Stereoselective synthesis of 3′-substituted 2′-deoxy C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and their 5′-phosphate nucleotides

Article abstract of DOI:10.1016/j.tetlet.2006.05.077

An efficient synthesis of novel 3′-substituted 2′,3′-dideoxynucleoside analogues in the pyrazolotriazine series was developed from the corresponding 3′-ketonucleoside via the Wittig reaction. On the other hand, a highly stereoselective addition of alkynyl

Full text of DOI:10.1016/j.tetlet.2006.05.077

Tetrahedron Letters 47 (2006) 5099–5103
Stereoselective synthesis of 30-substituted 20-deoxy
C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and
their 50-phosphate nucleotides
Romain Mathieu, Martine Schmitt* and Jean-Jacques Bourguignon
Laboratoire de Pharmacochimie de la Communication Cellulaire (CNRS, UMR 7081), Faculte´ de Pharmacie,
Universite´ Louis Pasteur, 74 route du Rhin, BP60024, 67401 Illkirch cedex, France
Received 28 February 2006; revised 9 May 2006; accepted 15 May 2006
Available online 6 June 2006
Abstract—An efficient synthesis of novel 30-substituted 20,30-dideoxynucleoside analogues in the pyrazolotriazine series was devel-
oped from the corresponding 30-ketonucleoside via the Wittig reaction. On the other hand, a highly stereoselective addition of
alkynylcerium reagents to the same precursor led to the 30-alkynyl-20-deoxynucleosides in one step with the natural stereochemistry.
Applications to produce novel P2Y1 receptor antagonists or new anti-retroviral nucleoside analogues are suggested.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
interest on replacement of the 30-phosphate group by
another functionality with increased in vivo stability.
A similar strategy consisting of uncharged substitution
of the phosphate group on an adenine scaffold has been
recently described.2 However, to the best of our knowl-
edge, there is no example of substitution at the 30-posi-
tion on pyrazolotriazine C-nucleoside (Fig. 1).
In our efforts to design novel purinergic P2Y1 receptor
antagonists as potent platelet aggregation inhibitors
with enhanced metabolic stability, we have recently
reported the synthesis of 8-(20-deoxy-b-D-ribofuranos-
yl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-
triazine-30,50-bisphosphate (1).1 With the goal to im-
prove potency of antagonists at the P2Y1 receptor, we
have adopted an efficient chemical pathway to introduce
substituents at the 30-position on the glycosyl moiety
leading to intermediate 2 in a diastereoselective manner.
In the second part of this work, we have focused our
2. Chemical synthesis
In an earlier publication, we have reported the synthesis
of compound 4a as a key intermediate leading to
NHCH3
N
NHCH3
NHCH3
N
N
N
N
O
N
O
N
N
O
N
O
H3C
H3C
H3C
N
N
N
O
HO
HO
HO
HO
P
HO
R
P
O
O
HO
HO
P
O
OH
CO2R
O
1
2
3
Figure 1. Nucleotide analogues acting on the P2Y1 receptor and a 30-substituted precursor.
Keywords: C-Nucleoside pyrazolotriazines; Nucleotides; Wittig reaction; Stereoselective addition.
*
Corresponding author. Tel.: +33 390 24 42 31; fax: +33 390 24 43 10; e-mail: schmitt@pharma.u-strasbg.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.077

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R. Mathieu et al. / Tetrahedron Letters 47 (2006) 5099–5103
bisphosphate 1.1 The electrophilic carbonyl at the 30-
position on the glycosyl moiety allowed versatile reactivity
and was an ideal group for the introduction of substitu-
tions and functionalities.
the 30-C–CH2 and the 50-H. The six member ring lactone
was obtained in this case due to the greater electrophilic-
ity of the ethyl ester relative to the tert-butyl ester under
kinetic conditions. Thus, starting from a a/b-diastereo-
meric mixture of nucleoside 7c, dibenzyl phosphate 10
was easily separated from lactone 11 by flash column
chromatography affording only the target final nucleo-
tide 3 after hydrogenolysis.11
Compound 4a may be protected as 50-O-tert-butyldi-
methylsilyl derivative 4b in good yield, followed by Wit-
tig reaction with stabilized ylide3 in toluene (Scheme 1).4
Protection of the 50-hydroxyl was not necessary for this
reaction, but the less polar 50-O-tert-butyldimethylsilyl
adducts were more easily separated from excess ylide
and triphenylphosphine oxide by column chromatogra-
phy. In each case, the Wittig reaction led to a Z/E mix-
ture of a,b-unsaturated esters 5a and 5b in excellent
yields. The next step consisted of hydrogenation of the
double bond in good yields.5 Both the bulky 10-pyrazolo-
triazinyl and the 50-O-tert-butyldimethylsilyl groups
generated steric hindrance, which favourably directed
reduction under the glycosyl face leading to an unsepa-
rable 30-a/b-diastereomeric mixture in a 2/3 ratio. Dis-
placement of the N-methyl-N-phenylamino group by
methylamine in a sealed tube afforded compounds 7a
and 7b in variable yields.6 50-O-Silylated derivative 7b
was deprotected with fluoride ion generating nucleoside
7c in good yield. At this stage, 30-a/b-diastereomeric
mixture 7c may be eventually separated by column
chromatography.
An efficient procedure for the preparation of 30-C-
branched nucleosides starting from the corresponding
30-ketonucleosides has been reported by Biellmann and
co-workers.12 This approach consisted of a highly stereo-
selective addition of an alkynylcerium reagent to 30-
ketonucleosides, affording the 30-alkynylnucleosides
with the required stereochemistry. The remarkable stereo-
selectivity observed in adenosine and uridine series, was
attributed to chelation control of the 50-hydroxyl, which
acted as a b-face directing group. Thus, this strategy
allowed efficient substitution of the 30-position on the
glycosyl moiety and keeping the 30-hydroxyl group in
the natural configuration. Our system differed from
adenosine by the nature of the base and the absence of
the 20-hydroxyl group.
As shown in Scheme 3, the addition of alkynylcerium–
lithium reagents onto 30-ketonucleoside 4a (synthesis
of 4a reported in an earlier publication)1 afforded
compounds 12a,b in good yield and was highly diaste-
reoselective (only a trace amount of the other diastereo-
mer was detected by TLC).13 The alkynylcerium–lithium
reagents were prepared from phenylacetylene or (tri-
methylsilyl)acetylene as described in the literature.12 At
this stage, the NOESY experiments did not allow
to establish the relative configuration of adducts
12a,b because the phenyl or the trimethylsilyl groups
borne by the triple bond were too far from the sugar
moiety. Nevertheless, the coupling constant observed
between the 10-H and the 20-b-H of the glycosyl moiety
(approximately 5.5 Hz) was in agreement with an ery-
thro 30-substituted 20-deoxynucleoside configuration.14
After deprotection of ethynyl derivative 12b by
tetrabutylammonium fluoride, the N-methyl-N-phenyl-
As shown in Scheme 2, nucleosides 7a and 7c were
phosphorylated7 in variable yields using the tetrabenzyl
pyrophosphate (TBPP) procedure,8 followed by hydro-
genation to remove the benzyl groups. In the case of
tert-butyl ester 7a, this methodology afforded the 30-a/
b-diastereomers mixture of nucleotide 9, which needed
preparative HPLC methods to separate them.9 How-
ever, the reactivity observed for ethyl ester 7c was differ-
ent. The 30-a-diastereomer nucleoside was transformed
to 30-a-diastereomer nucleotide 3, whereas the 30-b-dia-
stereomer nucleoside was cyclized into lactone 11 under
basic conditions.10 The relative configuration of this lac-
tone was unambiguously established by NOESY exper-
iments. These experiments revealed a strong NOE effect
between the 30-H and the 40-H of the sugar and between
H3C
N
Ph
N
H3C
N
Ph
N
H3C
N
Ph
N
H3C
N
N
N
NH
N
N
N
N
N
N
N
N
N
N
O
b
c
d
H3C
R' O
H3C
R'
H3C
R' O
H3C
R' O
O
O
O
O
O
CO2R
CO2R
(α /β mixture)
CO2R
mixture)
5a: R = tBu, R' = H
5b: R = Et, R' = TBDMS
4a: R' = H
4b: R' = TBDMS
(
Z
/
E
(α /β mixture)
a
6a: R = tBu, R' = H
7a: R = tBu, R' = H
7b: R = Et, R' = TBDMS
7c: R = Et, R' = H
6b: R = Et, R' = TBDMS
e
Scheme 1. Reagents and conditions: (a) TBDMS-Cl, imidazole, DMF, 35 ꢁC, 16 h, 73%; (b) Ph3P@CH–CO2R, toluene reflux, 18 h, 86–90%; (c) H2,
Pd/C, MeOH, 60 psi, rt, 24 h, 62–93%; (d) MeNH2, EtOH, sealed tube, 100 ꢁC, 16 h, 46–98%; (e) TBAF, THF, rt, 1 h, 86%.

R. Mathieu et al. / Tetrahedron Letters 47 (2006) 5099–5103
5101
H3C
NH
H3C
N
H3C
N
NH
N
NH
N
N
N
N
N
N
O
N
O
N
O
a
b
H3C
H3C
(HO)2P(O)
H3C
HO
N
(BnO)2P(O)
O
O
CO2tBu
CO2tBu
CO2tBu
7a
8
9
(
α
/
β
mixture)
(
α
/
β
mixture)
(
α
/
β
mixture)
H3C
N
H3C
N
H3C
NH
NH
NH
N
N
N
N
N
O
N
O
N
O
a
H3C
H3C
HO
H3C
R O
N
N
N
+
O
O
CO2Et
CO2Et
7c
11
10: R = P(O)(OBn)2
3: R = P(O)(OH)2
b
(
α
/
β
mixture)
Scheme 2. Reagents and conditions: (a) tBuOK, TBPP, THF, ꢀ40 ꢁC, 30 min, 50–87%; (b) H2, Pd/C, MeOH, 60 psi, rt, 20 h, 93–99%.
Ph
N
H3C
N
Ph
N
H3C
N
H3C
N
N
N
N
N
NH
N
N
N
N
N
O
a
c
H3C
HO
H3C
H3C
O
O
HO
R
HO
R
O
OH
OH
4a
12a: R = C≡C-Ph
12b: R = C≡C-Si(CH3)3
12c: R = C≡CH
2a: R = C≡C-Ph
2b: R = C≡CH
2c: R = CH2CH3
b
d
Scheme 3. Reagents and conditions: (a) R–Li/CeCl3, THF, ꢀ78 ꢁC, 1–3 h, 86–90%; (b) TBAF, THF, rt, 1 h; (c) MeNH2, EtOH, sealed tube, 100 ꢁC,
16 h, 81–89%; (d) H2, Pd/C, MeOH, 60 psi, rt, 20 h, 99%.
amino group was displaced by methylamine in a sealed
tube to afford products 2a and 2b in good yields.15
as slow substrates or inhibitors of HIV reverse transcrip-
tase during viral DNA chain elongation.17
A
catalytic hydrogenation of compound 2b was finally
carried out with the aim to confirm the relative configu-
ration of these nucleosides by NOESY experiments.16
Especially the NOE effect observed between 30-C–CH2
and 50-H, as well as between the methyl of 30-C–
CH2CH3 and 50-H confirmed the presence of the 30-C-
substituent at the b-face of the pentofuranose ring.
These 30-substituted 20-deoxynucleoside analogues ob-
tained in pyrazolotriazine series appeared as the direct
precursors of novel P2Y1 receptor antagonists. They
could also interfere with the biosynthesis of nucleic
acids, since 30-C-branched deoxynucleotides could act
In conclusion, we have developed an expedient and effi-
cient procedure for the synthesis of novel 30-substituted
20,30-dideoxynucleoside analogues in the pyrazolotri-
azine series via the Wittig reaction. Reduction of the
double bond leads to a a/b-diastereomeric mixture of
the 30-substituted nucleoside. The scope of this strategy
results in a different reactivity of each diastereomer
affording only the final nucleotide in the desired
configuration. These novel compounds are currently
under biological evaluation for their platelet aggregation
inhibition properties as P2Y1 receptor antagonists. On

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R. Mathieu et al. / Tetrahedron Letters 47 (2006) 5099–5103
the solvent was removed under reduced pressure and the
crude product was purified by flash chromatography
(EtOAc/CH2Cl2/EtOH 4/5/1) to yield 7a (a/b-diastereo-
meric mixture, 113 mg, 46%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): d 1.46, 1.47 (s, 9H, C(CH3)3), 2.04–
2.13 (m, 1H, 20-HA), 2.24–2.33 (m, 1H, 20-HB), 2.55 (s, 3H,
2-CH3), 2.45–2.66 (m, 3H, 30-H+30-CH2), 3.21 (d,
J = 5.0 Hz, 3H, N–CH3), 3.51–3.57, 3.61–3.69 (m, 1H,
50-HA), 3.75–3.82 (m, 1H, 50-HB), 4.05–4.14 (m, 1H, 40-H),
4.74 (dd, J = 2.5, 11.6 Hz, 1H, 10-H), 6.52 (br s, 1H, NH),
7.94 (s, 1H, 7-H). 13C NMR (75 MHz, CDCl3): d 26.0 (2-
CH3), 27.2 (N–CH3), 28.1 (C(CH3)3), 36.7, 37.4 (CH2),
40.0 (20-C), 49.4, 49.8 (30-C), 63.7 (50-C), 71.1 (10-C), 81.2
(40-C), 109.5 (8-C), 143.3 (7-C), 145.9 (9-C), 149.0 (4-C),
163.6 (2-C), 173.4 (CO2tBu). MS: m/z 378 (M+H)+.
7. A typical procedure for the phosphorylation: 1.0 M
potassium tert-butoxide solution in THF (0.19 mL,
0.190 mmol) was added dropwise to a stirred solution of
7a (60 mg, 0.159 mmol) in anhydrous THF (5 mL) at
ꢀ40 ꢁC. After 5 min, tetrabenzyl pyrophosphate (103 mg,
0.190 mmol) was added and the resulting mixture was
stirred at ꢀ40 ꢁC for 30 min. The reaction was quenched
by adding saturated aqueous NH4Cl (10 mL) and the
mixture was allowed to warm to room temperature. The
mixture was diluted with water (50 mL) and extracted with
ethyl acetate (2 · 50 mL). The combined organic layer was
dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (AcOEt/CH2Cl2/EtOH 4/5/1) to give 8
(a/b-diastereomeric mixture, 50 mg, 49%) as a yellow
the other hand, a stereoselective addition of alkynylce-
rium reagents allows us to synthesize in one step the
30-alkynyl-20-deoxynucleosides with the required stereo-
chemistry from the corresponding 30-ketonucleoside.
These findings represent useful methodologies for the
synthesis of analogue systems of adenine nucleosides
and nucleotides.
Acknowledgement
The authors thank Cyril Antheaume for NOESY experi-
ments assistance.
References and notes
1. Raboisson, P.; Baurand, A.; Cazenave, J.-P.; Gachet, C.;
Schultz, D.; Spiess, B.; Bourguignon, J.-J. J. Org. Chem.
2002, 67, 8063–8071.
2. Xu, B.; Stephens, A.; Kirschenheuter, G.; Greslin, A. F.;
Cheng, X.; Sennelo, J.; Cattaneo, M.; Zighetti, M. L.;
Chen, A.; Kim, S.-A.; Kim, H. S.; Bischofberger, N.;
Cook, G.; Jacobson, K. A. J. Med. Chem. 2002, 45, 5694–
5709.
3. (a) Denney, D. B.; Ross, S. T. J. Org. Chem. 1962, 27,
998–1000; (b) Nader, F. W.; Brecht, A.; Kreisz, S. Chem.
Ber. 1986, 119, 1196–1207.
1
4. A typical procedure for the Wittig reaction: A solution of
4a (300 mg, 0.849 mmol) and tert-butyl triphenylphos-
phoranylidene acetate (1.28 g, 3.40 mmol) in toluene
(10 mL) was refluxed overnight. After cooling to room
temperature, the solvent was removed under reduced
pressure and the crude product was purified by flash
chromatography (EtOAc/hexane 1/2) to afford 5a (Z/E
syrup. H NMR (300 MHz, CDCl3): d 1.42, 1.44 (s, 9H,
C(CH3)3), 2.08–2.43 (m, 4H, 20-H+30-CH2), 2.52, 2.54 (s,
3H, 2-CH3), 2.68–2.77 (m, 1H, 30-H), 3.19 (d, J = 4.9 Hz,
3H, N–CH3), 3.55–3.66 (m, 1H, 50-HA), 3.74–3.81 (m, 1H,
50-HB), 4.18–4.29 (m, 1H, 40-H), 4.71–4.81 (m, 1H, 10-H),
5.03, 5.10 (d, 4H, 2 · CH2Ph), 6.69 (br s, 1H, NH), 7.32,
7.35 (s, 10H, 2 · Ph), 7.91 (s, 1H, 7-H). 13C NMR
(50 MHz, CDCl3): d 25.9 (2-CH3), 27.2 (N–CH3), 28.1
(C(CH3)3), 36.7, 37.8 (CH2), 38.9 (20-C), 60.4 (50-C), 69.4,
69.5 (2 · CH2Ph), 70.5 (10-C), 80.6 (40-C), 109.0 (8-C),
128.0, 128.5, 128.6 (2 · Ph), 143.2 (7-C), 146.0 (9-C), 148.9
(4-C), 163.8 (2-C), 171.1 (CO2tBu). 31P NMR (121 MHz,
CDCl3): d ꢀ0.75 (s, a-diastereomer), ꢀ0.55 (s, b-diastereo-
mer). MS: m/z 638 (M+H)+.
mixture, 330 mg, 86%) as
a
yellow oil. 1H NMR
(200 MHz, CDCl3): d 1.48 (s, 9H, C(CH3)3), 2.55 (s, 3H,
2-CH3), 2.76 (dd, J = 5.3, 16.1 Hz, 1H, 20-HA), 3.26–3.44
(m, 1H, 20-HB), 3.73 (s, 3H, N–CH3), 3.98–4.23 (m, 2H, 50-
H), 4.63–4.68, 5.31–5.36 (m, 1H, 40-H), 5.02, 5.16 (dd,
J = 5.5, 11.4 Hz, 1H, 10-H), 5.78, 5.86 (s, 1H, C@CH),
6.30 (br s, 1H, OH), 7.12–7.18, 7.33–7.45 (m, 5H, Ph), 7.61
(s, 1H, 7-H). MS: m/z 452 (M+H)+.
8. Vacca, J. P.; deSolms, S. J.; Huff, J. R. J. Am. Chem. Soc.
1987, 109, 3478–3479.
5. A typical procedure for the reduction: A mixture of 5a
(320 mg, 0.709 mmol) and 10% Pd/C (75 mg) in MeOH
(100 mL) was shaken in a hydrogenation apparatus under
60 psi pressure at room temperature for 24 h. The catalyst
was removed by filtration and washed with MeOH and
CH2Cl2. The filtrate was concentrated to dryness and the
product was purified by trituration in Et2O to furnish 6a
(a/b-diastereomeric mixture, 300 mg, 93%) as a white
9. A typical procedure for the hydrogenolysis: A suspension
of 8 (45 mg, 70.6 lmol) and 10% Pd/C (15 mg) in MeOH
(70 mL) was shaken in a hydrogenation apparatus under
60 psi pressure at room temperature for 24 h. The catalyst
was removed by filtration and washed with MeOH and
CH2Cl2. The filtrate was concentrated to dryness and the
product was purified by recrystallization from EtOH and
Et2O to give 9 (a/b-diastereomeric mixture, 30 mg, 93%)
1
solid; mp 49–51 ꢁC. H NMR (200 MHz, CDCl3): d 1.46
(s, 9H, C(CH3)3), 2.14–2.51, 2.70–2.89 (m, 5H, 20-H+30-
H+30-CH2), 2.55 (s, 3H, 2-CH3), 3.72 (s, 3H, N–CH3),
3.89–4.06 (m, 2H, 50-H), 4.20–4.27 (m, 1H, 40-H), 5.03 (dd,
J = 5.4, 11.1 Hz, 1H, 10-H), 6.60 (br s, 1H, OH), 7.10–
7.18, 7.33–7.41 (m, 5H, Ph), 7.60 (s, 1H, 7-H). 13C NMR
(50 MHz, CDCl3): d 28.1 (C(CH3)3), 37.2, 38.1 (CH2), 40.0
(20-C), 62.1 (50-C), 71.0 (10-C), 81.2 (40-C), 108.5 (8-C),
125.9 (Cmeta), 127.2 (Cpara), 129.0 (Cortho), 143.2 (7-C),
144.0 (9-C), 149.1 (4-C), 162.4 (2-C). MS: m/z 454
(M+H)+.
1
as a white solid. H NMR (300 MHz, DMSO-d6): d 1.41
(s, 9H, C(CH3)3), 1.95–2.23 (m, 4H, 20-H+30-CH2), 2.42
(s, 3H, 2-CH3), 2.75–2.83 (m, 1H, 30-H), 3.01 (d,
J = 4.1 Hz, 3H, N–CH3), 3.58–3.68, 3.72–3.77 (m, 1H,
50-HA), 3.85–3.94 (m, 1H, 40-H), 4.08 (dd, J = 4.4,
10.6 Hz, 1H, 50-HB), 4.61–4.69 (m, 1H, 10-H), 8.08 (s,
1H, 7-H), 8.66 (br s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6):
d
26.0 (2-CH3), 27.6 (N–CH3), 28.2
(C(CH3)3), 70.5 (10-C), 80.4 (40-C), 109.0 (8-C), 143.6 (7-
C), 145.8 (9-C), 149.2 (4-C), 163.0 (2-C), 171.6 (CO2tBu).
31P NMR (81 MHz, DMSO-d6): d ꢀ0.50 (s, b-diastereo-
mer), ꢀ0.33 (s, a-diastereomer).
6. A typical procedure for the N-methyl-N-phenylamino
group displacement:
A
solution of 6a (298 mg,
10. Physical data for lactone 11: 1H NMR (300 MHz, CDCl3):
d 1.86 (ddd, 1H, 20-HA), 2.52–2.61 (m, 1H, 20-HB), 2.56
(s, 3H, 2-CH3), 2.64 (d, J = 4.9, 2H, 30-CH2), 3.02–3.13
0.657 mmol) and 2 M methylamine solution (2.0 mL,
4.00 mmol) in ethanol (5 mL) was stirred at 100 ꢁC in a
sealed tube for 16 h. After cooling to room temperature,

R. Mathieu et al. / Tetrahedron Letters 47 (2006) 5099–5103
5103
(m, 1H, 30-H), 3.22 (d, J = 5.2 Hz, 3H, N–CH3), 4.23 (dd,
J = 2.6, 12.4 Hz, 1H, 50-HA), 4.43 (ddd, 1H, 40-H), 4.51
(dd, J = 2.1, 12.4 Hz, 1H, 50-HB), 5.15 (dd, J = 4.5,
10.9 Hz, 1H, 10-H), 6.49 (br s, 1H, NH), 7.99 (s, 1H, 7-
H). 13C NMR (50 MHz, CDCl3): d 26.0 (2-CH3), 27.2 (N–
CH3), 33.5 (30-CH2), 35.2 (30-C), 39.4 (20-C), 69.4 (50-C),
71.5 (10-C), 74.2 (40-C), 106.9 (8-C), 143.5 (7-C), 146.7 (9-
C), 149.0 (4-C), 164.0 (2-C), 171.8 (CO2R). MS: m/z 304
(M+H)+.
Cpara), 129.0 (N–Ph, Cortho), 131.8 (C„C–Ph, Cortho),
144.3 (7-C), 147.8 (9-C), 149.1 (4-C), 162.8 (2-C). MS: m/z
1
456 (M+H)+. Physical data for compound 12b: H NMR
(300 MHz, CDCl3): d 0.20 (s, 9H, Si(CH3)3), 2.52 (s, 3H,
2-CH3), 2.59 (dd, J = 5.6, 13.9 Hz, 1H, 20-HA), 2.86 (dd,
J = 9.4, 13.9 Hz, 1H, 20-HB), 3.74 (s, 3H, N–CH3), 3.91–
3.96 (m, 1H, 50-HA), 4.03–4.10 (m, 2H, 50-HB+40-H), 5.15
(dd, J = 5.6, 9.4 Hz, 1H, 10-H), 7.13–7.19, 7.32–7.43 (m,
5H, Ph), 7.64 (s, 1H, 7-H). 13C NMR (50 MHz, CDCl3): d
ꢀ0.12 (Si(CH3)3), 25.1 (2-CH3), 42.3 (N–CH3), 48.8 (20-
C), 61.7 (50-C), 70.6 (10-C), 74.9 (30-C), 86.4
(40-C), 89.4, 104.9 (C„C), 107.3 (8-C), 126.1 (Cmeta),
127.4 (Cpara), 129.0 (Cortho), 144.3 (7-C), 147.7 (9-C), 149.0
(4-C), 162.7 (2-C). MS: m/z 452 (M+H)+.
11. Physical data for nucleotide 3: 1H NMR (300 MHz,
CDCl3): d 1.28 (t, J = 7.1 Hz, 3H, CH3), 1.98–2.12 (m, 1H,
20-HA), 2.23–2.32 (m, 1H, 20-HB), 2.38–2.49 (m, 1H, 30-H),
2.57 (s, 3H, 2-CH3), 2.61–2.75 (m, 2H, CH2), 3.19 (d, 3H,
N–CH3), 3.80–3.88 (m, 1H, 40-H), 3.94–4.09 (m, 2H, 50-
H), 4.10 (q, J = 7.1 Hz, 2H, CH2), 5.28–5.36 (m, 1H, 10-
H), 6.50 (br s, 1H, NH), 8.04 (s, 1H, 7-H). 13C NMR
(75 MHz, DMSO-d6): d 14.6 (CH3), 26.1 (2-CH3), 27.5
(N–CH3), 29.5 (30-CH2), 37.5 (20-C), 60.4 (CH2), 66.9 (50-
C), 70.9 (10-C), 109.5 (8-C), 144.1 (7-C), 146.1 (9-C), 149.2
(4-C), 162.9 (2-C), 172.3 (CO2Et). 31P NMR (81 MHz,
DMSO-d6): d 0.18 (s).
12. (a) Jung, P. M. J.; Burger, A.; Biellmann, J.-F. Tetra-
hedron Lett. 1995, 36, 1031–1034; (b) Jung, P. M. J.; Burger,
A.; Biellmann, J.-F. J. Org. Chem. 1997, 62, 8309–
8314.
13. A typical procedure for the stereoselective addition: A
suspension of anhydrous CeCl3 (174 mg, 0.707 mmol) in
dry THF (1.5 mL) under argon was stirred at room
temperature overnight. Independently, 1.6 M BuLi solu-
tion in hexane (0.44 mL, 0.707 mmol) was added dropwise
14. Ko¨rner, S.; Bryant-Friedrich, A.; Giese, B. J. Org. Chem.
1999, 64, 1559–1564.
15. For a typical procedure see Ref. 6. Physical data for
compound 2a: 1H NMR (200 MHz, CDCl3): d 2.55 (s, 3H,
2-CH3), 2.73 (dd, J = 6.1, 13.7 Hz, 1H, 20-HA), 3.01 (dd,
J = 9.0, 13.7 Hz, 1H, 20-HB), 3.25 (d, J = 5.1 Hz, 3H, N–
CH3), 4.07–4.12 (m, 1H, 50-HA), 4.13–4.18 (m, 2H, 50-
HB+40-H), 5.29 (dd, J = 6.1, 9.0 Hz, 1H, 10-H), 6.63 (br s,
1H, NH), 7.30–7.36, 7.46–7.53 (m, 5H, Ph), 7.91 (s, 1H, 7-
H). 13C NMR (75 MHz, CDCl3): d 25.5 (2-CH3), 27.3 (N–
CH3), 49.1 (20-C), 61.9 (50-C), 70.7 (10-C), 75.2 (30-C), 86.5
(40-C), 88.7, 122.4 (C„C), 109.0 (8-C), 128.2 (Cmeta),
128.5 (Cpara), 131.8 (Cortho), 144.5 (7-C), 145.5 (9-C), 149.1
(4-C), 164.0 (2-C). MS: m/z 380 (M+H)+. Physical data
for compound 2b: 1H NMR (200 MHz, CDCl3): d 2.53 (s,
3H, 2-CH3), 2.62 (s, 1H, C„CH), 2.65 (dd, J = 5.9,
13.9 Hz, 1H, 20-HA), 2.92 (dd, J = 9.3, 13.9 Hz, 1H, 20-
HB), 3.24 (d, J = 5.1 Hz, 3H, N–CH3), 3.95–4.02 (m, 1H,
50-HA), 4.07–4.12 (m, 2H, 50-HB+40-H), 5.25 (dd, J = 5.9,
9.3 Hz, 1H, 10-H), 6.62 (br s, 1H, NH), 7.89 (s, 1H, 7-H).
13C NMR (75 MHz, CDCl3): d 25.5 (2-CH3), 27.3 (N–
CH3), 48.8 (20-C), 61.7 (50-C), 70.6 (10-C), 73.1, 83.7
(C„C), 74.5 (30-C), 86.3 (40-C), 108.9 (8-C), 144.5 (7-C),
145.5 (9-C), 149.1 (4-C), 164.0 (2-C). MS: m/z 304
(M+H)+.
16. For a typical procedure see Ref. 5. Physical data for
compound 2c: 1H NMR (300 MHz, CDCl3): d 1.07 (t, J =
7.3 Hz, 3H, 30-CH2CH3), 1.76–1.88 (m, 1H, 30-CHA2 ),
1.59–1.72 (m, 1H, 30-CH2B), 2.35 (dd, J = 7.6, 13.4 Hz, 1H,
20-HA), 2.51 (dd, J = 8.1, 13.4 Hz, 1H, 20-HB), 2.53 (s, 3H,
2-CH3), 3.21 (d, J = 5.0 Hz, 3H, N–CH3), 3.71–3.76 (m,
1H, 50-HA), 3.93–4.00 (m, 2H, 50-HB+40-H), 5.06
(t, J = 7.9 Hz, 1H, 10-H), 6.81 (br s, 1H, NH), 7.84 (s,
1H, 7-H). 13C NMR (50 MHz, CDCl3): d 8.3 (CH3), 25.5
(2-CH3), 27.3 (N–CH3), 30.9 (30-CH2), 46.7 (20-C), 63.0
(50-C), 70.5 (10-C), 81.7 (30-C), 84.8 (40-C), 110.0 (8-C),
144.3 (7-C), 145.5 (9-C), 149.1 (4-C), 163.7 (2-C). MS: m/z
308 (M+H)+.
to
a
stirred solution of phenylacetylene (78 lL,
0.707 mmol) in dry THF (2 mL) under argon at ꢀ78 ꢁC.
The reaction temperature was raised to ꢀ20 ꢁC over a 1 h
period. This lithium acetylide solution was cooled to
ꢀ78 ꢁC and added, via a cannula, to the CeCl3 suspension
at the same temperature (prepared above). The mixture
was stirred for 1 h and a cooled solution (ꢀ78 ꢁC) of 4a
(50 mg, 0,141 mmol) in dry THF (1.5 mL) was rapidly
added via a cannula. After 3 h at ꢀ78 ꢁC, the reaction was
quenched by adding saturated aqueous NH4Cl (10 mL)
and the mixture was allowed to warm to room temper-
ature. The mixture was diluted with water (50 mL) and
extracted with ethyl acetate (2 · 50 mL). The combined
organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product
was purified by flash chromatography (EtOAc/hexane 1/1)
to give 12a (55 mg, 86%) as a white solid, mp: 67–68 ꢁC.
1H NMR (300 MHz, CDCl3): d 2.56 (s, 3H, 2-CH3), 2.71
(dd, J = 5.7, 13.9 Hz, 1H, 20-HA), 2.97 (dd, J = 9.5,
13.9 Hz, 1H, 20-HB), 3.75 (s, 3H, N–CH3), 4.02–4.07 (m,
1H, 50-HA), 4.12–4.19 (m, 2H, 50-HB+40-H), 5.22 (dd,
J = 5.7, 9.5 Hz, 1H, 10-H), 7.14–7.19, 7.31–7.42, 7.47–7.53
(m, 10H, N–Ph+C„C–Ph), 7.67 (s, 1H, 7-H). 13C NMR
(50 MHz, CDCl3): d 25.2 (2-CH3), 42.3 (N–CH3), 48.9 (20-
C), 61.8 (50-C), 70.7 (10-C), 75.2 (30-C), 86.4 (40-C), 88.7,
122.4 (C„C), 107.4 (8-C), 126.2 (N–Ph, Cmeta), 127.4 (N–
Ph, Cpara), 128.2 (C„C–Ph, Cmeta), 128.5 (C„C–Ph,
17. Fedorov, I. I.; Kazmina, E. M.; Novicov, N. A.;
Gurskaya, G. V.; Bochkarev, A. V.; Jasko, M. V.;
Victorova, L. S.; Kukhanova, M. K.; Balzarini, J.; De
Clercq, E.; Krayevsky, A. A. J. Med. Chem. 1992, 35,
4567–4575.