New dinucleoside analogues via cross-coupling metathesis

Article abstract of DOI:10.1081/NCN-60595

Synthesis of 3′-3′, 5′-5′, and 3′-5′ dimeric thymidine, linked by an olefinic chain between glycosidic moieties is described. Cross metathesis reaction of 3′ or 5′ O-allyl analogues of thymidine led to the expected 3′-3′ and 5′-5′ dimeric compounds, respe

Full text of DOI:10.1081/NCN-60595

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New Dinucleoside Analogues via Cross-Coupling
Metathesis
Vincent Roy a , Rachida Zerrouki a & Pierre Krausz a
a Laboratoire de Chimie des Substances Naturelles, Faculté des Sciences et Techniques ,
Université de Limoges , 123, Ave. Albert Thomas, Limoges, France , 87060
Published online: 24 Jun 2011.
To cite this article: Vincent Roy , Rachida Zerrouki & Pierre Krausz (2005) New Dinucleoside Analogues via Cross-Coupling
Metathesis, Nucleosides, Nucleotides and Nucleic Acids, 24:4, 289-301
To link to this article: http://dx.doi.org/10.1081/NCN-60595
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (4):289–301, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060595
NEW DINUCLEOSIDE ANALOGUES VIA
CROSS-COUPLING METATHESIS
5
Vincent Roy, Rachida Zerrouki, and Pierre Krausz
Laboratoire de Chimie
des Substances Naturelles, Faculteꢀ des Sciences et Techniques, Universiteꢀ de Limoges,
Limoges, France
5
Synthesis of 3’-3’, 5’-5’, and 3’-5’ dimeric thymidine, linked by an olefinic chain between glycosidic
moieties is described. Cross metathesis reaction of 3’ or 5’ O-allyl analogues of thymidine led to
the expected 3’-3’ and 5’-5’ dimeric compounds, respectively. In order to obtain the 3’-5’ dimer, 5’-O-
allyl and 3’-O-allyl monomers were first linked by their free 3’ OH and 5’ OH groups through a
glutaryl spacer; ring closing metathesis was then operated upon this temporary dimer, followed by
glutaryl removal.
Keywords Dinucleoside Analogues, Cross Metathesis, Grubbs Catalyst, Selective Allylation
INTRODUCTION
Novel oligonucleotide analogues that can form stable duplexes or triplexes
with nucleic acids are being investigated as a new generation of pharmaceu-
ticals.[1–5] One of the most important modifications is the complete substitution of
the phosphate internucleoside bridge, in order to achieve stronger affinity for the
nucleic acid target, enhanced nuclease resistance, and improved membrane
permeability and cellular uptake.
RESULTS AND DISCUSSION
Our research effort in this area has focused on the synthesis and evaluation of
three new dinucleoside analogues in which glycosidic moieties are linked by an
olefinic chain between positions 3’-3’, 5’-5’, or 3’-5’. The strategy of synthesis of 3’-3’
dimer is presented in Scheme 1.
Financial support from the ‘‘Conseil Regional du Limousin’’ is gratefully acknowledged. The authors are
grateful to Dr. Michel Guilloton for useful comments on the manuscript.
Address correspondence to Rachida Zerrouki, Laboratoire de Chimie des Substances Naturelles, Faculteꢀ
des Sciences et Techniques, Universiteꢀde Limoges, 123, Ave. Albert Thomas, Limoges 87060, France; Fax: 33(0)5-
55-45-72-02; E-mail: rachida.zerrouki@unilim.fr
289
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290
V. Roy, R. Zerrouki, and P. Krausz
SCHEME 1 (i) TBDMSCl, DMAP, pyridine, 12 h, 90%; (ii) NaH, THF, allylbromide, ultra sonication, 4.5 h, 79%;
(iii) metathesis catalyst (see text), CH2Cl2, 35°C; 12 h; (iv) TBAF, THF, 2 h, 55%.
First, 5’-hydroxyl of thymidine was protected with a TBDMS group to give 5’-O-
(tert-butyldimethylsilyl)-thymidine 1[6,7] (95%). The 3’-hydroxyl was then allylated
using Chattopadhyaya method’s[8] to give compound 2. The next step consisted of
self-cross metathesis reaction. We chose to use a ruthenium carbene complex
catalyst developed by Grubbs and coworkers,[9–14] catalyst Grubbs II, for its strong
reactivity, stability, and remarkable functional group tolerance. Metathesis was
effected in dry dichloromethane under reflux with 20% mol. catalyst for 8 h. The
reaction gave a mixture of two products (Table 1). Structural elucidation of these
products indicated that one of them was the expected product 3a obtained in low
yield (35%) and that the second one 3b (50%) resulted from double bond
transposition. Metathesis was then realized using Grubbs I catalyst, leading to the
expected compound 3a in 51% yield (Figure 1).
1H NMR chemical shifts do not allow the identification of Z and E isomers of
3a but 13C chemical shifts of the carbon atom close to the double bond (C-a) are
different for the Z and E isomers.[15] The upper value (da = 69.05 ppm) has been
assigned to the E isomer and the lower one (da = 65.07 ppm) to the Z isomer. The
Z/E ratio of 3a was about 15/85 with both catalysts. Deprotection of 3a was
achieved using TBAF/THF system. After 2 h, the solvent was removed and the
crude residue purified to give compound 4 in 55% yield.
Synthesis of the 5’-5’ dinucleoside analogue is summarized in Scheme 2. For
selective allylation of 5’ hydroxyl, the effect of various activation means was studied
(classical stirring, ultrasonication, or microwave activation). The best result was
TABLE 1 Metathesis Yield with Grubbs II or I Catalyst
Metathesis catalyst
Compound 3a (%)
Compound 3b (%)
Grubbs II
Grubbs I
35
51
50
7

New Dinucleoside Analogues via Cross-Coupling Metathesis
291
FIGURE 1 Grubbs catalyst used.
obtained with microwave activation. Starting from thymidine, NaH and 1.2 equiv.
of allylbromide in DMF, 5’-O-allylthymidine (5) was obtained after purification in
excellent yield (97%) along with remarkable decrease in reaction time (4 min) and a
good selectivity as well.[16] Acetylation was also achieved under microwave
activation in the presence of acetic anhydride (20 equiv) during 1 min to give
compound 6 in 92% yield.[17] After acetylation, metathesis was realized during 12 h,
in dichloromethane, using Grubbs I catalyst, to give dimer product 7 in 61% yield
(Z/E = 1/4). Finally, deprotection was achieved using ammonia in methanol (7 N)
and the expected compound 8 was obtained in 85% yield.
Synthesis of the 3’-5’ dinucleoside analogue was first performed using cross
metathesis reaction between olefinic compounds 2 and 6. The reaction gave a
mixture of three products, 3’-3’, 5’-5’, and 3’-5’ dimers with 5’-5’ dimer as a major
product. This result led us to investigate another route. To avoid this self-metathesis
drawback, we designed and used ring-closing metathesis (RCM) in conjunction
with prearranged O-allyl nucleosides, by switching from intermolecular (CM) to
intramolecular (RCM) reaction. Glutaryl group was used for the synthesis of spacer-
linked O-allyl nucleosides. The first test was realized according to Scheme 3.
Compound 2 was deprotected using TBAF in THF during 2 h, to give
compound 9 in good yield (92%). The glutaryl spacer was introduced by acylation
of primary hydroxyl group of 9 with glutaric anhydride in presence of DMAP; after
SCHEME 2 (i) NaH, DMF, allylbromide, MW, 4 min, 97%; (ii) acetic anhydride, MW, 1 min; (iii) metathesis
catalyst Grubbs I, CH2Cl2, 35°C; 12 h, 61%; (Z/E: 1/4); (iv) NH3, MeOH (7N), CH2Cl2, 6 h.

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V. Roy, R. Zerrouki, and P. Krausz
SCHEME 3 (i) TBAF, THF, 2 h, 92%; (ii) DMAP, glutaric anhydride, pyridine, 10 h, 55%; (iii) 5, DCC, DMAP,
CH2Cl2, toluene.
10 h, product 10 was isolated in acceptable yield (55%). Compound 10 was then
coupled with 5 in the presence of DCC and DMAP in CH2Cl2 and toluene
as cosolvent.
Two products were obtained, dimer 11a where the acid function reacted with
N-H group of 5, and compound 11b that resulted from reaction of 11a with a
second molecule of 10.
The second strategy is summarized in Scheme 4. Compound 5 was selectively
benzoylated[18] on N-H position, to give compound 12 in 53% yield. Reaction with
glutaric anhydride gave product 13 in good yield (85%). Esterification, in this case,
gave the desired compound 14 in 88% yield. Treated with metathesis Grubbs I
catalyst in dichloromethane, compound 14 gave the dimer 15 in 45% yield
(E/Z = 2). Finally, deprotection in MeOH with MeONa gave compound 16 in
70% yield.
SCHEME 4 (i) BzCl, Et3N, 9 h, 53%; (ii) DMAP, glutaric anhydride, pyridine, 10 h, 85%; (iii) DCC, DMAP,
CH2Cl2, toluene, 88%; (iv) metathesis catalyst Grubbs I, CH2Cl2, 39% (E/Z = 2); (v) MeONa (0.5 M in MeOH),
CH2Cl2, 70%.

New Dinucleoside Analogues via Cross-Coupling Metathesis
293
1
The above-mentioned structures were assigned from their H- and 13C-NMR
spectral data. Additional DEPT experiments and correct assignment were
1
confirmed by H-13C heteronuclear correlation experiments.
This article presents a new and efficient route for the synthesis of 3’-3’, 5’-5’, and
3’-5’ thymidine dimers. The approach described herein could be applied to other
purines and/or pyrimidines nucleoside analogues.
EXPERIMENTAL SECTION
All solvents and chemicals were commercially available and, unless otherwise
stated, were used as received. DMF, CH2Cl2, and CH3CN were distilled twice over
P2O5 and over CaH2 just before use. Reactions were monitored by thin-layer
chromatography (TLC) on precoated 0.2-mm silica gel 60 F254 (Merck) plates and
visualized in several ways: with an ultraviolet light source at 254 nm, by spraying
sulfuric acid (6N) and heating to 200°C. Silica gel (Merck Kieselgel 60, 15–40 mm)
was used for flash chromatography. Microwave irradiations were performed by
means of a monomode reactor (MicroSYNTH from Milestone) with focused waves
1
(T = 40°C, P = 100 W). H NMR spectra were recorded at 400.13 MHz with a
Bruker DPX spectrometer. Chemical shifts (d) are expressed in ppm with Me4Si as
internal standard (d = 0). Data are reported as follows: chemical shift, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; qt, quintet; m, multiplet; and br, broad),
coupling constants (Hz), and assignment. Melting points (mp) were determined
with a Kofler block and are uncorrected. Rotatory dispersions were measured with
a Jasco (DIP-370) polarimeter in a 1 dm quartz cell at 22°C. IR spectra were
recorded on a Perkin Elmer 1310 grating spectrophotometer and are reported in
wave number (cmÀ1).
Synthesis of 5’-O-tert-butyldimethylsilylthymidine (1). Thymidine (1.5 g,
6.19 mmol) was solubilized in anhydrous pyridine with 0.05 equiv of 4-
dimethylaminopyridine (38 mg, 0.309 mmol). This solution was placed under
argon, and 1.1 equiv of tertio-butyldimethylsilyl chloride (1.026 g, 6.809 mmol) was
then added. The mixture was stirred overnight at room temperature. The solution
was removed under reduced pressure and the crude residue purified using flash
chromatography with an elution gradient petroleum ether/CHCl3/EtOH. Pure
product was recovered as a viscous oil in 95% yield. Rf = 0.44 (CHCl3/EtOH; 9/1; V/
22
1
V); [a]D = +6,957° (c = 1, CHCl3); H RMN (CDCl3): Thymine: 8.70 (s, 1H, N-
H), 7.50 (q, 1H, JH6,CH3 = 1.1 Hz, H6), 1.91 (d, 3H, JCH3,H6 = 1.1 Hz, CH3); ose: 6.36
(dd, 1H, J = 5.7 Hz, J = 8.1 Hz, H1’), 4.46 (dt, 1H, J = 2.4 Hz, J = 5.4 Hz, H3’), 4.03
(q, 1H, J = 2.6 Hz, H4’), 3.89 (dd, 1H, J = 2.8 Hz, J = 11.3 Hz, H5’a), 3.83 (dd, 1H,
J = 2.8 Hz, J = 11.3 Hz, H5’b), 2.36 (ddd, 1H, J = 5.7 Hz, J = 2.4 Hz, J = 13.6 Hz,
H2’a), 2.10 (ddd, 1H, J = 5. 4 Hz, J = 8.1 Hz, J = 13.6 Hz, H2’b); TBDMS: 0.92 (s,
9H, tert-but), 0.12 (s, 3H, CH3), 0.11 (s, 3H, CH3).

294
V. Roy, R. Zerrouki, and P. Krausz
3’-O-(prop-2-enyl)-5’-O-tert-butyldimethylsilylthymidine (2). To a
solution of compound 1 (1.929 g, 5.59 mmol) in dry THF (30 mL), were added
2.1 equivalents of NaH (60%, 470 mg, 11.75 mmol) and the mixture was activated
by ultrasonication during 30 min. Two equivalents of allyl bromide (0.994 mL,
11.19 mmol) were then added and the mixture was activated during 4 h. After
work-up and purification by chromatography with an elution of petroleum ether/
chloroform/ethanol, 2 was recovered in 79% yield (1.723 g) as a viscous oil.
22
1
Rf = 0.44 (CHCl3/EtOH, 95/5, V/V); [a]D = +27.77° (3.5, CHCl3); H NMR
(CDCl3): thymine: 9.04 (s, 1H, N-H), 7.5 (q, 1H, J = 1.1 Hz, H6), 1.91 (d, 3H, J = 1.1
Hz, CH3); ose: 6.30 (dd, 1H, J = 5.6 Hz, J = 8.3 Hz, H1’), 4.11 (m, 2H, H3’, H4’), 3.90
(dd, 1H, J = 2. 4 Hz, J = 11.4 Hz, H5’a), 3.78 (dd, 1H, J = 2.1 Hz, J = 11.4 Hz, H5’b),
2.44 (ddd, 1H, J = 5.6 Hz, J = 1.8 Hz, J = 12.7 Hz, H2’a), 1.93 (ddd, 1H, J = 5.9 Hz,
J = 8.3 Hz, J = 12.7 Hz, H2’b); TBDMS: 0.92 (s, 9H, tert-but), 0.11 (s, 6H, CH3);
allyl: 5.89 (ddt, 1H, J = 5.5 Hz, J = 10.5 Hz, J = 17.2 Hz, Hb), 5.28 (dd, 1H, J = 1.3
Hz, J = 17.2 Hz, Hg), 5.21 (dd, 1H, J = 1.2 Hz, J = 10.4 Hz, Hg’), 4.04 (ddt, 1H,
J = 1.2 Hz, J = 5.5 Hz, J = 12.7 Hz, Ha), 3.95 (ddt, 1H, J = 1.3 Hz, J = 5.5 Hz,
J = 12.7 Hz, Ha’).
1,4-bis-O-(5’-O-tert-butyldimethylsilylthymidin-3’-yl)but-2-ene (3a). 1.16
mmol of 2 (462 mg) dissolved in 3.5 mL of dry dichloromethane were intro-
duced in a round flask, under argon atmosphere, 216 mg (0.26 mmol) of Grubbs I
catalyst dissolved in 2 mL of dry dichloromethane were added slowly. Under
stirring, the purple reaction mixture was heated to 35°C for 12 h. The solvent of the
resulting dark solution was removed under reduced pressure. The residue was
purified by chromatography with an elution of chloroform/ethanol (98/02), 3a was
recovered in 51% yield (227 mg) as colored viscous oil. Rf = 0.35 (CHCl3/EtOH, 95/
1
5, V/V). H NMR (CDCl3): E isomer: thymine: 8.45 (brs, 1H, H6), 1.89 (d, 3H,
J = 1.0 Hz, CH3); ose: 6.27 (dd, 1H, J = 5.5 Hz, J = 8.5 Hz, H1’), 4.09–4.11 (m, 2H,
H3’ and H4’), 3.89 (dd, 2H, J = 2.4 Hz, J = 11.3 Hz, H5’a), 3.78 (dd, 2H, J = 2.4 Hz,
J = 11.3 Hz, H5’b), 2.43 (ddd, 1H, J = 1.4 Hz, J = 5.4 Hz, J = 14.4 Hz, H2’a), 1.96
(ddd, 1H, J = 5.6 Hz, J = 8.5 Hz, J = 14.4 Hz, H2’b); TBDMS: 0.92 (s, 9H, tert-but),
0.12 (s, 3H, CH3), 0.11 (s, 3H, CH3); butene: 5.71 (t, 2H, J = 3.8 Hz, Hb), 3.95–4.04
(m, 4H, Ha); 13C NMR (CDCl3): thymine: 163.53 (C-4), 150.13 (C-2), 135.33 (C-6),
12.53 (CH3), 110.83 (C-5); ose: 85.13 (C-4’), 85.06 (C-1’), 79.49 (C-3’), 63.68 (C-5’),
37.75 (C-2’); butene: 128.94 (C-Hb), 65.07 (C-Ha); TBDMS: 25.93 (tert-but), À5.32
(CH3), À5.44 (CH3). Z isomer: thymine: 8.38 (brs, 1H, H6), 1.91 (d, 3H, J = 1.0 Hz,
CH3); ose: 6.26 (dd, 1H, J = 5.5 Hz, J = 8.5 Hz, H1’), 4.09–4.11 (m, 2H, H3’ and H4’),
3.89 (dd, 2H, J = 2.4 Hz, J = 11.3 Hz, H5’a), 3.78 (dd, 2H, J = 2.4 Hz, J = 11.3 Hz,
H5’b), 2.43 (ddd, 1H, J = 1.4 Hz, J = 5.4 Hz, J = 14.4 Hz, H2’a), 1.96 (ddd, 1H,
J = 5.6 Hz, J = 8.5 Hz, J = 14.4 Hz, H2’b); TBDMS: 0.92 (s, 9H, tert-but), 0.12 (s, 3H,
CH3), 0.11 (s, 3H, CH3); butene: 5.71 (t, 2H, J = 2.7 Hz, Hb), 3.95–4.04 (m, 4H, Ha);
13C NMR (CDCl3): thymine: 163.53 (C-4), 150.13 (C-2), 135.33 (C-6), 12.53 (CH3),
110.83 (C-5); ose: 85.13 (C-4’), 85.06 (C-1’), 79.49 (C-3’), 63.68 (C-5’), 37.91

New Dinucleoside Analogues via Cross-Coupling Metathesis
295
(C-2’); butene: 128.86 (C-Hb), 69.05 (C-Ha); TBDMS: 25.93 (tert-but), À5.32 (CH3),
À5.44 (CH3).
1,4-bis-O-(thymidin-3’-yl)but-2-ene (4). The deprotection of 3a (285 mg,
0.373 mmol) was realized in 4 mL of THF. One mL (1 mmol, 2.7 equiv) of a
solution of TBAF (1 M) in THF was added. The mixture was stirred at room
temperature for 2 h. The solvent was then removed and the crude residue purified
by thin-layer preparative chromatography on silica gel (CHCl3/EtOH; 9/1) to yield
compound 4 as a white solid in 55% yield (110 mg). Rf = 0.44 (CHCl3/EtOH, 9/1,
V/V); mp = 119°C; 1H NMR (CDCl3 + CD3OD): thymine: 7.61 (q, 2H, J = 1.0 Hz,
H6), 1.9 (d, 6H, J = 1.0 Hz, CH3); ose: 6.20 (dd, 2H, J = 5.6 Hz, J = 8.3 Hz, H1’), 4.11
(m, 2H, H3’, H4’), 3.90 (dd, 1H, J = 2. 4 Hz, J = 11.4 Hz, H5’a), 3.78 (dd, 1H, J = 2.1
Hz, J = 11.4 Hz, H5’b), 2.44 (ddd, 1H, J = 5.6 Hz, J = 1.8 Hz, J = 12.7 Hz, H2’a), 1.93
(ddd, 1H, J = 5.9 Hz, J = 8.3 Hz, J = 12.7 Hz, H2’b); TBDMS: 0.92 (s, 9H, tert-but),
0.11 (s, 6H, CH3); butene: 5.89 (ddt, 1H, J = 5.5 Hz, J = 10.5 Hz, J = 17.2 Hz, Hb),
5.28 (dd, 1H, J = 1.3 Hz, J = 17.2 Hz, Hg), 5.21 (dd, 1H, J = 1.2 Hz, J = 10.4 Hz,
Hg’), 4.04 (ddt, 1H, J = 1.2 Hz, J = 5.5 Hz, J = 12.7 Hz, Ha), 3.95 (ddt, 1H, J = 1.3
Hz, J = 5.5 Hz, J = 12.7 Hz, Ha’).
5’-O-(prop-2-enyl) thymidine (5). To a solution of thymidine (300 mg, 1.24
mmol) in dry DMF (10 ml) was added NaH (60%, 57 mg, 1.425 mmol) and the
mixture was stirred (first activation) under argon. Allyl bromide (129 mL, 1.49
mmol) was then added and the reaction mixture was stirred (second activation).
After removal of the solvent, the syrup was purified on a silica gel column, 5 was
recovered in 97% yield as a viscous oil (339 mg). Rf = 0.45 (CHCl3/EtOH, 9/1, V/V);
22
1
mp = 97°C; [a]D = 27.96° (c 0.8, EtOH); H NMR (400 MHz, CD3OD, d ppm):
Thymine: 7.85 (q, 1-H, JH6,CH3 1.0 Hz, H-6), 1.91 (d, 3H, CH3); Ose: 6.30 (t, 1-H, J1’,2’
6.8 Hz, H-1’), 4.39 (dt, 1-H, J3’,4’ 3.5 Hz, H-3’), 3.91 (q, 1-H, J4’,5’ 3.5 Hz, H-4’), 3.80
(dd, 1-H J5’b,5’a 12.0 Hz, H-5’b), 3.72 (dd, 1-H, J5’a,5’b 12 Hz, H-5’a), 2.27 (ddd, 1-H,
J
2’b,3’ 6.4 Hz, H-2b’), 2.20 (ddd, 1-H, J2’a,3’ 3.6 Hz, J2’a,2’b 13.7 Hz, H-2a’); Allyl: 5.86
(ddt, 1-H, Jb,g 10.4 Hz, Jb,g’ 17.0 Hz, H-b), 5.16 (dq, 1-H, H-g’), 5.12 (dq, 1-H,
g,g’ = 1.4 H-g), 4.51 (dt, 2H, Ja,b 5.6 Hz, Ja,g 1.4 Hz, H-a). Anal. Calcd for
J
C13H18O5N2: C, 55.31; H, 6.43; N, 9.92. Found: C, 55.36; H, 6.39; N, 9.87.
3,3’-N,O-diacetyl-5’-O-prop-2-enylthymidine (6). To a solution of 5 (157
mg, 0.557 mmol) in excess of acetic anhydride (1.06 mL, 11.14 mmol), was added
4-(dimethylamino)pyridine (20.4 mg, 0.167 mmol) and the mixture was stirred
under microwave irradiation over 1 min (P: 100 W). The reaction mixture was
quenched by an saturated aqueous NaHCO3 solution and extracted with
chloroform. The chloroform solution was dried over MgSO4 and the solvent was
removed by evaporation under reduced pressure. The crude product was purified
by chromatography on silica gel (elution with a gradient of petroleum ether/
chloroform). Compound 6 was isolated as a viscous oil (189 mg, 92%). Rf = 0.49

296
V. Roy, R. Zerrouki, and P. Krausz
22
1
(CHCl3/EtOH; 98/2; V/V); [a]D = +4.799 (0.7, CHCl3); H NMR (CD3OD):
thymine: 7.28 (s, 1H, H6), 1.95 (s, 3H, CH3); ose: 6.35 (dd, 1H, J = 5.7 Hz, J = 8.4 Hz,
H1’), 5.22 (dt, 1H, J = 2.1 Hz, J = 6.7 Hz, H3’), 4.24 (m, 1H, H4’), 4.37 (dd, 1H,
J = 4.1 Hz, J = 12.2 Hz, H5’a), 3.72 (dd, 1H, J = 3.4 Hz, J = 12.2 Hz, H5’b), 2.48
(ddd, 1H, J = 2.0 Hz, J = 5.7 Hz, J = 14.5 Hz, H2’a), 2.15 (ddd, 1H, J = 6.7 Hz,
J = 8.4 Hz, J = 14.5 Hz, H2’b); allyl: 5.86 (ddt, 1H, J = 5.9 Hz, J = 10.3 Hz, J = 16.8
Hz, Hb), 5.26 (dd, 1H, J = 1.0 Hz, J = 16.8 Hz, Hg), 5.19 (dd, 1H, J = 1.0 Hz,
J = 10.3 Hz, Hg), 4.55 (br d, 2H, J = 5.9 Hz, Ha); acetyl: 2.12 (s, 3H, CH3), 2.10 (s,
3H, CH3).
1,4-bis-O-(3’,3-N,O-Diacetylthymidin-5’-yl)but-2-ene (7). Compound 7
was prepared according to the procedure described for 3a starting from 6 (435
mg, 1.15 mmol) using 200 mg (0.242 mmol) of t Grubbs I catalyst. 245 mg of 7 was
obtained (61%, Z/E: 1/4). Rf = 0.35 (CHCl3/EtOH; 98/2; V/V); 1H NMR (CDCl3): E
isomer: thymine: 7.24 (d, 1H, J = 0.9 Hz, H6), 1.95 (d, 3H, J = 0.9 Hz, CH3); ose: 6.37
(dd, 1H, J = 5.5 Hz, J = 8.5 Hz, H1’), 5.21 (dt, 2H, J = 2.3 Hz, J = 6.7 Hz, H3’), 4.24
(m, 2H, H4’), 4.37 (dd, 2H, J = 4.1 Hz, J = 12.2 Hz, H5’a), 4.33 (dd, 2H, J = 3.2 Hz,
J = 12.2 Hz, H5’b), 2.48 (ddd, 1H, J = 2.1 Hz, J = 5.5 Hz, J = 14.2 Hz, H2’a), 2.13
(ddd, 1H, J = 6.7 Hz, J = 8.5 Hz, J = 14.2 Hz, H2’b); allyl group: 5.66 (t, 2H, J = 4.6
Hz, Hb), 4.82 (m, 4H, Ha); acetyl groups: 2.13 (s, 6H, CH3), 2.10 (s, 6H, CH3). Z
isomer: thymine: 7.25 (d, 1H, J = 0.9 Hz, H6), 1.95 (d, 3H, J = 0.9 Hz, CH3); ose: 6.36
(dd, 1H, J = 5.6 Hz, J = 8.5 Hz, H1’), 5.21 (dt, 2H, J = 2.3 Hz, J = 6.7 Hz, H3’), 4.24
(m, 2H, H4’), 4.37 (dd, 2H, J = 4.1 Hz, J = 12.2 Hz, H5’a), 4.33 (dd, 2H, J = 3.2 Hz,
J = 12.2 Hz, H5’b), 2.48 (ddd, 1H, J = 1.9 Hz, J = 5.5 Hz, J = 14.2 Hz, H2’a), 2.13
(ddd, 1H, J = 6.7 Hz, J = 8.5 Hz, J = 14.2 Hz, H2’b); butene: 5.66 (m, 2H, Hb), 4.82
(m, 4H, Ha); acetyl groups: 2.13 (s, 6H, CH3), 2.10 (s, 6H, CH3).
1,4-bis-O-(Thymidin-5’-yl)but-2-ene (8). A solution of compound 7 (245
mg, 0.348 mmol) in 3 mL of methanol, 2 mL of dichloromethane, and 5 mL of
solution of ammonia in methanol (7 M) was stirred at room temperature for 3 h.
The solution was evaporated to dryness and the crude product was purified using
preparative TLC (CHCl3/EtOH; 8/2; V/V). Pure 8 was recovered as a foam in 85%
yield (158 mg). Rf = 0.49 (CHCl3/EtOH; 7/3; V/V); 1H NMR (CD3OD): E isomer:
thymine: 7.83 (q, 2H, J = 1.0 Hz, H6), 1.89 (d, 6H, J = 1.0 Hz, CH3); ose: 6.27 (t, 2H,
J = 6.7 Hz, H1’), 4.38 (dt, 2H, J = 3.4 Hz, J = 6.4 Hz, H3’), 3.89 (q, 2H, J = 3.1 Hz,
H4’), 3.79 (dd, 2H, J = 3.1 Hz, J = 12.0 Hz, H5’a), 3.72 (dd, 2H, J = 3.7 Hz, J = 12.0
Hz, H5’b), 2.31–2.22 (m, 2H, H2’a), 2.19 (ddd, 2H, J = 6.5 Hz, J = 7.0 Hz, J = 13.5
Hz, H2’b); butene: 5.73 (m, 2H, Hb), 4.46 (m, 4H, Ha); 13C NMR (CD3OD): thymine:
165.22 (C-4), 152.22 (C-2), 136.75 (C-6), 13.30 (CH3), 110.88 (C-5); ose: 89.00 (C-4’),
87.30 (C-1’), 72.18 (C-3’), 62.88 (C-5’), 41.50 (C-2’); butene: 128.76 (C-Hb), 43.29 (C-
Ha). Z isomer: thymine: 7.83 (q, 2H, J = 1.0 Hz, H6), 1.91 (d, 6H, J = 1.0 Hz, CH3);
ose: 6.30 (t, 2H, J = 6.8 Hz, H1’), 4.38 (dt, 2H, J = 3.4 Hz, J = 6.4 Hz, H3’), 3.90 (q,
2H, J = 3.1 Hz, H4’), 3.80 (dd, 2H, J = 3.1 Hz, J = 12.0 Hz, H5’a), 3.73 (dd, 2H,

New Dinucleoside Analogues via Cross-Coupling Metathesis
297
J = 3.1 Hz, J = 12.0 Hz, H5’b), 2.31–2.22 (m, 4H, H2’); butene: 5.59 (m, 2H, Hb), 4.76
(m, 4H, Ha); 13C NMR (CD3OD): thymine: 165.34 (C-4), 152.34 (C-2), 136.75 (C-6),
13.30 (CH3), 110.88 (C-5); ose: 89.00 (C-4’), 87.30 (C-1’), 72.18 (C-3’), 62.88 (C-5’),
41.50 (C-2’); butene: 128.76 (C-Hb), 39.72 (C-Ha).
3’-O-(prop-2-enyl)thymidine (9). Deprotection of 2 (1.723 g, 4.48 mmol)
was realized in 30 mL of dry THF. Five mL (5.38 mmol, 1.2 equiv) of a solution of
TBAF (1 M) in THF was added. The mixture was stirred at room temperature for
1.5 h. The solvent was then removed and the crude residue purified by flash
chromatography on silica gel (elution with a gradient of CHCl3/EtOH) to yield
compound 9 in 88% yield (1.191 g). Rf = 0.44 (CHCl3/EtOH, 95/05, V/V);
22
1
mp = 139°C; [a]D = +37.44 (1.8, CHCl3). H NMR (CD3OD): thymine: 7.78 (brs,
1H, H6), 1.85 (brs, 3H, T-CH3); ose, 6.22 (dd, 1H, J = 5.9 Hz, J = 8.0 Hz, H1’), 4.19
(dt, 1H, J = 2.4 Hz, J = 5.6 Hz, H3’), 4.05 (m, 3H, Ha, H4’, Ha’), 3.78 (dd, 1H, J = 3.5
Hz, J = 12.0 Hz, H5’a), 3.71 (dd, 1H, J = 3.6 Hz, J = 12.0 Hz, H5’b), 2.35 (ddd, 1H,
J = 2.4 Hz, J = 5.9 Hz, J = 13.8 Hz, H2’a), 2.15 (ddd, 1H, J = 5.6 Hz, J = 8.0 Hz,
J = 13.8 Hz, H2’b); allyl: 5.92 (ddt, 1H, J = 5.4 Hz, J = 10.4 Hz, J = 17.1 Hz, Hb),
5.29 (br dd, 1H, J = 1.6 Hz, J = 17.1 Hz, Hg), 5.21 (br dd, 1H, J = 1.3 Hz, J = 10.4
Hz, Hg’).
3-N-benzoyl-3’-O-(prop-2-enyl)thymidine (12). To a solution of 1.025 g
(3.63 mmol) of 5 in 25 mL of dichloromethane, under argon, was added 1.1 equiv
of triethylamine (557 mL, 3.99 mmol). The mixture was stirred for 15 min and then
1.1 equiv of benzoyl chloride (453 mL, 3.99 mmol) was added. After 3 h at room
temperature, the solvent was removed and the crude product purified on a silica gel
column; compound 12 was recovered in 53% yield as a viscous oil (742 mg).
22
1
Rf = 0.46 (CH2Cl2/EtOH; 95/5; V/V); [a]D = À17.628 (2.37, CH2Cl2); H NMR,
(CDCl3): thymine: 7.24 (brs, 1H, H6), 1.7 (brs, 3H, CH3); ose: 6.35 (t, 1H, J = 6.5 Hz,
H1’), 4.52 (m, 1H, H3’), 4.25 (m, 1H, H4’), 4.64 (dd, 1H, J = 3.1 Hz, J = 12.0 Hz,
H5’a), 4.5 (dd, 1H, J = 4.9 Hz, J = 12.0 Hz, H5’b), 2.48 (ddd, 1H, J = 4.3 Hz, J = 6.5
Hz, J = 13.7 Hz, H2’a), 2.19 (dt, 1H, J = 6.5 Hz, J = 13.7 Hz, H2’b); allyl: 5.85 (ddt,
1H, J = 5.8 Hz, J = 10.5 Hz, J = 16.2 Hz, Hb), 5.23 (brd, 1H, J = 16.2 Hz, Hg), 5.16
(brd, 1H, J = 10.5 Hz, Hg), 4.63–4.52 (m, 2H, Ha); benzoyl group: 8.02 (d, 2H, J = 7.4
Hz, Hortho), 7.6 (brt, 1H, J = 7.4 Hz, Hpara), 7.46 (t, 2H, J = 7.4 Hz, Hmeta).
(3-N-benzoyl-5’-O-allylthymidin-3’-yl)glutaric acid (13). Compound 12
(275 mg, 0.712 mmol) was solubilized in 15 mL of anhydrous pyridine with 1.5
equiv of DMAP (243 mg, 2.13 mmol) and 3 equiv of glutaric anhydride (243 mg,
2.13 mmol). The reaction was heated at 60°C during 5 h. The mixture was
concentrated and the crude product purified by preparative TLC (CHCl3/EtOH;
95/5; V/V). Compound 13 was recovered in 74% yield (261 mg) as a white solid.
22
Rf = 0.42 (CH2Cl2/EtOH; 94/6; V/V); mp = 90°C; [a]D = À21.569° (2.25;
1
CH2Cl2); H NMR (CDCl3): thymine: 7.21 (q, 1H, J = 0.7 Hz, H6), 1.64 (d, 3H,

298
V. Roy, R. Zerrouki, and P. Krausz
J = 0.7 Hz, CH3); ose: 6.37 (brt, 1H, J = 5.8 Hz, H1’), 5.39 (de, 1H, J = 5.7 Hz, H3’),
4.37 (m, 1H, H4’), 4.72 (dd, 1H, J = 2.2 Hz, J = 12.2 Hz, H5’a), 4.58 (dd, 1H, J = 2.7
Hz, J = 12.2 Hz, H5’b), 2.55 (m, 1H, H2’a), 2.22 (m, 1H, H2’b); allyl group: 5.85 (ddt,
1H, J = 5.7 Hz, J = 10.4 Hz, J = 16.6 Hz, Hb), 5.23 (de, 1H, J = 16.6 Hz, Hg), 5.17
(brd, 1H, J = 10.4 Hz, Hg), 4.52 (de, 2H, J = 5.7 Hz, Ha); benzoyl group: 8.02 (d, 2H,
J = 7.2 Hz, Hortho), 7.6 (brt, 1H, J = 7.4 Hz, Hpara), 7.46 (t, 2H, J = 7.8 Hz, Hmeta);
spacer: 2.43 (m, 4H), 1.96 (m, 2H).
Glutaric anhydride of (3-N-benzoyl-5’-O-allylthymidin-3’-yl) and (3’-O-
allylthymidin-5’-yl) (14). Compound 13 (200 mg, 0.4 mmol) and 9 (56.5 mg,
0.2 mmol) were solubilized in 6 mL of dry dichloromethane and 3 mL of anhydrous
toluene with 0.8 equiv of DMAP (39 mg, 0.32 mmol) and 3 equiv of 1,3-
dicyclohexylcarbodiimide (247.5 mg, 1.2 mmol). The solution was stirred under
argon during 24 h at room temperature. The reaction mixture was quenched by an
acid aqueous solution and extracted with chloroform. The chloroform solution was
dried over MgSO4 and solvent was removed by evaporation under reduced
pressure. The crude product was purified by preparative TLC (AcOEt/EP; 5/5; 7/3).
Compound 14 was recovered in 88% yield as a viscous oil (134.5 mg). Rf = 0.51
(AcOEt/EP; 8/2). 1H NMR (CDCl3): thymine: 8.41 (s, 1H, N-H), 7.23 (d, 1H, J = 1.1
Hz, H6), 7.21 (d, 1H, J = 1.1 Hz, H6), 1.93 (d, 3H, J = 1.1 Hz, CH3), 1.65 (d, 3H,
J = 1.1 Hz, CH3); ose 1: 6.36 (dd, 1H, J = 6.2 Hz, J = 8.0 Hz, H1’), 5.38 (dt, 1H,
J = 1.7 Hz, J = 6.7 Hz, H3’), 4.36 (td, 1H, J = 3.6 Hz, J = 5.7 Hz, H4’), 4.71 (dd, 1H,
J = 3.6 Hz, J = 12.2 Hz, H5’a), 4.58 (dd, 1H, J = 3.6 Hz, J = 12.2 Hz, H5’b), 2.53
(ddd, 1H, J = 6.7 Hz, J = 8.0 Hz, J = 14.1 Hz, H2’a), 2.22 (ddd, 1H, J = 1.7 Hz,
J = 6.2 Hz, J = 14.1 Hz, H2’b); ose 2: 6.22 (dd, 1H, J = 6.2 Hz, J = 7.3 Hz, H1’), 4.05
(m, 1H, H3’), 4.36 (dt, 1H, J = 3.5 Hz, J = 5.3 Hz, H4’), 4.36 (dd, 1H, J = 3.5 Hz,
J = 12.0 Hz, H5’a), 4.28 (dd, 1H, J = 3.5 Hz, J = 12.0 Hz, H5’b), 2.47 (m, 1H, H2’a),
2.04 (ddd, 1H, J = 6.9 Hz, J = 7.3 Hz, J = 14.0 Hz, H2’b); allyl group 1: 5.84 (ddt, 1H,
J = 5.9 Hz, J = 10.2 Hz, J = 17.1 Hz, Hb), 5.24 (dq, 1H, J = 1.3 Hz, J = 17.1 Hz,
Hgtrans), 5.17 (dq, 1H, J = 1.2 Hz, J = 10.2 Hz, Hgcis), 4.52 (brd, 2H, J = 5.9 Hz, Ha);
allyl group 2: 5.89 (ddt, 1H, J = 5.5 Hz, J = 10.4 Hz, J = 17.2 Hz, Hb), 5.3 (dq, 1H,
J = 1.4 Hz, J = 17.2 Hz, Hgtrans), 5.22 (dq, 1H, J = 1.4 Hz, J = 10.4 Hz, Hgcis), 4.05
(ddt, 1H, J = 1.4 Hz, J = 5.5 Hz, J = 12.6 Hz, Ha), 3.97 (ddt, 1H, J = 1.4 Hz, J = 5.5
Hz, J = 12.6 Hz, Ha); spacer: 2.43 (m, 4H), 1.96 (m, 2H); benzoyl group: 8.02 (dd, 2H,
J = 1.2 Hz, J = 7.8 Hz, Hortho), 7.61 (tt, 1H, J = 1.2 Hz, J = 8.5 Hz, Hpara), 7.47 (tt, 2H,
J = 1.2 Hz, J = 8.0 Hz, Hmeta).
Compound (15). Compound 15 was prepared according to the proce-
dure described for 3a starting from 14 (136 mg, 0.178 mmol) in 15 mL of
CH2Cl2 using 44 mg (0.053 mmol) of Grubbs I catalyst. The crude product was
purified using preparative TLC (AcOEt/E P; 80/20; V/V) to give compound 15 in
45% yield. Thirty percent of E isomer (39 mg) and 15% of Z isomer (20 mg). E
isomer: Rf = 0.47 (AcOEt); 1H NMR (CDCl3): thymine: 7.25 (d, 1H, J = 0.9 Hz, H6),

New Dinucleoside Analogues via Cross-Coupling Metathesis
299
7.19 (d, 1H, J = 0.8 Hz, H6), 1.93 (d, 3H, J = 0.8 Hz, CH3), 1.68 (d, 3H, J = 0.9 Hz,
CH3); ose 1: 6.34 (dd, 1H, J = 4.8 Hz, J = 9.3 Hz, H1’), 5.38 (br d, 1H, J = 5.6 Hz,
H3’), 4.49 (m, 1H, H4’), 4.71 (dd, 1H, J = 3.3 Hz, J = 12.2 Hz, H5’a), 4.56 (dd, 1H,
J = 3.3 Hz, J = 12.2 Hz, H5’b), 2.56 (ddd, 1H, J = 1 Hz, J = 4.8 Hz, J = 14.1 Hz,
H2’a), 2.15 (ddd, 1H, J = 5.6 Hz, J = 9.3 Hz, J = 14.1 Hz, H2’b); ose 2: 6.17 (t, 1H,
J = 6.4 Hz, H1’), 4.13–4.08 (m, 1H, H3’), 4.13–4.08 (m, 1H, H4’), 4.32 (dd, 1H,
J = 2.2 Hz, J = 12.0 Hz, H5’a), 4.23 (dd, 1H, J = 6.9 Hz, J = 12.0 Hz, H5’b), 2.35
(ddd, 1H, J = 2.8 Hz, J = 6.4 Hz, J = 13.8 Hz, H2’a), 1.96 (m, 1H, H2’b); spacer: 2.44–
2.51 (m, 4H), 2.02–2.10 (m, 2H); butene: 5.66 (dt, 1H, J = 4.7 Hz, J = 15.2 Hz, Hb),
5.49 (dddd, 1H, J = 1.7 Hz, J = 5.8 Hz, J = 8.4 Hz, J = 15.2 Hz, Hb), 4.56 (brd, 2H,
J = 4.7 Hz, Ha), 4.20 (ddd, 1H, J = 0.8 Hz, J = 5.8 Hz, J = 13 Hz, Ha), 3.81 (dd, 1H,
J = 8.4 Hz, J = 13 Hz, Ha); benzoyl group: 8.04 (dd, 2H, J = 1.1 Hz, J = 7.9 Hz,
Hortho), 7.63 (tt, 1H, J = 7.9 Hz, J = 1.1 Hz, Hpara), 7.46 (br t, 2H, J = 7.9 Hz, Hmeta; Z
isomer: Rf = 0.37 (AcOEt); thymine: 7.28 (d, 2H, J = 0.9 Hz, H6), 1.67 (d, 6H,
J = 0.9 Hz, CH3); benzoyl group: 8.02 (dd, 2H, J = 1.1 Hz, J = 7.9 Hz, Hortho), 7.62
(brt, 1H, J = 7.9 Hz, Hpara), 7.48 (brt, 2H, J = 7.9 Hz, Hmeꢀta); ose: 6.33 (dd, 1H,
J = 4.7 Hz, J = 10.0 Hz, H1’), 5.42 (brd, 1H, J = 5.3 Hz, H3’), 4.45 (br t, 1H, J = 3.3
Hz, H4’), 4.68 (dd, 1H, J = 3.3 Hz, J = 12.2 Hz, H5’a), 4.56 (dd, 1H, J = 3.3 Hz,
J = 12.2 Hz, H5’b), 2.51 (ddd, 1H, J = 1.3 Hz, J = 4.7 Hz, J = 14.0 Hz, H2’a), 2.11
(ddd, 1H, J = 5.3 Hz, J = 10.0 Hz, J = 14.0 Hz, H2’b), ose: 6.25 (dd, 1H, J = 5.6 Hz,
J = 8.5 Hz, H1’), 4.32 (m,1H, H3’), 4.41 (m, 1H, H4’), 4.35 (m, 1H, H5’a), 4.28 (dd,
1H, J = 5.8 Hz, J = 11.9 Hz, H5’b), 2.45 (m, 1H, H2’a), 1.98 (ddd, 1H, J = 6.2 Hz,
J = 8.5 Hz, J = 14.3 Hz, H2’b); spacer: 2.39–2.59 (m, 4H, Ha1 et Ha3), 2.03–2.08 (m,
2H, Ha2); butene: 5.70 (dt, 1H, J = 6.4Hz, J = 10.5 Hz, Hb), 5.58 (dt, 1H, J = 7.3 Hz,
J = 10.5 Hz, Hb), 4.53 (br d, 2H, J = 7.3 Hz, Ha), 4.39 (br dd, 1H, J = 6.4 Hz,
J = 13.0 Hz, Ha), 4.29 (dd, 1H, J = 6.4 Hz, J = 13.0 Hz, Ha).
1-(thymidin-3’-yl)-4-(thymidin-5’-yl)but-2-ene (E) (16). A solution of
15 (E) (38 mg, 0.516 mmol) in 4 mL of methanol and 1 mL of CH2Cl2 as
cosolvent with 3 equiv. of sodium methoxide (0.5 M solution in methanol) was
stirred at room temperature for 3 h. The solution was neutralized by addition of
Amberlite IRN 77 H+ resin (Aldrich) and filtered. The solvent was evaporated to
dryness and the crude product was purified using preparative TLC (CHCl3/EtOH;
80/20; V/V). Pure 16 (E) was recovered in 74% yield (21 mg). Rf = 0.43 (CHCl3/
1
EtOH; 85/15; V/V); mp = 70°C; H NMR (CD3OD): thymine: 7.84 (q, 1H, J = 1.0
Hz, H6), 7.76 (q, 1H, J = 1.0 Hz, H6), 1.90 (d, 3H, J = 1.0 Hz, CH3); 1.87 (d, 3H,
J = 1.0 Hz, CH3); ose 1: 6.19 (dd, 1H, J = 6.0 Hz, J = 7.8 Hz, H1’), 4.14 (dt, 1H,
J = 2.6 Hz, J = 6.0 Hz, H3’), 3.98 (m, 1H, H4’), 3.80 (dd, 1H, J = 3.1 Hz, J = 12.0 Hz,
H5’a), 3.71 (dd, 1H, J = 3.6 Hz, J = 12.0 Hz, H5’b), 2.31 (ddd, 1H, J = 2.6 Hz, J = 6.0
Hz, J = 13.9 Hz, H2’a), 2.14 (ddd, 1H, J = 6.0 Hz, J = 7.8 Hz, J = 13.9 Hz, H2’b); ose
2: 6.29 (t, 1H, J = 6.8 Hz, H1’), 4.39 (dt, 1H, J = 3.5 Hz, J = 6.4 Hz, H3’), 3.90 (q, 1H,
J = 3.4 Hz, H4’), 3.75 (dd, 1H, J = 3.5 Hz, J = 12.1 Hz, H5’a), 3.68 (dd, 1H, J = 3.6
Hz, J = 12.1 Hz, H5’b), 2.28 (ddd, 1H, J = 2.6 Hz, J = 6.2 Hz, J = 13.5 Hz, H2’a), 2.14

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V. Roy, R. Zerrouki, and P. Krausz
(ddd, 1H, J = 6.6 Hz, J = 7.2 Hz, J = 13.5 Hz, H2’b); butene: 5.79 (dt, 1H, J = 6.0 Hz,
J = 15.6 Hz, Hb), 5.72 (dt, 1H, J = 5.1 Hz, J = 15.6 Hz, Hb), 4.51 (br d, 2H, J = 4.0
Hz, Ha), 4.02 (m, 2H, Ha). 13C NMR (CD3OD): thymine: 166.55 (C-4), 165.21 (C-4),
152.50 (C-2), 152.26 (C-2), 138.28 (C-6), 136.79 (C-6), 111.77 (C-5), 110.89 (C-5),
13.32 (CH3), 12.59 (CH3); ose: 89.05 (C-4’), 87.31 (C-1’), 86.83 (C-4’), 86.52 (C-1’),
72.25 (C-3’) 70.36 (C-3’), 63.25 (C-5’), 62.91 (C-5’), 41.49 (C-2’), 38.65 (C-2’); butene:
131.27 (C-b), 127.92 (C-b), 80.21 (C-a), 43.27 (C-a).
1-(thymidin-3’-yl)-4-(thymidin-5’-yl)but-2-ene (Z) (16). A solution of
15 (Z) (65 mg, 0.088 mmol) in 4 mL of methanol and 1 mL of CH2Cl2 as
cosolvent with 3 equiv of sodium methoxide (0.5 M solution in methanol) was
stirred at room temperature for 3 h. The solution was neutralized by addition of
Amberlite IRN 77 H+ resin (Aldrich) and filtered. The solvent was evaporated to
dryness and the crude product was purified using preparative TLC (CHCl3/EtOH;
80/20; V/V). Pure 16 (Z) was recovered in 72% yield (34 mg) as a viscous oil.
1
Rf = 0.45 (CHCl3/EtOH; 82/18; V/V); H NMR (CD3OD): thymine: 7.83 (q, 1H,
J = 1.0 Hz, H6), 7.81 (q, 1H, J = 1.0 Hz, H6), 1.90 (d, 3H, J = 1.0 Hz, CH3), 1.88 (d,
3H, J = 1.0 Hz, CH3); ose 1: 6.23 (dd, 1H, J = 6.0 Hz, J = 7.8 Hz, H1’), 4.25 (dt, 1H,
J = 2.7 Hz, J = 5.7 Hz, H3’), 4.05 (m, 1H, H4’), 3.79 (dd, 1H, J = 3.1 Hz, J = 12.0 Hz,
H5’a), 3.72 (dd, 1H, J = 3.7 Hz, J = 12.0 Hz, H5’b), 2.40 (ddd, 1H, J = 2.7 Hz, J = 6.0
Hz, J = 13.7 Hz, H2’a), 2.14–2.26 (m, 1H, H2’b). ose 2: 6.29 (t, 1H, J = 6.8 Hz, H1’),
4.39 (dt, 1H, J = 3.4 Hz, J = 6.3 Hz, H3’), 3.90 (q, 1H, J = 3.4 Hz, H4’), 3.81 (dd, 1H,
J = 3.4 Hz, J = 12.0 Hz, H5’a), 3.75 (dd, 1H, J = 3.4 Hz, J = 12.0 Hz, H5’b), 2.26
(ddd, 1H, J = 3.6 Hz, J = 6.8 Hz, J = 13.7 Hz, H2’a), 2.16–2.26 (m, 1H, H2’b); butene:
5.70 (dt, 1H, J = 6.2 Hz, J = 11.1 Hz, Hb), 5.57 (dt, 1H, J = 6.9 Hz, J = 11.1 Hz, Hb),
4.58 (d, 2H, J = 6.9 Hz, Ha), 4.32 (brd, 2H, Ha). 13C NMR (CD3OD): thymine:
166.47 (C-4), 165.10 (C-4), 152.43 (C-2), 152.16 (C-2), 136.65 (C-6), 138.23 (C-
6), 110.64 (C-5), 110.78 (C-5), 13.21 (CH3), 12.51 (CH3); ose 1: 86.81 (C-4’), 86.47 (C-
1’), 80.21 (C-3’), 62.81 (C-5’), 38.54 (C-2’), ose 2: 87.18 (C-1’), 86.47 (C-4’), 72.14
(C-3’), 63.25 (C-5’), 41.37 (C-2’); butene: 131.44 (C-b), 127.75 (C-b), 66.11 (C-a),
39.46 (C-a).
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