .
2
ꢀAcetamidoꢀ1ꢀOꢀbenzylꢀ2ꢀdeoxyꢀβꢀDꢀglucofuranose (13). Oxazolidine 4 (100 mg, 0.41
mmol) was dissolved in BnOH (3 mL), and a catalytic amount of TFA (50 ꢃL) was added.
The mixture was stirred for 24 h at room temperature until disappearance of the starting
material based on TLC analysis. The mixture was subjected to silica column chromatography
2 2
(EtOAc/hexane, 1:3) to remove excess BnOH, followed by elution with CH Cl /MeOH (10:1)
6 2 2 f
to give the desired product 13 (83 mg, 65%). C15H21NO ; TLC (CH Cl /MeOH, 10:1) R = 0.3;
1
3
H NMR (CD OD, 400 MHz) δ 7.36–7.24 (5 H, m), 4.96 (1 H, s, anomeric), 4.73 (1 H, d, J =
12.0 Hz), 4.53 (1 H, d, J = 12.0 Hz), 4.23–4.21 (2 H, m), 4.11–4.07 (1 H, m), 4.03–3.98 (1 H,
1
3
m), 3.83 (1 H, dd, J = 11.2, 3.2 Hz), 3.65 (1 H, dd, J = 11.2, 5.6 Hz), 1.95 (3 H, s); C NMR
(
CD OD, 100 MHz) δ 173.0, 138.9, 129.3 (2 ×), 129.0 (2 ×), 128.7, 107.3, 82.6, 76.2, 71.9,
3
6
70.7, 65.2, 64.3, 22.6; HRMS (ESI) calcd for C15H20NO : 310.1291, found: m/z 310.1295
–
[
M – H] .
28

Page 33 of 116
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C3OB41622D
2
ꢀAcetamidoꢀ1ꢀOꢀbenzylꢀ2ꢀdeoxyꢀβꢀDꢀxylofuranose (14). Compound 13 (100 mg, 0.32
4
mmol) was dissolved in EtOH (4 mL), and NaIO (110 mg, 0.48 mmol) in water (2 mL) was
o
o
added at 0 C. The mixture was stirred for 3 h at 0 C to give a white suspension, then NaBH
4
(27 mg, 0.48 mmol) was added. After stirring for 12 h at room temperature, the mixture was
2 2
concentrated by rotary evaporation. The residue was extracted with CH Cl and water. The
4
organic phase was dried (MgSO ), filtered, concentrated, and purified by silica gel column
chromatography (CH
2
Cl
2
5
/MeOH, 15:1) to give product 14 (54 mg, 60%). C14H19NO ; TLC
1
(CHCl
3
/MeOH, 10:1) R
f
= 0.3; H NMR (CDCl
3
, 400 MHz) δ 7.36–7.27 (5 H, m), 5.91 (1 H,
br s, NH), 4.99 (1 H, s, anomeric), 4.77 (1 H, d, J = 11.6 Hz), 4.54 (1 H, d, J = 12.0 Hz),
4.33–4.28 (3 H, m), 4.16–4.14 (1 H, m), 3.91–3.87 (1 H, m), 3.83–3.80 (1 H, m), 2.81 (1 H,
13
br s, OH), 1.98 (3 H, s); C NMR (CDCl , 100 MHz) δ 171.1, 136.7, 128.7 (2 ×), 128.3,
3
1
28.2 (2 ×), 105.2, 81.8, 76.8, 70.2, 63.6, 62.5, 23.4; HRMS (ESI) calcd for C H NO :
1
4
18
5
–
2
80.1185, found: m/z 280.1188 [M – H] .
2
ꢀAcetamidoꢀ1ꢀOꢀbenzylꢀ2ꢀdeoxyꢀ5ꢀmethanesulfonylꢀβꢀ
D
ꢀxylofuranose
(15).
Compound 14 (53 mg, 0.19 mmol) and methanesulfonyl chloride (26 mg, 0.23 mmol) were
o
dissolved in anhydrous CH
2
Cl
2
(5 mL) at 0 C. NEt
3
(78 ꢃL, 0.57 mmol) was added dropwise
29