Palladium-catalyzed alkynylation (Sonogashira coupling) at C-5 of the uracil moiety in modified unsaturated pyranosyl nucleosides

Article abstract of DOI:10.1055/s-2007-965976

Various unsaturated 4-(5-substituted-uracil-1-yl)glycopyranosides were synthesized in good yields by a palladium-catalyzed cross-coupling reaction of ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-4-[5-iodo-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl]-α-

Full text of DOI:10.1055/s-2007-965976

1890
PRACTICAL SYNTHETIC PROCEDURES
Palladium-Catalyzed Alkynylation (Sonogashira Coupling) at C-5 of the
Uracil Moiety in Modified Unsaturated Pyranosyl Nucleosides
P
alladium-Cat
r
alyze
d
A
a
lkynylation
n
a
t
C-5 of
U
c
racil Moiet
i
y
sco J. B. Mendonça, Jr. a,b Janaína V. dos Anjos,a,c Denis Sinou,*a Sebastiao J. de Melo,b
Rajendra M. Srivastava*c
a
Laboratoire de Synthèse Asymétrique, UMR 5246-ICBMS, ESCPE Lyon, Université Claude Bernard Lyon 1, 43 boulevard
du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax 33(4)78898914; E-mail: sinou@univ-lyon1.fr
Departamento de Antibióticos, Universidade Federal de Pernambuco, Cidade Universitária,
b
50670-901, Recife, PE, Brazil
Departamento de Química Fundamental, Universidade Federal de Pernambuco,
c
PSP
Cidade Universitária, 50740-540, Recife, PE, Brazil
Fax 55 8121268440; E-mail: rms@ufpe.br
Received 25 January 2007
No88
Abstract: Various unsaturated 4-(5-substituted-uracil-1-yl)glycopyranosides were synthesized in good yields by a palladium-catalyzed
cross-coupling reaction of ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-4-[5-iodo-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-a-D-
erythro-hex-2-enopyranoside with a range of acetylenic derivatives.
Key words: palladium, unsaturated carbohydrates, cross-coupling, nucleoside
TBDMSO
MeO2CO
TBDMSO
TBDMSO
O
O
i
ii
O
OEt
OEt
OEt
N
O
O
N
O
O
1
NH
NH
I
R
2
3a–j
R
O
N
N
(92%)
(41%)
a: -CH2CH2CH2CH3 (72%)
b: -CH2CH2CH2CH2OH (82%)
c: -C(Me)2OH (64%)
j:
Ph
O
d: (R,S) -C(Me)(Et)OH (76%)
e: (R,S) -CH(Ph)OAc (74%)
f: (R,S) -CH(Ph)OH (85%)
g: -SiMe3 (92%)
O
O
O
k:
O
iii
iv
–H2C
O
AcO
h: -H (80%)
O
(89%)
l:
i: -C6H4-4-CN (97%)
AcO
O
CH2–
Scheme 1 Reagents and conditions: (i) 5-iodouracil, Pd(Ph3P)4 (5 mol%), dppb (10 mol%), THF, 60 °C, 45%; (ii) RC≡CH, Pd(OAc)2 (10
mol%), Ph3P (30 mol%), CuI, DMF, Et3N, r.t., 2 h; (iii) K2CO3, MeOH, H2O, r.t., 18 h; (iv) MeONa, MeOH, r.t., 1 h.
SYNTHESIS 2007, No. 12, pp 1890–1897
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x.
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x
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2
0
0
7
Advanced online publication: 12.03.2007
DOI: 10.1055/s-2007-965976; Art ID: Z02607SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Palladium-Catalyzed Alkynylation at C-5 of Uracil Moiety
1891
During the last three decades, there has been an increasing 5.75), =CHN (d = 7.51 and 7.61), and NH (d = 8.15 and
interest in the chemistry of nucleosides and modified nu- 8.20). The same 1:1 ratio was obtained when the reaction
cleosides, since nucleosides analogues are active antiviral was performed in the presence of a large excess of racem-
drugs.1 Unsaturated analogues of nucleosides are of cur- ic acetylenic alcohol or acetate, showing that no kinetic
rent interest, since they have been shown to be highly ef- resolution occurred in this case.
fective as antiviral and antitumor agents.2 Although
TBDMSO
significant attention has been paid to the development of
synthetic methods for five-membered-ring structures,3
few examples have been published on the corresponding
unsaturated pyranosyl4 or cyclohexenyl5 analogues.
O
C4H9-C CH
3a
2
+
cat. Pd(OAc)2, Ph3P,
CuI, DMF, Et3N, r.t.
OEt
O
N
We have recently shown that the palladium-catalyzed
alkylation of 2,3-unsaturated carbohydrates with hetero-
cyclic amines, such as 5-halogenouracil, allowed an easy
access to unsaturated glycopyranosyl nucleosides.6 The
Sonogashira reaction has been shown to be a robust and
versatile C–C coupling reaction, and has been used suc-
cessfully in nucleoside and nucleobase chemistry,7 allow-
ing an easy access to various C-5 substituted nucleosides.
We present in this paper the application of this methodol-
ogy for the introduction of acetylenic substituents at C-5
of the uracil portion in modified nucleosides.
N
O
C4H9
4
Scheme 2
5-Ethynyluracil9 underwent palladium-catalyzed cou-
pling with carbohydrate 2, giving compound 3g in 92%
yield. The trimethylsilyl group was easily removed using
NaOMe in methanol affording uracil derivative 3h bear-
ing a terminal acetylenic group in 80% yield. This com-
pound 3h could be the precursor of a large variety of
glycoconjugates using the copper-catalyzed condensation
with azidocarbohydrates, the so-called ‘click’ chemis-
try.10 Copper(I)-catalyzed condensation of 3h with unsat-
urated azidocarbohydrate 511 afforded effectively 1,2,3-
triazole linked disaccharide 6 in 75% yield (Scheme 3).
The key carbohydrate precursor was 4-(5-iodouracil-1-yl)
derivative 2 prepared from unsaturated carbohydrate 1 by
palladium-catalyzed alkylation with 5-iodouracil as previ-
ously described.6 Treatment of compound 2 with hex-1-
yne for two hours in DMF/Et3N at room temperature in
the presence of a catalytic amount of Pd(OAc)2/Ph3P and
CuI gave coupling product 3a in 72% yield (Scheme 1),
together with a small amount of 3-glycosyl-6-butylfura-
no[2,3-d]pyrimidin-2-one (4, 5% yield) (Scheme 2).
Keeping the reaction mixture at room temperature for five
days gave compounds 3a and 4 in 62% and 29% yield, re-
spectively. The formation of such furanopyrimidine by-
products has already been described in the literature.1e,8
Increasing the reaction temperature provides such cy-
clized products in almost quantitative yields.
4-Ethynylbenzonitrile and 5-(4-ethynylphenyl)-3-phenyl-
1,2,4-oxadiazole reacted also with compound 2 in the
presence of palladium catalyst to give the corresponding
coupling products 3i and 3j in 97% and 92% yield, respec-
tively. The last coupling allows the easy introduction of
the 1,2,4-oxadiazole moiety, exhibiting generally a wide
range of biological activities, on the unsaturated 4-(uracil-
1-yl)glycopyranoside.
Analogous coupling of compound 2 with hex-5-yn-1-ol
and 2-methylbut-3-yn-2-ol gave the expected compounds
3b and 3c in 82 and 64% yields, respectively. Racemic 3-
methylpent-1-yn-3-ol and 1-phenylprop-2-ynyl acetate
underwent catalytic coupling with compound 2 to give 3d
and 3e in 76% and 74% yield, respectively. Compounds
3d and 3e are obtained as a 1:1 mixture of the two epimers
as shown by 1H NMR spectroscopy; compound 3d shows
two signals for CH3CH2C(OH) at d = 1.72 and 1.73, and
compound 3e two different signals for H-3 (d = 5.73 and
We extended this palladium-catalyzed coupling reaction
to more complex propargylic substrates. Condensation of
compound 2 with 1,2;5,6-bis-O-isopropylidene-3-O-
(prop-2-yn-1-yl)-a-D-glucofuranose12 and prop-2-yn-1-yl
4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyran-
oside13 afforded disaccharides 3k and 3l, bearing two dif-
ferent carbohydrate units on the uracil framework, in 41%
and 89% yields, respectively.
TBDMSO
TBDMSO
TBDMSO
Cu(OAc)2 (20 mol%),
sodium ascorbate (40 mol%)
O
O
O
+
H2O–t-BuOH (1:1), r.t., 15 h
75%
OEt
OEt
OEt
N3
N
O
O
N
O
O
OEt
N
O
5
TBDMSO
NH
NH
N
N
3 h
6
Scheme 3
Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York

1892
F. J. B. Mendonça, Jr. et al.
PRACTICAL SYNTHETIC PROCEDURES
TBDMSO
O
TBDMSO
TBDMSO
OEt
TBDMSO
O
O
cat. Pd(OAc)2, Ph3P
N
O
O
O
+
CuI, DMF, Et3N, r.t.
51%
NH
OEt
O
N
O
N
O
O
O
O
N
O
O
NH
NH
I
NH
2
4
8
Scheme 4
TBDMSO
TBDMSO
O
O
cat. Pd(OAc)2, Ph3P
CuI, DMF, Et3N, r.t.
2
+
OEt
O
OEt
N
N
O
n
HN
NH
O
O
9a: n = 1 (60%)
9b: n = 2 (12%)
Scheme 5
Cross-coupling of iodo derivative 2 with the ethynylated
nucleoside 7, obtained by a palladium(0)-catalyzed alky-
lation of carbonate of propynyl 6-O-(tert-butyldimethyl-
silyl)-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside with
uracil using a methodology described previously by our
group,6 gave disaccharide 8, bearing two uracil as well as
two unsaturated carbohydrate moieties linked by an acet-
ylenic bond, in 51% chemical yield (Scheme 4).
TBDMSO
O
Bu3Sn-CH=CH2
2
cat. Pd(PPh3)2Cl2
DMF, Et3N, 70 °C
86%
OEt
N
O
NH
O
10
This coupling reaction was extended also to multivalent
alkynes, in order to investigate the potentiality of this
methodology for the preparation of polyvalent glycocon-
jugate clusters. Palladium-catalyzed coupling of carbohy-
drate 2 in excess with 1,4-diethynylbenzene afforded
disaccharide 9a in 60% yield, together with compound 9b,
in 12% yield (Scheme 5). The later compound was proba-
bly formed by the homocoupling of the acetylenic inter-
mediate obtained from the monoalkynylation of
diethynylbenzene.
Scheme 6
Solvents were dried and distilled by standard methods before use.
Most reagents were of commercial quality and used without further
purification. Air- and moisture-sensitive reactions were performed
under inert atmosphere.
All reactions were monitored by TLC analysis (TLC plates GF254
Merck). Column chromatography was performed on silica gel 60
(230–240 mesh, Merck). Optical rotations were recorded using a
PerkinElmer 241 polarimeter. Melting points were obtained using a
Büchi apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded at 300 MHz and 75 MHz, respectively, on a Bruker AMX
300 spectrometer. Chemical shifts (d) are reported in ppm down-
field from TMS or from residual solvent peak; coupling constants
It is to be noticed that compound 2 is a very important pre-
cursor for use not only in Sonogashira coupling, but also
in other palladium-catalyzed carbon–carbon coupling re-
action. For example, palladium-catalyzed coupling of
unsaturated 4-(5-iodouracil-1-yl)glycoside 2 with tri- (J) are reported in Hz and refer to apparent peak multiplicity. Exact
mass measurements of the molecular ions were obtained on a Finni-
butylvinyltin at 70 °C in DMF–Et3N afforded the cou-
gan Mat 95 XL spectrometer.
pling product 10 in 86% yield (Scheme 6).
Ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-4-[5-iodo-2,4-
In conclusion the palladium-catalyzed Sonogashira cou-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-a-D-erythro-hex-2-enopyr-
pling between ethyl 4-(5-iodouracil-1-yl)-2,3,4-trideoxy-
a-D-erythro-hex-2-pyranoside and different functional-
ized alkynes afforded in good yields a large variety of new
unsaturated pyranosyl nucleosides.
anoside (2),6 5-[2-(trimethylsilyl)ethynyl]uracil,9 (prop-2-yn-1-yl)
2,3-dideoxy-6-O-(tert-butyldimethylsilyl)-a-D-erythro-hex-2-eno-
pyranoside (7),14 1,2;5,6-bis-O-isopropylidene-3-O-(prop-2-yn-1-
yl)-a-D-glucofuranose,12
prop-2-yn-1-yl
4,6-di-O-acetyl-2,3-
dideoxy-a-D-erythro-hex-2-enopyranoside,13 and ethyl 4-azido-6-
Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Palladium-Catalyzed Alkynylation at C-5 of Uracil Moiety
1893
O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythro-hex-2-pyr-
anoside (5)11 were prepared according to reported procedures. Hex-
anes used had bp 40–65 °C.
13C NMR (CDCl3): d = –5.1, –5.0, 18.7, 26.2, 51.0, 55.2, 63.9, 71.5,
75.4, 79.3, 92.2, 103.4, 129.6, 130.5, 141.5, 151.7, 163.9.
Anal. Calcd for C19H28N2O5Si: C, 58.14; H, 7.19. Found: C, 57.92;
H, 7.31.
5-(4-Ethynylphenyl)-3-phenyl-1,2,4-oxadiazole
To a solution of benzamidoxime (0.5 g, 3.47 mmol) in anhyd
CH2Cl2 was added at r.t. and under N2, 4-ethynylbenzoic acid (1.01
g, 6.94 mmol) and DCC (1.43 g, 6.94 mmol). After stirring for 3 h,
the solid was filtered off, the solvent was evaporated under reduced
pressure, and the residue was submitted to the thermal cyclization
reaction at 110–120 °C for 4 h. The resulting mixture was submitted
to column chromatography on silica gel (hexanes–EtOAc, 7:3) to
give 5-(4-ethynylphenyl)-3-phenyl-1,2,4-oxadiazole (461 mg,
54%) as a colorless solid; mp 99–100 °C; Rf = 0.6 (hexanes–EtOAc,
7:3).
Palladium-Catalyzed Preparation of Compounds 3a–e,g,i–l;
General Procedure
A solution of Pd(OAc)2 (6.8 mg, 0.03 mmol) and Ph3P (23.4 mg,
0.09 mmol) in DMF (2 mL) was stirred at r.t. in a Schlenk tube un-
der argon for 15 min. This solution was added to a mixture of the
carbohydrate derivative 2 (0.3 mmol), CuI (11.4 mg, 0.06 mmol),
and Et3N (1.21 mL, 9 mmol), in DMF (1 mL), followed by the ad-
dition of the alkyne (0.9 mmol). After stirring for 2 hours at r.t., the
solution was filtered through Celite, and the solid was washed with
EtOAc (2 × 5 mL). Evaporation of the solvent under reduced pres-
sure gave a residue that was purified by column chromatography on
silica gel using the indicated solvents.
1H NMR (CDCl3): d = 3.21 (s, 1 H, C≡CH), 7.51–7.63 (m, 5 Harom),
8.13 (br d, J = 6.7 Hz, 2 Harom), 8.21 (br d, J = 6.7 Hz, 2 Harom).
13C NMR (CDCl3): d = 79.7, 83.5, 124.5, 125.3, 127.5, 127.8,
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-hex-1-
yn-1-yl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-a-D-erythro-
hex-2-enopyranoside (3a)
Prepared from 2 and hex-1-yne; colorless solid; yield: 100 mg
(72%); mp 43–46 °C; Rf = 0.77 (CH2Cl2–EtOAc, 7:3); [a]D25 +87.7
(c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.83 (s, 9 H, t-C4H9),
0.93 (t, J = 7.1 Hz, 3 H, CH3), 1.27 (t, J = 7.1 Hz, 3 H, CH3CH2O),
1.41 (sext, J = 6.8 Hz, 2 H, CH2), 1.54 (quint, J = 6.8 Hz, 2 H, CH2),
2.40 (t, J = 7.1 Hz, 2 H, CH2), 3.60 (dq, J = 9.6, 7.1 Hz, 1 H,
CH3CH2O), 3.68–3.72 (m, 2 H, H-6), 3.84–3.94 (m, 2 H,
CH3CH2O, H-5), 5.07 (br s, 1 H, H-1), 5.20 (br d, J = 8.5 Hz, 1 H,
H-4), 5.76 (br d, J = 10.1 Hz, 1 H, H-3), 6.09 (ddd, J = 10.1, 2.6, 2.6
Hz, 1 H, H-2), 7.37 (s, 1 H, =CHN), 9.22 (br s, 1 H, NH).
128.6, 129.5, 133.0, 133.2, 168.7, 176.3.
HRMS (EI): m/z [M]+ calcd for C16H10N2O: 246.0793; found:
246.0805.
Prop-2-yn-1-yl 6-O-(tert-Butyldimethylsilyl)-2,3-dideoxy-4-O-
(methoxycarbonyl)-a-D-erythro-hex-2-enopyranoside
To a solution of prop-2-yn-1-yl 2,3-dideoxy-6-O-(tert-butyldimeth-
ylsilyl)-a-D-erythro-hex-2-enopyranoside (3.77 g, 12.64 mmol) in
CH2Cl2 (50 mL) maintained at 0 °C was added pyridine (2.15 mL,
25.1 mmol), 4-dimethylaminopyridine (800 mg, 6.55 mmol), and
methyl chloroformate (1.95 mL, 25.1 mmol). After stirring at r.t. for
20 h, H2O (5 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 20 mL). Evaporation of the solvent under reduced pres-
sure followed by column chromatography on silica gel (hexanes–
EtOAc, 5:1) gave the corresponding carbonate (3.3 g, 73%) as a col-
orless oil; Rf = 0.63; [a]D25 +144.5 (c = 1.1, CH2Cl2).
1H NMR (CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.82 (s, 9 H, t-C4H9),
2.36 (t, J = 2.4 Hz, 1 H, C≡CH), 3.69 (dd, J = 11.2, 4.7 Hz, 1 H, H-
6), 3.72 (s, 3 H, OCH3), 3.74 (dd, J = 11.2, 2.6 Hz, 1 H, H-6), 3.86
(ddd, J = 9.4, 4.7, 2.6 Hz, 1 H, H-5), 4.24 (d, J = 2.4 Hz, 2 H,
CH2C≡), 5.11 (br d, J = 9.4 Hz, 1 H, H-4), 5.15 (br s, 1 H, H-1), 5.76
(ddd, J = 10.1, 2.6, 2.4 Hz, 1 H, H-3), 5.92 (br d, J = 10.1 Hz, 1 H,
H-2).
13C NMR (CDCl3): d = –5.1, –5.0, 14.0, 15.6, 18.7, 19.7, 22.4, 26.2,
30.9, 51.5, 64.1, 64.6, 71.1, 77.6, 93.9, 96.1, 101.8, 128.9, 131.3,
143.2, 150.6, 162.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H38N2O5Si + Na:
485.2448; found: 485.2446.
Ethyl 6-O-(tert-Butyldimethylsilyl)-4-[6-butyl-2-oxofuro[2,3-
d]pyrimidin-3(2H)-yl]-2,3,4-trideoxy-a-D-erythro-hex-2-eno-
pyranoside (4)
Obtained from 2 and hex-1-yne; yellow solid; yield: 7 mg (5%); mp
91.5–94 °C; Rf = 0.53 (CH2Cl2–EtOAc, 1:1); [a]D –16 (c = 1.3,
CH2Cl2).
13C NMR (CDCl3): d = –5.1, 18.7, 26.2, 55.0, 55.2, 62.7, 69.2, 69.7,
25
75.1, 79.5, 92.7, 127.9, 129.8, 155.4.
Anal. Calcd for C17H28O6Si: C, 57.28; H, 7.92. Found: C, 57.04; H,
8.03.
1H NMR (CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.81 (s, 9 H, t-C4H9),
0.94 (t, 3 H, J = 7.3 Hz, CH3), 1.27 (t, J = 7.0 Hz, 3 H, CH3CH2O),
1.40 (sext, J = 7.3 Hz, 2 H, CH2), 1.67 (quint, J = 7.5 Hz, 2 H, CH2),
2.64 (t, J = 7.3 Hz, 2 H, CH2), 3.60 (dq, J = 9.6, 7.0 Hz, 1 H,
CH3CH2O), 3.73 (dd, J = 11.5, 7.4 Hz, 1 H, H-6), 3.76 (dd, J = 11.5,
6.3 Hz, 1 H, H-6), 3.88–3.98 (m, 2 H, CH3CH2O, H-5), 5.13 (br s,
1 H, H-1), 5.61 (br d, J = 8.2 Hz, 1 H, H-4), 5.77 (dd, J = 9.9, 1.5
Hz, 1 H, H-3), 6.06 (s, 1 H, = CH-), 6.12 (ddd, J = 9.9, 2.6, 2.6 Hz,
1 H, H-2), 7.80 (s, 1 H, CHN).
Prop-2-yn-1-yl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-
[2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-a-D-erythro-hex-2-
enopyranoside (7)
To a solution of Pd(Ph3P)4 (31 mg, 34 mmol), dppb (58 mg, 136
mmol), and the unsaturated carbohydrate (500 mg, 1.4 mmol) in
THF (5 mL) was added uracil (235 mg, 2.1 mmol) in THF (2 mL).
The solution was stirred at 50 °C for 4 h. Evaporation of the solvent
under reduced pressure gave a residue that was directly purified by
column chromatography on silica gel (hexanes–EtOAc, 4:1) to give
carbohydrate 7 (350 mg, 42%) as a colorless solid; mp 158–159 °C;
Rf = 0.28 (hexanes–EtOAc, 4:1); [a]D25 +31.5 (c = 1.0, CH2Cl2).
13C NMR (CDCl3): d = –5.1. –5.0. 14.1, 15.6, 18.6, 22.5, 26.2, 28.4,
29.2, 52.7, 63.9, 64.5, 73.7, 93.8, 98.8, 108.9, 129.6, 151.1, 156.0,
160.9, 162.7.
HRMS (ESI): m/z [M + Na]+ calcd for C24H38N2O5Si + Na:
1H NMR (CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3),
0.87 (s, 9 H, t-C4H9), 2.47 (t, J = 2.3 Hz, 1 H, C≡CH), 3.69 (dd,
J = 11.3, 5.4 Hz, 1 H, H-6), 3.73 (dd, J = 11.3, 4.3 Hz, 1 H, H-6),
3.83–3.88 (m, 1 H, H-5), 4.33 (d, J = 2.3 Hz, 2 H, CH2C≡C), 5.21
(br d, J = 9.7 Hz, 1 H, H-4), 5.28 (br s, 1 H, H-1), 5.73 (d, J = 8.1
Hz, 1 H, =CHCO), 5.78 (br d, J = 10.0 Hz, 1 H, H-3), 6.09 (ddd,
J = 10.0, 2.8, 2.6 Hz, 1 H, H-2), 7.21 (d, J = 8.1 Hz, 1 H, =CHN),
8.09 (br s, 1 H, NH).
485.2448; found: 485.2446.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-(6-hy-
droxyhex-1-yn-1-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl]-a-D-erythro-hex-2-enopyranoside (3b)
Prepared from 2 and hex-5-yn-1-ol; colorless solid; yield: 115 mg
(82%); mp 50–52 °C; Rf = 0.28 (CH2Cl2–EtOAc, 1:1); [a]D25 +74.4
(c = 1.0, CH2Cl2).
Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York

1894
F. J. B. Mendonça, Jr. et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (CDCl3): d = 0.04 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3),
0.88 (s, 9 H, t-C4H9), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.69–1.75
(m, 5 H, CH2, OH), 2.46 (t, J = 6.5 Hz, 2 H, CH2C≡), 3.60 (dq,
J = 9.6, 7.1 Hz, 1 H, CH3CH2O), 3.66–3.74 (m, 4 H, H-6, CH2OH),
3.85–3.96 (m, 2 H, CH3CH2O, H-5), 5.09 (br s, 1 H, H-1), 5.23 (br
d, J = 8.1 Hz, 1 H, H-4), 5.76 (br d, J = 10.1 Hz, 1 H, H-3), 6.10
(ddd, J = 10.1, 2.6, 2.6 Hz, 1 H, H-2), 7.42 (s, 1 H, =CHN), 8.85 (br
s, 1 H, NH).
(br s, 1 H, H-1), 5.21 (br d, J = 7.3 Hz, 1 H, H-4), 5.73 and 5.75 [2
br d, J = 10.0 Hz, 1 H, H-3, R and S], 6.10 (ddd, J = 10.0, 2.6, 2.6
Hz, 1 H, H-2), 6.66 (s, 1 H, CHC≡C), 7.35–7.43 (m, 3 Harom), 7.51
and 7.61 [2 s, 1 H, = CHN, R and S], 7.58 (dd, J = 7.9, 2.1 Hz, 2
Harom), 8.15 and 8.20 [2 br s, 1 H, NH, R and S].
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.7, 21.5, 26.2, 51.7, 64.1,
64.3, 64.7, 66.3, 69.2, 71.2, 78.2, 91.0, 93.9, 100.1, 128.3, 128.6,
128.8, 129.1, 129.4, 131.5, 136.9, 144.9, 150.6, 151.4, 160.5, 161.7,
170.2.
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.7, 19.7, 25.0, 26.2, 32.2,
51.5, 62.5, 64.1, 64.7, 71.2, 71.6, 93.9, 96.0, 101.7, 128.9, 131.3,
143.3, 150.6, 162.4.
HRMS (ESI): m/z [M + Na]+ calcd for C29H38N2O7Si + Na:
577.2346; found: 577.2348.
HRMS (ESI): m/z [M + Na]+ calcd for C24H38N2O6Si + Na:
501.2397; found: 501.2397.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[2,4-dioxo-
5-(trimethylsilylethynyl)-3,4-dihydropyrimidin-1(2H)-yl]-a-D-
erythro-hex-2-enopyranoside (3g)
Prepared from 2 and ethynyltrimethylsilane; yellow solid; yield:
131.5 mg (92%); mp 68–71 °C; Rf = 0.72 (CH2Cl2–EtOAc, 4:1);
[a]D25 +106.5 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3),
0.24 (s, 9 H, t-C4H9), 0.87 (s, 9 H, t-C4H9), 1.28 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 3.62 (dq, J = 9.6, 7.1 Hz, 1 H, CH3CH2O), 3.66 (dd,
J = 11.1, 5.2 Hz, 1 H, H-6), 3.71 (dd, J = 11.1, 4.7 Hz, 1 H, H-6),
3.84–3.95 (m, 2 H, CH3CH2O, H-5), 5.08 (br s, 1 H, H-1), 5.22 (br
d, J = 8.7 Hz, 1 H, H-4), 5.76 (br d, J = 10.1 Hz, 1 H, H-3), 6.10
(ddd, J = 10.1, 2.4, 2.4 Hz, 1 H, H-2), 7.50 (s, 1 H, =CHN), 8.09 (br
s, 1 H, NH).
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-(3-hy-
droxy-3-methylbut-1-yn-1-yl)-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl]-a-D-erythro-hex-2-enopyranoside (3c)
Prepared from 2 and 2-methylbut-3-yn-2-ol; yellow solid; yield: 90
mg (64%); mp 66–68 °C; Rf = 0.38 (CH2Cl2–EtOAc, 1:1); [a]D
+83.2 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.05 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3),
0.88 (s, 9 H, t-C4H9), 1.29 (t, J = 7.1 Hz, 3 H, CH3CH2O), 2.88 (br
s, 1 H, OH), 3.62 (dq, J = 9.6, 7.1 Hz, 1 H, CH3CH2O), 3.70 (dd,
J = 11.1, 4.1 Hz, 1 H, H-6), 3.75 (dd, J = 11.1, 4.1 Hz, 1 H, H-6),
3.86–3.96 (m, 2 H, CH3CH2O, H–5), 5.10 (br s, 1 H, H-1), 5.23 (br
d, J = 5.4 Hz, 1 H, H-4), 5.77 (br d, J = 10.1 Hz, 1 H, H-3), 6.12
(ddd, J = 10.1, 2.4, 2.2 Hz, 1 H, H-2), 7.46 (s, 1 H, =CHN), 8.76 (br
s, 1 H, NH).
25
13C NMR (CDCl3): d = –5.3, –5.2, 15.4, 18.5, 26.0, 51.3, 63.8, 64.5,
71.0, 93.7, 94.9, 100.2, 101.0, 128.6, 131.0, 144.7, 150.3, 161.4.
HRMS (ESI): m/z [M + Na]+ calcd for C23H38N2O5Si + Na:
501.2217; found: 501.2218.
13C NMR (CDCl3) d = –5.1, –5.0, 15.6, 18.7, 26.2, 31.5, 31.6, 51.2,
64.0, 64.7, 65.6, 71.4, 72.9, 93.9, 99.8, 100.8, 128.8, 131.4, 143.8,
150.5, 162.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H36N2O6Si + Na:
487.2240; found: 487.2240.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[2,4-dioxo-
5-(4-cyanophenylethynyl)-3,4-dihydropyrimidin-1(2H)-yl]-a-D-
erythro-hex-2-enopyranoside (3i)
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-(R,S)-3-
hydroxy-3-methylpent-1-yn-1-yl)-2,4-dioxo-3,4-dihydropyrim-
idin-1(2H)-yl]-a-D-erythro-hex-2-enopyranoside (3d)
Prepared from 2 and 4-ethynylbenzonitrile; yellow solid; yield: 147
mg (97%); mp 137–139 °C; Rf = 0.52 (CH2Cl2–EtOAc, 4:1); [a]D
+148.9 (c = 1.0, CH2Cl2).
25
Prepared from 2 and 3-methylpent-1-yn-3-ol; colorless solid; yield:
109 mg (76%); mp 56–60 °C; Rf = 0.47 (CH2Cl2–EtOAc, 1:1).
1H NMR (CDCl3): d = –0.01 (s, 3 H, SiCH3), 0.00 (s, 3 H, SiCH3),
0.82 (s, 9 H, t-C4H9), 1.24 (t, J = 7.1 Hz, 3 H, CH3CH2O), 3.57 (dq,
J = 9.6, 7.1 Hz, 1 H, CH3CH2O), 3.66 (dd, J = 11.1, 5.6 Hz, 1 H, H-
6), 3.71 (dd, J = 11.1, 4.5 Hz, 1 H, H-6), 3.81–3.91 (m, 2 H,
CH3CH2O, H-5), 5.05 (br s, 1 H, H-1), 5.24 (br d, J = 7.9 Hz, 1 H,
H-4), 5.74 (br d, J = 10.1 Hz, 1 H, H-3), 6.09 (ddd, J = 10.1, 2.4, 2.4
Hz, 1 H, H-2), 7.54–7.60 (m, 5 H, 4 Harom, =CHN), 8.82 (br s, 1 H,
NH).
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.7, 26.2, 52.0, 64.3, 64.8,
71.3, 84.8, 92.8, 94.0, 100.4, 112.1, 118.8, 127.8, 128.7, 131.6,
132.4, 132.5, 144.8, 150.5, 161.5.
HRMS (ESI): m/z [M + Na]+ calcd for C27H33N3O5Si + Na:
530.2087; found: 530.2084.
1H NMR (CDCl3): d = –0.01 [s, 6 H, Si(CH3)2], 0.82 (s, 9 H, t-
C4H9), 1.03 (t, J = 7.4 Hz, 3 H, CH3CH2), 1.23 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 1.50 (s, 3 H, CH3), 1.72 and 1.73 [2 q, J = 7.4 Hz, 2 H,
CH3CH2C, R and S], 2.58 (br s, 1 H, OH), 3.56 (dq, J = 9.6, 7.1 Hz,
1 H, CH3CH2O), 3.65 (dd, J = 11.3, 5.5 Hz, 1 H, H-6), 3.69 (dd,
J = 11.3, 4.3 Hz, 1 H, H-6), 3.80–3.91 (m, 2 H, CH3CH2O, H-5),
5.04 (br s, 1 H, H-1), 5.18 (br d, J = 7.3 Hz, 1 H, H-4), 5.71 (br d,
J = 10.1 Hz, 1 H, H-3), 6.06 (ddd, J = 10.1, 2.4, 2.4 Hz, 1 H, H-2),
7.40 (s, 1 H, =CHN), 8.60 (br s, 1 H, NH).
13C NMR (CDCl3): d = –5.1, –5.0, 9.4, 15.5, 18.7, 26.2, 29.36, 29.2,
29.3, 36.7, 36.8, 51.5, 64.0, 64.6, 69.2, 71.3, 74.0, 93.9, 98.7, 100.9,
128.7, 131.3, 143.5, 150.6, 162.0.
HRMS (ESI): m/z [M + Na]+ calcd for C24H38N2O6Si + Na:
501.2397; found: 501.2395.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[2,4-dioxo-
5-{[4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl]ethynyl}-3,4-dihy-
dropyrimidin-1(2H)-yl]-a-D-erythro-hex-2-enopyranoside (3j)
Prepared from 2 and 5-(4-ethynylphenyl)-3-phenyl-1,2,4-oxadi-
azole; yellow solid; yield: 172 mg (92%); mp 84–86 °C; Rf = 0.45
(CH2Cl2–EtOAc, 9:1); [a]D25 +124.2 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.05 [s, 6 H, Si(CH3)2], 0.88 (s, 9 H, t-C4H9),
1.29 (t, J = 7.1 Hz, 3 H, CH3CH2O), 3.62 (dq, J = 9.7, 7.1 Hz, 1 H,
CH3CH2O), 3.71 (dd, J = 11.1, 5.3 Hz, 1 H, H-6), 3.76 (dd, J = 11.1,
4.7 Hz, 1 H, H-6), 3.86–3.96 (m, 2 H, CH3CH2O, H-5), 5.10 (br s,
1 H, H-1), 5.28 (br d, J = 7.9 Hz, 1 H, H-4), 5.80 (br d, J = 10.1 Hz,
1 H, H-3), 6.14 (ddd, J = 10.1, 2.4, 2.8 Hz, 1 H, H-2), 7.53–7.64 (m,
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-(R,S)-3-
acetoxy-3-phenylprop-1-yn-1-yl)-2,4-dioxo-3,4-dihydropyrimi-
din-1(2H)-yl]-a-D-erythro-hex-2-enopyranoside (3e)
Prepared from 2 and 1-phenylprop-2-ynyl acetate; brown solid;
yield: 122 mg (74%); mp 62–65 °C; Rf = 0.46 (CH2Cl2–EtOAc,
4:1).
1H NMR (CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.86 (s, 9 H, t-C4H9),
1.27 and 1.28 [2 t, J = 7.1 Hz, 3 H, CH3CH2O, R and S], 1.50 (s, 3
H, CH3), 2.12 (s, 3 H, CH3CO), 3.54–3.64 (m, 1 H, CH3CH2O),
3.65–3.76 (m, 2 H, H-6), 3.83–3.94 (m, 2 H, CH3CH2O, H-5), 5.07
Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Palladium-Catalyzed Alkynylation at C-5 of Uracil Moiety
1895
4 H, 3 Harom, =CHN), 7.67 (d, J = 8.5 Hz, 2 Harom), 8.05 (br s, 1 H,
NH), 8.17 (d, J = 8.5 Hz, 2 Harom), 8.22 (dd, J = 8.3 Hz, 2 Harom).
13C NMR (CDCl3): d = –5.08, –5.02, 15.6, 18.8, 26.2, 53.8, 64.3,
64.8, 71.3, 82.4, 94.0, 94.1, 101.0, 124.6, 125.8, 127.2, 1278, 128.6,
128.8, 129.5, 132.5, 133.2, 145.9, 150.5, 161.4, 168.8, 176.2.
HRMS (ESI): m/z [M + Na]+ calcd for C34H38N4O6Si + Na:
649.2458; found: 649.2454.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-(R,S)-3-
hydroxy-3-phenylprop-1-yn-1-yl)-2,4-dioxo-3,4-dihydropyrim-
idin-1(2H)-yl]-a-D-erythro-hex-2-enopyranoside (3f)
A mixture of compound 3e (30 mg, 0.052 mmol), and K2CO3 (300
mg, 2.17 mmol) in MeOH (5 mL) and H2O (2 mL) was stirred at r.t.
for 18 h. The solution was concentrated under reduced pressure, and
the product was extracted with EtOAc (3 × 5 mL). Evaporation of
the solvent under reduced pressure gave a residue that was submit-
ted to column chromatography on silica gel (CH2Cl2–EtOAc, 7:3)
to give compound 3f (23.4 mg, 85%) as a colorless solid; mp 68–
70 °C; Rf = 0.29 (CH2Cl2–EtOAc, 7:3).
1H NMR (CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.83 (s, 9 H, t-C4H9),
1.22 (t, J = 7.1 Hz, 3 H, CH3CH2O), 2.87 and 2.94 [2 br s, 1 H, OH,
R and S], 3.55 (dq, J = 9.4, 7.1 Hz, 1 H, CH3CH2O), 3.64 (dd,
J = 11.3, 5.8 Hz, 1 H, H-6), 3.69 (dd, J = 11.3, 4.5 Hz, 1 H, H-6),
3.79–3.89 (m, 2 H, CH3CH2O, H-5), 5.03 (br s, 1 H, H-1), 5.19 (br
d, J = 5.4 Hz, 1 H, H-4), 5.67 and 5.69 (2 s, 1 H, C≡CH, R and S],
5.70 (br d, J = 10.0 Hz, 1 H, H-3), 6.06 (br d, J = 10.0 Hz, 1 H, H-
2), 7.27–7.38 (m, 3 Harom), 7.47 (s, 1 H, =CHN), 7.56 (d, J = 7.1 Hz,
2 Harom), 8.56 (br s, 1 H, NH).
Ethyl 6-O-(tert-Butyldimethylsilyl)-4-[5-{3-(2,3;5,6-di-O-iso-
propylidene-a-D-glucofuranos-3-yl)prop-1-yn-1-yl}-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl]-2,3,4-trideoxy-a-D-erythro-
hex-2-enopyranoside (3k)
Prepared from 2 and 1,2;5,6-di-O-isopropylidene-3-O-propargyl-a-
D-glucofuranose; colorless solid; yield: 83.5 mg (41%); mp 69–
25
71 °C; Rf = 0.31 (CH2Cl2–EtOAc, 4:1); [a]D +55.7 (c = 1.0,
CH2Cl2).
1H NMR (CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.86 (s, 9 H, t-C4H9),
1.27 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.32 (s, 3 H, CH3), 1.35 (s, 3
H, CH3), 1.42 (s, 3 H, CH3), 1.49 (s, 3 H, CH3), 3.60 (dq, J = 9.6,
7.0 Hz, 1 H, CH3CH2O), 3.68 (dd, J = 11.1, 5.6 Hz, 1 H, H-6), 3.73
(dd, J = 11.1, 4.5 Hz, 1 H, H-6), 3.83–3.93 (m, 2 H, CH3CH2O, H-
5), 4.00 (dd, J = 8.5, 5.3 Hz, 1 H, H-4¢), 4.08–4.15 (m, 3 H, H-6¢, H-
5¢), 4.26–4.33 (m, 1 H, H-3¢), 4.45 (d, J = 15.8 Hz, 1 H, CH2C≡),
4.52 (d, J = 15.8 Hz, 1 H, CH2C≡), 4.70 (d, J = 3.7 Hz, 1 H, H-2¢),
5.08 (br s, 1 H, H-1), 5.24 (br d, J = 8.8 Hz, 1 H, H-4), 5.74 (br d,
J = 10.0 Hz, 1 H, H-3), 5.88 (d, J = 3.7 Hz, 1 H, H-1¢), 6.11 (ddd,
J = 10.0, 2.8, 2.6 Hz, 1 H, H-2), 7.50 (s, 1 H, = CHN), 8.02 (br s, 1
H, NH).
13C NMR (CDCl3): d = –5.0, 15.6, 18.8, 26.2, 51.7, 64.1, 64.7, 65.2,
71.3, 77.2, 77.6, 93.9, 94.9, 100.4, 127.1, 127.2, 128.6, 128.7,
129.0, 130.5, 140.6, 144.5, 150.4, 162.0.
Anal. Calcd for C27H36N2O6Si: C, 63.25; H, 7.08. Found: C, 63.08;
H, 7.12.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-ethynyl-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-a-D-erythro-hex-2-
enopyranoside (3h)
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.7, 25.8, 26.2, 26.2, 27.2,
27.3, 51.8, 59.2, 64.2, 64.7, 67.6, 71.2, 72.8, 77.4, 81.5, 82.2, 83.1,
90.3, 93.9, 100.3, 105.6, 109.4, 112.2, 128.6, 131.6, 145.0, 150.5,
161.6.
To a solution of compound 3g (822 mg, 1.72 mmol) in MeOH (1.5
mL) maintained at 0 °C was added a solution of MeONa (1.5 g, 7.74
mmol) in MeOH (5.3 mL). After stirring for 1 h at r.t., a sat. aq so-
lution of NH4Cl (5 mL) was added, and the mixture was extracted
with EtOAc (3 × 5 mL). Evaporation of the solvent under reduced
pressure gave a residue that was purified directly purified by col-
umn chromatography on silica gel (CH2Cl2–EtOAc, 4:1) to give
carbohydrate 3h (562 mg, 80%) as a colorless solid; mp 153–
155 °C; Rf = 0.36; [a]D25 +73.4 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.86 (s, 9 H, t-C4H9),
1.27 (t, J = 7.1 Hz, 3 H, CH3CH2O), 3.22 (s, 1 H, HC≡C), 3.60 (dq,
J = 9.6, 7.1 Hz, 1 H, CH3CH2O), 3.68 (dd, J = 11.1, 5.4 Hz, 1 H, H-
6), 3.72 (dd, J = 11.1, 4.7 Hz, 1 H, H-6), 3.83–3.93 (m, 2 H,
CH3CH2O, H-5), 5.08 (br s, 1 H, H-1), 5.24 (br d, J = 6.8 Hz, 1 H,
H-4), 5.75 (br d, J = 10.1 Hz, 1 H, H-3), 6.11 (ddd, J = 10.1, 2.8, 2.6
Hz, 1 H, H-2), 7.52 (s, 1 H, =CHN), 8.26 (br s, 1 H, NH).
Anal. Calcd for C33H50N2O11Si: C, 58.39; H, 7.42. Found: C, 58.06;
H, 7.48.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-{3-[(4,6-
di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranosyl)oxy]-
prop-1-yn-1-yl}-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-a-D-
erythro-hex-2-enopyranoside (3l)
Prepared from 2 and prop-2-yn-1-yl-4,6-di-O-acetyl-2,3-dideoxy-
a-D-erythro-hex-2-enopyranose; yellow solid; yield: 173 mg
25
(89%); mp 52–55 °C; Rf = 0.45 (CH2Cl2–EtOAc, 7:3); [a]D
+146.9 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.86 (s, 9 H, t-C4H9),
1.27 (t, J = 7.1 Hz, 3 H, CH3CH2O), 2.08 (s, 3 H, CH3), 2.11 (s, 3
H, CH3), 3.60 (dq, J = 9.6, 7.1 Hz, 1 H, CH3CH2O), 3.69–3.71 (m,
2 H, H-6), 3.83–3.93 (m, 2 H, CH3CH2O, H-5), 4.08–4.14 (m, 1 H,
H-5¢), 4.19 (dd, J = 12.0, 2.6 Hz, 1 H, H-6¢), 4.25 (dd, J = 12.0, 5.1
Hz, 1 H, H-6¢), 4.48 (d, J = 15.8 Hz, 1 H, CH2C≡), 4.55 (d, J = 15.8
Hz, 1 H, CH2C≡), 5.07 (br s, 1 H, H-1), 5.24 (br d, J = 10.0 Hz, 1 H,
H-4), 5.26 (br s, 1 H, H-1¢), 5.34 (ddd, J = 9.6, 1.5, 1.5 Hz, 1 H, H-
4¢), 5.74 (br d, J = 10.2 Hz, 1 H, H-3), 5.86 (ddd, J = 10.2, 2.4, 1.6
Hz, 1 H, H-3¢), 5.93 (br d, J = 10.2 Hz, 1 H, H-2), 6.11 (ddd,
J = 10.2, 2.6, 2.6 Hz, 1 H, H-2¢), 7.51 (s, 1 H, =CHN), 8.07 (br s, 1
H, NH).
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.7, 21.2, 21.3, 26.2, 51.9,
56.2, 63.2, 64.2, 64.7, 65.6, 67.6, 71.2, 77.5, 89.9, 93.2, 93.9, 100.2,
127.7, 128.5, 130.1, 131.6, 144.9, 150.4, 161.5, 170.6, 171.1.
HRMS (ESI): m/z [M + Na]+ calcd for C34H44N2O11Si + Na:
671.2612; found: 671.2611.
13C NMR (CDCl3): d = –5.1, –5.0, 15.5, 18.7, 26.2, 51.8, 64.2, 64.7,
71.2, 74.7, 82.9, 93.9, 100.0, 128.7, 131.4, 145.3, 150.7, 161.9.
HRMS (ESI): m/z [M + Na]+ calcd for C20H30N2O5Si + Na:
429.1822; found: 429.1822.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[5-{1-[eth-
yl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythro-hex-
2-enopyranosid-4-yl]-1H-1,2,3-triazol-4-yl}-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl]-a-D-erythro-hex-2-enopyranoside (6)
Azido sugar 5 (164.5 mg, 0.53 mmol) and alkyne 3h (405 mg, 1
mmol) were suspended in t-BuOH–H2O (1:1, 4 mL). To this solu-
tion was added a mixture of Cu(OAc)2 (18 mg, 0.10 mmol) and so-
dium ascorbate (40 mg, 0.2 mmol) in t-BuOH–H2O (1:1, 1 mL).
The mixture was stirred overnight at r.t. under N2. H2O (3 mL) was
then added, and the product was extracted with CH2Cl2 (3 × 5 mL).
Evaporation of the solvent under reduced pressure gave a residue
that was purified by column chromatography on silica gel (CH2Cl2–
EtOAc, 4:1) to give compound 6 (286 mg, 75%) as a colorless solid;
25
mp 83–84 °C; Rf = 0.36 (CH2Cl2–EtOAc, 4:1); [a]D +119.7 (c =
1.0, CH2Cl2).
Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York

1896
F. J. B. Mendonça, Jr. et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (CDCl3): d = 0.02 (s, 3 H, SiCH3), 0.03 (s, 6 H, 2 SiCH3),
0.04 (s, 3 H, SiCH3), 0.85 (s, 9 H, t-C4H9), 0.89 (s, 9 H, t-C4H9), 1.28
(t, J = 7.1 Hz, 3 H, CH3CH2), 1.29 (t, J = 7.1 Hz, 3 H, CH3CH2),
3.57–3.66 (m, 3 H, H-6), 3.69 (br d, J = 11.7 Hz, 1 H, H-6), 3.72–
3.81 (m, 2 H, CH2CH3), 3.87–3.95 (m, 2 H, CH2CH3), 4.04 (m, 1 H,
H-5¢), 4.17 (ddd, J = 9.8, 2.1, 1.6 Hz, 1 H, H-5), 5.10 (br s, 1 H, H-
1), 5.16 (br s, 1 H, H-1¢), 5.33 (br d, J = 5.4 Hz, 1 H, H-4¢), 5.40 (br
d, J = 9.8 Hz, 1 H, H-4), 5.83 (br d, J = 10.1 Hz, 1 H, =CH), 5.97
(br d, J = 10.1 Hz, 1 H, =CH), 6.05 (ddd, J = 10.1, 2.5, 2.5 Hz, 1
H, =CH), 6.11 (br d, J = 10.1 Hz, 1 H, =CH), 8.25 (s, 1 H, =CHN),
8.26 (s, 1 H, =CHN), 8.64 (br s, 1 H, NH).
5,5¢-[1,4-Phenylenebis(ethyne-2,1-diyl)]bis[1-{4-[ethyl 6-O-
(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythro-hex-2-eno-
pyranosid-4-yl]}pyrimidine-2,4(1H,3H)-dione] (9a)
Yellow solid; mp 116–119 °C; Rf = 0.70 (CH2Cl2–EtOAc, 6:4);
[a]D25 +194.7 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.00 [s, 12 H, Si(CH3)2], 0.83 (s, 18 H, t-
C4H9), 1.24 (t, J = 7.1 Hz, 6 H, CH3CH2O), 3.56 (dq, J = 9.4, 7.1
Hz, 2 H, CH3CH2O), 3.66 (dd, J = 11.1, 5.4 Hz, 2 H, H-6), 3.71 (dd,
J = 11.1, 5.0 Hz, 2 H, H-6), 3.80–3.90 (m, 4 H, CH3CH2O, H-5),
5.05 (br s, 2 H, H-1), 5.22 (br d, J = 7.7 Hz, 2 H, H-4), 5.74 (br d,
J = 9.9 Hz, 2 H, H-3), 6.08 (ddd, J = 9.9, 2.4, 2.4 Hz, 2 H, H-2), 7.45
(s, 4 Harom), 7.52 (s, 2 H, =CHN), 8.21 (br s, 2 H, NH).
13C NMR (CDCl3): d = –5.2, –5.1, –5.0, 15.6, 18.7, 26.2, 55.3, 62.7,
64.3, 64.5, 71.2, 94.1, 94.2, 107.0, 121.5, 128.3, 128.8, 129.4,
139.5, 151.1, 161.4.
13C NMR (CDCl3): d = –5.2, –5.1, 15.6, 18.7, 26.2, 51.5, 64.5, 71.2,
85.2, 93.3, 94.6, 100.6, 123.5, 129.0, 129.2, 131.9, 132.4, 132.6,
145.0, 151.6, 162.6.
Anal. Calcd for C34H57N5O8Si2: C, 56.72; H, 7.98. Found: C, 56.78;
H, 8.65.
HRMS (ESI): m/z [M + Na]+ calcd for C43H62N4O10Si2 + Na:
909.3902; found: 909.3901.
Ethyl 6-O-(tert-Butyldimethylsilyl)-4-[5-(3-{[6-O-(tert-butyl-
dimethylsilyl)-2,3,4-trideoxy-4-(2,4-dioxo-3,4-dihydropyrimi-
din-1(2H)-yl)-a-D-erythro-hex-2-enopyranosid-4-yl]oxy}prop-
1-yn-1-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-2,3,4-
trideoxy-a-D-erythro-hex-2-enopyranoside (8)
5,5¢-[Buta-1,3-diyne-1,4-diylbis(4,1-phenyleneprop-1-yne-3,1-
diyl)]bis[1-{4-[ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-tri-
deoxy-a-D-erythro-hex-2-enopyranosid-4-yl]}pyrimidine-
2,4(1H,3H)-dione] (9b)
A solution of Pd(OAc)2 (5.7 mg, 0.025 mmol) and Ph3P (19.5 mg,
0.075 mmol) in DMF (3 mL) was stirred at r.t. in a Schlenk tube un-
der argon for 15 min. This solution was added to a mixture of the
carbohydrate derivative 2 (126.2 mg, 0.25 mmol), CuI (9.5 mg, 0.05
mmol), and Et3N (1.0 mL, 7.4 mmol), in DMF (1 mL), followed by
the addition of 1,4-diethynylbenzene (294 mg, 0.75 mmol). After
stirring for 2 h at r.t., the solution was filtered through Celite, and
the solid was washed with EtOAc (2 × 5 mL). Evaporation of the
solvent under reduced pressure gave a residue that was purified by
column chromatography on silica gel (CH2Cl2–EtOAc, 1:1) to give
compound 8 (98.5 mg, 51%) as a colorless solid; mp 103–106 °C;
Rf = 0.28 (CH2Cl2–EtOAc, 1:1); [a]D25 +70.2 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.03 [s, 6 H,
Si(CH3)2], 0.87 (s, 18 H, t-C4H9), 1.27 (t, J = 7.0 Hz, 3 H,
CH3CH2O), 3.60 (dq, J = 9.6, 7.0 Hz, 1 H, CH3CH2O), 3.66–3.75
(m, 4 H, H-6, H-6¢), 3.83–3.94 (m, 3 H, CH3CH2O, H-5, H-5¢), 4.48
(d, J = 15.7 Hz, 1 H, CH2C≡), 4.56 (d, J = 15.7 Hz, 1 H, CH2C≡),
5.08 (br s, 1 H, H-1), 5.23 (br d, J = 9.6 Hz, 2 H, H-4, H-4¢), 5.31
(br s, 1 H, H-1¢), 5.74 (d, J = 8.1 Hz, 1 H, =CHCO), 5.74 (br d,
J = 10.1 Hz, 1 H, H-3¢), 5.79 (br d, J = 10.1 Hz, 1 H, H-3), 6.11
(ddd, J = 10.1, 2.6, 2.4 Hz, 2 H, H-2, H-2¢), 7.22 (d, J = 8.1 Hz, 1
H, =CHN), 7.51 (s, 1 H, =CHN), 8.10 (br s, 1 H, NH), 8.18 (br s, 1
H, NH).
Yellow solid; mp 113–116 °C; Rf = 0.81 (CH2Cl2–EtOAc, 6:4);
[a]D25 +202.5 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.04 [s, 12 H, Si(CH3)2], 0.86 (s, 18 H, t-
C4H9), 1.28 (t, J = 7.1 Hz, 6 H, CH3CH2O), 3.56 (dq, J = 9.6, 7.1Hz,
2 H, CH3CH2O), 3.70 (dd, J = 11.1, 5.4 Hz, 2 H, H-6), 3.75 (dd,
J = 11.1, 4.5 Hz, 2 H, H-6), 3.85–3.95 (m, 4 H, CH3CH2O, H-5),
5.09 (br s, 2 H, H-1), 5.22 (br d, J = 9.9 Hz, 2 H, H-4), 5.78 (br d,
J = 10.1 Hz, 2 H, H-3), 6.13 (ddd, J = 10.1, 2.4, 2.4 Hz, 2 H, H-2),
7.49 (s, 8 Harom), 7.57 (s, 2 H, =CHN), 8.31 (br s, 2 H, NH).
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.8, 26.2, 51.2, 64.3, 64.8,
71.3, 76.2, 82.5, 94.0, 101.0, 122.2, 123.8, 128.8, 131.9, 132.0,
132.8, 144.3, 150.4, 161.4.
HRMS (ESI): m/z [M + Na]+ calcd for C56H66N4O10Si2 + Na:
1033.4215; found: 1033.4218.
Ethyl 6-O-(tert-Butyldimethylsilyl)-2,3,4-trideoxy-4-[2,4-dioxo-
5-vinyl-3,4-dihydropyrimidin-1(2H)-yl]-a-D-erythro-hex-2-eno-
pyranoside (10)
A solution of Pd(Ph3P)2Cl2 (7.15 mg, 0.01 mmol) and compound 2
(101 mg, 0.2 mmol) in DMF (3 mL) was stirred at r.t. in a Schlenk
tube under argon for 15 min. To this solution was added tributyl-
vinyltin (0.12 mL, 0.4 mmol), and Et3N (0.03 mL, 0.24 mmol), in
DMF (1 mL), followed by the addition of 1,4-diethynylbenzene
(18.9 mg, 0.15 mmol). After stirring for 5 h at 70 °C, the solution
was filtered through Celite, and the solid was washed with EtOAc
(2 × 5 mL). Evaporation of the solvent under reduced pressure gave
a residue that was purified by column chromatography on silica gel
(CH2Cl2–EtOAc, 7:3) to give compound 10 (70 mg, 86%) as a col-
orless solid; mp 54.5–56.5 °C; Rf = 0.65 (CH2Cl2–EtOAc, 7:3);
[a]D25 +63.3 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): d = 0.00 [s, 6 H, Si(CH3)2], 0.83 (s, 9 H, t-C4H9),
1.24 (t, J = 7.1 Hz, 3 H, CH3CH2O), 3.57 (dq, J = 9.6, 7.1 Hz, 1 H,
CH3CH2O), 3.67 (dd, J = 11.3, 5.6 Hz, 1 H, H-6), 3.70 (dd, J = 11.3,
4.3 Hz, 1 H, H-6), 3.81–3.92 (m, 2 H, CH3CH2O, H-5), 5.06 (br s,
1 H, H-1), 5.21 (br m, 1 H, H-4), 5.24 (dd, J = 11.4, 1.3 Hz, 1
H, =CH2), 5.74 (dd, J = 10.1, 1.3 Hz, 1 H, H-3), 5.99 (dd, J = 17.5,
1.3 Hz, 1 H, = CH2), 6.06 (ddd, J = 10.1, 2.6, 2.6 Hz, 1 H, H-2), 6.34
(dd, J = 17.5, 11.4 Hz, 1 H, =CH), 7.21 (s, 1 H, =CHN), 8.76 (br s,
1 H, NH).
13C NMR (CDCl3): d = –5.2, –5.1, –5.0, –4.9, 15.6, 18.6, 18.7, 26.1,
26.2, 50.9, 51.7, 56.0, 63.9, 64.4, 64.7, 71.4, 77.8, 89.6, 92.3, 93.9,
100.2, 103.4, 128.6, 129.4, 130.6, 131.6, 141.7, 144.7, 150.8, 151.7,
162.0, 164.0.
Anal. Calcd for C37H56N4O10Si2: C, 57.49; H, 7.30. Found: C,
56.96; H, 7.41.
Palladium-Catalyzed Condensation of Compound 2 with 1,4-
Diethynylbenzene
A solution of Pd(OAc)2 (6.8 mg, 0.03 mmol) and Ph3P (23.4 mg,
0.09 mmol) in DMF (2 mL) was stirred at r.t. in a Schlenk tube un-
der argon for 15 min. This solution was added to a mixture of the
carbohydrate derivative 2 (151.5 mg, 0.3 mmol), CuI (11.4 mg, 0.06
mmol), and Et3N (1.22 mL, 9 mmol), in DMF (1 mL), followed by
the addition of 1,4-diethynylbenzene (18.9 mg, 0.15 mmol). After
stirring for 2 h at r.t., the solution was filtered through Celite, and
the solid was washed with EtOAc (2 × 5 mL). Evaporation of the
solvent under reduced pressure gave a residue that was purified by
column chromatography on silica gel (CH2Cl2–EtOAc, 6:4) to give
compound 9a (80 mg, 60%) and 9b (27 mg, 12%).
13C NMR (CDCl3): d = –5.1, –5.0, 15.6, 18.7, 26.2, 51.3, 64.1, 64.6,
71.3, 93.9, 113.6, 116.9, 127.8, 129.0, 131.3, 138.2, 150.9, 162.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H32N2O5Si + Na:
431.1978; found: 431.1980.
Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Acknowledgment
Palladium-Catalyzed Alkynylation at C-5 of Uracil Moiety
1897
(6) de Oliveira, R. N.; Mendonça, F. J. B. Jr.; Sinou, D.; de
Melo, S. J.; Srivastava, R. M. Synlett 2006, 3049.
(7) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003,
103, 1875.
(8) (a) Robins, M. J.; Barr, P. J. Tetrahedron Lett. 1981, 22,
421. (b) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48,
1854. (c) Robins, M. J.; Vinayah, R. S.; Wood, S. G.
Tetrahedron Lett. 1990, 31, 3731. (d) McGuigan, C.;
Yarnold, C. J.; Jones, G.; Velázquez, S.; Barucki, H.;
Brancale, A.; Andrei, G.; Snoeck, R.; De Clercq, E.;
Balzarini, J. J. Med. Chem. 1999, 42, 4479.
We are indebted to the CAPES/COFECUB programme no. 334/01
for financial support, and CAPES and CNPq-Brazil for providing
fellowships (J.B.M.Jr. and J.A.).
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Synthesis 2007, No. 12, 1890–1897 © Thieme Stuttgart · New York