An approach towards the synthesis of sialyl nucleoside mimetics

Article abstract of DOI:10.1016/j.tetasy.2005.01.035

An approach towards the synthesis of novel sialyl nucleoside mimetics based on d-fructose is described. The synthesis of these mimetics is achieved in good overall yield in seven steps. The key synthetic step is the coupling reaction of pyrimidine bases (uracil, 5-fluorouracil and cytosine) to the C-1 position of the modified D-tagatofructofuranoside.

Full text of DOI:10.1016/j.tetasy.2005.01.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1425–1434
An approach towards the synthesis of sialyl nucleoside mimetics
I. Darren Grice, Catherine Whelan, Gregory D. Tredwell and Mark von Itzstein*
Institute for Glycomics, Griffith University, PMB 50 Gold Coast Mail Centre, Gold Coast, 9726Qld, Australia
Received 9 December 2004; accepted 25 January 2005
Available online 3 March 2005
Abstract—An approach towards the synthesis of novel sialyl nucleoside mimetics based on D-fructose is described. The synthesis of
these mimetics is achieved in good overall yield in seven steps. The key synthetic step is the coupling reaction of pyrimidine bases
(uracil, 5-fluorouracil and cytosine) to the C-1 position of the modified D-tagatofructofuranoside.
ꢀ 2005 Elsevier Ltd. All rights reserved.
NH2
N
1. Introduction
2M
HO
O
P
The role of carbohydrates and in particular sialic acids,
and the malignancy of tumour cells is now evident.1–7
The correlation between levels of sialylation and specific
cancerous processes such as metastasis, can in principle
be due to changes in the activities of a range of sialic
acid metabolizing enzymes.
N
O
H
OH
O
O
HO
O
O
O
CO2
R
H
HO
OH OH
CMP-Neu5Ac (R = NHAc) 2
CMP-KDN (R = OH) 3
R
S
Pyrimidine Base
O
O
tions with sialyl nucleotide-recognizing proteins, but
may also possess improved pharmacological profiles.
Functional group manipulations and glycosidation reac-
tions of sialic acids and carbohydrate-based compounds
in general are inherently difficult to successfully carry
out. This fact has in part resulted in the current interest
in the development of sialic acid mimetics.9–12 As a con-
sequence of this interest, there have been numerous sial-
yl mimetic studies that have validated such an approach.
For example, sialyl mimetic inhibitors of sialidases13–17
and sialyl mimetic inhibitors of sialyl transferases.18,19
CO2
OMe
1
R = methyl, ethyl, phenyl
As part of our ongoing efforts to elucidate important
recognition features required in the specific inhibition
of sialic acid recognizing proteins in general, we have
synthesized a range of sialyl nucleoside mimetics based
on the very inexpensive carbohydrate D-fructose. Our
ongoing interest in fructose chemistry8 and the develop-
ment of novel sialyl mimetics initiated our present inves-
tigation on the synthesis of sialyl mimetic nucleosides of
the general structure 1, which can be considered as
mimetics of CMP-Neu5Ac 2, or CMP-KDN 3.
2. Results and discussion
Inspection of the sialyl mimetic 1 in relation to naturally
occurring substrates 2 and 3 shows that the sialic acid-
phosphate portion has been replaced by a thio-linked
carboxylate functionality associated with a variable
group ꢀRꢁ. This approach was adopted to explore the
effects of replacing the entire sialic acid moiety with a
group that maintains one of the charges present in the
natural substrates. The variable ꢀRꢁ group in 1 would
allow an investigation into the effects of hydrophobicity,
Our design concept towards the synthesis of compounds
of the general structure 1 was to produce sialyl mimetics
that retained the structural features essential for interac-
*
Corresponding author. Tel.: +61 7 55527025; fax: +61 7 55529040;
e-mail: m.vonitzstein@griffith.edu.au
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.035

1426
I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
hydrophilicity and steric bulk for sialic acid recognizing
proteins. While the carboxylate functionality in 1 is not
maintained in the exact same relative position as the
carboxylate group in 2 and 3, it maintains a charged
moiety in the same spacial location of the phosphate
and carboxylate groups. This is not an unreasonable ap-
proach as reports exist indicating that the replacement
of the entire sialic acid moiety by a carboxylate group
gives an equivalent if not improved affinity for some
proteins.10
R
S
Base
O
O
CO2
y
OMe
x
1
route-a (y,x)
route-b (x,y)
R
S
OTf
AcS
+
Base
The sialyl transferase enzyme inhibitor KI-8110 4 has a
Ki = 40 nM, which is 1000 times greater in affinity than
the natural substrate CMP-Neu5Ac 2. While 4 mimics
the natural substrate in possessing a phosphate linkage,
this linkage is highly acid labile and was viewed as a
feature that might advantageously be replaced. In an
attempt to improve metabolic stability, we utilized
some of our previous work20 and incorporated the
thio-linkage between the fructose and the sialic acid
mimetic.
CO2Me
O
O
O
O
CO2Me
Base +
R
X
OMe
OMe
6
5
7
AcS
OTf
AcS
OH
CO2Me
O
O
O
O
+ Base
+
R
X
OMe
OMe
9
6
8
Scheme 1. Retrosynthetic approach towards sialyl mimetics of general
structure 1.
NH2
N
O
P
2M
O
N
O
O
O
O
O
AcHN
HO
P
OH
HO
OH
OMe
HO
O
O
OH
OH
O
OH OH
OH
a
O
HO
HO
4
OH
OH
12
OH
10
α = 34%
β = 38%
From a retrosynthetic viewpoint, there are two distinct
pathways towards the sialyl mimetics of the general
structure 1 (Scheme 1). The first approach (route-a) in-
volves coupling the sialyl mimetic group to the fructose
derivative followed by coupling of the pyrimidine base
to the sialyl mimetic sugar. Alternatively, (route-b) the
pyrimidine base could be coupled to the activated C-1
of the fructose derivative followed by coupling to the
sialyl mimetic. We decided that the more attractive se-
quence would likely be route-a. We have routinely cou-
pled thiolacetyl groups to sugars21 and found them to be
relatively robust functionalities in regard to their pres-
ence during other functional group transformations.
We were more comfortable with the thiolacetyl group
being present on the sugar, then proceeding with
attempts at the previously unreported coupling of the
pyrimidine base onto the C-1 secondary alcohol of the
modified fructose.
AcS
OH
HO
OH
c
O
O
O
O
b
OMe
OMe
8
13
α = 94%
α = 70%
β = 88%
β = 75%
AcS
Base
AcS
OTf
e
O
O
O
O
d
OMe
OMe
9
7α Base = Uracil (99%)
14α Base = 5-F-Uracil (54%)
15α Base = Cytosine (79%)
α = 79%
R
S
Base
R1
S
Base
O
O
O
O
g
f
CO2
CO2R2
OMe
OMe
α = 59-99%
16 R1 = methyl, R2 = ethyl, Base = Uracil
17 R1 = ethyl, R2 = methyl, Base = Uracil
18 R1 = phenyl, R2 = methyl, Base = Uracil
19 R1 = methyl, R2 = ethyl, Base = 5-F-Uracil
20 R1 = ethyl, R2 = methyl, Base = 5-F-Uracil
21 R1 = phenyl, R2 = methyl, Base = 5-F-Uracil
22 R1 = ethyl, R2 = methyl, Base = Cytosine
23 R1 = phenyl, R2 = methyl, Base = Cytosine
24 R = methyl, Base = Uracil
25 R = ethyl, Base = Uracil
Our overall approach to the formation of sialyl nucleo-
side mimetics 1 from readily available D-fructose 10 is
detailed in Scheme 2, with the key step being the cou-
pling of 9 to the pyrimidine base. To stabilize the ano-
meric configuration of D-fructose, the methyl glycoside
of 10 was prepared via a Fischer type methodology22
to give methyl b-D-fructopyranoside 11 (20%), 12a
(38%) and 12b (34%) after separation on a Dowex
(1 · 8-200, ꢀOH-form) resin. Although the C-1 and C-
6 hydroxyls are known to be more reactive than C-3
and C-4,8,23 we wanted to protect C3 and C4 in order
to prevent any unwanted side reactions.
26 R = phenyl, Base = Uracil
27 R = methyl, Base = 5-F-Uracil
28 R = ethyl, Base = 5-F-Uracil
29 R = phenyl, Base = 5-F-Uracil
30 R = ethyl, Base = Cytosine
31 R = phenyl, Base = Cytosine
Scheme 2. Synthesis of sialyl mimetic nucleosides. Reagents and
conditions: (a) MeOH, AcCl, rt, 16 h; (b) PPh3, DIAD, DMF, rt, 40 h;
(c) PPh3, DIAD, AcSH, THF, 4 ꢁC, 24 h; (d) Tf2O, CH2Cl2, 0 ꢁC, 1 h;
(e) (i) HMDS, TMSCl, base, reflux, 16 h; (ii) 9, 1,2-DCE, 60 ꢁC, Ar,
2 days; (f) a-halo-ester, H2NNH2ÆAcOH, Et3N, DMF, rt, 3.5 h; (g)
1 M NaOH, MeOH, rt, 16 h.

I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
1427
The 3,4-epoxidation reaction under Mitsunobu condi-
tions24–26 was performed in one-step in separate reac-
tions on 12a and 12b, in relatively high yield, to give
13a and 13b following flash column chromatography.
The presence of the 3,4-epoxide would allow for poten-
tial derivatization at later stages in the synthesis,
although this was not explored in this study.
as the base, co-elution between the product and uncou-
pled base was encountered in the chromatography puri-
fication process, requiring repeated chromatography
steps and resulting in a low yield. This is a modified ver-
sion of a method employed to synthesize anti-HIV 20,30-
dideoxy- and 20,30-didehydro-20,30-dideoxynucleosides28,29
and 5-fluoro-40-thiouridinenucleosides.30 These methods
were employed to couple the base to the anomeric posi-
tion of the sugar, a much more reactive position than the
primary carbon in this work. Therefore, it was not sur-
prising to us that we encountered some degree of diffi-
culty in achieving this coupling. Activation of the C-1
hydroxyl group using O-mesylation and iodination/bro-
mination31 was carried out, but the attempted coupling
of these to the base or the silylated-base proved unsuc-
cessful. Interestingly, when we attempted to couple the
1-O-mesylated-6-thio-b-D-sugar 35 with the silyl-acti-
vated base, we obtained the dimeric-6-S-linked sugar
36 under various conditions (Scheme 4).
Retrosynthetically, the next step provided us with a fur-
ther two distinct pathways towards obtaining the cou-
pling of the sialyl mimetic to the derivatized D-fructose
(Scheme 3). We either introduced the thiolacetyl group
to form the derivatized fructose 8 before coupling with
an a-halo-ester derivative (e.g., 6) (ꢀroute-aꢁ), or we cou-
pled a C-6 activated fructose like 33 with an a-thiolacet-
yl carboxylate derivative 32 (ꢀroute-bꢁ). A number of a-
halo-ester derivatives are commercially available, and
we therefore decided to take advantage of this and fol-
low route-a.
AcS
S
S
OMe
OMe
OMe
a
O
O
O
O
O
a
O
b
OMs
36
MsO
OMs
35
R
S
O
O
CO2
Scheme 4. Reagents and conditions: (a) 35 (1 equiv), uracil (4 equiv),
HMDS, TMSCl (0.1 equiv), DMF, 125 ꢁC, 5 h.
OMe
Our previous work21 enabled us to readily facilitate the
hydrazine acetate mediated coupling between the C-6
thiolacetate derivatives 7a (uracil), 14a (5-fluorouracil)
and 15a (cytosine) and the methyl, ethyl and phenyl 2-
bromopropionate moieties (excluding R = methyl,
base = cytosine) to afford the sialyl mimetics 16–23 as
mixtures of diastereomers in respectable yield. Treat-
ment of the sialyl mimetics 16–23 with dilute NaOH
(1.0 M) provided the de-esterified sialyl mimetics in
good yield following purification by HPLC.
route-a
AcS
route-b
X
OH
OH
CO2Me
CO2Me
O
O
O
O
+
+
R
SAc
R
X
OMe
OMe
32
6
8
33
Scheme 3. Retrosynthetic strategy towards 1.
Utilizing the strategy of route-a and employing knowl-
edge from our previous work on 3,4-anhydro-b-D-taga-
tofuranosides,8 we were able to selectively thiolacetylate
C-6 on 13 to give 8 in good yield for both the a- and b-
anomers. Only minor amounts of the 1,6-di-SAc-func-
tionalized materials, 34a and 34b, were formed in this
reaction.
3. Conclusions
We have developed a route for the preparation of sialyl-
nucleoside mimetics based on the common inexpensive
carbohydrate D-fructose that will provide an interesting
series of chemical probes for biological investigations of
sialylnucleotide recognizing proteins.
We decided to proceed with the a-anomer of 8 selec-
tively in our remaining synthetic strategy, as it most clo-
sely resembled the configuration of CMP-Neu5Ac 2 and
CMP-KDN 3. In order to couple the pyrimidine base to
the derivatized tagatofuranoside 8a, requisite activation
of the C-1 hydroxyl group was achieved by O-triflation27
to give 9a. The pyrimidine base was also activated via
silylation using hexamethyldichlorosilizane (HMDS)
and trimethylsilylchloride (TMSCl) to give the aroma-
tized silylated base. The optimized coupling reaction be-
tween the activated sugar and base was found to proceed
quite slowly, but respectable yields were obtained after
several days stirring at 60 ꢁC under Ar. Yields for the
formation of 7a, 14a and 15a after chromatography
were 99%, 54% and 79% when the base was uracil, 5-flu-
orouracil and cytosine, respectively. With 5-fluorouracil
4. Experimental
1H and 13C NMR spectra were recorded using a Bruker
¨
Avance 300 MHz spectrometer. Chemical shifts are
given in ppm relative to the solvent used (CDCl3: 7.26
for H, 77.0 for 13C; D2O: 4.70 for H; MeOD: 3.30
1
1
for H, 49.0 for 13C). Assignments indicated with an
1
asterisk (*) correspond to resonances clearly due to the
corresponding diastereomer where such mixtures exist.
Assignments indicated with a (ꢂ) denote assignments,
which are interchangeable. Two-dimensional COSY
and HSQC experiments were recorded to assist with
spectral assignment. Low-resolution ESI mass spectra

1428
I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
were obtained using a Bruker Daltonics Esquire 3000
¨
under N2 at 0 ꢁC. Diisopropyl azodicarboxylate (DIAD;
5.0 mL, 25.4 mmol, 2.6 equiv) was added dropwise with
stirring. The mixture was warmed to rt, stirred for 40 h
and concentrated under reduced pressure. Crude mate-
rial was taken up in H2O (300 mL), washed with EtOAc
(3 · 75 mL) and concentrated. This material was puri-
fied by flash column chromatography (20:1 ! 3:2,
CHCl3–acetone) to afford 13a as a pale yellow amor-
phous mass (1.22 g, 70%).24 A small portion of material
was per-acetylated (see the above procedure) for charac-
terization purposes. 1H NMR (300 MHz, CDCl3): d
2.05, 2.07 (6H, 2 · s, 2 · OAc), 3.27 (3H, s,
OMe), 3.66 (1H, d, J3,4 = 2.7 Hz, H-3ꢂ), 3.74 (1H, d,
Ion Trap LC mass spectrometer, using ESI in the posi-
tive mode. High-resolution mass spectrometry was per-
formed at the Department of Chemistry, University of
Queensland, Australia, using a Finnigan MAT 900 XL
Trap with a Finnigan AP1 III sprayer. Elemental analy-
ses were performed by the microanalysis service at the
Department of Chemistry, University of Queensland,
Australia and were recorded on a Carlo Erba Elemental
Microanalyser, model 1106. High pressure liquid chro-
matography (HPLC) was performed on an Agilent
1100 series system. All solvents were distilled prior to
use or were of HPLC grade.
J4,3 = 2.7 Hz, H-4ꢂ), 3.91 (1H, d, J1,1 = 12.0 Hz, H-1),
0
4.1. Methyl a/b-D-fructofuranosides 12a and 12b and
methyl b-D-fructopyranoside 11
4.19 (3H, s, H-5, H-6, H-60), 4.44 (1H, d,
J1 ,1 = 12.0 Hz, H-10).
0
To a solution of D-fructose (20.0 g, 0.111 mol) in dry
MeOH (1000 mL) was added acetyl chloride (1 mL) at
rt, N2, and stirred for 16 h. It was neutralized with
Amberlite IRA-400 (OHꢀ) resin, filtered, washed with
MeOH and concentrated. The crude material was puri-
fied by anion exchange chromatography (Dowex 1 · 8-
200, ꢀOH form; distilled H2O as the mobile phase),
which yielded three products: 12a (7.56 g, 38%, Rf 0.60
[6:4:1, EtOAc–i-PrOH–H2O]), 12b (6.68 g, 34%, Rf
0.45) and 11 (4.02 g, 20%, Rf 0.32) and a mixture of
12b and 11 (1.48 g, 8%) all as clear amorphous masses,
giving a total yield of 92%.24 Small samples of com-
pounds 12a and b and 11 were acetylated for character-
ization purposes. The methyl fructosides (ꢁ100 mg)
were dissolved in pyridine (2 mL) before adding acetic
anhydride (1 mL) at rt, under N2 and stirring for 20 h.
Diluted with EtOAc (15 mL), washed with HCl
(0.1 M, 10 mL), H2O (2 · 15 mL), dried over Na2SO4
and concentrated. Compound 12a per-acetylated: 1H
NMR (300 MHz, CDCl3): d 2.04, 2.08, 2.09, 2.10
(12H, 4 · s, 4 · OAc), 3.31 (3H, s, OMe), 4.11 (1H, d,
4.3. Methyl 3,4-anhydro-b-D-tagatofuranoside 13b
The following was prepared in a similar manner to 13a.
Reaction of 12b (3.76 g, 19.35 mmol) yielded 13b
(3.01 g, 88%) as a clear amorphous mass.24 A small por-
tion of material was per-acetylated (see procedure
above) for characterization purposes. 1H NMR
(300 MHz, CDCl3): d 2.07 (6H, s, 2 · OAc), 3.46 (3H,
s, OMe), 3.65 (1H, d, J3,4 = 2.7 Hz, H-3ꢂ), 3.68 (1H, d,
J4,3 = 2.7 Hz, H-4ꢂ), 4.01 (1H, d, J1,1 = 12.0 Hz, H-1),
0
0
4.14 (1H, d, J5,6/6 = 5.7 Hz, H-5), 4.21(1H, d,
0
J1 ,1 = 12.0 Hz, H-10), 4.26 (2H, d, J6/6 ,5 = 5.7 Hz, H-6/
0
60).
4.4. Methyl 6-S-acetyl-3,4-anhydro-6-thio-a-D-tagatofur-
anoside 8a and
4.5. Methyl 1,6-di-S-acetyl-3,4-anhydro-1,6-di-thio-a-D-
tagatofuranoside 34a
0
J1,1 = 12.3 Hz, H-1), 4.12 (2H, m, H-5, H-6), 4.42
To a solution of 13a (0.91 g, 5.16 mmol) in dry THF
(1H, d, J1 ,1 = 12.3 Hz, H-10), 4.44 (1H, dd, J6 ,5 = 3.0,
(20 mL) and 4 A molecular sieves, were added PPh3
˚
0
0
J6 ,6 = 11.4 Hz, H-60), 4.93 (1H, dd, J4,3 = 1.8,
(1.60 g, 6.10 mmol, 1.2 equiv) and DIAD (1.20 mL,
6.10 mmol, 1.2 equiv) at ꢀ10 ꢁC, under N2, stirred for
15 min and then warmed to 0 ꢁC for solubility purposes.
Thiolacetic acid (370 lL, 5.18 mmol, 1.0 equiv) was
added and the mixture warmed to 4 ꢁC and stirred for
20 h, at which time an additional 0.2 equiv of thiolacetic
acid was added (80 lL, 1.04 mmol) and stirred for a fur-
ther 4 h. The reaction mixture was filtered, washed with
EtOAc and concentrated. The organic phase extracted
into EtOAc (300 mL) and washed with HCl (0.1 M,
100 mL), H2O (100 mL), satd aq NaHCO3 (100 mL),
dried (Na2SO4) and concentrated. Upon TLC of aque-
ous washes, the presence of the desired material was
identified, and the aqueous phases combined, washed
with EtOAc (2 · 100 mL), dried over Na2SO4 and the
organic phase added to the original organic phase and
concentrated. This material was purified by flash col-
umn chromatography (CHCl3 ! 10:1, CHCl3–acetone)
to yield 8a (1.14 g, 94%) as a pale yellow amorphous
mass and 34a (25.1 mg, 2%) as a yellow oil. Compound
8a: HRMS: [M+Na]+ 315.0340; C11H16O5S2 + Na re-
0
J4,5 = 5.1 Hz, H-4), 5.30 (1H, d, J3,4 = 1.8 Hz, H-3).
Compound 12b per-acetylated: 1H NMR (300 MHz,
CDCl3): d 2.08, 2.09, 2.10, 2.12 (12H, 4 · s, 4 · OAc),
0
3.37 (3H, s, OMe), 4.17 (1H, d, J1,1 = 12.0 Hz, H-1),
4.17–4.23 (2H, m, H-5, H-6), 4.26 (1H, d,
J1 ,1 = 12.0 Hz, H-10), 4.35 (1H, dd, J6 ,5 = 6.6,
0
0
J6 ,6 = 14.1 Hz, H-60), 5.41 (1H, dd, J4,5 = 5.7,
0
J4,3 = 7.2 Hz, H-4), 5.49 (1H, d, J3,4 = 7.2 Hz, H-3).
Compound 11 per-acetylated: 1H NMR (300 MHz,
CDCl3): d 1.98, 2.08, 2.11, 2.17 (12H, 4 · s, 4 · OAc),
3.35 (3H, s, OMe), 3.81 (1H, dd, J6,5 = 1.5,
0
0
J6,6 = 13.2 Hz, H-6), 3.87 (1H, dd, J6 ,5 = 1.5,
0
J6 ,6 = 13.2 Hz, H-60), 4.09 (1H, d, J1,1 = 12.0 Hz, H-
0
1), 4.31 (1H, d, J1 ,1 = 12.0 Hz, H-10), 5.32–5.37 (2H,
m, H-3, H-5), 5.53 (1H, dd, J4,5 = 1.8, J4,3 = 11.7 Hz,
H-4).
0
4.2. Methyl 3,4-anhydro-a-D-tagatofuranoside 13a
To a solution of 1 (1.93 g, 9.92 mmol; dried over P2O5
overnight) in N,N-DMF (30 mL) was added triphenyl-
phosphine (PPh3; 6.63 g, 25.3 mmol, 2.5 equiv) at rt,
1
quires 315.0337. H NMR (300 MHz, CDCl3): d 2.37
0
(3H, s, SAc), 3.10 (1H, dd, J6,5 = 6.9, J6,6 = 13.8 Hz,

I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
1429
H-6), 3.16 (1H, dd, J6 ,5 = 6.6, J6 ,6 = 13.8 Hz, H-60),
NMR (75.5 MHz, CDCl3): d 28.6 (C-6), 30.4, 30.5
(2 · SC(O)CH3), 33.9 (C-1), 52.7 (OCH3), 54.5 (C-4),
57.1 (C-3), 74.8 (C-5), 104.7 (C-2), 194.8, 194.9
(2 · SC(O)CH3).
0
0
0
3.34 (3H, s, OMe), 3.65 (1H, d, J1,1 = 11.7 Hz, H-1),
3.73 (1H, d, J3,4 = 3.0 Hz, H-3ꢂ), 3.76 (1H, d,
J4,3 = 3.0 Hz, H-4ꢂ), 3.81 (1H, d, J1 ,1 = 11.7 Hz, H-10),
0
4.14 (1H, dd, J5,6 = 6.6, J5,6 = 6.9 Hz, H-5). 13C NMR
0
(75.5 MHz, CDCl3): d 28.8 (C-6), 30.5 (SC(O)CH3),
4.8. Methyl 6-S-acetyl-3,4-anhydro-6-thio-1-O-trifluo-
romethanesulfonate-a-D-tagatofuranoside 9
49.5 (OCH3), 56.0 (C-3ꢂ), 57.6 (C-4ꢂ), 60.0 (C-1), 76.4
1
(C-5), 105.3 (C-2), 195.0 (SC(O)CH3). 34a: H NMR
(300 MHz, CDCl3): d 2.36, 2.37 (6H, 2 · s, 2 · SAc),
A solution of 8a (1.00 g, 4.27 mmol) in dry CH2Cl2
(20 mL) under Ar was cooled to ꢀ78 ꢁC before the addi-
tion of pyridine (1.10 mL, 13.7 mmol, 3.2 equiv), then
trifluoromethanesulfonic anhydride (Tf2O; 1.08 mL,
6.40 mmol, 1.5 equiv) dropwise. This mixture was stir-
red for 10 min, warmed to 0 ꢁC, stirred for 1 h and con-
centrated. The crude material was taken up in CH2Cl2
(10 mL) and washed with HCl (1 M, 20 mL), H2O
(2 · 20 mL), dried over Na2SO4 and concentrated.
It was purified by flash column chromatography (4:1,
hexane–EtOAc) to furnish 9 (1.24 g, 79%) as a pale
yellow viscous oil. HRMS: [M+Na]+ 388.9953;
C10H13F3O7S2 + Na requires 388.9952. 1H NMR
(300 MHz, CDCl3): d 2.38 (3H, s, SAc), 3.09 (1H, dd,
3.14 (2H, dd, J6/6 ,4 = 1.2, J6/6 ,5 = 6.6 Hz, H-6/60), 3.27
0
0
0
(3H, s, OMe), 3.28 (1H, d, J1,1 = 14.4 Hz, H-1), 3.42
0
(1H, d, J1 ,1 = 14.4 Hz, H-10), 3.59 (1H, d,
J3,4 = 2.7 Hz, H-3ꢂ), 3.71 (1H, d, J4,3 = 2.7 Hz, H-4ꢂ),
4.09 (1H, dd, J5,6 = J5,6 = 6.6 Hz, H-5). 13C NMR
0
(75.5 MHz, CDCl3): d 28.8 (C-6), 29.5 (C-1), 30.4,
30.5 (2 · SC(O)CH3), 49.5 (OCH3), 56.1 (C-3ꢂ), 58.3
(C-4ꢂ), 76.7 (C-5), 105.1 (C-2), 194.2, 195.0
(2 · SC(O)CH3).
4.6. Methyl 6-S-acetyl-3,4-anhydro-6-thio-b-D-tagatofur-
anoside 8b and
0
J6,5 = 6.9, J6,6 = 13.8 Hz, H-6), 3.14 (1H, dd,
0
J6 ,5 = 6.3, J6 ,6 = 13.8 Hz, H-60), 3.36 (3H, s, OMe),
0
4.7. Methyl 1,6-di-S-acetyl-3,4-anhydro-1,6-di-thio-b-D-
tagatofuranoside 34b
3.76 (1H, d, J3,4 = 3.0 Hz, H-3ꢂ), 3.83 (1H, d,
J4,3 = 3.0 Hz, H-4ꢂ), 4.19 (1H, dd, J5,6 = 6.3,
0
0
J5,6 = 6.9 Hz, H-5), 4.38 (1H, d, J1,1 = 10.8 Hz, H-1),
To a solution of 13b (3.71 g, 21.1 mmol) in dry THF
4.61 (1H, d, J1 ,1 = 10.8 Hz, H-10). 13C NMR
˚
(60 mL) and 4 A molecular sieves, were added PPh3
0
(6.64 g, 25.3 mmol, 1.2 equiv) and DIAD (5.0 mL,
25.4 mmol, 1.2 equiv) at ꢀ10 ꢁC, under N2 and stirred
for 15 min, after which it was allowed to warm to
0 ꢁC. Thiolacetic acid (1.5 mL, 21.0 mmol, 1.0 equiv)
was added and the mixture stirred at 4 ꢁC for 18 h.
The reaction mixture was filtered, washed with EtOAc
and concentrated. The organic phase extracted into
EtOAc (300 mL) and washed with HCl (0.1 M,
75 mL), H2O (75 mL), satd aq NaHCO3 (75 mL), dried
over Na2SO4 and concentrated. The aqueous phases
were combined, washed with EtOAc (2 · 100 mL) and
organic phase dried over Na2SO4, added to the original
organic phase and concentrated. Ph3PO was partially re-
moved by recrystallization from EtOAc and hexane. The
mother liquor was purified initially by passing through a
plug of silica (CHCl3), then flash column chromatogra-
phy (3:1, hexane–EtOAc ! 3:2, EtOAc–hexane) to yield
8b (3.71 g, 75%) as a pale yellow powder and 34b (1.33 g,
22%) as a yellow amorphous mass. Compound 8b:
HRMS: [M+Na]+ 315.0341; C11H16O5S2 + Na requires
(75.5 MHz, CDCl3): d 28.6 (C-6), 30.5 (SC(O)CH3),
49.7 (OCH3), 56.7 (C-4ꢂ), 57.4 (C-3ꢂ), 69.9 (C-1), 77.2
(C-5), 102.8 (C-2), 112.2, 116.4, 120.6, 124.9 (CF3),
194.8 (SC(O)CH3).
4.9. 1-(Methyl 6-S-acetyl-3,4-anhydro-6-thio-a-D-tagato-
furanoside)-uracil 7a
Method A: To a suspension of uracil (3.8 g, 33.8 mmol,
10 equiv), dried over P2O5, in hexamethyl disilazane
(HMDS; 30 mL), was added TMSCl (43 lL,
0.338 mmol, 0.1 equiv) at rt, under N2. The mixture
was heated to reflux and stirred for 16 h before concen-
trating under reduced pressure and opening to an atmo-
sphere of Ar. A solution of 9 (1.24 g, 3.38 mmol) in 1,2-
dichloroethane (30 mL) was added to the silylated uracil
at 0 ꢁC, under Ar and stirred for 10 min and then
warmed to 60 ꢁC for 2 days. The reaction mixture was
filtered through Celite, washed with CH2Cl2 and con-
centrated. The crude material was absorbed onto non-
flash silica and purified by flash column chromatogra-
phy (3:2, EtOAc, hexane) affording the desired material
7a as a white foam (1.10 g, 99%), which was then recrys-
tallized from EtOAc/hexane to yield the white crystalline
product (0.70 g, 63%). HRMS: [M+Na]+ 351.0625;
C13H16N2O6S + Na requires 351.0627. 1H NMR
(300 MHz, CDCl3): d 2.37 (3H, s, SAc), 3.01 (1H, dd,
1
315.0337. H NMR (300 MHz, CDCl3): d 2.37 (3H, s,
SAc), 3.20 (2H, d, J6/6 ,5 = 6.6 Hz, H-6/60), 3.52 (3H, s,
0
0
OCH3), 3.53 (1H, d, J1,1 = 11.7 Hz, H-1), 3.64 (1H, d,
0
J1 ,1 = 11.7 Hz, H-10), 3.68 (1H, dd, J4,5 = 0.9,
J4,3 = 3.0 Hz, H-4), 3.73 (1H, d, J3,4 = 3.0 Hz, H-3),
0
3.99 (1H, ddd, J5,4 = 0.9, J5,6 = J5,6 = 6.6 Hz, H-5).
13C NMR (75.5 MHz, CDCl3): d 28.8 (C-6), 30.5
(SC(O)CH3), 52.6 (OCH3), 54.7 (C-4), 57.0 (C-3), 65.1
(C-1), 75.2 (C-5), 104.9 (C-2), 195.1 (SC(O)CH3). 34b:
1H NMR (300 MHz, CDCl3): d 2.36, 2.37 (6H, 2 · s,
J6 a,5 = 6.9, J6 a,6 b = 13.8 Hz, H-60a), 3.12 (1H, dd,
0
0
0
J6 b,5 = 6.9, J6 b,6 a = 13.8 Hz, H-60b), 3.36 (3H, s,
0
0
0
OMe), 3.65 (1H, d, J1 a,1 b = 14.4 Hz, H-10a),
0
0
ꢂ
2 · SAc) 3.14 (1H, d, J1,1 = 14.1 Hz, H-1), 3.19 (2H,
3.68 (1H, d, J3 ,4 = 2.7 Hz, H-30 ), 3.73 (1H, d,
0
0
0
ꢂ
d, J6/6 ,5 = 6.9 Hz, H-6/60), 3.20 (1H, d, J1 ,1 = 14.1 Hz,
H-10), 3.47 (3H, s, OMe), 3.58 (1H, d, J3,4 = 3.0 Hz,
H-3), 3.68 (1H, dd, J4,5 = 0.9, J4,3 = 3.0 Hz, H-4), 4.03
J4 ,3 = 2.7 Hz, H-40 ), 4.16 (1H, dd, J5 ,6 a = J5 ,6 b
0
0
0
0
0
0
0
0
=
6.9 Hz, H-50), 4.43 (1H, d, J1 b,1 a = 14.4 Hz, H-10b),
5.66 (1H, dd, J5,3 = 1.5, J5,6 = 8.1 Hz, H-5), 7.20 (1H,
d, J6,5 = 8.1 Hz, H-6), 8.62 (1H, br s, NH-3). 13C
0
0
(1H, ddd, J5,4 = 0.9, J5,6 = J5,6 = 6.9 Hz, H-5). 13C
0

1430
I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
NMR (75.5 MHz, CDCl3):
d
28.7 (C-60), 30.5
4.12. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(ethyl prop-
ionate)]-a-D-tagatofuranoside)-uracil 16
ꢂ
(SC(O)CH3), 48.2 (C-10), 50.2 (OCH3), 55.8 (C-40 ),
ꢂ
58.2 (C-30 ), 77.2 (C-50), 101.5 (C-5), 103.6
(C-20), 145.3 (C-6), 151.0 (C-2), 163.5 (C-4), 194.9
(SC(O)CH3).
A solution of 7a (200 mg, 0.609 mmol) in N,N-DMF
(5 mL) was degassed with N2 for 5 min before the addi-
˚
tion of 4 A molecular sieves. Hydrazine acetate (84 mg,
Method B: Uracil (245 mg, 2.18 mmol, 4 equiv), dried
over P2O5, was suspended in HMDS (10 mL), to which
TMSCl (7.0 lL, 0.0546 mmol, 0.1 equiv) was added at
rt, under N2. The mixture was heated to reflux and stir-
red for 16 h before concentrating under reduced pres-
sure and opening to an atmosphere of Ar. To a
solution of 9 (200 mg, 0.546 mmol) in 1,2-DCE at
0 ꢁC, under Ar, was added the silylated uracil and
Et3N (67 lL; 0.546 mmol, 1 equiv) with stirring for
10 min before heating to 50 ꢁC for 6 days. The reaction
mixture was filtered through Celite (washed with
CH2Cl2), concentrated and purified by flash column
chromatography (3:2, EtOAc–hexane) to yield 7a
(122 mg, 68%) as a white foam.
0.914 mmol, 1.5 equiv) was added at rt, under N2 and
stirred for 30 min, after which Et3N (93 lL, 0.670 mmol,
1.1 equiv) and ethyl 2-bromopropionate (87 lL,
0.670 mmol, 1.1 equiv) were added under the same con-
ditions and stirring continued for a further 3 h. The
reaction mixture was filtered through Celite, washed
with EtOAc and concentrated and purified by flash col-
umn chromatography (neat EtOAc) to yield 16 as a
clear, pale yellow oil (140 mg, 60%). HRMS: [M+Na]+
409.1041; C16H22N2O7S + Na requires 409.1045. 1H
NMR (300 MHz, CDCl3): d 1.29, 1.30* (3H, t,
00 00
J = 070 .2 Hz, COOCH2CH3), 1.46 (3H, d, J3 ,2 = 6.9 Hz,
H-3 ), 2.71, 2.79* (1H, dd, J6 a,5 = 7.5, J6 a,6 b = 13.2 Hz,
0
0
0
0
H-60a),
2.85,
2.91*
(1H,
dd,
0 0
J6 b,5 = 6.6,
0
J6 b,6 a = 13.2 Hz, H-6 b), 3.36, 3.37* (3H, s, OMe),
0
0
00
3.43, 3.46* (1H, q, J2 ,3 = 6.9 Hz, H-2 ), 3,64, 3.65*
00 00
4.10. 1-(Methyl 6-S-acetyl-3,4-anhydro-6-thio-a-D-taga-
tofuranoside)-5-fluorouracil 14a
0
(1H, d, J1 a,1 b = 14.4 Hz, H-1 a), 3.68. 3.69* (1H, d,
0
0
ꢂ
0
J3 ,4 = 2.7 Hz, H-3 ) , 3.79, 3.81* (1H, d, J4 ,3 = 2.7 Hz,
0
0
0
0
The following compound was prepared in a similar
manner to Method A from Section 4.9. Product 14a
was obtained in 54% yield as a fine white powder.
HRMS: [M+Na]+ 369.0534; C13H15FN2O6S + Na re-
H-40)ꢂ, 4.20 (2H, q, J = 7.2 Hz, COOCH2CH3), 4.22
0
(1H, dd, J5 ,6 b = 6.6, J5 ,6 a = 7.5 Hz, H-5 ), 4.42, 4.43*
0
0
0
0
0
(1H, d, J1 b,1 a = 14.4 Hz, H1 b), 5.65, 5.66* (1H, dd,
J5,3 = 2.1, J5,6 = 7.8 Hz, H-5), 7.22, 7.23* (1H, d,
J6,5 = 7.8 Hz, H-6), 8.33 (1H, br s, NH-3). 13C NMR
(75.5 MHz, CDCl3): d 14.1 (COOCH2CH3), 17.2, 17.3*
(C-300), 30.5, 31.0* (C-60), 41.4, 41.9* (C-200), 48.1 (C-
10), 50.1 (OCH3), 55.7, 55.8* (C-40), 58.1, 58.2* (C-30),
61.3 (COOCH2CH3), 77.7, 78.0* (C-50), 101.4, 101.5*
(C-5), 103.5, 103.6* (C-20), 145.3 (C-6), 151.3 (C-2),
163.8 (C-4), 172.4, 172.8* (C-100).
0
0
1
quires 369.0533. H NMR (300 MHz, CDCl3): d 2.36
0
0
0
0
=
(3H, s, SAc), 3.00 (1H, dd, J6 a,5 = 6.6, J6 a,6 b
0
13.8 Hz, H-60a), 3.12 (1H, dd, J6 b,5 = 6.6,
0
J6 b,6 a = 13.8 Hz, H-60b), 3.35 (3H, s, OMe), 3.62 (1H,
0
0
d, J1 a,1 b = 14.4 Hz, H-10a), 3.71 (1H, d, J3 ,4 = 2.7 Hz,
0
0
0
ꢂ
0
ꢂ
H-30) , 3.73 (1H, d, J4 ,3 = 2.7 Hz, H-40) , 4.17 (1H,
0
0
dd, J5 ,6 a = J5 ,6 b = 6.6 Hz, H-50), 4.41 (1H, d,
0
0
0
0
J1 b,1 a = 14.4 Hz, H-10b), 7.32 (1H, d, J6,F = 5.7 Hz,
0
0
13
H-5). C NMR (75.5 MHz, CDCl3): d 28.7 (C-60),
4.13. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(methyl
butyrate)]-a-D-tagatofuranoside)-uracil 17
30.5 (SC(O)CH3), 48.6 (C-10), 50.3 (OCH3), 55.7 (C-
40)ꢂ, 58.0 (C-30)ꢂ, 77.1 (C-50), 103.5 (C-20), 129.6 (d,
J6,F = 33.8 Hz, C-6), 140.0 (d, J5,F = 241 Hz, C-5),
150.2 (C-2), 157.5 (d, J4,F = 26.2 Hz, C-4), 194.9
(SC(O)CH3).
The title compound was prepared in a similar manner to
that described in Section 4.12. Thus, 17 was prepared in
92% yield by coupling between 7a and methyl 2-bromo-
butyrate (chromatography neat EtOAc) as a clear oil.
HRMS: [M+Na]+ 409.1043; C16H22N2O7S + Na re-
4.11. 1-(Methyl 6-S-acetyl-3,4-anhydro-6-thio-a-D-taga-
tofuranoside)-cytosine 15a
1
quires 409.1045. H NMR (300 MHz, CDCl3): d 1.00
(3H, t, J4 ,3 = 7.2 Hz, H-400), 1.80 (2H, ddq, H-300),
00 00
2.68, 2.75* (1H, dd, J6 a,5 = 7.8, J6 a,6 b = 13.5 Hz, H-
0
0
0
0
The following compound was prepared in a similar
manner to Method A from Section 4.9. The desired
material 15a was furnished as a fine white powder
0
6 a), 2.81, 2.86* (1H, dd, J6 b,5 = 6.3, J6 b,6 a = 13.5 Hz,
0
0
0
0
0
H-6 b), 3.21, 3.25* (1H, dd, J2 ,3 a = 7.2, J2 ,3 b = 8.1 Hz,
00 00
00 00
in
79%
yield.
HRMS:
[M+Na]+
350.0793;
H-200), 3.36, 3.37* (3H, s, OMe), 3.62, 3.64* (1H, d,
C13H17N3O5S + Na requires 350.0787. 1H NMR
J1 a,1 b = 14.4 Hz, 0H-10a), 3.68, 3.69* (1H, d,
0
0
(300 MHz, MeOD): d 2.35 (3H, s, SAc), 3.02 (1H, dd,
J3 ,4 = 2.7 Hz, H-3 ), 3.74, 3.75* (3H, s, COOMe),
0 0
J6 a,5 = 6.6, J6 a,6 b = 13.5 Hz, H-60a), 3.10 (1H, dd,
3.77, 3.80* (1H, dd, J4 ,5 = 0.6, J4 ,3 = 2.7 Hz, H-40),
0
0
0
0
0
0
0
0
J6 b,5 = 6.6, J6 b,6 a = 13.5 Hz, H-60b), 3.36 (3H, s,
4.190 (1H, ddd, J5 ,4 = 0.6, J5 ,6 b = 6.3, J5 ,6 a = 7.8 Hz,
0
0
0
0
0
0
0
0
0
0
ꢂ
OMe), 3.68 (1H, d, J3 ,4 = 3.0 Hz, H-30) , 3.76 (1H, d,
H-5 ), 4.43, 4.44* (1H, d, J1 b,1 a = 14.4 Hz, H-10b),
5.64, 5.65* (1H, dd, J5,3 = 2.4, J5,6 = 8.1 Hz, H-5), 7.22,
7.23 (1H, d, J6,5 = 8.1 Hz, H-6), 8.80 (1H, br s, NH-3).
13C NMR (75.5 MHz, CDCl3): d 11.9 0 (C-400) 24.8,
25.0*00 (C-300), 30.5, 30.9* (C-60), 48.2 (C-1 ), 48.6, 49.0*
(C-2 ), 50.2 (OCH3), 52.3 (COOCH3), 55.7, 55.8* (C-
40), 58.1, 58.2* (C-30), 77.8, 78.0* (C-50), 101.4, 101.5*
(C-5), 103.4, 103.6* (C-20), 145.3 (C-6), 151.3 (C-2),
163.9 (C-4), 172.9, 173.0* (C-100).
0
0
0
0
ꢂ
J4 ,3 = 3.0 Hz, H-40) , 3.86 (1H, d, J1 a,1 b = 14.1 Hz,
0
0
0
0
H-10a), 4.12 (1H, dd, J5 ,6 a = J5 ,6 b = 6.6 Hz, H-50),
0
0
0
0
4.40 (1H, d, J1 b,1 a = 14.1 Hz, H-10b), 5.82 (1H, d,
J5,6 = 7.2 Hz, H-5), 7.46 (1H, d, J6,5 = 7.2 Hz, H-6).
13C NMR (75.5 MHz, MeOD): d 29.6 (C-60), 30.4
(SC(O)CH3), 50.3 (C-10), 50.5 (OCH3), 56.6 (C-40)ꢂ,
59.5 (C-30)ꢂ, 78.3 (C-50), 95.3 (C-5), 105.2 (C-20), 148.5
(C-6), 159.2 (C-2), 167.8 (C-4), 196.4 (SC(O)CH3).
0
0

I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
1431
4.14. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(methyl-2-phen-
ylacetate)]-a-D-tagatofuranoside)-uracil 18
(300 MHz, CDCl3): d 1.00 (3H, t, H-400), 1.81 (2H, dq,
00
H-3 ), 2.69, 2.75* (1H, dd, J6 a,5 = 7.2, J6 a,6 b = 13.2 Hz,
0
0
0
0
H-60a),
2.82,
2.87*
(1H,
dd,
0 0
J6 b,5 = 6.6,
0
J6 b,6 a = 13.2 Hz, H-6 b), 3.20, 3.25* (1H, t, H-200),
0
0
The title compound was prepared in a similar manner to
that described in Section 4.12. Thus, 18 was prepared in
59% yield by coupling between 7a and methyl a-bromo-
phenylacetate (chromatography 2:1, EtOAc–hexane)
3.36, 3.37* (3H, s, OMe), 3.59, 3.61* (1H, d,
J1 a,1 b = 14.4 Hz, H-10a), 3.71, 3.72* (1H, d,
0
0
ꢂ
J3 ,4 = 2.7 Hz, H-30) , 3.75 (3H, s, COOMe), 3.78,
0
0
ꢂ
clear oil. HRMS: [M+Na]+ 457.1040;
3.80* (1H, d, J4 ,3 = 2.7 Hz, H-4 )0 , 4.21, 4.22* (1H,
0
0
0
as
a
C20H22N2O7S + Na requires 457.1045. 1H NMR
dd, J5 6 b = 6.6, J5 6 a = 7.2 Hz, H-5 ), 4.42, 4.44* (1H,
0 0
0 0
(300 MHz, CDCl3): d 2.55, 2.65* (1H, dd, J6 a,5 = 7.2/
d, J1 b,1 a = 14.4 Hz, H-10b), 7.35, 7.36* (1H, d,
J6,F = 6.0 Hz, H-6), 9.38 (NH-3). 13C NMR
(75.5 MHz, CDCl3): d 11.9 (C-400), 24.3, 25.0* (C-300),
30.6, 30.9* (C-60), 48.5 (C-10), 48.6, 49.1* (C-200), 50.2
(OCH3), 52.3 (COOCH3), 55.7 (C-40)ꢂ, 58.0, 58.1* (C-
30)ꢂ, 77.9, 78.0 (C-50), 103.3, 103.4 (C-20), 129.6
(J6,F = 33.2 Hz, C-6), 139.9 (J5,F = 234.8 Hz, C-5),
150.1 (C-2), 157.3 (J4,F = 25.7 Hz, C-4), 172.9, 173.0*
(C-100).
0
0
0
0
0
7.8*, J6 a,6 b = 13.5 Hz, H-6 a), 2.73, 2.74* (1H, dd,
0
0
0
J6 b,5 = 6.3/6.6*, J6 b,6 a = 13.5 Hz, H-6 b), 3.32, 3.33*
0
0
0
0
(3H, s, OMe), 3.59 (1H, d, J1 a,1 b = 14.4 Hz, H-10a),
0
0
ꢂ
0
3.65, 3.68* (1H, d, J3 ,4 = 2.7 Hz, H-3 ) , 3.70, 3.77*
0
0
ꢂ
0
*
0
(1H, d, J4 ,3 = 2.7 Hz, H-4 ) , 3.73, 3.74 (3H, s,
0
0
0
0
0
COOMe), 4.09 (1H, dd, J5 ,6 b = 6.6, J5 ,6 a = 7.2 Hz,
H-50), 4.41 (1H, d, J1 b,1 a = 14.4 Hz, H-10b), 4.63,
4.64* (1H, s, H-200), 5.56, 5.60* (1H, dd, J5,3 = 2.1,
J5,6 = 7.8 Hz, H-5), 7.14, 7.16* (1H, d, J6,5 = 7.8 Hz,
H-6), 7.31–7.41 (5H, m, Ph), 8.82, 8.84* (1H, s, NH-3).
13C NMR (75.5 MHz, CDCl3): d 30.8, 31.3* (C-60),
48.2 (C-10), 50.1 (OCH3), 52.6, 52.7* (COOCH3), 52.9
(C-200), 55.6 (C-4)ꢂ, 58.3 (C-3)ꢂ, 77.8 (C-50), 101.5 (C-
5), 103.4 (C-20), 128.3, 128.4, 128.5, 128.9 (Ph), 145.2
(C-6), 151.2 (C-2), 163.5 (C-4), 170.9 (C-100).
0
0
4.17. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(methyl-2-phen-
ylacetate)]-a-D-tagatofuranoside)-5-fluorouracil 21
The title compound was prepared in a similar manner to
that described in Section 4.12. Thus, 21 was prepared in
90% yield by coupling between 14a and methyl a-bromo-
phenylacetate (chromatography 3:1, EtOAc–hexane)
4.15. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(ethyl prop-
ionate)]-a-D-tagatofuranoside)-5-fluorouracil 19
as
a
white foam. HRMS: [M+Na]+ 475.0946;
C20H21FN2O7S + Na requires 475.0951. 1H NMR
(300 MHz, CDCl3): d 2.58, 2.66* (1H, dd, J6 a,5 = 7.5,
0
0
J6 a,6 b = 13.2 Hz, H-60a), 2.76, 0 2.77* (1H, dd,
0
0
The title compound was prepared in a similar manner to
that described in Section 4.12. Thus, 19 was prepared in
84% yield by coupling between 14a and ethyl 2-bromo-
propionate (chromatography 3:2, EtOAc–hexane) as a
clear amorphous mass. HRMS: [M+Na]+ 427.0947;
C16H21FN2O7S + Na requires 427.0951. 1H NMR
J6 b,5 = 6.3, J6 b,6 a = 13.2 Hz, H-6 b), 3.32, 3.33* (3H,
0
0
0
0
s, OMe), 3.57 (1H, d, J1 a,1 b = 14.4 Hz, H-10a), 3.66,
0
0
ꢂ
0
3.68* (1H, d, J3 ,4 = 3.0 Hz, H-3 ) , 3.73, 3.78* (1H, d,
0
0
ꢂ
J4 ,3 = 3.0 Hz, H-40) , 3.75 (3H, s, COOMe), 4.10,
0
0
4.12* (1H, dd, J5 ,6 b = 6.3, J5 ,6 a = 7.5 Hz, H-50), 4.39
0
0
0
0
0
(1H, d, J1 b,1 a = 14.4 Hz, H-1 b), 4.62, 4.65* (1H, s, H-
200), 7.28, 7.31* (1H, d, J6,F = 6.0 Hz, H-6), 7.29–7.46
(5H, m, Ph). 13C NMR (75.5 MHz, CDCl3): d 30.9,
31.4* (C-60), 48.6 (C-10), 50.2, 50.3* (OCH3), 52.7,
52.9* (COOCH3), 55.6, 55.7* (C-40)ꢂ, 58.0, 58.1* (C-
30)ꢂ, 77.8 (C-50), 103.3, 103.4* (C-20), 128.3, 128.4,
128.5, 128.6, 128.9 (Ph), 129.5, 129.6* (J6,F = 33.2 Hz,
C-6), 135.5, 135.6* (ipso-Ph), 139.9 (J5,F = 236.3 Hz, C-
5), 150.0 (C-2), 157.2 (J4,F = 26.4 Hz, C-4), 170.9,
171.1 (C-100).
0
0
(300 MHz, CDCl3):
COOCH2CH3), 1.46 (3H, d, J3 ,2 = 7.2 Hz, H-300),
d
1.29 (3H, t, J = 7.2 Hz,
00 00
2.730, 2.80* (1H, dd, J6 a,5 = 7.5, J6 a,6 b = 13.5 Hz,
0
0
0
0
H-6 a), 2.86, 2.93* (1H, dd, J6 b,5 = 6.3, J6 b,6 a
0
0
0
0
=
13.5 Hz, H-60b), 3.36, 3.37* (3H, s, OMe), 3.42, 3.46*
00
(1H, q, J2 ,3 = 7.2 Hz, H-2 ), 3.60, 3.62* (1H, d,
00 00
J1 a,1 b = 14.4 Hz, H-10a), 3.70, 3.71* (1H, d,
0
0
ꢂ
0
J3 ,4 = 2.7 Hz, H-3 ) , 3.80, 3.82* (1H, d, J4 ,3 = 2.7 Hz,
0
0
0
0
H-40)ꢂ, 4.20 (2H, q, J = 7.2 Hz, COOCH2CH3), 4.24
0
(1H, dd, J5 ,6 b = 6.3, J5 ,6 a = 7.5 Hz, H-5 ), 4.41, 4.42*
0
0
0
0
0
(1H, d, J1 b,1 a = 14.4 Hz, H-1 b), 7.35, 7.36* (1H, d,
J6,F = 6.0 Hz, H-6). 13C NMR (75.5 MHz, CDCl3): d
14.1 (C-300), 17.1, 17.2* (COOCH2CH3), 30.6, 30.9* (C-
60), 41.4, 41.9* (C-200), 48.5 (C-10), 50.2 (OCH3), 55.7
(C-40)ꢂ, 58.0, 58.1* (C-30)ꢂ, 61.3 (COOCH2CH3), 77.7,
77.9* (C-50), 103.3, 103.4* (C-20), 129.6 (J6,F = 33.2 Hz,
C-6), 139.9 (J5,F = 235.6 Hz, C-5), 150.2 (C-2), 157.4
(J4,F = 26.4 Hz, C-4), 172.7, 172.8* (C-100).
0
0
4.18. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(methyl
butyrate)]-a-D-tagatofuranoside)-cytosine 22
The title compound was prepared in a similar manner
to that described in Section 4.12. Thus, 22 was prepared
in 92% yield by coupling between 15a and methyl
2-bromobutyrate (chromatography 5:1, EtOAc–MeOH)
as
a
white foam. HRMS: [M+Na]+ 408.1209;
4.16. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(methyl
C16H23N3O6S + Na requires 408.1205. 1H NMR
00 00
butyrate)]-a-D-tagatofuranoside)-5-fluorouracil 20
(300 MHz, MeOD): d 1.01 (3H, t, J4 ,3 = 7.2 Hz, H-
400), 1.65–1.93 (2H, m, H-300), 2.68, 2.74* (1H, dd,
0
J6 a,5 = 7.2, J6 a,6 b = 13.5 Hz, H-6 a), 2.80, 2.84* (1H,
0
0
0
0
The title compound was prepared in a similar manner to
that described in Section 4.12. Thus, 20 was prepared in
87% yield by coupling between 14a and methyl 2-bro-
mobutyrate (chromatography 3:2, EtOAc–hexane) as a
clear amorphous mass. HRMS: [M+Na]+ 427.0948;
C16H21FN2O7S + Na requires 427.0951. 1H NMR
dd, J6 b,5 = 6.6, J6 b,6 a = 13.5 Hz, H-60b), 3.32–3.41
0
0
0
0
(1H, m, H-200), 3.38, 3.39* (3H, s, OMe), 3.69, 3.70*
ꢂ
0
(1H, d, J3 ,4 = 2.7 Hz, H-3 ) , 3.73, 3.74* (3H, s,
0
0
ꢂ
COOMe), 3.82 (1H, dd, J4 ,3 = 2.7 Hz, H-40) , 3.85,
0
0
0
3.87* (1H, d, J1 a,1 b = 14.1 Hz, H-1 a), 4.20, 4.22* (1H,
0
0

1432
I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
0
dd, J5 ,6 b = 6.6, J5 ,6 a = 7.2 Hz, H-5 ), 4.41, 4.42* (1H,
4.31* (1H, d, J1 b,1 a = 14.4 Hz, H-10b), 4.31 (1H, dd,
0
0
0
0
0
0
d, J1 b,1 a = 14.1 Hz, H-10b), 5.84, 5.85* (1H, d,
J5 ,6 b = 6.6, J5 ,6 a = 7.8 Hz, H-5 ), 5.60, 5.61* (1H, d,
J5,6 = 7.8 Hz, H-5), 7.47, 7.48* (1H, d, J6,5 = 7.8 Hz,
0
0
0
0
0
0
0
J5,6 = 7.2 Hz, H-5), 7.49, 7.50* (1H, d, J6,5 = 7.2 Hz,
13
13
H-6). C NMR (75.5 MHz, MeOD): d 12.2, 12.3* (C-
H-6). C NMR (75.5 MHz, MeOD): d 0019.1, 19.3* (C-
400), 26.1, 26.3* (C-300), 31.9, 32.3* (C-60), 49.6, 50.2*
(C-200), 50.5 (C-10), 50.7 (OCH3), 52.9 (COOCH3), 56.9
(C-40), 59.7, 59.8* (C-30), 079.3, 79.6* (C-50), 95.4, 95.5*
(C-5), 105.2, 105.3* (C-2 ), 148.6, 1040 8.7* (C-6), 159.4
(C-2), 167.8 (C-4), 175.0, 175.1* (C-1 ).
300), 31.5, 32.2* (C-60), 46.6, 47.4* (C-2 ), 49.3 (C-10),
50.5 (OCH3), 57.0, 57.1* (C-40)ꢂ, 59.5 (C-30)ꢂ, 79.3,
79.8* (C-50), 101.4 (C-5), 104.8, 104.9* (C-20), 148.3,
148.4* (C-6), 153.3 (C-2), 167.0 (C-4).
4.21. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium
butyrate)]-a-D-tagatofuranoside)-uracil 25
4.19. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(methyl-2-phen-
ylacetate)]-a-D-tagatofuranoside)-cytosine 23
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 17
gave in 62% yield 25 (HPLC: Phenomenex Aqua C18 re-
verse phase column, 70:30 H2O–CH3CN, 2.5 mL/min)
as a white solid. Anal. Calcd for C15H19N2O7SNa +
1.5H2O: C, 42.73; H, 5.26; N, 6.65. Found: 42.24; H,
5.10; N, 6.20. HRMS: [M+H]+ 395.0888; C15H19N2O7-
SNa + H requires 395.0889. 1H NMR (300 MHz,
The title compound was prepared in a similar manner to
that described in Section 4.12. Thus, 23 was prepared in
99% yield by coupling between 15a and methyl a-bromo-
phenylacetate (chromatography 9:1, EtOAc–MeOH)
as
a
white foam. HRMS: [M+H]+ 434.1382;
C20H23N3O6S+H requires 434.1386. 1H NMR (300
0
0
0
0
=
MHz, MeOD): d 2.55 (1H, dd, J6 a,5 = 7.2, J6 a,6 b
0
13.8 Hz, 0 H-6 a), 2.66* (2H, d, J6 a/6 b ,5 = 6.9 Hz, H-
MeOD): d 0.95 (3H, t, J4 ,3 = 7.2 Hz, H-400), 1.64,
0
0
0
00 00
*
0
00
6 a*, H-6 b*), 2.73 (1H, dd, J6 b,5 = 6.6, J6 b,6 a = 13.8 Hz,
1.80* (2H, ddq, H-3 ), 2.58, 2.66* (1H, dd, J6 a,5 = 8.1,
0
0
0
0
0
0
H-60b), 3.33, 3.34* (3H, s, OMe), 3.67, 3.69* (1H, d,
J6 a,6 b = 13.5 Hz, H-60a), 2.76, 0 2.83* (1H, dd,
0
0
0
J3 ,4 = 3.0 Hz, H-3 ), 3.71, 3.72* (3H, s, COOMe),
J6 b,5 = 6.0, J6 b,6 a = 13.5 Hz, H-6 b), 3.14, 3.19* (1H,
0
0
0
0
0
0
3.78, 3.80* (1H, dd, J4 ,5 = 0.6, J4 ,3 = 03.0 Hz, H-40),
dd, J2 ,3 a = 7.2, J2 ,3 b = 8.1 Hz, H-2 ), 3.36, 3.37*
00
0
0
0
0
00 00
00 00
3.83, 3.84* (1H, d, J1 a,1 b = 14.1 Hz, H-1 a), 4.11, 4.13*
(3H, s, OMe), 3.64 (1H, dd, J4 ,3 = J4 ,5 = 2.7 Hz, H-
0
0
0
0
0
0
0
(1H, ddd, J5 ,4 = 0.6, J5 ,6 b = 6.6, J5 ,6 a = 7.2 Hz, H-
40), 3.81 (1H, d, J1 a,1 b = 14.4 Hz, H-1 a), 3.88, 3.90*
0
0
0
0
0
0
0
0
0
50), 4.39 (1H, d, J1 b,1 a = 14.1 Hz, H-1 b), 4.82, 4.83*
(1H, s, H-200), 5.79, 5.83* (1H, d, J5,6 = 7.8 Hz, H-5),
7.31–7.48 (5H, m, Ph), 7.35 (1H, d, J6,5 = 7.8 Hz, H-6).
13C NMR (75.5 MHz, MeOD): d 32.1, 32.5* (C-60),
50.5 (C-10), 50.6, 50.7* (OCH3), 53.4 (COOCH3), 53.6,
53.7* (C-200), 56.8, 57.0* (C-40), 59.8, 59.9* (C-30), 79.3,
79.4* (C-50), 95.4 (C-5), 105.1, 105.2* (C-20), 129.5,
129.7, 129.8, 129.9, 130.0 (Ph), 137.8, 137.9* (ipso-Ph),
148.8 (C-6), 158.8 (C-2), 167.4 (C-4), 173.0, 173.1* (C-
100).
(1H, d, J3 ,4 = 2.7Hz, H-3 ), 4.30, 4.32* (1H, d,
0
0
0
0
0
J1 b,1 a = 14.4 Hz, H-10b), 4.33 (1H, ddd, J5 ,4 = 2.7,
0
0
0
0
J5 ,6 b = 6.0, J5 ,6 a = 8.1 Hz, H-50), 5.61 (1H, d,
J5,6 = 8.1 Hz, H-5), 7.47, 7.48* (1H, d, J6.5 = 8.1 Hz,
0
0
0
0
13
H-6). C NMR (75.5 MHz, MeOD): d 12.6, 12.7* (C-
400), 27.1, 27.3* (C-300), 31.5, 32.3* (C-60), 49.3 (C-1),
50.5 (OCH3), 53.9, 54.7* (C-200), 57.0, 57.1* (C-30)ꢂ,
59.5 (C-40)ꢂ0, 79.3, 79.7* (C-50), 101.4 (C-5), 104.8,
104.9* (C-2 ), 148.3, 148.4* (C-6), 153.2 (C-2), 166.9
(C-4), 180.0 (C-100).
4.20. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium prop-
4.22. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium-2-phen-
ionate)]-a-D-tagatofuranoside)-uracil 24
ylacetate)]-a-D-tagatofuranoside)-uracil 26
To a solution of 16 (107 mg, 0.277 mmol) in MeOH
(5 mL) was added 1 M NaOH (1 mL) at rt, under N2
and stirred for 16 h. It was neutralized by Amberlite
IR-120 (H+) resin (to ꢁpH 5), filtered, washed with
aqueous MeOH and concentrated under reduced pres-
sure. The crude material was dissolved in MeOH (5-
10 mL) and the pH adjusted to 7.3–7.5 with 0.5–
0.05 M NaOH to form the sodium salt, concentrated
and then freeze-dried. The residue was purified by
HPLC (Phenomenex Aqua C18 reverse phase column,
85:15 H2O–CH3CN, 2.5 mL/min) to give 24 (65.8 mg,
63%) as a white solid. Anal. Calcd for C14H17N2O7S-
Na + 1.5H2O: C, 41.25; H, 4.95; N, 6.87. Found: C,
40.95; H, 4.81; N, 6.52. HRMS: [M+H]+ 381.0728;
C14H17N2O7SNa + H requires 381.0732. 1H NMR
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 18
gave 26 in 49% yield (HPLC: Phenomenex Aqua C18 re-
verse phase column, 85:15 H2O–CH3CN, 3.0 mL/min)
as a white solid. Anal. Calcd for C19H19N2O7SNa +
1.5H2O: C, 48.58; H, 4.72; N, 5.96. Found: C, 48.56;
H, 4.63; N, 5.65. HRMS: [M+H]+ 443.0885; C19H19N2O7-
SNa + H requires 443.0889. 1H NMR (300 MHz,
MeOD):
0
2.42, 2.48* (1H, dd, J6 a,5 = 8.1/7.2*,
0 0
d
J6 a,6 b = 13.5 Hz, H-60a), 2.54, 2.60* (1H, dd,
0
J6 b,5 = 6.3/6.0*, J6 b,6 a = 13.5 Hz, H-60b), 3.34 (3H, s,
0
0
0
0
ꢂ
OMe), 3.61, 3.63* (1H, d, J3 ,4 = 2.7 Hz, H-30) , 3.75,
0
0
0
3.77* (1H, d, J1 a,1 b = 14.4 Hz, H-1 a), 3.82, 3.85* (1H,
0
0
ꢂ
d, J4 ,3 = 2.7 Hz, H-40) , 4.03, 4.109* (1H, dd,
0
0
J5 ,6 a = 6.3/6.9, J5 6 b = 6.6/6.9 Hz, H-5 ), 4.29, 4.31*
0
0
0 0
0
(300 MHz, MeOD): d 1.36, 1.38* (3H, d, J3 ,2 = 7.2 Hz,
(1H, d, J1 b,1 a = 14.4 Hz, H-1 b), 4.57, 4.58* (1H, s, H-
00 00
0
0
00
H-30 ), 2.58, 2.66* (1H, dd, J6 a,5 = 7.8, J6 a,6 b = 13.5 Hz,
200), 5.51, 5.52* (1H, d, J5,6 = 7.8 Hz, H-5), 7.37, 7.40*
0
0
0
0
H-6 a), 2.77, 2.83* (1H, dd, J6 b,5 = 6.6, J6 b,6 a
=
(1H, d, J6 ,5 = 7.8 Hz, H-6), 7.18–7.31 (3H, m, Ph),
7.50–7.55 (2H, m, Ph). 13C NMR (75.5 MHz, MeOD):
d 31.7, 31.9* (C-60), (C-10 under MeOD peak), 50.4,
50.5* (OCH3), 56.7, 57.0* (C-40)ꢂ,0 58.6, 58.8* (C-200),
59.4, 59.6* (C-30)ꢂ, 79.3, 79.8* (C-5 ), 101.4, 101.5* (C-
0
0
0
0
0
0
13.5 Hz, H-60b), 3.36, 3.37* (3H, s, OMe), 3.39, 3.42*
00
(1H, q, J2 ,3 = 7.2 Hz, H-2 ), 3.63, 3.64* (1H, d,
00 00
ꢂ
J3 ,4 = 3.0 Hz, H-30) , 3.81 (1H, d, J1 a,1 b = 14.4 Hz,
0
0
0
0
ꢂ
0
H-1 a), 3.88, 3.89* (1H, d, J4 ,3 = 3.0 Hz, H-30) , 4.30,
0
0

I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
1433
5), 104.6, 104.8* (C-20), 128.2, 129.3, 129.7, 129.8 (Ph),
141.1, 141.6* (ipso-Ph), 148.2, 148.3* (C-6), 153.2,
153.3* (C-2), 166.9 (C-4), 171.9, 172.0* (C-100).
gave 29 in 66% yield (HPLC: Phenomenex Aqua Semi-
Preparative Column, 90:10 H2O–CH3CN, 4.0 mL/
min). HRMS: [M+H]+ 461.0787; C19H18FN2O7-
SNa + H requires 461.0795. 1H NMR (300 MHz,
4.23. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium prop-
ionate)]-a-D-tagatofuranoside)-5-fluorouracil 27
MeOD):
0
d
2.39, 2.47* (1H, dd, J6 a,5 = 8.7,
J6 a,6 b = 13.5 Hz, H-60a), 2.56, 2.62* (1H, dd,
0
0
0
J6 b,5 = 6.3, J6 b,6 a = 13.5 Hz, H-60b), 3.34 (3H, s,
0
0
0
0
OMe), 3.61, 3.64* (1H, d, J3 ,4 = 2.7 Hz, H-30), 3.74,
0
0
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 19
gave 27 in 52% yield (HPLC: Phenomenex Aqua Semi-
Preparative Column, Gradient: 6:94, CH3CN–H2O,
3.5 mL/min ! 60:40, CH3CN–H2O, 4.0 mL/min !
6:94, CH3CN–H2O, 4.0 mL/min). HRMS: [M+H]+
0
3.75* (1H, d, J1 a,1 b = 14.1 Hz, H-10a), 3.83, 3.88* (1H,
0
0
dd, J4 ,5 = 0.6, J4 ,3 = 2.7 Hz, H-4 ), 4.02, 4.19* (1H,
0
0
0
0
ddd, J5 ,4 = 0.6, J5 ,6 b = 6.3, J5 ,6 a =0 8.7 Hz, H-50),
0
0
0
0
0
0
4.25, 4.26* (1H, d, J1 b,1 a = 14.1 H-1 b), 4.56, 4.57*
(1H, s, H-200), 7.16–7.31 (3H, m, Ph), 7.48–7.54 (2H,
m, Ph), 7.59, 7.60* (1H, d, J6,F = 6.3 Hz, H-6). 13C
NMR (75.5 MHz, MeOD): d 31.5, 31.9* (C-60), 49.5
(C-10), 50.5, 50.6* (OCH3), 56.7, 57.0* (C-40), 58.6,
58.9* (C-200), 59.3, 59.7* (C-30), 79.2, 79.5* (C-50),
104.6, 104.8* (C-20), 128.2, 128.3, 129.3, 129.7, 129.8
(Ph), 131.9, 132.4* (J6,F = 33.2 Hz, C-6), 141.0
(J5,F = 231.0 Hz, C-5), 141.1, 141.5* (ipso-Ph), 152.1
(C-2), 160.5 (C-4), 177.2, 177.6* (C-100).
0
0
1
399.0632; C14H16FN2O7SNa + H requires 399.0638. H
NMR (300 MHz, MeOD): d 1.37, 1.38* (3H, d,
00
J3 ,2 = 7.2 Hz, H-3 ), 2.59, 2.67* (1H, dd, J6 a,5 = 8.1,
00 00
0
0
0
J6 a,6 b = 13.5, H-6 a), 2.78, 2.86* (1H, dd, J6 b,5 = 6.3,
0
0
0
0
0
J6 b,6 a = 13.5 Hz, H-6 b), 3.36, 3.37* (3H, s, OMe),
0
0
00
3.39, 3.42* (1H, q, J2 ,3 = 6.9 Hz, H-2 ), 3.65, 3.66*
00 00
ꢂ
0
(1H, d, J3 ,4 = 2.7 Hz, H-3 ) , 3.79, 3.80* (1H, d,
0
0
0
J1 a,1 b = 14.4 Hz, H-1 a), 3.90, 3.91* (1H, d, J4 ,3
=
0
0
0
0
ꢂ
0
2.7 Hz, H-4 ) , 4.27, 4.28* (1H, d, J1 b,1 a = 14.4 Hz, H-
0
0
10b), 4.33 (1H, dd, J5 ,6 b = 6.3, J5 ,6 a = 8.1 Hz, H-50),
7.68, 7.69* (1H, d, J6,F = 6.6 Hz, H-6). 13C NMR
(75.5 MHz, MeOD): d 19.0, 19.2* (C-300), 31.6, 32.1*
(C-60), 49.5 (C-10), (C-2000 under MeOD peak), 50.6
(OCH3), 57.0, 57.1* (C-4 )ꢂ, 509.4, 59.5* (C-30)ꢂ, 79.3,
79.5* (C-50), 104.7, 104.8* (C-2 ), 132.3 (J6,F = 34.0 Hz,
C-6), 140.9 (J5,F = 231.0 Hz, C-5), 151.9 (C-2), 160.0
(J4,F = 25.7 Hz, C-4), 170.1 (C-100).
4.26. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium
butyrate)]-a-D-tagatofuranoside)-cytosine 30
0
0
0
0
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 22
gave 30 in 33% yield (HPLC: Phenomenex Aqua Semi-
Preparative Column, 90:10 H2O–CH3CN, 4.0 mL/
min). Anal. Calcd for C15H20N3O6SNa + 2.5H2O: C,
41.07; H, 5.74; N, 9.58. Found: C, 41.35; H, 5.30; N,
9.22. HRMS: [M+H]+ 394.1050; C15H20N3O6SNa + H
requires 394.1049. 1H NMR (300 MHz, MeOD): d
4.24. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium
butyrate)]-a-D-tagatofuranoside)-5-fluorouracil 28
0.99 (3H, t, J4 ,3 = 7.5 Hz, H-400), 1.54–1.89 (2H, m,
00 00
00
H-30 ), 2.58, 2.65* (1H, dd, J6 a,5 = 7.8, J6 a,6 b = 13.5 Hz,
0
0
0
0
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 20
gave 28 in 34% yield (HPLC: Phenomenex Aqua Semi-
Preparative Column, 93:7 H2O–CH3CN, 4.0 mL/min).
Anal. Calcd for C15H18FN2O7SNa + 0.5H2O: C, 42.73;
H, 4.54; N, 6.65. Found: C, 42.51; H, 4.43; N, 6.35.
HRMS: [M+H]+ 413.0793; C15H18FN2O7SNa + H re-
H-6 a), 2.76, 2.81* (1H, dd, J6 b,5 = 6.3, J6 b,6 a
=
=
0
0
0
0
13.5 Hz, H-60b), 3.14, 3.19* (1H, dd, J2 ,3 a
00 00
00
J2 ,3 b = 6.3/6. 6* Hz, H-2 ), 3.35, 3.36* (3H, s, OMe),
00 00
0
3.63, 3.64* (1H, d, J3 ,4 = 2.7 Hz, H-3 ), 3.81, 3.82*
0
0
(1H, d, J1 a,1 b = 14.1 Hz, H-10a), 3.84 (1H, m, H-40),
0
0
4.26, 4.28* (1H, ddd, J5 ,4 = 0.6, J5 ,6 b = 6.3,
0
0
0
0
1
H-50),
4.36,
4.37*
(1H,
d,
0
0
quires 413.0795. H NMR (300 MHz, MeOD): d 0.99,
J5 ,6 a = 7.2 Hz,
0
1.00* (3H, t, J4 ,3 = 7.5 Hz, H-400), 1.72 (2H, dq, H-
J1 b,1 a = 14.1 Hz, H-10b), 5.81, 5.82* (1H, d,
J5,6 = 7.2 Hz, H-5), 7.45, 7.46* (1H, d, J6,5 = 7.2 Hz,
00 00
0
00
3 ), 2.57, 2.66* (1H, dd, J6 a,5 = 8.4, J6 a,6 b = 13.5 Hz,
0
0
0
0
13
H-60a),
2.77,
2.85*
(1H,
dd,
H-6). C NMR (75.050 MHz, MeOD): d 12.6, 12.7* (C-
0 0
J6 b,5 = 6.0,
J6 b,6 a = 13.5 Hz, 00H-60b), 3.16, 3.18* (1H, t,
400), 27.2, 27.3* (C-3 ), 31.5, 32.4* (C-60), 50.4 (C-10),
50.1 (OCH3), 54.0, 54.8* (C-200), 56.8, 56.9* (C-40)ꢂ,
59.6 (C-30)ꢂ, 79.1, 79.5* (C-50), 95.2 (C-5), 105.1 (C-20),
148.4, 148.5 (C-6), 159.4 (C-2), 168.0 (C-4), 180.1,
180.5* (C-100).
0
0
J2 ,3 = 8.4 Hz, H-2 ), 3.36, 3.37* (3H, s, OMe), 3.64,
00 00
ꢂ
0
3.65* (1H, d, J3 ,4 = 3.0 Hz, H-3 ) , 3.78, 3.79 (1H, d,
*
0
0
J1 a,1 b = 14.1 Hz, H-10a), 3.90, 3.91* (1H, d,
0
0
ꢂ
0
J4 ,3 = 3.0 Hz, H-4 ) , 4.27, 4.28* (1H, d, J1 b,1 a = 14.1
H-10b), 4.32, 4.34* (1H, m, H-50), 7.66, 7.67* (1H, d,
J6,F = 6.6 Hz, H-6). 13C NMR (75.5 MHz, MeOD): 0 d
12.6, 12.7* (C-400), 27.2, 27.4* (C-300), 31.5, 32.3* (C-6 ),
49.5 (C-10), 50.6 (OCH3), 54.0, 54.8* (C-200), 57.0, 57.1*
(C-30)ꢂ, 59.4, 59.5* (C-40)ꢂ, 79.3, 79.5* (C-50), 104.8,
104.9* (C-20), 132.0, 132.4* (C-6), 139.5 (C-5), 142.5
(C-2), 152.2 (C-4), 180.1, 180.5* (C-100).
0
0
0
0
4.27. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium-2-phen-
ylacetate)]-a-D-tagatofuranoside)-cytosine 31
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 23
gave 31 in 5% yield (HPLC: Phenomenex Aqua Semi-
Preparative Column, 80:20 H2O–CH3CN, 3.5 mL/
min). HRMS: [M+H]+ 442.1039; C19H20N3O6SNa + H
requires 422.1049. 1H NMR (300 MHz, MeOD): d
4.25. 1-(Methyl 3,4-anhydro-6-thio-6-[20-(sodium-2-phen-
ylacetate)]-a-D-tagatofuranoside)-5-fluorouracil 29
2.43, 2.47* (1H, dd, J6 a,5 = 7.2, J6 a,6 b = 13.5, H-60a),
0
0
0
0
2.51, 2.55* (1H, dd, J6 b,5 = 6.6, J6 b,6 a = 13.5, H-60b),
0
0
0
0
The title compound was prepared in a similar manner to
that described in Section 4.20. De-esterification of 21
3.31, 3.33* (3H, s, OMe), 3.68, 3.69* (1H, d, J3 ,4
0
0
=

1434
I. D. Grice et al. / Tetrahedron: Asymmetry 16(2005) 1425–1434
ꢂ
0
2.7 Hz, H-3 ) , 3.78, 3.79* (1H, d, J1 a,1 b = 14.1 Hz, H-
0
0
8. Norton, A. K.; von Itzstein, M. Aust. J. Chem. 1996, 49,
281–283.
9. Barchi, J. J. Curr. Pharm. Des. 2000, 6, 485.
10. Sears, P.; Wong, C. H. Angew. Chem., Int. Ed. 1999, 38,
2300.
11. Huwe, C. M.; Woltering, T. J.; Jiricek, J.; Weitz-Schmidt,
G.; Wong, C. H. Bioorg. Med. Chem. 1999, 7, 773.
12. Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471–
490.
13. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel,
D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am.
Chem. Soc. 1997, 199, 681.
ꢂ
0
1 a), 3.81, 3.83* (1H, d, J4 ,3 = 2.7 Hz, H-4) , 4.01,
4.13* (1H, dd, J5 ,6 b = 6.6, J5 ,6 a = 7.2 Hz, H-50), 4.37,
0
0
0
0
0
0
4.38* (1H, d, J1 b,1 a = 14.1 Hz, H-10b), 4.72 (H-200 not
seen), 5.78, 5.80* (1H, d, J5,6 = 7.2 Hz, H-5), 7.22–7.52
(5H, m, Ph), 7.25, 7.40* (1H, d, J6,5 = 7.2 Hz, H-6). 13C
NMR (75.5 MHz, MeOD): d 31.6, 31.9* (C-60), 50.4
(C-10), 50.7, 50.8* (OCH3), 56.6 (C-200), 58.4, 58.7* (C-
4)ꢂ, 59.5 (C-3)ꢂ, 78.8, 79.3* (C-50), 95.5 (C-5), 104.7,
104.9* (C-20), 128.5, 129.4, 129.5 (Ph), 140.9 (ipso-Ph),
148.5 (C-6), 159.3 (C-2), 167.7 (C-4), 177.3 (C-100).
0
0
14. Florio, P.; Thomson, R. J.; Alafaci, A.; Abo, S.; von
Itzstein, M. Bioorg. Med. Chem. Lett. 1999, 9, 2065.
15. Florio, P.; Thomson, R. J.; von Itzstein, M. Carbohydr.
Res. 2000, 328, 445.
16. Smith, P. W.; Robinson, J. E.; Evans, D. N.; Sollis, S. L.;
Howes, P. D.; Trivech, N.; Bethell, R. C. Bioorg. Med.
Chem. Lett. 1999, 9, 601.
4.28. Methyl 6-S-(methyl-3,4-anhydro-6-thio-b-D-tagato-
furanoside)-3,4-anhydro-6-thio-b-D-tagatofuranoside 36
LRMS: [M+Na]+ 561.0; C16H26O12S4Na requires 561.0.
1H NMR (300 MHz, CDCl3): d 3.02 (2H, d, J6/6 ,5
=
0
6.9 Hz, H-6/60), 3.08 (3H, s, OMs), 3.51 (3H, s,
OCH3), 3.80 (1H, d, J3,4 = 2.8 Hz, H-3), 3.90 (1H, dd,
J4,3 = 2.8 Hz, J4,5 = 0.8 Hz, H-4), 4.13 (1H, d,
17. Mann, M. C.; Thomson, R. J.; von Itzstein, M. Bioorg.
Med. Chem. Lett. 2004, 14, 5555–5558.
J1,1 = 11.0, H-1), 4.30 (1H, d, J1 ,1 = 11.0 Hz, H-10),
0
0
18. Muller, B.; Schaub, C.; Schmidt, R. R. Angew. Chem.
1998, 110, 3021–3024; Muller, B.; Schaub, C.; Schmidt, R.
R. Angew. Chem., Int. Ed. 1998, 37, 2893–2897.
19. Schaub, C.; Muller, B.; Schmidt, R. R. Glycoconjugate J.
1998, 15, 345–354.
20. Kiefel, M. J.; Thomson, R. J.; Radovanovic, M.; von
Itzstein, M. J. Carbohydr. Chem. 1999, 18, 937–959.
21. Bradley, S. J.; Fazli, A.; Kiefel, M. J.; von Itzstein, M.
Bioorg. Med. Chem. Lett. 2001, 11, 1587–1590.
22. Pater, R. H.; Coelho, R. A.; Mowery, D. F. J. Org. Chem.
1973, 38, 3272–3277.
0
4.31 (1H, dd, J5,4 = 0.8, J5,6 = J5,6 = 4.8 Hz, H-5).
Acknowledgments
We gratefully acknowledge the financial support of the
Australian Research Council (MvI, Federation Fellow-
ship and an ARC Grant) and the support of the
National Health and Medical Research Council.
23. Guthrie, R. D.; Jenkins, I. D.; Yamasaki, R. Aust. J.
Chem. 1982, 35, 1003–1018.
24. Guthrie, R. D.; Jenkins, I. D.; Yamasaki, R.; Skelton, B.
W.; White, A. H. J. Chem. Soc., Trans. Perkin 1 1981,
2328–2334.
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