Efficient synthesis of various acycloalkenyl derivatives of pyrimidine using cross-metathesis and Pd(0) methodologies

Article abstract of DOI:10.1016/j.tet.2004.11.019

Novel acyclonucleosides (9a-d, 10a-d, 18a,b and 19a,b) have been prepared using Pd(0) and cross-metathesis methodologies. The allylic N-alkylation under Tsuji-Trost conditions was used to introduce the nucleobase, while the Suzuki-Miyaura reaction afforded C-5 substituted uracil analogues. The cross-metathesis performed with a ruthenium catalyst was used to provide new acycloalkenyl nucleosides. The antiviral activities of all final compounds have been evaluated. Novel acyclonucleosides (9a-d, 10a-d, 18a,b and 19a,b) were prepared using Pd(0) and cross-metathesis methodologies. The allylic N-alkylation under Tsuji-Trost conditions was used to introduce the nucleobase, meanwhile the Suzuki-Miyaura reaction afforded C-5 substituted uracil analogues. A ruthenium-based cross-metathesis reaction was used to synthesize new acycloalkenyl nucleosides.

Full text of DOI:10.1016/j.tet.2004.11.019

Tetrahedron 61 (2005) 537–544
Efficient synthesis of various acycloalkenyl derivatives of
pyrimidine using cross-metathesis and Pd(0) methodologies
Franck Amblard,a Steven P. Nolan,b Raymond F. Schinazic and Luigi A. Agrofoglioa,
*
aICOA UMR CNRS 6005, BP 6759, 45067 Orleans Cedex 2, France
bDepartment of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
cVeterans Affairs Medical Center and Lab. Biochem. Pharmacol., Emory University, Atlanta, GA 30033, USA
Received 3 September 2004; revised 8 November 2004; accepted 9 November 2004
Available online 26 November 2004
Abstract—Novel acyclonucleosides (9a–d, 10a–d, 18a,b and 19a,b) have been prepared using Pd(0) and cross-metathesis methodologies.
The allylic N-alkylation under Tsuji–Trost conditions was used to introduce the nucleobase, while the Suzuki–Miyaura reaction afforded C-5
substituted uracil analogues. The cross-metathesis performed with a ruthenium catalyst was used to provide new acycloalkenyl nucleosides.
The antiviral activities of all final compounds have been evaluated.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
been made to use a combination of olefin cross-metathesis11
and palladium-assisted routes12 to make acyclonucleosides;
our aim was thus to fill this gap. As part of our drug
Interest in acyclic nucleosides began in the mid-1970s when
acyclovir was first reported as a potent anti-herpes drug.1
The unprecedented selectivity of acyclovir as an antiviral
drug and the subsequent clarification of its behavior towards
virally coded enzymes provided massive impetus for further
synthesis of such compounds and for the investigation of
their biochemical fate. Many variations, both of the acyclic
glycone and of the heterocyclic base, have been described.2,3
Acyclonucleosides are commonly synthesized by reaction
of nucleic bases with a-chloromethyl ethers in the presence
of strong bases4 or by reaction of persilylated nucleic bases
with an activated aglycone catalyzed by various Lewis acid5
(Vorbru¨ggen conditions).6 Others’ approaches have
employed an acid catalyzed transglycosylation,7 an oxi-
dative cleavage of the pentose moiety of cyclic nucleo-
sides.8 Acycloalkenyl nucleosides can be produced through
the alkylation of 1,4-dichloro-2-butyne with the heterocycle
followed by an acetylene–allene isomerization,9 or from a
protected glyceraldehydes using a Wittig–Horner–Emmons
reaction; nevertheless, in the later case, only the Z-a,b-
unsaturated ester was obtained exclusively without any
trace of the E-isomer.10
discovery program, we have previously reported13
a
preliminary account of methodologies leading to acyclo-
alkenyl nucleosides. In this paper, we report an extension of
this strategy as a powerful route for the synthesis and the
diversification of new acycloalkenyl pyrimidine nucleosides
including trisubstituted alkene and allylic phosphonate
(Fig. 1).
Efforts aimed at synthesizing and isolating new actives
nucleosides now require the development and elaboration of
new strategy yielding facile and rapid access to a large
variety of compounds. To our knowledge, no attempt has
Keywords: Cross-metathesis; Acyclonucleosides; Suzuki–Miyaura; Pd(0).
* Corresponding author. Tel.: C33 2 3849 4582; fax: C33 2 3851 0728;
e-mail: luigi.agrofoglio@univ-orleans.fr
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.019

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F. Amblard et al. / Tetrahedron 61 (2005) 537–544
2. Results and discussion
on the selectivity observed in the coupling. Optimization of
the desired alkene as well as the stereocontrol of the formed
double bond is a crucial issue to access its usefulness for the
synthesis of unsaturated acyclonucleosides.
2.1. Allylic n-alkylation by Tsuji–Trost reaction
The first step of this synthetic approach consists in the
regioselective synthesis of N-allyl derivatives of nucleo-
bases using Pd(0)-catalyzed reaction of commercially
available allylic acetate with various pyrimidines under
Tsuji–Trost conditions (Scheme 1).
In order to achieve diversification within the acyclic
nucleoside family, we have explored and optimized the
cross-metathesis reaction of two terminal olefins, 2,2-
dimethyl-4-vinyl-[1,3]dioxolane17 (4) and 5-methylene-2-
phenyl-[1,3]dioxane18 (5), with allyluracils (3a–d). Under
optimized conditions moderate to good yields of the desired
products were achieved (Scheme 3).
Scheme 1.
Thus, treatment of uracil derivatives 2a–d with allyl acetate
1 in the presence of freshly prepared Pd(PPh3)4 and dppf
[(1,10-bis(diphenyl-phosphinoferocene)] in a mixture of
THF/DMF, led to the desired N-1 allylic pyrimidine
derivatives 3a–d in moderate yield. It is interesting to
note that in the case of uracil (entry 1) and 5-fluorouracil
(entry 4), the Tsuji–Trost allylic alkylation led to a 4/1 and
5/2 mixture of N-1 monoallylated (3a or 3d, respectively)
and N1,N3-diallylated analogues. The formation of bis-
alkylated product has been reported14 previously as has the
influence of the solvent on the regioselectivity of the Pd(0)-
catalyzed allylation of uracils.15
Scheme 3.
2.2. Cross-metathesis
It is interesting to note that: (1) no self-metathesis products
were observed; (2) those metathetical coupling reactions all
proceed with a high or exclusive degree of trans selectivity.
In contrast to the vast number of successful ring-closing
metathesis reactions, only a few examples of selective
cross-metathesis in the presence of functional groups have
been reported.16 In fact, the metal carbene catalyzed
intermolecular coupling between two different olefins
potentially yields four new alkenes as depicted in Scheme 2.
Thus, the allylthymine cross-metathesis efficiency depends
1
The H NMR clearly showed that only the E-isomer was
produced as the major compound with no detectable
corresponding Z-isomer. Even though its origin is not
clear at present, the stereoselectivity of this reaction seems
to be substrate dependant; (3) the synthesis of trisubstituted
carbon–carbon double bonds such as in 8a–d, which still
remains an ongoing challenge, proceeded smoothly with the
ruthenium–carbene species bearing one imidazol-2-ylidene
ligand 6.19 This catalyst displays a great tolerance towards
an array of polar groups.
The acidic deprotection (TFA/H20, 2/1, v/v) of 7a–d and
8a–d afforded in quantitative yields the acycloalkenyl
nucleosides 9a–d and 10a–d, respectively.
Scheme 2.
Based on the well-known potent and broad spectrum of

F. Amblard et al. / Tetrahedron 61 (2005) 537–544
539
antiviral acyclic phosphonate nucleosides (ANP),3a,b,20 we
3. Suzuki–Miyaura coupling
then turned our attention to the introduction of a
phosphonate moiety using the cross-metathesis method-
ology. Vinyl or allyl phosphonates have been already
reported to be viable cross-metathesis partners in metathesis
reaction catalyzed by second generation catalyst.21 Thus,
the allylthymine 3b was used as substrate in a cross-
metathesis reaction with the commercially available allyl
phosphonic acid dimethyl ester (11) under various con-
ditions (Scheme 4). When a first-generation ruthenium
catalyst (up to 1 equiv) was employed (entry 1), no reaction
occurred; the starting material was always recovered after
allowing the reaction to proceed as long as a few days.
When the second generation catalyst 6 was used, the starting
material 3b was rapidly consumed generating a complex
mixture of products, which could not be separated by silica
gel column chromatography. Any attempt in modifying the
solvent or increasing the amount of allylic phosphonate 11
3.1. With alkenyl boronic derivatives
To bring further structural modifications and diversity to the
synthesized acycloalkenyl nucleosides, we turned our
attention to the coupling of various organoboron compounds
with iodinated acycloalkenyl pyrimidine 7c under Suzuki–
Miyaura conditions.23,24 This reaction is suitable in
numerous synthetic pathways to pharmaceutical agents, as
boron derivatives are non-toxic, easily prepared and stable.
Thus the 5-iodinated derivative 7c was reacted in THF, at rt,
with two boronic acid compounds in the presence of
Pd(OAc)2, AsPh3 and K2CO3 (Scheme 5).
1
(entries 2–4) always led to the same results. The H NMR
data suggests that two compounds (12,13) issuing from the
self-metathesis of 11 and 3b, respectively are present in the
complex mixture.
Scheme 5.
Scheme 4.
During the Pd(0) transmetallation coupling between 7c
with pentylboronic acid, we observed the formation of two
non-separable compounds, one (14) resulting from the
expected Suzuki–Miyaura reaction and the second (140)
from an unexpected Heck reaction. This competition
between both reactions has been already reported in the
literature25 for non-aromatic boronic acid. Owing to the low
nucleophilicity of an alkenylboronic acid compared with
aryl derivatives, the transmetallation step on the Pd(0)
catalyst slowly proceeded and a Heck type side reaction
took place competitively. In order to accelerate the
transmetallation step and suppress the formation of the
isomer 140, a stronger base such as KOH was used instead of
K2CO3. This resulted in an increase of the amount of the
expected compound 14; nevertheless, the presence of the
byproduct 140 led us to consider other derivatives. Similar
results were obtained with the vinylbenzeneboronic acid
affording an inseperable mixture of 15 and 150. We thus
To explain the lack of formation of the desired cross
coupling compound, we hypothesized first that the allylic
phosphonate 11 may be more reactive than the allylic
thymine 3b in the cross-metathesis reaction; the phospho-
nate dimer 12 could be initially formed allowing thus the
allylic thymine to react only with itself affording the
bipyrimidinic derivative 13. Another hypothesis is based on
the reversible nature of the cross-metathesis reaction which
ensures the preferential formation of the most thermo-
dynamically stable product, for example, the homodimers in
the present case. These results are in agreement with the
recently reported general empirical model for olefin
reactivity in the cross-metathesis reaction.22 In fact,
categorizing olefins by their relative ability to undergo
homodimerization via cross-metathesis, the allyl phospho-
nate is able to rapidly produce the homodimers.

540
F. Amblard et al. / Tetrahedron 61 (2005) 537–544
turned our attention to the more reactive heterocyclic
boronic acids.
using appropriate tin derivatives in the presence of
Pd2(dba)3 (20 mol%) and AsPh3 (40 mol%).
The acidic deprotection (TFA/H20, 2/1, v/v) of nucleosides
16 and 17 afforded in quantitative yields the acycloalkenyl
nucleosides 18 and 19, respectively.
3.2. With heterocyclic boronic acid
Herdewijn et al.26 have described the synthesis and marked
antiviral activities of uridine derivatives bearing a thiophene
ring at the C-5 position of the nucleobase. Therefore the
Suzuki–Miyaura coupling reaction between iodinated
derivatives 7c and 8c, with the commercially available
thiophene (XZS) - or furan (XZO) boronic acids, in the
presence of Pd(OAc)2, AsPh3 and K2CO3, at rt in THF
overnight afforded the desired compounds 16a,b and 17a,b,
respectively, in good yields (Scheme 6). These compounds
have been obtained by Stille reaction, in similar yields,
4. Biological results
The synthesized compounds 9a–d, 10a–d, 18a,b and 19a,b,
along with the known antiviral compounds (acyclovir for
HSV and AZT for HIV), were tested for their anti-HIV and
anti-HSV activity in vitro, and the results are shown in
Table 1.
Among these nucleosides analogues, only compounds 10d,
18a and 18b were found to exhibit moderate anti-HIV
activity, with an EC50 of 72.9, 10.1 and 3.9 mM, respect-
ively. Compounds 18a and 18b exhibited also moderate
anti-HSV activity with and EC50 of 12.2 and 8.8 mM,
respectively. Nevertheless, those compounds and especially
18b showed toxicity against PBM, CEM or VERO cells.
The antiviral27 and cytotoxicity28 assays were done as
previously described.
5. Conclusion
An efficient route to various acycloalkenyl nucleosides
(9a–d, 10a–d, 18a,b and 19a,b) has been developed using a
combination of Pd(0) and cross-metathesis methodologies.
The allylic N-alkylation under Tsuji–Trost conditions was
used to introduce the nucleobase, meanwhile the Suzuki–
Miyaura reaction afforded C-5 substituted uracil
analogues. The cross-metathesis, with a ruthenium catalyst,
was used to access new acycloalkenyl nucleosides. The
antiviral activities of all final compounds have been
determined.
Scheme 6.
Table 1. Evaluation of synthesized acyclic nucleosides antiviral activity against human immunodeficiency virus (HIV), herpes simplex virus (HSV-1) and
cytotoxicity against PBM, CEM and VERO cells in vitro, expressed in mM
Compound
Anti-HIV-1 activity in
PBMCs
EC50
HSV-1 plaque
Reduction assay
EC50
Toxicity (IC50) in:
CEM
PBM
VERO
AZTa
0.016
O100
(100
(100
(100
NDb
(100
(100
(100
72.9
10.1
3.9
O10
0.11
(100
(100
(100
ND
(100
(100
(100
(100
12.2
8.8
O100
O100
(100
(100
(100
ND
(100
(100
(100
64.9
20.5
13.4
(100
70.9
14.0
O100
(100
(100
(100
ND
(100
(100
(100
49.3
16.8
6.6
29.0
O100
(100
(100
(100
ND
(100
(100
(100
(100
27.6
4.9
Acyclovira
9a
9b
9c
9d
10a
10b
10c
10d
18a
18b
19a
19b
(100
(100
(100
(100
(100
65.1
(100
(100
a Reference compounds.
b ND: not determined.

F. Amblard et al. / Tetrahedron 61 (2005) 537–544
541
1
6. Experimental
6.1. General methods
(3d).30 Eluant PE/EtOAc 3/7; white solid; mp 101 8C; H
NMR (CDCl3) d 4.35 (d, 2H, JZ5.9 Hz), 5.35 (dd, 2H, JZ
10.9, 16.1 Hz), 5.78–5.96 (m, 1H), 7.27 (d, 1H, JZ5.4 Hz),
9.65 (sl, NH); 13C NMR (DMSO) d 50.9 (CH2), 120.9
(CH2), 128.5 (CH), 131.5 (CH), 141.1 (C–F), 150.3, 158.1;
MS: m/z 171 [MCH]C; UV (MeOH) lmax 270 nm.
Commercially available chemicals were reagent grade and
used as received. THF was distilled from sodium/benzo-
phenone and CH2Cl2 from CaH2 immediately prior use. The
reactions were monitored by thin-layer chromatography
(TLC), analysis using silica gel plates (kieselgel 60 F254, E.
Merck). Compounds were visualized by UV irradiation
and/or spraying with 20% H2SO4 in EtOH, followed by
charring at 150 8C. Column chromatography was performed
on Silica Gel 60 M (0.040–0.063 mm, E. Merck). NMR
spectra were recorded with a Brucker AVANCE DPX 250
Fourier transform 250 spectrometer, with Me4Si as the
internal standard, unless otherwise stated. Chemical shifts
are given in ppm (d). High Resolution Mass spectra were
performed by the Centre regional de Mesures Physiques de
l’Ouest (University of Rennes, France).
6.3. General procedure for cross-metathesis reaction
To a solution of allyl derivative (0.66 mmol) in freshly
distilled CH2Cl2 (12.5 mL) were successively added the
protected diol 4 or 5 (3.32 mmol) and ruthenium catalyst 6
(56 mg, 0.06 mmol). The reaction mixture was stirred at
40 8C during 5 h. After evaporation of volatiles the crude
residue was purified by flash chromatography.
6.3.1. 1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-pro-
penyl]-2,4(1H,3H)-pyrimidinedione (7a). Eluant PE/
EtOAc 2/8; yield 78%; pale yellow gum; 1H NMR
(CDCl3) d 1.37 (s, 3H), 1.41 (s, 3H), 3.58 (dd, 1H, JZ
8.0 Hz), 4.10 (dd, 1H, JZ6.4, 8.0 Hz), 4.25–4.47 (m, 2H),
4.48–4.57 (m, 1 H), 5.63–5.78 (m, 2H), 5.83 (dt, 1H, JZ5.3,
15.7 Hz), 7.13 (d, 1H, JZ7.8 Hz), 9.45 (s, NH); 13C NMR
(CDCl3) d 25.9 (CH3), 26.8 (CH3), 49.0 (CH2), 69.3 (CH2),
76.8 (CH), 102.8 (CH), 109.8, 126.9 (CH), 133.2 (CH),
143.8 (CH), 150.8 (CO), 163.8 (CO); HRMS EI Obsd,
m/z 237.0892; calcd for C11H13N2O4, m/z 237.08753 [MK
CH3]C; UV (MeOH) lmax 265 nm.
6.2. General procedure for Tsuji–Trost reaction
To a solution of pyrimidine (2) (8.40 mmol) in DMF/THF
(100 mL, 1/1) was added NaH (202 mg, 8.40 mmol, 60%
dispersion in oil). After heating this suspension at 60 8C for
45 min, allyl acetate 1 (0.45 mL, 4.20 mmol), dppf (232 mg,
0.42 mmol) and freshly prepared Pd(PPh3)4 (485 mg,
0.42 mmol) were successively added. The reaction was
heated to 40 8C until complete conversion was reached. The
mixture was allowed to return to room temperature, diluted
with EtOAc (25 mL) and washed with an aqueous saturated
solution of NH4Cl. The organic layer was dried over
anhydrous MgSO4, filtered then concentrated in vacuo and
the residue was finally purified by column flash chroma-
tography to afford (3).
6.3.2. 1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-pro-
penyl]-5-methyl-2,4(1H,3H)-pyrimidinedione (7b).
Eluant PE/EtOAc 2/8; yield 50%; pale yellow gum; H
1
NMR (CDCl3) d 1.37 (s, 3H), 1.42 (s, 3H), 1.90 (s, 3H), 3.58
(dd, 1H, JZ8.0 Hz), 4.10 (dd, 1H, JZ6.4, 8.0 Hz), 4.22–
4.41 (m, 2H), 4.47–4.57 (m, 1H), 5.69 (dd, 1H, JZ6.6,
15.2 Hz), 5.82 (dt, 1H, JZ7.0, 15.2 Hz) 6.94 (s, 1H), 9.32
(s, NH); 13C NMR (CDCl3) d 12.4 (CH3), 25.9 (CH3), 26.7
(CH3), 48.8 (CH2), 69.4 (CH2), 76.0 (CH), 109.8, 111.3,
127.3 (CH), 132.7 (CH), 139.7 (CH), 150.9, 164.4; HRMS
EI Obsd, m/z 266.1269; calcd for C13H18N2O4, m/z
266.12666 [M]C.; UV (MeOH) lmax 270 nm.
6.2.1. 1-Allyl-2,4(1H,3H)-pyrimidinedione (3a).15 Eluant
PE/EtOAc 5/5; white solid; mp 102 8C; 1H NMR (CDCl3) d
4.30 (d, 2H, JZ5.7 Hz), 5.22 (dd, 2H, JZ9.4, 16.3 Hz),
5.68 (d, 1H, JZ7.8 Hz), 5.72–5.93 (m, 1H), 7.10 (d, 1H, JZ
7.8 Hz), 9.84 (br s, NH); 13C NMR (CDCl3) d 50.1 (CH2),
102.5 (CH), 119.5 (CH2), 131.5 (CH), 143.9 (CH), 151.0,
164.2; MS: m/z 153 [MCH]C; 175 [MCNa]C; UV
(MeOH) lmax 265 nm.
6.3.3. 1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-pro-
penyl]-5-iodo-2,4(1H,3H)-pyrimidinedione (7c). Eluant
PE/EtOAc 5/5; yield 56%; pale yellow gum; 1H NMR
(CDCl3) d 1.39 (s, 3H), 1.43 (s, 3H), 3.61 (dd, 1H, JZ7.3,
8.1 Hz), 4.12 (dd; 1H, JZ6.3, 8.1 Hz), 4.31–4.44 (m, 2H),
4.51–4.59 (m, 1H), 5.71–5.90 (m; 2H), 7.57 (s, 1H), 9.03
(bs, NH); 13C NMR (CDCl3) d 25.9, 26.8, 49.5, 68.4, 69.3,
75.8, 109.9, 126.3, 133.9, 148.2, 150.4, 160.4; HRMS EI
Obsd, m/z 378.087; calcd for C12H15N2O4I, m/z 300.9450
[M]C.; UV (MeOH) lmax 288 nm.
6.2.2. 1-Allyl-5-methyl-2,4(1H,3H)-pyrimidinedione
(3b).29 Eluant PE/EtOAc 3/7; yield 55%; white solid; mp
1
122 8C; H NMR (CDCl3) d 1.89 (s, 3H), 4.31 (d, 2H, JZ
5.8 Hz), 5.18–5.33 (m, 2H), 5.77–5.92 (m, 1H), 6.96 (s, 1H),
9.74 (br s, NH); 13C NMR (CDCl3) d 14.1 (CH3), 51.6
(CH2), 112.8, 120.9 (CH2), 133.6 (CH), 141.5 (CH), 152.8,
166.3; MS: m/z 167 [MCH]C; UV (MeOH) lmax 269 nm.
6.2.3. 1-Allyl-5-iodo-2,4(1H,3H)-pyrimidinedione (3c).
Eluant PE/EtOAc 4/6; yield 35%; white solid; mp 204 8C;
1H NMR (DMSO-d6) d 4.26–4.30 (m, 2H), 5.10–5.5.21 (m,
2H), 5.79–5.94 (m, 1H), 8.12 (s, 1H), 11.64 (br s, NH); 13C
NMR (DMSO-d6) d 49.4 (CH2), 68.3, 117.7 (CH2), 132.9
(CH), 149.6 (CH), 150.4, 161.1; HRMS ESI Obsd, m/z
300.9451; calcd for C7H7N2O4INa, m/z 300.9450 [MC
Na]C; UV (MeOH) lmax 290 nm.
6.3.4. 1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-pro-
penyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione (7d). Eluant
PE/EtOAc 4/6; yield 62%; pale yellow gum; 1H NMR
(CDCl3) d 1.39 (s, 3H), 1.43 (s, 3H), 3.60 (dd, 1H, JZ7.3,
8.1 Hz), 4.12 (dd; 1H, JZ6.3, 8.1 Hz), 4.33–4.42 (m, 2H),
4.51–4.61 (m, 1H), 5.72–5.90 (m, 2H), 7.23 (d, 1H, JZ
5.4 Hz,), 9.60 (s, NH); 13C NMR (CDCl3) d 25.8 (CH3),
26.7 (CH3), 49.3 (CH2), 69.3 (CH2), 75.8 (CH), 109.9, 126.0
(CH), 127.8 (CH), 134.1 (CH), 140.1 (C–F), 149.5, 157.3;
6.2.4. 1-Allyl-5-fluoro-2,4(1H,3H)-pyrimidinedione

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F. Amblard et al. / Tetrahedron 61 (2005) 537–544
1
Eluant PE/EtOAc 5/5; yield 94%; pale yellow gum; H
HRMS ESI Obsd, m/z 293.1604; calcd for C12H15FN2O4Na,
m/z 293.1608 [MCNa]C; UV (MeOH) lmax 270 nm.
NMR (CDCl3) d 1.37 (s, 3H), 1.42 (s, 3H), 3.60 (dd, 1H, JZ
8.1 Hz), 4.11 (dd, 1H, JZ6.3, 8.1 Hz), 4.42 (d, 2H, JZ
5.3 Hz), 4.49–4.57 (m, 1H), 5.76 (dd, 1H, JZ6.6, 15.7 Hz),
5.89 (dt, 1H, JZ5.65 Hz, JZ15.7 Hz), 6.43 (dd, 1H, JZ
1.8, 3.5 Hz), 7.04 (d, 1H, JZ3.5 Hz), 7.33 (d, 1H, JZ
1.8 Hz), 7.61 (s, 1H), 10.01 (s, NH); 13C NMR (CDCl3) d
25.9 (CH3), 26.7 (CH3), 49.5 (CH2), 69.3 (CH2), 75.9 (CH),
107.4, 109.5, 109.8 (CH), 111.9 (CH), 126.8 (CH), 133.1
(CH), 137.5 (CH), 141.2 (CH), 145.6, 150.0, 160.7; HRMS
ESI Obsd, m/z 341.1106; calcd for C16H18N2O5Na, m/z
341.1113 [MCNa]C; UV (MeOH) lmax 284 nm.
6.3.5. 1-[2-(2-Phenyl-1,3-dioxan-5-yliden)ethyl]-2,4(1H,
3H)-pyrimidinedione (8a). Eluant PE/EtOAc 2/8; yield
53%; pale yellow gum; H NMR (DMSO-d6) d 4.28–4.55
1
(m, 5H), 4.96–5.05 (m, 1H), 5.43–5.51 (m, 1H), 5.58 (d, 1H,
JZ7.3 Hz), 5.69 (s, 1H), 7.28–7.49 (m, 5H), 7.63 (d, 1H,
JZ7.3 Hz), 11.29 (s, NH); 13C NMR (DMSO-d6) d 43.6
(CH2), 65.3 (CH2), 70.6 (CH2), 100.5 (CH), 101.2 (CH),
119.6 (CH), 126.1 (CH !2), 128.1 (CH !2), 128.7 (CH),
133.9, 138.3, 145.2 (CH), 150.8, 163.7; HRMS ESI Obsd,
m/z 323.1007; calcd for C16H16N2O4Na, m/z 323.1008 [MC
Na]C; UV (MeOH) lmax 265 nm.
6.4.2. 1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-pro-
penyl]-5-(2-thienyl)-2,4(1H,3H)-pyrimidinedione (16b).
Eluant PE/EtOAc 5/5; yield 68%; pale yellow gum; H
1
6.3.6. 5-Methyl-1-[2-(2-phenyl-1,3-dioxan-5-yliden)-
ethyl]-2,4(1H,3H)-pyrimidinedione (8b). Eluant PE/
EtOAc 2/8; yield 64%; pale yellow gum; 1H NMR
(DMSO-d6) d 1.76 (s, 3H), 4.26–4.60 (m, 5H), 4.92–5.05
(m, 1H), 5.41–5.52 (m, 1H), 5.69 (s, 1H), 7.29–7.61 (m,
6H), 11.28 (s, NH); 13C NMR (DMSO-d6) d 11.9 (CH3),
43.4 (CH2), 65.3 (CH2), 70.7 (CH2), 100.4 (CH), 108.8,
119.7 (CH), 126.1 (CH !2), 128.0 (CH !2), 128.7 (CH),
133.7, 138.3, 140.9 (CH), 150.7, 164.2; HRMS ESI Obsd,
m/z 337.3415; calcd for C17H18N2O4Na, m/z 337.3417 [MC
Na]C; UV (MeOH) lmax 270 nm.
NMR (CDCl3) d 1.38 (s, 3H), 1.43 (s, 3H), 3.61 (dd, 1H, JZ
8.0 Hz), 4.12 (dd, 1H, JZ6.3, 8.0 Hz), 4.38–4.48 (m, 2H),
4.53–4.60 (m, 1H), 5.78 (dd, 1H, JZ6.6, 15.7 Hz), 5.90 (dt,
1H, JZ5.6 Hz, JZ15.7 Hz), 7.00–7.05 (m, 1H), 7.25–7.29
(m, 1H), 7.37–7.40 (m, 1H), 7.48 (s, 1H), 9.98 (s, NH); 13C
NMR (CDCl3) d 25.8 (CH3), 26.7 (CH3), 49.4 (CH2), 69.3
(CH2), 75.8 (CH), 109.8, 110.4, 124.5 (CH), 125.6 (CH),
126.7, 127.1, 133.2 (CH), 138.7 (CH), 150.1, 161.7; HRMS
ESI Obsd, m/z 357.0889; calcd for C16H18N2O4NaS, m/z
357.0885 [MCNa]C; UV (MeOH) lmax 260, 324 nm.
6.3.7. 5-Iodo-1-[2-(2-phenyl-1,3-dioxan-5-yliden) ethyl]-
2,4(1H,3H)-pyrimidinedione (8c). Eluant PE/EtOAc 4/6;
yield 57%; pale yellow gum; 1H NMR (CDCl3) d 4.17–4.26
(m, 1H), 4.42–4.55 (m, 4H), 4.93–4.99 (m, 1H), 5.45 (t, 1H,
JZ6.7 Hz), 5.68 (s, 1H), 7.36–7.40 (m, 3H), 7.47–7.51 (m,
2H), 7.61 (s, 1H), 8.91 (s, 1H); 13C NMR (CDCl3) d 44.8
(CH2), 66.1 (CH2), 68.8, 71.9 (CH2), 102.0 (CH), 118.6
(CH), 126.4 (CH !2), 128.7 (CH !2), 129.5 (CH), 136.7,
137.9, 148.3 (CH), 150.6, 160.5; HRMS ESI Obsd, m/z
448.9980; calcd for C16H15N2O4INa, m/z 448.9974 [MC
Na]C; UV (MeOH) lmax 290 nm.
6.4.3. 5-(2-Furyl)-1-[2-(2-phenyl-1,3-dioxan-5-yliden)-
ethyl]-2,4(1H,3H)-pyrimidinedione (17a). Eluant PE/
EtOAc 5/5; yield 75%; pale yellow gum; 1H NMR
(CDCl3) d 4.18–4.33 (m, 1H), 4.42–4.68 (m, 4H), 4.93–
5.07 (m, 1H), 5.51 (t, 1H, JZ6.4 Hz), 5.68 (s, 1H), 6.45–
6.47 (m, 1H), 7.08–7.10 (m, 1H), 7.28–7.42 (m, 4H),
7.47–7.55 (m, 2H), 7.65 (s, 1H), 10.05 (s, NH); 13C NMR
(CDCl3) d 44.6 (CH2), 65.8 (CH2), 71.6 (CH2), 101.5 (CH),
107.5, 109.6 (CH), 111.9 (CH), 118.7 (CH), 126.2 (CH !
2), 128.4 (CH !2), 129.1 (CH), 135.7, 137.3 (CH), 137.8,
141.3 (CH), 145.6, 150.1, 160.7; HRMS ESI Obsd, m/z
389.3741; calcd for C20H18N2O5Na, m/z 389.3748 [MC
Na]C; UV (MeOH) lmax 284 nm.
6.3.8. 5-Fluoro-1-[2-(2-phenyl-1,3-dioxan-5-yliden)-
ethyl]-2,4(1H,3H)-pyrimidinedione (8d). Eluant PE/
EtOAc 5/5; yield 70%; pale yellow gum; 1H NMR
(DMSO-d6) d 4.23–4.55 (m, 5H), 4.95–5.00 (m, 1H), 5.48
(t, 1H, JZ6.6 Hz), 5.69 (s, 1H), 7.34–7.41 (m, 5H), 8.08 (d,
1H, JZ6.6 Hz), 11.81 (s, NH); 13C NMR (DMSO-d6) d 43.9
(CH2), 65.3 (CH2), 70.6 (CH2), 100.5 (CH), 119.2 (CH),
126.1 (CH !2), 128.1 (CH !2), 129.4 (CH), 129.7 (CH,
JZ132.3 Hz), 134.1, 138.3, 139.7 (C–F), 149.4, 157.5;
HRMS ESI Obsd, m/z 341.3052; calcd for C16H15FN2O4Na,
m/z 341.3048 [MCNa]C; UV (MeOH) lmax 269 nm.
6.4.4. 1-[2-(2-Phenyl-1,3-dioxan-5-yliden)ethyl]-5-(2-
thienyl)-2,4(1H,3H)-pyrimidinedione (17b). Eluant PE/
EtOAc 5/5; yield 76%; pale yellow gum; 1H NMR (DMSO-
d6) d 4.35–4.56 (m, 5H), 5.00–5.09 (m, 1H), 5.48–5.61 (m,
1H), 5.71 (s, 1H), 6.99–7.12 (m, 1H), 7.28–7.52 (m, 8H),
8.30 (s, 1H), 11.69 (s, NH); 13C NMR (DMSO-d6) d 44.2
(CH2), 65.3 (CH2), 70.6 (CH2), 100.4 (CH), 107.9, 119.6
(CH), 122.6 (CH), 125.6 (CH), 126.1 (CH !2), 126.4 (CH),
128.1 (CH !2), 128.7 (CH), 133.8, 133.9, 138.3, 140.7
(CH), 149.8, 161.7; HRMS ESI Obsd, m/z 405.0880; calcd
for C20H18N2O4NaS, m/z 405.0885 [MCNa]C; UV
(MeOH) lmax 260, 324 nm.
6.4. General procedure for Suzuki reaction
Under dry nitrogen, to a solution of iodo derivatives
(0.132 mmol) in THF (1 mL), boronic acid derivatives
6.5. General procedure for deprotection
(0.529 mmol),
Pd(OAc)2
(0.053 mmol),
Ph3As
(0.026 mmol) and K2CO3 (1.188 mmol) were added. The
reaction was stirred at room temperature until complete
conversion was reached. After evaporation of volatiles the
crude residue was purified by column flash chromatography.
Acetal derivatives (0.22 mmol) were stirred at room
temperature during 3 h in mixture of TFA/H2O
(10 mL/5 mL). After evaporation of volatiles, crude residue
are purified by flash chromatography.
6.4.1. 1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-pro-
penyl]-5-(2-furyl)-2,4(1H,3H)-pyrimidinedione (16a).
6.5.1. 1-[(E)-4,5-dihydroxy-2-pentenyl]-2,4 (1H,3H)-
pyrimidinedione (9a). Eluant CH2Cl2/MeOH 8/2; yield

F. Amblard et al. / Tetrahedron 61 (2005) 537–544
543
1
98%; pale yellow gum; H NMR (DMSO-d6) d 3.20–3.26
Obsd, m/z 249.0850; calcd for C10H14N2O4Na, m/z
249.0851 [MCNa]C; UV (MeOH) lmax 270 nm.
(m, 2H), 3.82–3.97 (m, 1H), 4.27–4.31 (m, 2H), 4.57 (t, OH,
JZ5.6 Hz), 4.79 (d, OH, JZ4.8 Hz), 5.51–5.65 (m, 3H),
7.43 (d, 1H, JZ7.6 Hz), 11.17 (s, NH); 13C NMR (DMSO-
d6) d 38.8 (CH2), 65.9 (CH2), 71.4 (CH), 99.8 (CH), 123.8
(CH), 134.1 (CH), 140.8 (CH), 151.2, 162.8; HRMS ESI
Obsd, m/z 235.0697; calcd for C9H12N2O4Na, m/z 235.0695
[MCNa]C; UV (MeOH) lmax 265 nm.
6.5.7. 1-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-5-
iodo-2,4(1H,3H)-pyrimidinedione (10c). Eluant CH2Cl2/
MeOH 9/1; yield 92%; pale yellow gum; 1H NMR (DMSO-
d6) d 3.94 (d, 2H, JZ5.0 Hz), 4.02 (d, 2H, JZ5.0 Hz), 4.40
(d, 2H, JZ6.9 Hz), 4.76 (t, OH, JZ5.0 Hz), 4.83 (t, OH,
JZ5.0 Hz), 5.44 (t, 1H, JZ6.9 Hz), 8.13 (s, 1H), 11.60 (s,
NH); 13C NMR (DMSO-d6) d 44.6 (CH2), 56.9 (CH2), 62.4
(CH2), 68.3, 118.7 (CH), 144.9, 149.6 (CH), 150.7, 161.1;
HRMS ESI Obsd, m/z 360.9666; calcd for C9H11N2O4INa,
m/z 360.9661 [MCNa]C; UV (MeOH) lmax 290 nm.
6.5.2. 1-[(E)-4,5-dihydroxy-2-pentenyl]-5-methyl-2,4-
(1H,3H)-pyrimidinedione (9b). Eluant CH2Cl2/MeOH
8/2; yield 96%; pale yellow gum; H NMR (DMSO-d6) d
1
1.74 (s, 3H), 3.22–3.32 (m, 2H), 3.89–4.01 (m, 1H), 4.18–
4.25 (m, 2H), 4.60 (t, OH, JZ5.8 Hz), 4.85 (d, OH, JZ
5.0 Hz), 5.57–5.65 (m, 2H), 7.44 (s, 1H), 11.23 (s, NH); 13C
NMR (DMSO-d6) d 12.0 (CH3), 48.1 (CH2), 65.8 (CH2),
71.3 (CH), 108.7, 124.2 (CH), 135.2 (CH), 141.0 (CH),
150.7, 164.3; HRMS ESI Obsd, m/z 249.0851; calcd for
C10H14N2O4Na, m/z 249.0851 [MCNa]C; UV (MeOH)
lmax 270 nm.
6.5.8. 5-Fluoro-1-[4-hydroxy-3-(hydroxymethyl)-2-but-
enyl]-2,4(1H,3H)-pyrimidinedione (10d). Eluant CH2Cl2/
MeOH 9/1; yield 95%; pale yellow gum; 1H NMR (DMSO-
d6) d 3.94 (d, 2H, JZ5.0 Hz), 4.02 (d, 2H, JZ5.0 Hz), 4.34
(d, 2H, JZ7.2 Hz), 4.75–4.85 (m, OH !2), 5.45 (t, 1H, JZ
7.2 Hz), 8.01 (d, 1H, JZ6.9 Hz), 11.78 (s, NH); 13C NMR
(DMSO-d6) d 44.5 (CH2), 56.9 (CH2), 62.4 (CH2), 118.4
(CH), 129.7 (CH), 139.2 (C–F), 145.1, 149.6, 157.4; HRMS
ESI Obsd, m/z 253.1952; calcd for C9H11FN2O4Na, m/z
253.1955 [MCNa]C; UV (MeOH) lmax 270 nm.
6.5.3. 1-[(E)-4,5-dihydroxy-2-pentenyl]-5-iodo-2,4(1H,
3H)-pyrimidinedione (9c). Eluant CH2Cl2/MeOH 8/2;
yield 97%; pale yellow gum; 1H NMR (DMSO-d6) d
3.21–3.35 (m, 2H), 3.91–4.03 (m, 1H), 4.22–4.36 (m, 2H),
5.61–5.79 (m, 2H), 8.12 (s, 1H), 11.64 (s, NH); 13C NMR
(DMSO-d6) d 48.9 (CH2), 65.7 (CH2), 68.4, 71.4 (CH),
124.2 (CH), 135.8 (CH), 149.8 (CH), 150.6, 161.3; HRMS
ESI Obsd, m/z 361.1015; calcd for C9H11IN2O4Na, m/z
361.1011 [MCNa]C; UV (MeOH) lmax 290 nm.
6.5.9. 1-[(E)-4,5-dihydroxy-2-pentenyl]-5-(2-furyl)-
2,4(1H,3H)-pyrimidinedione (18a). Eluant CH2Cl2/
MeOH 9/1; yield 93%; pale yellow gum; 1H NMR
(DMSO-d6) d 3.18–3.32 (m, 2H), 3.88–4.03 (m, 1H), 4.37–
4.41 (m, 2H), 4.60 (t, OH, JZ5.6 Hz), 4.87 (d, OH, JZ
5.0 Hz), 5.66–5.81 (m, 2H), 6.52 (dd, 1H, JZ1.0, 3.4 Hz),
6.85 (d, 1H, JZ3.4 Hz), 7.65 (d, 1H, JZ1.0 Hz), 8.00 (s, 1H),
11.62 (s, NH); 13C NMR (DMSO-d6) d 48.7 (CH2), 65.8
(CH2), 71.3 (CH), 105.1, 107.8 (CH), 111.7 (CH), 124.0 (CH),
135.5 (CH), 139.4 (CH), 141.4 (CH), 146.4, 149.7, 160.6;
HRMS ESI Obsd, m/z 301.0806; calcd for C13H14N2O5Na,
m/z 301.0800 [MCNa]C; UV (MeOH) lmax 284 nm.
6.5.4. 1-[(E)-4,5-dihydroxy-2-pentenyl]-5-fluoro-2,4(1H,
3H)-pyrimidinedione (9d). Eluant CH2Cl2/MeOH 8/2;
yield 97%; pale yellow gum; 1H NMR (DMSO-d6) d
3.14–3.32 (m, 2H), 3.94–3.99 (m, 1H), 4.18–4.35 (m, 2H),
4.61 (t, OH, JZ5.6 Hz), 4.85 (d, OH, JZ4.8 Hz), 5.62–5.78
(m, 2H), 7.99 (d, 1H, JZ6.6 Hz), 11.77 (brs, NH); 13C NMR
(DMSO-d6) d 48.6 (CH2), 65.7 (CH2), 71.3 (CH), 123.6
(CH), 129.5 (CH), 135.7 (CH), 139.6 (C–F), 149.4, 157.2;
HRMS ESI Obsd, m/z 253.1957; calcd for C9H11FN2O4Na,
m/z 253.1953 [MCNa]C; UV (MeOH) lmax 270 nm.
6.5.10. 1-[(E)-4,5-dihydroxy-2-pentenyl]-5-(2-thienyl)-
2,4(1H,3H)-pyrimidinedione (18b). Eluant CH2Cl2/
MeOH 9/1; yield 90%; pale yellow gum; 1H NMR
(DMSO-d6) d 3.19–3.32 (m, 2H), 3.88–4.02 (m, 1H),
4.31–4.48 (m, 2H), 4.60 (t, OH, JZ5.7 Hz), 4.86 (d, OH,
JZ5.0 Hz), 5.68–5.85 (m, 2H), 7.06 (dd, 1H, JZ4.2 Hz),
7.44 (d, 2H, JZ4.2 Hz), 8.21 (s, 1H), 11.65 (s, NH); 13C
NMR (DMSO-d6) d 48.8 (CH2), 65.7 (CH2), 71.3 (CH),
107.9, 122.6 (CH), 124.0 (CH), 125.5 (CH), 126.4 (CH),
133.9, 135.6 (CH), 140.7 (CH), 149.7, 161.8; HRMS ESI
Obsd, m/z 317.0572; calcd for C13H14N2O4NaS, m/z
317.0572 [MCNa]C; UV (MeOH) lmax 260, 324 nm.
6.5.5. 1-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-
2,4(1H,3H)-pyrimidinedione (10a). Eluant CH2Cl2/
MeOH 9/1; yield 98%; pale yellow gum; 1H NMR
(DMSO-d6) d 3.94 (d, 2H, JZ5.0 Hz), 4.03 (d, 2H,, JZ
5.3 Hz), 4.38 (d, 2H,, JZ7.0 Hz), 4.75 (t, OH, JZ5.0 Hz),
4.82 (t, OH, JZ5.3 Hz), 5.44 (t, 1H, JZ7.0 Hz), 5.55 (d,
1H, JZ7.2 Hz), 7.59 (d, 1H, JZ7.2 Hz), 11.24 (s, NH); 13C
NMR (DMSO-d6) d 44.2 (CH2), 56.9 (CH2), 62.4 (CH2),
101.1 (CH), 118.7 (CH), 144.7, 145.3 (CH), 150.9, 163.7;
HRMS ESI Obsd, m/z 235.0690; calcd for C9H12N2O4Na,
m/z 235.0695 [MCNa]C; UV (MeOH) lmax 265 nm.
6.5.11. 5-(2-Furyl)-1-[4-hydroxy-3-(hydroxymethyl)-2-
butenyl]-2,4(1H,3H)-pyrimidinedione (19a). Eluant
CH2Cl2/MeOH 9/1; yield 96%; pale yellow gum; 1H
NMR (DMSO-d6) d 3.95 (d, 2H,, JZ4.4 Hz), 4.05 (d, 2H,
JZ5.1 Hz), 4.51 (d, 2H, JZ6.6 Hz), 4.78–4.84 (m, OH !
2), 5.47 (t, 1H, JZ6.6 Hz), 6.21–6.22 (m, 1H), 6.79–6.81
(m, 1H), 7.34–7.36 (m, 1H), 7.90 (s, 1H), 11.59 (s, NH); 13C
NMR (DMSO-d6) d 44.7 (CH2), 57.0 (CH2), 62.4 (CH2),
105.0, 108.8 (CH), 109.5 (CH), 118.9 (CH), 139.2 (CH),
144.7 (CH), 145.9, 149.8, 152.4, 160.5; HRMS ESI Obsd,
m/z 301.2647; calcd for C13H14N2O5Na, m/z 301.2642 [MC
Na]C; UV (MeOH) lmax 284 nm.
6.5.6. 1-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-5-
methyl-2,4(1H,3H)-pyrimidinedione (10b). Eluant
CH2Cl2/MeOH 9/1; yield 97%; pale yellow gum; 1H
NMR (DMSO-d6) d 1.74 (s, 3H), 3.94 (d, 2H, JZ5.0 Hz),
4.03 (d, 2H,, JZ5.3 Hz), 4.35 (d, 2H,, JZ7.0 Hz), 4.72 (t,
OH, JZ5.0 Hz), 4.80 (t, OH, JZ5.3 Hz), 5.43 (t, 1H, JZ
7.0 Hz), 7.47 (s, 1H), 11.22 (s, NH); 13C NMR (DMSO-d6) d
11.9 (CH3), 43.9 (CH2), 56.9 (CH2), 62.4 (CH2), 108.7,
118.9 (CH), 141.0, 144.4 (CH), 150.9, 164.3; HRMS ESI

544
F. Amblard et al. / Tetrahedron 61 (2005) 537–544
10. (a) Lee, M.-G.; Du, J. F.; Chun, M. W.; Chu, C. K. J. Org.
Chem. 1997, 62, 1991–1995. (b) Lee, M.-G.; Lee, D.; Zhao,
Y.; Newton, M. G.; Chun, M. W.; Chu, C. K. Tetrahedron Lett.
1995, 36, 3499–3506.
6.5.12. 1-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-5-
(2-thienyl)-2,4(1H,3H)-pyrimidinedione (19b). Eluant
CH2Cl2/MeOH 9/1; yield 93%; pale yellow gum; 1H
NMR (DMSO-d6) d 3.96 (d, 2H, JZ5.0 Hz), 4.07 (d, 2H,
JZ5.3 Hz), 4.50 (d, 2H, JZ7.0 Hz), 4.77–4.83 (m, OH !
2), 5.53 (t, 1H, JZ7.0 Hz), 7.05 (dd, 1H, JZ3.8, 5.0 Hz),
7.43 (t, 2H, JZ5.0 Hz), 8.25 (s, 1H), 11.65 (s, NH); 13C
NMR (DMSO-d6) d 44.8 (CH2), 56.9 (CH2), 62.4 (CH2),
107.8, 118.9 (CH), 122.5 (CH), 125.5 (CH), 126.4 (CH),
133.9, 140.8 (CH), 144.8, 149.8, 161.7; HRMS ESI Obsd,
m/z 317.0574; calcd for C13H14N2O4NaS, m/z 317.0572
[MCNa]C; UV (MeOH) lmax 260, 324 nm.
11. For recent reviews see: (a) Schuster, M.; Blechert, S. Angew.
Chem. Int. Ed. Engl. 1997, 36, 2037–2056. (b) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012–3043. (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (d)
Buchmeiser, M. R. Chem. Rev. 2000, 100, 1565–1604.
12. Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003,
103, 1875–1916.
13. Amblard, F.; Nolan, S. P.; Gillaizeau, I.; Agrofoglio, L. A.
Tetrahedron Lett. 2003, 44, 9177–9180.
14. Coe, D. M.; Roberts, S. M.; Storer, R. J. Chem. Soc., Perkin
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Acknowledgements
´
15. Goux, C.; Sigismondi, S.; Sinou, D.; Perez, M.; Moreno-
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9521–9534.
We thank J. Grier, M. Bennett and K. Rapp for excellent
technical assistance. L. A. A. thanks the CNRS and MENRT
for financial support. F. A. thanks the MENRT for a PhD
fellowship. For work performed at the University of New
Orleans, S. P. N. gratefully acknowledges the National
Science Foundation for generous support. R. F. S. was
supported by Emory’s Center for AIDS Research NIH grant
2P30-AI-50409 and by the Department of Veterans Affairs.
16. Crowe, W. E.; Zhang J. Am. Chem. Soc. 1993, 115,
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