Straightforward synthesis of labeled and unlabeled pyrimidine d4Ns via 2′,3′-diyne seco analogues through olefin metathesis reactions

Article abstract of DOI:10.1002/ejoc.200390107

The synthesis of dideoxynucleosides (ddNs) or didehydro-dideoxynucleosides (d4Ns) from nucleosides has been extensively reviewed. While previously described methods are based on the modification of the 2′- and/or 3′-OH group of the intact ribose moiety, t

Full text of DOI:10.1002/ejoc.200390107

FULL PAPER
Straightforward Synthesis of Labeled and Unlabeled Pyrimidine d4Ns via
2Ј,3Ј-Diyne seco Analogues through Olefin Metathesis Reactions
Isabelle Gillaizeau,[a][‡] Irene M. Lagoja,[b][‡] Steve P. Nolan,[c] Vincent Aucagne,[a]
Jef Rozenski,[b] Piet Herdewijn,[b] and Luigi A. Agrofoglio*[a]
Keywords: Ring-closing metathesis / Alkynes / Nucleosides / Isotopic labeling
The synthesis of dideoxynucleosides (ddNs) or didehydro-di-
a straightforward synthesis of 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxy-
deoxynucleosides (d4Ns) from nucleosides has been extens- uridine (d4U) and [1Ј,2Ј,3Ј,4Ј,5Ј-13C5,6-13C,1,3-15N2]d4T us-
ively reviewed. While previously described methods are
based on the modification of the 2Ј- and/or 3Ј-OH group of
ing the RCM protocol. This paper discusses the preparation
of nucleoside dienes and the activity of ruthenium-based
the intact ribose moiety, the use of a ring-closing metathesis metathesis catalysts.
(RCM) for the formation of the unsaturated cyclic system of
nucleosides could be a straightforward approach to the d4Ns.
Thus, as part of our drug labeling program, this paper reports
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
This finding has triggered new developments in the chem-
istry of these and related compounds and analogues.[2] For
instance, labeled nucleosides, recently reviewed by Lagoja et
al.[3a] and Milecki et al.,[3b] are of great interest for pharma-
cokinetics studies by NMR spectroscopy. In fact, NMR
analysis has not only yielded atomic resolution structures
of macromolecules in solution but has also enabled the
study of living systems, giving rise to whole new fields in-
cluding in vivo NMR spectroscopy[4] and magnetic reson-
ance imaging (MRI). The power of in vivo NMR spectro-
scopy lies not in determining structures de novo, but in ob-
serving changes in the structures of biological macromolec-
ules and in their interaction with other cellular components.
These techniques rely extensively on the introduction of iso-
topically labeled molecules. A new high-yielding ring con-
traction has recently been discovered and is the key inter-
mediate for a straightforward synthesis of [1Ј,2Ј,3Ј,4Ј,5Ј-
13C5,6-13C,1,3-15N2]d4T. Nevertheless, improvements in the
efficiency of the synthesis of those d4Ns are still a particu-
larly important issue due to the need to limit costs but also
to develop several corresponding 13C- and/or 15N-con-
taining analogues.[5]
The synthesis of dideoxynucleosides (ddNs) or didehy-
dro-dideoxynucleosides (d4Ns) from nucleosides has been
extensively reviewed.[6] It has been mainly achieved through
a radical reaction (Barton deoxygenation),[7] a fragmenta-
tion of 2Ј,3Ј-cyclic orthoformates (Eastwood olefination)[8]
or 2Ј,3Ј-cyclic thionocarbonates (CoreyϪWinter reac-
tion),[9] a reductive elimination of 2Ј(3Ј)-acetoxy-3Ј(2Ј)-halo
derivatives (Mattocks reaction),[10] a deoxygenation of 5Ј-
O-protected nucleoside 2Ј,3Ј-dimesylate by treatment with
Te2Ϫ or ArSeϪ,[11] stereoselective coupling from 2-phenyl-
In recent years, a number of dideoxynucleosides, such as
ddC (2Ј,3Ј-dideoxycytidine, 1), ddI (2Ј,3Ј-dideoxyinosine,
2), d4T (2Ј,3Ј-didehydro-3Ј-deoxythymidine, 3), 3TC (β--
3Ј-deoxy-3Ј-thicytidine, 4), and AZT (3Ј-azido-3Ј-deoxythy-
midine, 5), have been approved by the FDA as potent and
selective anti-HIV agents[1] (Figure 1).
Figure 1. Structures of ddC (1), ddI (2), d4T (3), 3TC (4), and
AZT (5)
[a]
Institut de Chimie Organique et Analytique (I.C.O.A), CNRS
´
´
UMR-6005, Universite d’Orleans,
´
B. P. 6759, 45067 Orleans, France
Laboratory of Medicinal Chemistry, Rega Institute for Medical
Research, Katholieke Universiteit Leuven,
[b]
Minderbroedersstraat 10, 3000 Leuven, Belgium
Department of Chemistry, University of New Orleans,
New Orleans, LA 70148, USA
[c]
[‡]
Both authors contributed equally.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
666
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0666 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 666Ϫ671

Synthesis of Labeled and Unlabeled Pyrimidine d4Ns
FULL PAPER
seleno[12] or 2Ј-phenylsulfeno sugars.[13] While those
Having in hand the dialdehydes (7a and 7b), our first aim
methods are based on the modification of the 2Ј- and/or 3Ј- (pathway A) was to synthesize the diene 13a directly from
OH group of the intact ribose moiety, the use of a ring- the corresponding dialdehyde 7a (Scheme 2).
closing metathesis (RCM) Ϫ a promising tool in nucleoside
chemistry[14Ϫ16] Ϫ for the formation of the unsaturated
cyclic system of nucleosides could be a straightforward ap-
proach to d4Ns. Incidentally, it is noteworthy that during
the course of our investigation, Ewing et al.[16] reported a
similar approach to unlabelled d4T. Thus, as part of our
drug labeling program, this contribution reports a straight-
forward synthesis of 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxyuridine
(d4U) and [1Ј,2Ј,3Ј,4Ј,5Ј-13C5,6-13C,1,3-15N2]d4T. This pa-
per exemplifies also the activity of ruthenium-based meta-
thesis catalysts.[17]
Results and Discussion
Uridine (6) was converted into the dialdehyde 7a by a
reported method (Scheme 1).[18] For the labeled counterpart
7b, after acetylation of [13C6]--glucose (8) to the corres-
ponding [13C6]pentaacetyl--glucose (9), a Vorbrüggen con-
densation with [6-13C,1,3-15N2]thymine was carried out to
obtain
[1Ј,2Ј,3Ј,4Ј,5Ј,6Ј-13C6]-(2Ј,3Ј,4Ј,6Ј-tetraacetyl-β--
glucopyranosyl)-[6-13C,1,3-15N2]thymine (10). After depro-
tection to the corresponding β--glucopyranoside (11),
monomethoxytritylation yielded the 1Ј,6Ј-substituted β--
glucopyranoside (12). Oxidative ring opening by cleavage of
the α-glycol group with periodic acid or with lead tetraacet-
ate has been described by Malaprade[19a] and Criegee,[19b]
respectively. Thus, to obtain the nucleoside dialdehyde
(7b)[20] from the corresponding 6Ј-protected glucopyrano-
side (12), an oxidation with 3 equiv. of lead tetraacetate was
carried out.
Scheme 2. Compounds indicated with * are fully 13C-labeled at the
sugar moiety and at the 6-13C and 1,3-15N2 positions on the base;
reagents: (i) Ph3PϩCH3BrϪ, 12-crown-4, nBuLi, THF, Ϫ78 °C to
room temp. 2 d; 18%; (ii) 3 equiv. CH3COC(N2)P(O)(OMe)2, 4
equiv. K2CO3, MeOH, 0 °C to room temp., 14a: 79%, 14b*: 70%;
(iii) H2, Lindlar Pd, quinoline, room temp. 18 h, 13a: 78%, 13b*:
82%; (iv) Nolan’s catalyst (17, 10 mol %), benzene, reflux, 4.5 h,
15a: 89%, 15b*: 90%; (v) Dowex 50 W, Hϩ form in MeOH, room
temp. 1 h, 16a: 86%, 16b*: 85%
Several attempts (Table 1) were carried out in order to
obtain the diolefins 13 under optimized conditions.
The overall yield remained very low despite employing
several strategies, such as the classical Wittig olefination
conditions (Ph3PϩCH3BrϪ, nBuLi, THF, Ϫ78 °C to room
temp.) (Entry 1), an alkene synthesis using CH2Br2/Zn in
the presence of a Lewis acid (Entry 2),[21] the Peterson reac-
tion (Entry 3),[22] or the use of the Tebbe reagent (Entry
4).[23] By performing the olefination step with
Ph3PϩCH3BrϪ and tBuOK in toluene (Entry 5), we ob-
tained a mixture of inseparable isomers in a 6:4 ratio, even
at low temperature. We presume that as the proton 1Ј-H is
very labile, the isomerisation at the anomeric position oc-
curs in alkaline media. The ratio of α- and β-isomers was
1
readily determined by H NMR spectroscopy. The best re-
sults were obtained by performing a Wittig olefination
(Ph3PϩCH3BrϪ, nBuLi, THF, Ϫ78 °C to room temp.) in
the presence of a catalytic amount of 12-crown-4 (Entry
6).[24] Under these conditions, the desired diene 8a was isol-
ated as a single isomer (β-isomer) but in only 18% yield.
Nevertheless, this optimized Wittig olefination with tri-
phenylphosphonium bromide is not efficient enough for la-
beling purposes.
Scheme 1. Compounds indicated with * are fully 13C-labeled at the
sugar moiety and at the 6-13C and 1,3-15N2 positions on the base;
reagents: (i) Ac2O, pyridine 98%; (ii) [6-13C,1,3-15N2]thymine, BSA,
TMSOTf, ClCH2CH2Cl, 98%; (iii) NH3/MeOH, 98%; (iv)
MMTrCl, pyridine, Et3N, 98%; (v) Pb(OAc)4, CH2Cl2, 92%
Eur. J. Org. Chem. 2003, 666Ϫ671
667

L. A. Agrofoglio et al.
FULL PAPER
Table 1. Preparation of olefin 13a and diyne 14a from dialdehyde 7a
Entry
Substrate
Product (yield)
Conditions
1
2
3
4
5
6
7
7a
7a
7a
7a
7a
7a
7a
13a (Ͻ 5%)
Ph3PϩCH3BrϪ, nBuLi, THF, Ϫ78 °C to room temp.
CH2Br2, Zn (with or without TiCl4)
1) TMSCH2MgCl; BF3·Et2O
13a (Ͻ 5%)
13a (Ͻ 5%)
13a (Ͻ 5%)
Cp2Ti(µ-Cl)(µ-CH2)AlMe2, THF
13a (10%) α/β ϭ 4:6[a]
13a (18%)
Ph3PϩCH3BrϪ, tBuOK, toluene, Ϫ78 °C to room temp.
Ph3PϩCH3BrϪ, nBuLi, 12-crown-4, THF, Ϫ78 °C to room temp.
14a (79%) α/β ϭ 20:80[a]
3 equiv. CH3COC(N2)P(O)(OMe)2, 4 equiv. K2CO3, MeOH, 0 °C to room temp.
[a]
Mixture of isomers separable in the last step.
In an attempt to increase the yield of the diene, we envis-
aged an alternative synthesis using the partial reduction of
the corresponding diyne (pathway B). Based on work first
described by Ohira,[25] the dialdehyde 7a or 7b was trans-
formed into the corresponding diyne (14a or 14b) upon re-
action with the in situ generated anion of dimethyl diazom-
ethylphosphonate, which was prepared by acyl cleavage of
dimethyl (1-diazo-2-oxopropyl)phosphonate [CH3COC-
(N2)P(O)(OMe)2] under argon.[26] This mild method has
been applied previously, without any reported racemization,
for the functionalization of chiral α-alkoxy aldehydes[27] or
chiral α-amino aldehydes.[28] To the best of our knowledge,
this is the first time that this method has been used to gen-
erate a diyne from a dialdehyde compound, and applied to
nucleoside chemistry. Thus, the dialdehyde (7a or 7b) was
treated with 3 equiv. of dimethyl (1-diazo-2-oxopropyl)pho-
sphonate in methanol in the presence of 4 equiv. of K2CO3
at 0Ϫ23 °C for 5 h (Entry 7, Table 1). The diacetylene deriv-
ative (14a or 14b) was isolated in good yield but as a mix-
ture of α- and β-isomers in a 17:83 ratio. Despite various
optimization experiments where solvent (1-propanol, but-
anol), temperature and quantities or nature of the base
(K2CO3, Cs2CO3) were modified, racemization was always
observed. Although the mixture of β- and α-isomers could
not be separated by classical chromatography techniques at
this stage, the desired β-d4Ns (16a and 16b) could be isol-
ated, without any problem, during the last step of this syn-
thesis. A catalytic hydrogenation of (14a or 14b) using Lind-
lar catalyst in the presence of quinoline afforded the desired
diene 13a or 13b.
Figure 2. Ruthenium catalysts for RCM
acidic hydrolysis (Dowex 50 W, Hϩ form in MeOH, 86%)
afforded, after a chromatographic purification, the β--d4U
(16a) as a unique stereoisomer. This approach (pathway B)
has been successfully applied to the synthesis of labeled
[1Ј,2Ј,3Ј,4Ј,5Ј-13C5,6-13C,1,3-15N2]d4T (16b, Figure 3). The
final compounds 16a,b have similar optical and physical
data to the known unlabeled species.
Figure 3. 13C NMR spectrum of labeled d4T (125 MHz,
[D4]MeOH)
With diene 13, as the unique isomer (or as an α/β mix-
ture) at hand, we turned our attention to establishing the
best conditions for ring-closing metathesis. In this area,
ring-closing metathesis has mainly been applied to the syn-
thesis of oxacycloalkenes.[29] Based on our previous results
Conclusion
illustrating
the
user-friendly
character of
new
rutheniumϪcarbene species bearing one imidazol-2-ylidene
In summary, we have described the preparation of
ligand (17, Figure 2) and on its known tolerance towards enantiomerically pure unsaturated nucleosides such as
an array of polar groups (particularly the amide group), 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxyuridine (d4U) and labeled
we were prompted to probe the performance of 17 in this [1Ј,2Ј,3Ј,4Ј,5Ј-13C5,6-13C,1,3-15N2]d4T, using an RCM strat-
particular application. RCM of the bis(olefinic) compound egy. We have realized the direct preparation of a diyne from
13 to the corresponding oxacycloalkene 15 was carried out a dialdehyde using a mild and very useful method that cer-
successfully in benzene at 80 °C with 10 mol % of 17 in tainly warrants further study. The ring-closing metathesis,
89% yield.[30]
which was performed with 17, represents an excellent tool
Finally, deprotection of the unlabeled 2Ј,3Ј-didehydro- for RCM by combining the activity of the classical molyb-
2Ј,3Ј-dideoxy-5Ј-O-monomethoxytrityluridine (15a), by denum systems with the stability and tolerance of ruth-
668
Eur. J. Org. Chem. 2003, 666Ϫ671

Synthesis of Labeled and Unlabeled Pyrimidine d4Ns
FULL PAPER
C), 163.5 (d, J ϭ 12 Hz, 4-C), 169.5, 169.6, 169.7, 170.5 (4 ϫ Cϭ
O) ppm. Exact mass: C12*C7H24*N2O11Na: calcd. 488.1452;
found 488.1460.
enium-based catalysts. This straightforward procedure of-
fers an alternative and valuable method that can be applied
to the synthesis of related labeled pyrimidine and purine
nucleosides and analogues. This area of investigation is cur-
rently ongoing in our laboratories.
[1Ј,2Ј,3Ј,4Ј,5Ј,6Ј-13C6]-(β- -Glucopyranosyl)-[6-13C,1,3-15N2]thymine
D
(11): A solution of the tetra-O-acetyl protected nucleoside (10;
4.2 mmol) in MeOH (10 mL) saturated with NH3 was stirred over-
night at ambient temperature. After removal of the solvent in vacuo
the precipitate was recrystallized from dichloromethane. Yield: 1.17
(98%). Rf (CH2Cl2/MeOH, 2:1) ϭ 0.76. M.p. 270Ϫ271 °C (MeOH).
13C NMR (125 MHz, [D6]DMSO): δ ϭ 12.1 (s, CH3), 60.9 (d, J ϭ
43 Hz, 6Ј-CH), 69.6 (t, J ϭ 43 Hz, 4Ј-CH), 70.8 (t, J ϭ 43 Hz, 2Ј-
CH), 77.0 (t, J ϭ 43 Hz, 3Ј-CH), 80.0 (t, J ϭ 43 Hz, 5Ј-CH), 82.4
(dd, J ϭ 14, J ϭ 45 Hz, 1Ј-CH), 109.7 (dd, J ϭ 6, J ϭ 64 Hz, 5-
CH), 137.0 (d, J ϭ 12 Hz, 6-CH), 151.3 (t, J ϭ 12 Hz, 2-C), 164.1
(d, J ϭ 11 Hz, 4-C) ppm. 15N NMR (50 MHz, [D6]DMSO): δ ϭ
Experimental Section
Materials and General Methods: THF and benzene were distilled
from sodium/benzophenone ketyl immediately prior to use. Dichlo-
romethane and dichloroethane were distilled from CaH2 and meth-
anol from magnesium turnings. The starting products are commer-
cially available. Isotopically labeled materials were obtained from
Campro Scientific. [6-13C,1,3-15N2]thymine[31]
, [1Ј,2Ј,3Ј,4Ј,5Ј,6Ј-
*
143.0 (N-1), 157.9 (N-3) ppm. Exact mass: C3 C7H17*N2O7: calcd.
13C6]-(2Ј,3Ј,4Ј,6Ј-tetraacetyl-β--glucopyranose (9)[32] and (mono-
methoxytrityl)uridinedialdehyde (7a)[33] were prepared according to
literature procedures. The reactions were monitored by thin-layer
chromatography (TLC) analysis on silica gel plates (Kieselgel 60
284.1055; found 284.1061.
[1Ј,2Ј,3Ј,4Ј,5Ј,6Ј-13C6]-6Ј-O-Monomethoxytrityl-(β-
D-glucopyr-
anosyl)-[6-13C,1,3-15N2]thymine (12): A mixture of glucopyranosyl-
nucleoside (11; 1.0 g, 3.5 mmol), and MMTrCl (2.16 g, 7.0 mmol)
in pyridine (20 mL) and triethylamine (5 mL) was stirred under an
inert gas at ambient temperature for 48 h. After removal of the
solvent in vacuo, the resultant oil was coevaporated with toluene
(4 ϫ 2 mL). The resultant foam was purified by column chromato-
graphy (silica gel, CH2Cl2/MeOH, 9:1). Yield: 1.95 g (98%); Rf
(CH2Cl2/MeOH, 9:1) ϭ 0.56. M.p. 170Ϫ172 °C (CH2Cl2). 13C
NMR (125 MHz, [D6]DMSO): δ ϭ 12.6 (s, CH3), 55.1 (s, CH3O),
64.0 (d, J ϭ 45 Hz, 6Ј-CH), 69.8 (t, J ϭ 45 Hz, 4Ј-CH), 70.7 (t,
J ϭ 45 Hz, 2Ј-CH), 76.9 (t, J ϭ 45 Hz, 3Ј-CH), 78.0 (t, J ϭ 45 Hz,
5Ј-CH), 82.4 (d ϫ d, J1 ϭ 14, J2 ϭ 45 Hz, 1Ј-CH), 85.8 (C, MMTr),
109.6 (d ϫ d, J1 ϭ 12, J2 ϭ 64 Hz, 5-CH), 113.3 (s, 2 CH, AAЈBBЈ,
MMTr), 126.9Ϫ130.3 (CAr, MMTr), 135.4 (s, 1 C, AAЈBBЈ,
MMTr), 136.8 (d, J ϭ 12 Hz, 6-CH), 144.7 (s, 2 ϫ 1 C, MMTr),
151.3 (t, J ϭ 12 Hz, 2-C), 158.3 (s, 4 C, AAЈBBЈ, MMTr), 163.3
(d, J ϭ 11 Hz, 4-C) ppm. Exact mass: C24*C7H32*N2O8Na: calcd.
592.2232; found 592.2297.
F254, E. Merck). Compounds were visualized by UV irradiation
and/or spraying with a solution of phosphomolybdic acid, followed
by charring at 150 °C. Column chromatography was performed on
Silica Gel 60 M (0.040Ϫ0.063 mm, E. Merck). Melting points were
determined with a Büchi SMP-20 capillary melting point appar-
1
atus. H and 13C NMR spectra were recorded with a Bruker AV-
ANCE DPX 250 Fourier Transform spectrometer at 250 MHz
(13C, 62.9 MHz), or with a Varian Unity 500 spectrometer (13C,
125.527 MHz, 15N, 50.586 MHz). 13C data are referenced to TMS
and 15N data to liquid NH3. Mass spectra were recorded with
PerkinϪElmer SCIEX API-300 (heated nebulizer) spectrometer.
HRMS spectra were recorded at the Rega Institute, Katholieke
Universiteit Leuven, using a quadrupole time-of-flight mass spec-
trometer (Q-Tof-2, Micromass, Manchester, UK) equipped with a
standard electrospray ionization (ESI) interface. Samples were in-
fused in a 2-propanol/water (1:1) mixture at 3 µL/min. HPLC to
purify d4T was performed on an HS Prep100 BDS C18 8u (250 ϫ
10 mm) column, using H2O/MeOH (93:7) as eluent. The nomen-
clature of the obtained compounds is in accordance with the
IUPAC rules and was checked with Autonome.[34] The numbering
and assignment of the chemical shifts for compounds 13 and 14
are related to the corresponding ribose derivatives. PE ϭ petro-
leum ether.
[1Ј,2Ј,3Ј,4Ј,5Ј-13C5]-5Ј-O-Monomethoxytrityl-[6-13C,1,3-15N2]thymi-
dinedicarbaldehyde (7b): Pb(OAc)4 (4.21 g, 9.5 mmol) was added
under nitrogen and with ice cooling to a solution of the 1Ј,6Ј-disub-
stituted β--glucopyranoside (12; 1.8 g, 3.17 mmol) in dry CH2Cl2
(30 mL) and Et3N (1 mL). The solution became warm and turned
yellow. After 2 h, a colorless precipitate of Pb(OAc)2 was formed.
Stirring was continued at room temperature for another 5 h. After
reducing the volume of the solvent in a rotary evaporator, the res-
idue was purified by column chromatography (silica gel, CH2Cl2/
MeOH, 95:5). MS measurements confirmed the structure of the
resultant foam. Because of the complicated equilibrium observed
by NMR spectroscopy it was not possible to interpret the NMR
spectra in a straightforward way. Yield: 1.52 g (92%). Rf (CH2Cl2/
MeOH, 95:5) ϭ 0.74. Exact mass: C23*C6H26*N2O8Na: calcd.
545.1774; found 545.1766.
[1Ј,2Ј,3Ј,4Ј,5Ј,6Ј-13C6]-(2Ј,3Ј,4Ј,6Ј-Tetraacetyl-β-
D-glucopyranosyl)-
[6-13C,1,3-15N2]-thymine (10): BSA (2.4 mL, 10 mmol) was added
to a suspension of [6-13C,1,3-15N2]thymine (0.50 g, 4.27 mmol) and
[13C6]glucosepenta-O-acetate (9; 1.63 g, 4.27 mmol) in dichloroe-
thane (40 mL). The mixture was stirred under nitrogen at ambient
temperature for 20 min to give a clear and colorless solution. After
addition of TMSOTf (3.60 mL, 20 mmol) under nitrogen the reac-
tion mixture was heated under reflux for 4 h. The resultant brown
mixture was cooled to ambient temperature and the solvents were
evaporated in vacuo to give an oil, which was diluted in ethyl acet-
ate (200 mL) and washed with NaHCO3 (sat.) (150 mL) and brine 1-[1-({1-[(Monomethoxytrityl)methyl]-2-propenyl}oxy)-2-propenyl]-
(2 ϫ 100 mL). After drying with Na2SO4 and evaporating the solv-
ent, the resultant oil was purified by column chromatography (silica
gel, EtOAc/PE, 2:1). Yield: 1.95 g (98%). Rf (EtOAc/PE, 3:2) ϭ
0.70. M.p. 156Ϫ158 °C (MeOH). 13C NMR (125 MHz, CDCl3):
uracil (13a) by Wittig Reaction: nBuLi (0.94 mL, 1.6  in n-hexane)
was slowly added to a stirring solution of Ph3PϩCH3BrϪ (5.2 g,
14.6 mmol) and 12-crown-4 (0.51 g, 2.89 mmol) in THF (50 mL)
under argon at Ϫ78 °C. The mixture was allowed to reach 0 °C,
δ ϭ 12.2 (s, CH3), 20.2, 20.3, 20.4, 20.6 (4 ϫ CH3 Ac), 61.5 (d, then cooled again to Ϫ78 °C and a solution of the crude dialdehyde
J ϭ 44 Hz, 6Ј-CH2), 67.8 (t, J ϭ 44 Hz, 4Ј-CH), 69.2 (t, J ϭ 44 Hz, 7a (2.92 mmol) in THF (5 mL) was added. The reaction mixture
2Ј-CH), 72.7 (t, J ϭ 44 Hz, 3Ј-CH), 75.0 (t, J ϭ 44 Hz, 5Ј-CH), was stirred for 48 h at room temperature, then water was added
80.3 (dd, J ϭ 15, J ϭ 46 Hz, 1Ј-CH), 112.1 (d ϫ d, J ϭ 6, J ϭ
64 Hz, 5-CH), 134.5 (d, J ϭ 12 Hz, 6-CH), 150.6 (t, J ϭ 12 Hz, 2-
and the mixture extracted with CH2Cl2 (3 ϫ). Drying (MgSO4) of
the organic phase and removal of the solvent under vacuum gave
Eur. J. Org. Chem. 2003, 666Ϫ671
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L. A. Agrofoglio et al.
FULL PAPER
the crude product, which was then purified by column chromato-
graphy (silica gel, toluene/ethyl acetate, 7:3 with 1% of Et3N), to
give the diene 13a. Yield: 268 mg (18%), only β-isomer. Rf (PE/
drogenated (1 atm, room temp.) for 18 h. The reaction mixture was
filtered, and the solvents were evaporated from the filtrate. The
crude oil was purified by flash chromatography (silica gel, PE/
EtOAc, 1:1) ϭ 0.3. 1H NMR (250 MHz, CDCl3): δ ϭ 3.09 (dd, EtOAc, 3:2 then 2:3) to give the diene 13a (180 mg, 78%) or 13b.
J ϭ 3.1, J ϭ 10.3 Hz, 1 H, 5Ј-H), 3.34 (dd, 1 H, J ϭ 8.17, J ϭ
13b: Yield: 196 mg (82%), β/α stereoisomer (83:17). Rf (PE/EtOAc,
10.3 Hz), 3.78 (s, 3 H, CH3), 3.90 (m, 1 H, 4Ј-H), 5.27Ϫ5.35 (m, 3
1:1) ϭ 0.33. 13C NMR (50 MHz, CDCl3) (β-isomer): δ ϭ 65.8 (d,
H, 6Ј-H2, 7Ј-H1), 5.53Ϫ5.67 (m, 2 H, 3Ј-H, 7Ј-H1), 5.73 (s, 1 H, 5-
J5Ј4Ј ϭ 44.0 Hz, 5Ј-CH2), 78.4 (d,d, J4Ј3Ј ϭ 45.9, J4Ј5Ј ϭ 44.9 Hz,
H), 5.81 (ddd, 1 H, J ϭ 3.5, J ϭ 10.4, J ϭ 17.2 Hz, 2Ј-H), 6.26 (m,
4Ј-CH), 80.4 (dd, J1Ј2Ј ϭ 52.7, J1ЈN ϭ 12.7 Hz, 1Ј-CH), 132.8 (d,
1 H, 1Ј-H), 6.83 (m, 2 H, Ar), 7.15Ϫ7.47 (m, 12 H, Ar), 7.49 (d,
J3Ј4Ј ϭ 45.9 Hz, 3Ј-C), 133.6 (d, J2Ј1Ј ϭ 54.7, J1ЈN ϭ 12.7 Hz, 2Ј-
J ϭ 8.15 Hz, 1 H, 6-H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ
*
C), 135.6 (d, J6N ϭ 12.7 Hz, 6-CH) ppm. Exact mass: C26*C6H28
N2O5Na: calcd. 551.2038; found 551.2109.
55.3 (CH3O), 66.1 (5Ј-CH2), 78.5 (4Ј-CH), 80.4 (1Ј-CH), 86.7
(CIV, MMTr), 103.2 (5-CH), 113.1 (CH, ar), 119.3 (CH2ϭ), 120.9
(CH2ϭ), 127.1, 127.9, 128.4, 128.5, 130.4 (CH, Ar), 132.9 (2Ј-CH),
133.6 (3Ј-CH),135.4 (CIV), 140.9 (6-CH), 144.4, 151.2 (CIV), 158.7,
163.7 (CϭO) ppm. MS IS: m/z ϭ 533 [M ϩ Na]. Exact mass:
C31H30N2O5Na: calcd. 533.2052; found 533.2059. IR: ν˜max ϭ 2925,
RCM General Procedure:
A solution of diene 13a or 13b
(0.258 mmol) and ruthenium catalyst 17 (23 mg, 0.027 mmol) in
degassed benzene was refluxed for 4 h (until TLC showed complete
conversion of the substrate). Evaporation of the solvent followed
by flash chromatography (silica gel, PE/EtOAc, 1:1) provided com-
pound 15a or 15b.
1686, 1508, 1250, 1072 cmϪ1
.
1-[1-({1-[(Monomethoxytritylmethoxy)methyl]-2-propynyl}oxy)-2-
propynyl]uracil (14a) and [1Ј,2Ј,3Ј,4Ј,5Ј-13C5]-1-[1-({1-[(Monometh-
oxytritylmethoxy)methyl]-2-propynyl}oxy)-2-propynyl]-[6-13C,1,3-
15N2]thymine (14b). General Procedure: Anhydrous K2CO3
(244.5 mg, 1.77 mmol) was added to a solution of dry dialdehyde
7b (0.443 mmol) in dry MeOH (10 mL) at 0 °C under argon. After
stirring for 10 min, dimethyl (1-diazo-2-oxopropyl)phosphonate
(255 mg, 1.33 mmol) was added. The mixture was allowed to reach
room temperature and was stirred until TLC showed complete con-
version of the substrate (4 h). The reaction mixture was then di-
luted with ethyl acetate (25 mL) and washed with an aqueous solu-
tion of NaHCO3 (5%). The aqueous layer was washed with ethyl
acetate (3 ϫ), and the combined organic layers were dried with
anhydrous MgSO4, filtered and concentrated in vacuo. Purification
by flash chromatography (silica gel, PE/EtOAc, 3:2) gave the dial-
kyne 14 in 79% yield as an inseparable mixture of β/α stereoiso-
mers (80:20).
15a (β-isomer):[35] Yield: 111 mg (89%). Colorless syrup which so-
lidified on standing. Rf (PE/EtOAc, 1:1) ϭ 0.15. 1H NMR
(250 MHz, CDCl3): δ ϭ 3.45 (m, 2 H, 5Ј-H), 3.79 (s, 3 H, CH3),
4.95 (br. s, 1 H, 4Ј-H), 5.02 (d, J ϭ 8.1 Hz, 1 H, 5-H), 5.87 (m, 1
H, 3Ј-H), 6.35 (m, 1 H, 2Ј-H), 6.83 (d, J ϭ 8.8 Hz, 2 H, Ar), 7.01
(m, 1 H, 1Ј-H), 7.22Ϫ7.45 (m, 12 H, Ar), 7.81 (d, J ϭ 8.3 Hz, 1 H,
6-H), 8.44 (br. s, 1 H, NH) ppm. 13C NMR (62.9 MHz, CDCl3):
δ ϭ 55.3 (CH3O), 64.4 (5Ј-CH2), 86.05 (4Ј-CH), 87.2 (CIV, MMTr),
89.7 (1Ј-CH), 102.3 (5-CH), 113.3 (CH, Ar), 126.4 (3Ј-CH), 127.3,
128.05, 128.6, 130.6 (CH, Ar), 134.5 (CIV, Ar), 134.6 (2Ј-CH), 141.4
(6-CH), 143.5, 143.8, 150.9, 158.8, 163.6 ppm. MS IS: m/z ϭ 505
[M ϩ Na]. Exact mass: C29H26N2O5Na: calcd. 505.1739; found
505.1746. IR: ν˜max ϭ 3196, 3059, 2933, 2874, 2837, 1686, 1608,
25
1461, 1253 cmϪ1. [α]D ϭ 37.5 (c ϭ 0.12, CHCl3).
15b: Yield: 117 mg (90%), β/α stereoisomer (83:17). Rf (PE/EtOAc,
1:1) ϭ 0.17. 13C NMR (125 MHz, CDCl3) (β-isomer): δ ϭ 64.6 (d,
J5Ј4Ј ϭ 43.9 Hz, 5Ј-CH2), 85.7 (dt, J4Ј3Ј ϭ 41.2, J4Ј5Ј ϭ 42.0 Hz, 4Ј-
CH), 89.6 (dd, J1Ј2Ј ϭ 43.9, J1ЈN ϭ 12.7 Hz, 1Ј-CH), 126.2 (dd,
1
14a: Rf (PE/EtOAc, 1:1) ϭ 0.31. H NMR (250 MHz, CDCl3) (β-
isomer): δ ϭ 2.53 (d, J ϭ 2 Hz, 1 H, ϵCH), 2.76 (d, J ϭ 2 Hz, 1
H, ϵCH), 3.28 (dd, J ϭ 3.8, J ϭ 10.4 Hz, 1 H, 5Ј-H), 3.46 (dd,
J ϭ 7.8, J ϭ 10.4 Hz, 1 H), 3.77 (s, 6 H, CH3), 4.17 (m, 1 H, 4Ј-
H), 5.82 (d, J ϭ 8.1 Hz, 1 H, 5-H), 6.75 (d, J ϭ 2 Hz, 1 H, 1Ј-H),
6.79Ϫ6.85 (m, 3 H, Ar), 7.19Ϫ7.48 (m, 10 H, Ar), 7.64 (d, J ϭ
8.2 Hz, 1 H, 6-H) ppm. 13C NMR (62.9 MHz, CDCl3) (β-isomer):
δ ϭ 55.3 (CH3O), 65.7 (5Ј-CH2), 67.8 (4Ј-CH), 72.5 (1Ј-CH), 76.6
(ϵCH), 78.8 (CIV), 86.9 (CIV, MMTr), 104.1 (5-CH), 111.0 (ϵCH),
113.3 (CH, ar), 127.1, 128.0, 128.4, 128.5, 130.4 (CH, Ar), 140.2
(6-CH), 144.2, 150.3 (CIV), 158.8, 163.1 (CϭO) ppm. MS IS:
m/z ϭ 529 [M ϩ Na]. Exact mass: C31H26N2O5Na: calcd. 529.1739;
found 529.1735. IR: ν˜max ϭ 3190, 3058, 2944, 2836, 2129, 1690,
J1Ј2Ј ϭ 43.9, J2Ј3Ј ϭ 67.4 Hz, 2Ј-C), 134.8 (dd, J3Ј4Ј ϭ 41.2, J2Ј3Ј
ϭ
67.4 Hz, 3Ј-C), 136.1 (d, J6N ϭ 12.7 Hz, 6-CH) ppm. Exact mass:
C24*C6H28*N2O5Na: calcd. 527.2038; found 527.2040.
1-[5-(Hydroxymethyl)-2,5-dihydro-2-furanyl]uracil (d4U) (16a) and
[1Ј,2Ј,3Ј,4Ј,5Ј-13C5]-1-[5-(hydroxymethyl)-2,5-dihydro-2-furanyl]-[6-
13C,1,3-15N2]thymine (Labeled d4T) (16b): Activated Dowex 50 W
(Hϩ form) was added to a solution of 15a or 15b (0.107 mmol) in
methanol (2 mL). After complete conversion of the substrate (TLC
control), the insoluble materiel was filtered off, washed with meth-
anol and the solvents were evaporated from the filtrate. Purification
of the crude mixture by column chromatography (silica gel,
CH2Cl2/MeOH, 10:1) afforded the desired compounds.
1509, 1250 cmϪ1
.
14b: Yield: 163 mg (70%), β/α stereoisomer (83:17). Rf (PE/EtOAc,
1:1) ϭ 0.33. 13C NMR (125 MHz, CDCl3) (β-isomer): δ ϭ 65.6 (d,
J5Ј4Ј ϭ 44.9 Hz, 5Ј-CH2), 67.5 (d, d, d, J4Ј3Ј ϭ 75.2, J4Ј5Ј ϭ 44.9,
J4Ј2Ј ϭ 4.9 Hz, 4Ј-CH), 72.0 (dd, J1Ј2Ј ϭ 90.8, J1ЈN ϭ 12.7 Hz, 1Ј-
16a: Yield: 19.5 mg (86%). Rf (CH2Cl2/MeOH, 9:1) ϭ 0.3. Exact
mass: C9H10N2O4Na: calcd. 233.0538; found 233.0534. The
physicochemical data are identical with those reported in the liter-
ature.[35]
CH), 76.8 (dd, J2Ј1Ј ϭ 88.9, J1ЈN ϭ 12.7 Hz, 2Ј-C), 78.0 (d, J3Ј4Ј
ϭ
16b: Yield: 19.8 mg (80%) (HPLC), β stereoisomer. Rf (CH2Cl2/
MeOH, 1:1) ϭ 0.33. M.p. 164Ϫ166 °C (Et2O) (163Ϫ165 °C ben-
zene[36]). 13C NMR (125 MHz, [D4]MeOH) (β isomer): δ ϭ 63.7
(d, J5Ј4Ј ϭ 41.9 Hz, 5Ј-CH2), 88.9 (dt, J4Ј3Ј ϭ 40.0, J4Ј5Ј ϭ 41.0 Hz,
4Ј-CH), 91.0 (dd, J1Ј2Ј ϭ 43.9, J1ЈN ϭ 12.7 Hz, 1Ј-CH), 127.1 (dd,
75.2 Hz, 3Ј-C), 135.5 (d, J6N ϭ 12.7 Hz, 6-CH) ppm. Exact mass:
C26*C6H28*N2O5Na: calcd. 551.2038; found 551.2109.
1-[1-({1-[(Monomethoxytrityl)methyl]-2-propenyl}oxy)-2-propenyl]-
uracil (13a) or [1Ј,2Ј,3Ј,4Ј,5Ј-13C5]-1-[1-({1-[(monomethoxytrityl)-
methyl]-2-propenyl}oxy)-2-propenyl]-[6-13C,1,3-15N2]thymine (13b) J1Ј2Ј ϭ 43.9, J2Ј3Ј ϭ 69.3 Hz, 2Ј-C), 135.7 (dd, J3Ј4Ј ϭ 41.2, J2Ј3Ј
ϭ
by Hydrogenation. General Procedure: Quinoline (2 mL) and Lind-
lar Pd (10% w/w) were added to a solution of 14a or 14b
(0.453 mmol) in MeOH (10 mL). The resultant suspension was hy-
68.4 Hz, 3Ј-C), 138.8 (d, J6N ϭ 12.7 Hz, 6-CH). 15N NMR
(50 MHz, [D4]MeOH): δ ϭ 146.3 (N-1), 151.3 (N-3) ppm. Exact
*
mass: C4 C6H12*N2O4Na: calcd. 255.0851; found 255.0840.
670
Eur. J. Org. Chem. 2003, 666Ϫ671

Synthesis of Labeled and Unlabeled Pyrimidine d4Ns
FULL PAPER
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2000, 41, 7801Ϫ7803.
K. Lee, C. Cass, K. A. Jacobsen,
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spectra. This work was supported in part by the Agence Nationale
de Recherches sur le SIDA (ANRS) and by the SIDACTION. I.
M. L. is a research associate of the Rega foundation. For financial
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671