Synthesis and absolute configuration of novel N,O-psiconucleosides using (R)-N-phenylpantolactam as a resolution agent

Article abstract of DOI:10.1021/jo800769m

(Chemical Equation Presented) A series of novel N,O-psiconucleosides has been prepared in both enantiomeric forms by resolution of an advanced racemic synthetic intermediate using (R)-N-phenylpantolactam as a chiral resolution agent. The absolute configur

Full text of DOI:10.1021/jo800769m

Synthesis and Absolute Configuration of Novel N,O-Psiconucleosides
Using (R)-N-Phenylpantolactam as a Resolution Agent
Pelayo Camps,*,† Ta`nia Go´mez,† Diego Mun˜oz-Torrero,† Jordi Rull,† Laura Sa´nchez,†
Francesca Boschi,† Mauro Comes-Franchini,‡ Alfredo Ricci,*,‡ Teresa Calvet,§
Merce` Font-Bardia,§ Erik De Clercq, and Lieve Naesens
Laboratori de Qu´ımica Farmace`utica (Unitat Associada al CSIC), Facultat de Farma`cia and Institut de
Biomedicina (IBUB), UniVersitat de Barcelona, AV. Diagonal 643, E-08028 Barcelona, Spain, Department
of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy,
SerVeis Cient´ıfico-Te`cnics, UniVersitat de Barcelona, AV. Mart´ı Franque`s s/n, E-08028 Barcelona, Spain,
and Rega Institute for Medical Research, Katholieke UniVersiteit LeuVen, Minderbroedersstraat 10,
B-3000 LeuVen, Belgium
camps@ub.edu; ricci@ms.fci.unibo.it
ReceiVed April 7, 2008
A series of novel N,O-psiconucleosides has been prepared in both enantiomeric forms by resolution of
an advanced racemic synthetic intermediate using (R)-N-phenylpantolactam as a chiral resolution agent.
The absolute configuration of all of these compounds has been unequivocally established by chemical
correlation with the novel (R)- or (S)-1-methyl-5-phenylpyrrolidine-2,3-dione, prepared from the known
(R)- and (S)-1-methyl-5-phenylpyrrolidin-2-one, respectively.
Introduction
Pantolactone is an efficient chiral auxiliary in Diels-Alder
reactions.1 In sharp contrast, only a few examples of the use of
(R)-pantolactone as chiral auxiliary in 1,3-dipolar cycloadditions
have been described,2–4 and the attained levels of asymmetric
induction were low to moderate [10-50% diastereomeric
excesses (de)]. Several years ago we described the enantiose-
lective synthesis of (R)- and (S)-3-hydroxy-4,4-dimethyl-1-
phenylpyrrolidin-2-one [(R)- and (S)-N-phenylpantolactam, (R)-
and (S)-1, Figure 1] as novel chiral auxiliaries,5,6 related to
pantolactone, and their efficient use in asymmetric Diels-Alder
FIGURE 1. Structures of (R)-N-phenylpantolactam, (R)-1, and the N,O-
psiconucleosides developed by the groups of Merino, Chiacchio, and
Romeo.
reactions.7 However, (R)- and (S)-1 have never been used in
1,3-dipolar cycloadditions.
† Laboratori de Qu´ımica Farmace`utica and IBUB, Universitat de Barcelona.
‡ University of Bologna.
This fact, together with our experience in the enantioselective
synthesis of isoxazolidines through 1,3-dipolar cycloaddition
of (Z)-R-phenyl-N-methylnitrone with enantiopure allylic fluo-
rides under environmentally friendly conditions (microwave
irradiation and metal triflate catalysis)8 prompted us to consider
the use of N-phenylpantolactam as a chiral auxiliary in 1,3-
dipolar cycloadditions of nitrones with alkenes.
§ Serveis Cient´ıfico-Te`cnics, Universitat de Barcelona.
Katholieke Universiteit Leuven.
(1) Camps, P.; Mun˜oz-Torrero, D. Curr. Org. Chem. 2004, 8, 1339–1380.
(2) Faure´, J. -L.; Re´au, R.; Wong, M. W.; Koch, R.; Wentrup, C.; Bertrand,
G. J. Am. Chem. Soc. 1997, 119, 2819–2824.
(3) Savinov, S. N.; Austin, D. J. Org. Lett. 2002, 4, 1415–1418.
(4) Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J.
Org. Chem. 2001, 66, 8447–8453.
(5) Camps, P.; Gime´nez, S.; Font-Bardia, M.; Solans, X. Tetrahedron:
Asymmetry 1995, 6, 985–990.
(6) Camps, P.; Pe´rez, F.; Soldevilla, N. Tetrahedron Lett. 1999, 40, 6853–
6856.
(7) Camps, P.; Font-Bardia, M.; Gime´nez, S.; Pe´rez, F.; Solans, X.; Soldevilla,
N. Tetrahedron: Asymmetry 1999, 10, 3123–3138.
10.1021/jo800769m CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6657–6665 6657

Camps et al.
SCHEME 1. Retrosynthetic Analysis of the Novel
N,O-Psiconucleosides Based on (R)-N-Phenylpantolactam as
a Chiral Auxiliary
As a continuation of our recent interest on the use of (R)-
and (S)-1 as chiral auxiliaries for the synthesis of biologically
active compounds,9–11 we focused our attention on the synthesis
of a series of N,O-psiconucleosides (Figure 1) through 1,3-
dipolar cycloadditions of nitrones with alkenes. N,O-Psico-
nucleosides constitute a particular class of modified nucleosides
bearing a heterocyclic system (isoxazolidine) instead of the
ribose ring and branched at the anomeric carbon atom with a
hydroxymethyl group, which could share the antiviral or
anticancer activity observed for other N,O-nucleosides.12–15
To the best of our knowledge, the sole groups that have
reported the synthesis of N,O-psiconucleosides (Figure 1) both
in racemic16–19 and in enantiopure20 form are those of Chiacchio,
Romeo, and Merino, who developed a synthetic procedure based
on the 1,3-dipolar cycloaddition of a suitable nitrone with a
2-(acetoxy)acrylate, followed by a Vorbrüggen nucleosidation
and NaBH4 reduction of the ester group at the anomeric position
to a hydroxymethyl function. The 1,3-dipolar cycloadditions
carried out for the synthesis of these compounds proceeded with
cis/trans selectivities ranging from 2.5:1 to 8.6:1. The sole
example reported of enantioselective synthesis of N,O-psico-
nucleosides, which used a chiral nitrone derived from 2,3-O-
isopropylidene-D-glyceraldehyde, afforded a moderate diaste-
reofacial selectivity (anti/syn ) 2.6:1). However, the absolute
configuration of the isoxazolidine moiety was assumed on the
basis of a theoretical study of the cycloaddition reaction20 but
was not unequivocally established by X-ray diffraction analysis
of any intermediate or final product or by correlation with
compounds of known absolute configuration.
correlation of advanced enantiopure intermediates with (R)- or
(S)-1-methyl-5-phenylpyrrolidine-2,3-dione, whose preparation
from (R)- and (S)-1-methyl-5-phenylpyrrolidin-2-one21 is also
herein described.
Results and Discussion
First, to study the regio- and the endo/exo stereoselectivity
of the 1,3-dipolar cycloaddition we carried out the reaction with
the known dipolarophile 822 and the known nitrone 10.23 Methyl
2-phenylthioacrylate, 8, was obtained from racemic methyl
2-bromopropionate, (()-2, by reaction with sodium thiophe-
noxide, followed by oxidation of the resulting methyl 2-phe-
nylthiopropionate, (()-3, with NaIO4 to give sulfoxide 6, as a
diastereoisomeric mixture of two racemic pairs (Scheme 2).
Reaction of the mixture of sulfoxides 6 with an excess (1.9
equiv) of an equimolar mixture of Ac2O and MsOH gave 8 in
good yield, via a Pummerer rearrangement followed by AcOH
elimination. Nitrone 10, whose configuration is known to be
(Z), was obtained as described23 by reaction of benzaldehyde
with N-methylhydroxylamine. Reaction of acrylate 8 and nitrone
10 in the presence of 10% indium(III) triflate under microwave
irradiation gave a mixture of (()-11 and (()-14 in an ap-
proximate ratio of 7:3, with a modest 41% yield. The mixture
could be separated by silica gel column chromatography, and
each stereoisomer was fully characterized by spectroscopic
means and HRMS. Compounds (()-11 and (()-14 correspond
to the exo- and endo-adducts with respect to the ester function,
respectively (Scheme 2). Noteworthy, when the cycloaddition
reaction was carried out with conventional heating under reflux,
yields were lower after much longer reaction times. Indeed, the
use of microwave irradiation as an alternative mode of heating
reaction mixtures in cycloaddition reactions has been reported
to drastically reduce reaction times, increase yields, and modify
product ratios.24
Herein we report (1) a study on the potential use of (R)-1 as
a chiral auxiliary for the enantioselective synthesis of a novel
series of N,O-psiconucleosides, which involves as the key step
a 1,3-dipolar cycloaddition of a nitrone with an acrylate derived
from (R)-1, according to the retrosynthetic analysis shown in
Scheme 1; (2) the preparation of these N,O-psiconucleosides
in enantiopure form by resolution of an advanced precursor
using (R)-1 as the resolving agent; and (3) the establishment of
the absolute configuration of all of these compounds by
(8) Bernardi, L.; Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Folegatti,
M.; Grilli, S.; Mazzanti, A.; Ricci, A. Tetrahedron: Asymmetry 2004, 15, 245–
250.
(9) Camps, P.; Mun˜oz-Torrero, D.; Sa´nchez, L. Tetrahedron: Asymmetry
2004, 15, 311–321.
(10) Camps, P.; Mun˜oz-Torrero, D.; Sa´nchez, L. Tetrahedron: Asymmetry
2004, 15, 2039–2044.
(11) Boschi, F.; Camps, P.; Comes-Franchini, M.; Mun˜oz-Torrero, D.; Ricci,
A.; Sa´nchez, L. Tetrahedron: Asymmetry 2005, 16, 3739–3745.
(12) Merino, P. Curr. Med. Chem.: Anti-Infect. Agents 2002, 1, 389–411.
(13) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistara`, V.;
Rescifina, A.; Romeo, R.; Valveri, V.; Mastino, A.; Romeo, G. J. Med. Chem.
2003, 46, 3696–3702.
(14) Chiacchio, U.; Balestrieri, E.; Macchi, B.; Iannazzo, D.; Piperno, A.;
Rescifina, A.; Romeo, R.; Saglimbeni, M.; Sciortino, M. T.; Valveri, V.; Mastino,
A.; Romeo, G. J. Med. Chem. 2005, 48, 1389–1394.
(15) Chiacchio, U.; Genovese, F.; Iannazzo, D.; Piperno, A.; Quadrelli, P.;
Antonino, C.; Romeo, R.; Valveri, V.; Mastino, A. Bioorg. Med. Chem. 2004,
12, 3903–3909.
(16) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Rescifina, A.;
Romeo, R.; Romeo, G. Tetrahedron Lett. 2001, 42, 1777–1780.
(17) Chiacchio, U.; Corsaro, A.; Pistara`, V.; Rescifina, A.; Iannazzo, D.;
Piperno, A.; Romeo, G.; Romeo, R.; Grassi, G. Eur. J. Org. Chem. 2002, 1206–
1212.
Cross signals in the NOESY experiment of (()-11 among
the pairs of signals of 4-HR/C-phenyl Hortho, 4-Hꢀ/3-H, and 4-Hꢀ/
S-phenyl Hortho, the last one of low intensity, clearly support
the syn-relationship among 4-HR and the phenyl group at C3
and among 4-Hꢀ and the phenylthio group at C5. The same
conclusion was obtained from NOE difference experiments: (a)
on irradiation at δ 2.83 ppm (4-Hꢀ) a positive NOE was
observed for the signals of 4-HR (δ 3.20 ppm) and S-phenyl
Hortho (δ 7.62-7.65 ppm) and (b) on irradiation at δ 3.20 ppm
(18) Iannazzo, D.; Piperno, A.; Pistara`, V.; Rescifina, A.; Romeo, R.
Tetrahedron 2002, 58, 581–587.
(19) Saita, M. G.; Chiacchio, U.; Iannazzo, D.; Corsaro, A.; Merino, P.;
Piperno, A.; Previtera, T.; Rescifina, A.; Romeo, G.; Romeo, R. Nucleosides,
Nucleotides Nucleic Acids 2003, 22, 739–742.
(20) Chiacchio, U.; Borrello, L.; Iannazzo, D.; Merino, P.; Piperno, A.;
Rescifina, A.; Richichi, B.; Romeo, G. Tetrahedron: Asymmetry 2003, 14, 2419–
2425. Corrigendum at Tetrahedron: Asymmetry 2005, 16, 3919.
(21) Iley, J.; Tolando, R.; Constantino, L. J. Chem. Soc., Perkin Trans. 2001,
2, 1299–1305.
(22) Leyendecker, F.; Comte, M. T. Tetrahedron 1986, 42, 1413–1421.
(23) Dicken, C. M.; De Shong, P. J. Org. Chem. 1982, 47, 2047–2051.
(24) de La Hoz, A.; D´ıaz-Ort´ıs, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem.
2000, 3659–3573.
6658 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis and Absolute Configuration of NoVel N,O-Psiconucleosides
SCHEME 2. Study of the Diastereoselectivity of the
1,3-Dipolar Cycloaddition of Nitrone 10 and Acrylates 8 and
(()-9
irradiation at δ 2.62 ppm (4-Hꢀ) a positive NOE was observed
for the signals of 4-ΗR (δ 4.13 ppm), C-phenyl Hortho (δ 7.03
ppm) and pyrimidinedione 6-H (δ 7.63 ppm), and (b) on
irradiation at δ 4.13 ppm (4-HR) a positive NOE was only
observed for the signals of 4-Hꢀ (δ 2.62 ppm) and 3-H (δ 3.75
ppm). The preferential formation of (()-18 is in agreement with
reported results in closely related cases.17 ꢀ-Anomers of
nucleosides derived from pyrimidine bases are preferentially
formed at room temperature, and these were the sole stereoi-
somers observed under equilibration conditions at 45 °C.17
To study the effect of the chiral auxiliary on the facial
selectivity of the 1,3-dipolar cycloaddition, we synthesized the
R-phenylthioacrylate derived from racemic N-phenylpantolac-
tam, (()-9, as the dipolarophile (Scheme 2). Racemic 2-phe-
nylthiopropionic acid, (()-5, prepared by reaction of racemic
ethyl 2-bromopropionate with sodium thiophenoxide25 followed
by saponification,26 was esterified with (()-1 in the presence
of DCC under DMAP catalysis to give in high yield the
corresponding ester 4, as a diastereomeric mixture of two
racemic pairs in an approximate ratio of about 7:3 (1H NMR),
which indicates partial epimerization of the R-ester stereogenic
center during the esterification. This mixture was oxidized as
such with NaIO4 to give in good yield sulfoxide 7, as a
diastereomeric mixture of four racemic pairs. Reaction of the
mixture of sulfoxides 7 with an excess (1.6 equiv) of an
equimolar mixture of Ac2O and MsOH in CH2Cl2 under reflux
gave (()-9 in high yield. Reaction of nitrone 10 and acrylate
(()-9 was carried out as before in toluene solution using
indium(III) triflate as the catalyst under microwave irradiation.
From this reaction, a stereoisomeric mixture of racemic cy-
cloadducts 12, 13, 15, and 16 was isolated in only 28% yield,
after column chromatography. Substantial amounts of (()-1
(41%) were also isolated, arising from hydrolysis of the ester
function either in the starting (()-9 or in the products formed
1
in the cycloaddition process. In the H NMR spectrum of the
mixture of racemic cycloadducts 12, 13, 15, and 16, four singlets
were observed in the range 5.25-5.40 ppm corresponding to
the 3-H proton of the pantolactam moiety of the four diaster-
eomeric racemic pairs. From the integral of these signals, an
approximate ratio for these cycloadducts (()-12/(()-13/(()-
15/(()-16 ) 2:2:1:1 was obtained. Taking into account the
regio- and stereoselectivity observed in the cycloaddition of 8
and 10 and the configuration of one of the minor cycloadducts
derived from (R)-1, which was obtained in pure form by a
different procedure (compound 26 or 27, see below), the main
diastereomers of the above mixture must be the exo-adducts
with respect to the ester function (()-12 and (()-13.
Since N-phenylpantolactam did not influence the facial
diastereoselectivity of the 1,3-dipolar cycloaddition of nitrone
10 and acrylate (()-9, we planned the use of (R)-1 as a
resolution agent for the preparation of enantiopure N,O-
psiconucleosides as shown in Scheme 3. The resolution agent
would be introduced in a late stage of the synthetic sequence,
just prior to the separation of the diastereomeric esters 20 and
21, to improve its recovery. However, although saponification
of (()-18 gave the corresponding carboxylic acid, (()-19,
attempted esterification of this acid with (R)-1, using DCC and
DMAP as catalyst, failed (Scheme 3).
(4-HR) a positive NOE was observed for the signals of 4-Hꢀ (δ
2.83 ppm) and C-phenyl Hortho (δ 7.24-7.32 ppm).
In the case of (()-14, cross signals in the NOESY experiment
among the pairs of signals of 4-Hꢀ/C-phenyl Hortho and 4-HR/
3-H were observed, among others. In this case, cross signals
between 4-Hꢀ or 4-HR and S-phenyl Hortho were not observed.
However, the NOE difference experiments were conclusive: (a)
on irradiation at δ 2.65 ppm (4-Hꢀ) a positive NOE was
observed for the signals of 4-HR (δ 3.41 ppm), C-phenyl Hortho
(δ 7.40-7.44 ppm) and S-phenyl Hortho (δ 7.61-7.65 ppm),
and (b) on irradiation at δ 3.41 ppm (4-HR) a positive NOE
was observed for the signal of 4-Hꢀ (δ 2.65 ppm), but not for
the signals of C-phenyl Hortho and S-phenyl Hortho
.
Worthy of note, reaction of the mixture of (()-11 and (()-
14 with the commercially available O,O-bis(trimethylsilyl)thy-
mine, 17, and NBS gave a crude product from which N,O-
nucleoside(()-18wasisolatedbysilicagelcolumnchromatography
in 65% yield. The relative configuration of (()-18 was
established as before through NOE experiments and cor-
responded to the ꢀ-anomer (nucleobase and phenyl group in a
cis-relationship). In the NOESY experiment, cross signals among
the pairs of protons 4-Hꢀ/C-phenyl Hortho and 3-H/4-HR were
observed among others. As in the case of (()-14, the NOE
difference experiments on (()-18 were conclusive: (a) on
Taking into account that this result could be due to the steric
hindrance of the carboxylic acid (()-19, we decided to introduce
(25) Minami, T.; Ishida, M.; Agawa, T. J. Chem. Soc., Chem. Commun. 1978,
1, 12–13.
(26) Kato, D.; Mitsuda, S.; Ohta, H. J. Org. Chem. 2003, 68, 7234–7242.
J. Org. Chem. Vol. 73, No. 17, 2008 6659

Camps et al.
SCHEME 3. Attempted Esterification of Acid (()-19 with
(R)-1
or 27 and was fully characterized, except for the absolute
configuration of the two stereogenic centers of the isoxazolidine
ring.
The diastereomeric mixture of 24-27 was reacted as such
with O,O-bis(trimethylsilyl)thymine, 17, and NBS, as before,
to give a mixture of only two diastereomeric N,O-nucleosides,
the ꢀ-anomers 20 and 21 in a ratio of 1:1 (Scheme 4), which
could be separated by silica gel column chromatography. At
this stage, their absolute configuration being unknown, each
anomer was merely distinguished by the elution time and by
the [R]20D value. Thus in the case of 20 and 21, the first eluted
product (Rf 0.18, CH2Cl2/MeOH 6:1) had an [R]20 -67.0 (c
D
0.25, AcOEt) and the second eluted product (Rf 0.12) had an
[R]20 +1.1 (c 0.19, AcOEt).
D
Similarly, the mixture of 24-27 was reacted with O,O-
bis(trimethylsilyl)-5-fluorouracil, 28, prepared as described
previously,27 and NBS to give a mixture of the ꢀ-anomers of
the corresponding N,O-nucleosides 29 and 30 in a ratio of 1:1,
which was efficiently separated by silica gel column chroma-
tography (Scheme 4). As before, at this stage, anomers 29 and
SCHEME 4. Preparation of Enantiopure Precursors of
N,O-Psiconucleosides
30 were distinguished by the elution time and by the [R]20
D
value. The first eluted product (Rf 0.31, CH2Cl2/MeOH 6:1) had
an [R]20D -48.0 (c 0.39, AcOEt) and the second eluted product
(Rf 0.21) had an [R]20 -18.1 (c 0.22, AcOEt).
D
Attempts to carry out the reduction of the ester function of
20 with NaBH4 in MeOH at 0 °C for 30 min, as described in a
related case,19,20 left the starting compound unchanged. When
this reaction was carried out at 50 °C for 48 h, transesterification
took place, the methyl ester (-)-18 being formed. Consequently,
we decided to carry out first the transesterification of compounds
20, 21, 29, and 30 with K2CO3 in MeOH. In this way we
obtained in good yields the corresponding methyl esters (-)-
18, (+)-18, (-)-31, and (+)-31, respectively, with complete
recovery of the resolution agent (R)-1. Reduction of the ester
function of compounds (-)-18, (+)-18, (-)-31, and (+)-31, was
carried out cleanly in moderate yields by reaction with a 65%
toluene solution of sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al), thus obtaining the corresponding N,O-
psiconucleosides (-)-32, (+)-32, (-)-33, and (+)-33, respec-
tively (Scheme 5).
All attempts to obtain a single crystal for X-ray diffraction
analysis of the foamy esters 20, 21, 29, and 30 were fruitless.
Consequently, to establish the absolute configuration of the
esters 20, 21, 29, 30, (-)- and (+)-18, and (-)- and (+)-31,
we planned the correlation study shown in Scheme 6.
Hydrogenation of pantolactam esters 20, 21, 29, or 30 or
methyl esters 18 or 31 could give alcohols 34 and 35 through
the shown intermediates,28 which imply (1) reduction of the
isoxazolidine N-O bond, (2) thymine or 5-fluorouracil elimina-
tion to give the corresponding ketone, (3) hydrogenation of the
ketone function to alcohol, and (4) condensation of the second-
ary amine formed in the first step with the ester function leading
to the lactam ring. Throughout this transformation, the config-
uration of C3 of the initial isoxazolidine derivative is retained,
while the configuration of C5 is lost. On the other hand, the
closely related lactams (+)- and (-)-37 are known oily
compounds,21 what allows a correlation between these known
compounds and those obtained by hydrogenation of the enan-
the resolution agent in the precursor of (()-18, i.e., the
diastereomeric mixture (()-11 and (()-14, since the phenylthio
group at the R-carboxylic position is less bulky than the thymine
substituent. Saponification of the diastereomeric mixture of (()-
11 and (()-14 gave the corresponding mixture of acids, (()-
22 and (()-23, which was reacted as such with the resolution
agent (R)-1 to give in good yield the corresponding mixture of
diastereomeric esters 24-27 (Scheme 4). Upon purification of
this mixture by silica gel column chromatography, most of the
product (94% yield) eluted as a diastereomeric mixture of 24/
25/26/27 in an approximate ratio of 3:3:1:1. The main compo-
nents of the mixture, 24 and 25, corresponded to the exo-adducts
with respect to the ester function. A small amount of the product
(about 1% yield) eluted as one of the minor diastereomers 26
(27) Holshouser, M. H.; Shipp, A. M.; Ferguson, P. W. J. Med. Chem. 1985,
28, 242–245.
(28) Huisgen, R.; Hauck, H.; Grashey, R.; Seidl, H. Chem. Ber. 1968, 101,
2568–2584.
6660 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis and Absolute Configuration of NoVel N,O-Psiconucleosides
SCHEME 5. Preparation of Enantiopure
N,O-Psiconucleosides
SCHEME 7. Preparation of the Enantiopure Ketolactams
(+)- and (-)-36
SCHEME 6. Proposed Correlation among the Ester
Precursors of N,O-Psiconucleosides and Known Lactams
(+)- and (-)-37, through their Conversion into New
Ketolactams 36
(R)- and (S)-1-methyl-5-phenylpyrrolidine-2,3-dione, (-)- and
(+)-36, were prepared as shown in Scheme 7. Methyl 4-oxo-
4-phenylbutanoate, 38, prepared by reaction of the corresponding
acid with MeOH under acidic catalysis,30 was subjected to
reductive amination by reaction with ammonium acetate in
MeOH using NaBH3CN as the reducing agent. From this
reaction, the known31 racemic 5-phenyl-γ-butyrolactam, (()-
39, was directly isolated in 70% yield. This compound had been
previously prepared by a tedious procedure involving reductive
amination of 4-oxo-4-phenylbutyric acid followed by cyclization
of the obtained 4-amino-4-phenylbutyric acid using 2-chloro-
1-methylpyridinium iodide (Mukaiyama’s reagent) to activate
the carboxylic group.31 Resolution of (()-39 was carried out
as previously described,21 by (1) conversion into a mixture of
diastereoisomeric derivatives 40 and 41 on reaction with (S)-
1-phenylethyl isocyanate, (2) silica gel column chromatography
separation of the diastereoisomers, and (3) methanolysis. The
absolute configuration of 40 had been previously established
as (5S,1′S) on the basis of NMR and chromatographic
parameters.21,32 In the present work, we have confirmed the
tiopure isoxazolidine esters. For strategic reasons, we decided
to carry out the correlation at the level of the pyrrolidine-2,3-
dione 36, which (1) contains only one stereogenic center, the
one corresponding to C3 in the starting isoxazolidine ester, and
(2) could be a solid compound, as it is the case for the known
racemic mixture.29 Conversion of 37 to the pyrrolidine-2,3-dione
36 could be carried out by R-hydroxylation of the lactam
R-position followed by chromic acid oxidation.29
(30) Hilborn, J. W.; Jurgens, A. R.; Senanayake, C. H. U.S. patent 5936124,
1999.
(31) Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem.
1992, 35, 285–294.
(32) Pirkle, W. H.; Robertson, M. R.; Hyun, M. H. J. Org. Chem. 1984, 49,
(29) Dagne, E.; Castagnoli, N., Jr. J. Med. Chem. 1972, 15, 356–360.
2433–2437.
J. Org. Chem. Vol. 73, No. 17, 2008 6661

Camps et al.
SCHEME 8. Chemical Correlation among Esters 18, 21, 29,
and 30 with Ketolactams (+)- or (-)-36
be (S). Moreover, since the relative configuration in (-)-18 was
previously known (phenyl and thymine groups in a cis-
relationship), its absolute configuration should be (3S,5S).
Also, Ra-Ni reduction of pantolactam ester 21 followed by
column chromatography gave a mixture of alcohols, which after
chromic acid oxidation gave ketone (R)-(-)-36. Consequently,
the absolute configuration of 21 should be (3R,5R,3′R). In a
similar way, in the 5-fluorouracil series, from pantolactam ester
29, ketone (+)-36 was obtained. Thus, the absolute configuration
of 29 should be (3S,5S,3′R). Similarly, from pantolactam ester
30, ketone (-)-36 was obtained. Consequently, the absolute
configuration of 30 should be (3R,5R,3′R). Knowing the absolute
configuration of the above esters [(3S,5S)-(-)-18, (3R,5R,3′R)-
(+)-21, (3S,5S,3′R)-(-)-29, and (3R,5R,3′R)-(-)-30], the ab-
solute configuration of the rest of enantiopure compounds herein
described could be easily deduced as follows: (3R,5R)-(+)-18,
(3S,5S,3′R)-(-)-20, (3S,5S)-(-)-31, (3R,5R)-(+)-31, (3S,5S)-
(-)-32, (3R,5R)-(+)-32, (3S,5S)-(-)-33, and (3R,5R)-(+)-33.
Antiviral Activity. Compounds (+)-32, (-)-32, and (-)-33
were evaluated for antiviral activity against a wide variety of
RNA and DNA viruses, including influenza (subtypes A/H1N1,
A/H3N2 and B) in Madin Darby Canine Kidney (MDCK) cells;
parainfluenza-3, reovirus-1, Sindbis virus, Coxsackie virus B4,
Punta Toro virus in Vero cells; herpes simplex virus-1 (KOS),
herpex simplex virus-2 (G), herpex simplex virus-1 (TK- KOS
ACVr), vaccinia virus, and vesicular stomatitis virus in human
embryonic lung (HEL) fibroblast cells; vesicular stomatitis virus,
Coxsackie virus B4, and respiratory syncytial virus in HeLa
cells; and feline corona virus (FIPV) and feline herpes virus in
Crandell-Rees Feline Kidney (CRFK) cells. None of these
compounds showed activity against any of the above viruses at
the highest concentration tested (100 µM).
previous assignment by X-ray diffraction analysis of a single
crystal of the solid derivative 40 (Figure 1 of Supporting
Information). Thus, its methanolysis product (-)-39 should be
(5S)-5-phenylpyrrolidin-2-one. Consequently, the oily derivative
41 and its methanolysis product (+)-39 should have (5R)-
configuration. Methylation of (-)- and (+)-39 as described gave
the corresponding compounds (-)- and (+)-37.21 The R-hy-
droxylation of (-)-37 was carried out with the Davis oxaziridine
(trans-3-phenyl-2-phenylsulfonyloxaziridine).33,34 Thus, reaction
of (-)-37 with LHMDS followed by reaction of the resulting
lithium enolate with the Davis oxaziridine gave, after column
chromatography, a solid product containing mainly (3R,5S)-
trans-3-hydroxy-1-methyl-5-phenylpyrrolidin-2-one, (+)-35, to-
gether with a small amount of the corresponding cis-stereoiso-
mer (1H NMR). An analytically pure sample of (+)-35 was
obtained by crystallization of the crude product from Et2O/
AcOEt. Chromic acid oxidation29 of a mixture of alcohols, from
the oxidation of (-)-37 with the Davis oxaziridine, gave in good
yield the corresponding (5S)-1-methyl-5-phenylpyrrolidine-2,3-
dione, (+)-36. Reduction of (+)-36 with NaBH4 in MeOH gave
a solid mixture containing mainly the (3S,5S)-cis-3-hydroxy-
1-methyl-5-phenylpyrrolidin-2-one, (-)-34, which was obtained
in pure form by crystallization from Et2O/AcOEt. Although,
the 1H NMR data of the cis-alcohol (-)-34 coincided with those
described for (()-34,29 the cis-configuration of (-)-34 was
clearly established by NOESY experiments, thus confirming the
relative stereochemistry of both alcohols 34 and 35.
Conclusion
We have developed a synthetic entry into enantiopure N,O-
psiconucleosides using (R)-N-phenylpantolactam as a resolution
agent, which is efficiently recovered. The absolute configuration
of these N,O-psiconucleosides was unambiguously established
through the conversion of significant intermediate esters into
the new ketones (+)- and (-)-36. These ketones were inde-
pendently synthesized in enantiopure form from the known
lactams (-)- and (+)-37, by R-hydroxylation with the Davis
oxaziridine followed by chromic acid oxidation. The absolute
configuration of (-)-37 was clearly established by X-ray
diffraction analysis of its precursor 40, thus confirming a
previous assignment based on NMR and chromatographic
parameters.21,32
Similarly, oxidation of (+)-37 with the Davis oxaziridine gave
mainly trans-alcohol (-)-35, which on oxidation with chromic
acid gave dione (-)-36 from which cis-alcohol (+)-34 was
obtained on reduction with NaBH4 in MeOH. Compounds (-)-
and (+)-34, (+)- and (-)-35, and (+)- and (-)-36 are all new
compounds that have been fully characterized.
Experimental Section
Knowing the absolute configuration of ketones (+)- and (-)-
36, we carried out the correlation study shown in Scheme 8.
Thus, Ra-Ni hydrogenation of methyl ester (-)-18 gave a
diastereomeric mixture of alcohols, containing mainly a cis-
alcohol, which after oxidation with chromic acid gave ketone
(S)-(+)-36. Since the configuration of the isoxazolidine C3
carbon atom of (-)-18 is not modified during its transformation
into ketone (+)-36, the configuration of C3 in (-)-18 should
Diastereoisomeric Mixture of Methyl (3R*,5R*)- and (3R*,5S*)-
2-Methyl-3-phenyl-5-(phenylthio)isoxazolidine-5-carboxylate (()-
11 and (()-14. A solution of acrylate 8 (6.00 g, 30.9 mmol) in
anhydrous toluene (24 mL) was placed in a microwave tube, nitrone
10 (4.60 g, 34.0 mmol, 1.1 equiv) and In(OTf)3 (1.73 g, 3.12 mmol,
0.1 equiv) were added, the tube was closed and the reaction mixture
was subjected to microwave irradiation at 110 °C (infrared
detection) for 5 min. After evaporation of the toluene in vacuo,
water (200 mL) was added and the mixture was extracted with
AcOEt (3 × 200 mL). The combined organic phases were dried
with anhydrous Na2SO4, filtered and concentrated in vacuo to give
a residue (9.1 g), which was subjected to column chromatography
[silica gel (230 g), hexane/AcOEt mixtures]. On elution with a
(33) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Organic Synthesis;
Wiley: New York, 1993; Collect. Vol. VIII, pp 546-550.
(34) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J.
Org. Chem. 1988, 53, 2087–2089.
6662 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis and Absolute Configuration of NoVel N,O-Psiconucleosides
mixture of hexane/AcOEt 90:10, a diastereomeric mixture of
cycloadducts (()-11 and (()-14 in an approximate ratio of 7:3 (4.12
g, 41% yield) was isolated as a yellow oil. A part of the above
mixture (220 mg) was subjected to column chromatography [silica
gel (10 g), hexane/AcOEt mixtures]. On elution with hexane/AcOEt
94:6, (()-11 (21 mg, 5% yield) and a mixture of (()-11 and (()-
14 (156 mg) were isolated as yellow oils. The last mixture was
subjected to a new column chromatography [silica gel (10 g),
hexane/AcOEt mixtures]. On elution with hexane/AcOEt 95:5, (()-
14 (106 mg, 20% yield) was isolated as a yellow oil.
Cpara C-phenyl), 128.9 (CH, Ar-Hortho C-phenyl), 129.8 (CH, Ar-
Cpara S-phenyl), 135.4 (C, Ar-Cipso C-phenyl), 135.5 (C, Ar-Cipso
S-phenyl), 136.2 (CH, Ar-Cortho S-phenyl), 171.6 (C, COO).
Diastereoisomeric Mixture of (R)-4,4-Dimethyl-2-oxo-1-phe-
nylpyrrolidin-3-yl 2-Methyl-3-phenyl-5-(phenylthio)isoxazolidine-
5-carboxylate 24, 25, 26, and 27. To a cold (0 °C) solution of the
diastereoisomeric mixture (()-22 and (()-23 (3.00 g, 9.5 mmol,
1.05 equiv) in anhydrous CH2Cl2 (15 mL) was added DCC (3.75
g, 18 mmol, 2 equiv) portionwise under an argon atmosphere, and
the mixture was stirred for 20 min at this temperature. A solution
of (R)-1 (1.85 g, 9.0 mmol) in anhydrous CH2Cl2 (25 mL) and
DMAP (148 mg, 1.2 mmol, 0.13 equiv) were added and the reaction
mixture was stirred at room temperature for 16 h. The precipitated
dicyclohexylurea (DCU) was filtered off through Celite, and the
filtrate was concentrated in vacuo to give a residue (7.5 g) that
was subjected to column chromatography [silica gel (220 g), hexane/
Et2O mixtures]. On elution with hexane/Et2O 4:1, in order of elution
a diastereoisomeric mixture of 24-27 (4.43 g, 94% yield, ap-
proximate dr 3:3:1:1) and a pure endo -cycloadduct 26 or 27 (54
mg, 1% yield, dr >98:2) were isolated as a yellow oil and as a
white solid, respectively.
(()-11: Rf 0.33 (hexane/AcOEt 4:1); IR (NaCl) ν 3061, 3031,
2996, 2952, 2920, 2850, 1734 (CdO st), 1603, 1584, 1495, 1474,
1439, 1276, 1257, 1199, 1137, 1113, 1089, 1050, 1016, 961, 918,
1
864, 829, 753, 700 cm-1; H NMR (CDCl3, 300 MHz) δ 2.68 (s,
3H, N-CH3), 2.83 (dd, J4-HR/4-Hꢀ ) 13.8 Hz, J3-H/4-Hꢀ ) 7.5 Hz, 1H,
4-Hꢀ), 3.20 (dd, J4-HR/4-Hꢀ ) 13.8 Hz, J3-H/4-HR ) 9.6 Hz, 1H, 4-HR),
3.54 (br signal, 1H, 3-H), 3.64 (s, 3H, OCH3), 7.24-7.32 (complex
signal, 5H, Ar-H C-phenyl), 7.32-7.43 (complex signal, 3H, Ar-
Hmeta and Ar-Hpara S-phenyl), 7.62-7.65 (m, 2H, Ar-Hortho S-
phenyl); 13C NMR (CDCl3, 75.4 MHz) δ 43.6 (CH3, N-CH3), 49.1
(CH2, C4), 52.8 (CH3, OCH3), 73.0 (CH, C3), 90.3 (C, C5), 127.8
(CH, Ar-Cortho C-phenyl), 128.2 (CH, Ar-Cpara C-phenyl), 128.6
(CH) and 128.8 (CH) (Ar-Cmeta C-phenyl and Ar-Hmeta S-phenyl),
129.7 (CH, Ar-Cpara S-phenyl), 129.9 (C, Ar-Cipso C-phenyl), 136.3
(CH, Ar-Cortho S-phenyl), 137.1 (C, Ar-Cipso S-phenyl), 170.3 (C,
COO); HRMS calcd for [C18H19NO3S + H]+ 330.1164, found
330.1151.
26 or 27: mp 172-174 °C (hexane/Et2O 3:2); Rf 0.77 (hexane/
AcOEt 1:1); [R]20D -129.7 (c 0.13, AcOEt); IR (KBr) ν 3064, 3031,
2970, 2942, 2872, 1742 (CdO st ester), 1704 (CdO st lactam),
1598, 1499, 1475, 1412, 1387, 1324, 1264, 1211, 1178, 1140, 1104,
1058, 966, 758, 693 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.98 (s,
3H, 4′R-CH3), 1.07 (s, 3H, 4′ꢀ-CH3), 2.75 (s, 3H, N-CH3), 2.76
(dd, J4-HR/4-Hꢀ ≈ 13.5 Hz, J3-H/4-Hꢀ ) 10.2 Hz, 1H, 4-Hꢀ), 3.42 (dd,
J4-HR/4-Hꢀ ) 13.5 Hz, J3-H/4-HR ≈ 7.5 Hz, 1H, 4-HR), 3.45 (d, J5′R-
H/5′ꢀ-H ) 9.6 Hz, 1H, 5′R-H), 3.54 (d, J5′R-H/5′ꢀ-H ) 9.6 Hz, 1H,
5′ꢀ-H), 3.77 (dd, J3-H/4-Hꢀ ) 10.2 Hz, J3-H/4-HR ) 7.5 Hz, 1H, 3-H),
(()-14: Rf 0.37 (hexane/AcOEt 4:1); IR (NaCl) ν 3061, 3036,
2999, 2953, 2918, 2875, 2850, 1738 (CdO st), 1476, 1455, 1439,
1289, 1265, 1198, 1178, 1137, 1116, 1079, 1063, 1026, 986, 956,
1
854, 751, 700 cm-1; H NMR (CDCl3, 300 MHz) δ 2.65 (dd, J4-
HR/4-Hꢀ ) 13.8 Hz, J3-H/4-Hꢀ ) 9.9 Hz, 1H, 4-Hꢀ), 2.72 (s, 3H, N-
CH3), 3.41 (dd, J4-HR/4-Hꢀ ) 13.8 Hz, J3-H/4-HR ) 7.5 Hz, 1H, 4-HR),
3.51 (s, 3H, OCH3), 3.59 (dd, J3-H/4-Hꢀ ) 9.9 Hz, J3-H/4-HR ) 7.5
Hz, 1H, 3-H), 7.31-7.40 (complex signal, 6H, Ar-Hmeta and Ar-
Hpara S-phenyl, Ar-Hmeta and Ar-Hpara C-phenyl), 7.40-7.44 (m,
2H, Ar-Hortho C-phenyl), 7.61-7.65 (m, 2H, Ar-Hortho S-phenyl);
13C NMR (CDCl3, 75.4 MHz) δ 43.0 (CH3, N-CH3), 50.5 (CH2,
C4), 52.6 (CH3, OCH3), 72.9 (CH, C3), 92.0 (C, C5), 128.0 (CH,
Ar-Cortho C-phenyl), 128.4 (CH, Ar-Cpara C-phenyl), 128.7 (CH)
and 128.8 (CH) (Ar-Cmeta S-phenyl and Ar-Hmeta C-phenyl), 129.3
(CH, Ar-Cpara S-phenyl), 131.5 (C, Ar-Cipso C-phenyl), 135.7 (CH,
Ar-Cortho S-phenyl), 136.8 (C, Ar-Cipso S-phenyl), 168.5 (C, COO);
HRMS calcd for [C18H19NO3S + H]+ 330.1164, found 330.1169.
Mixture of (3R*,5R*)- and (3R*,5S*)-2-Methyl-3-phenyl-5-
(phenylthio)isoxazolidine-5-carboxylic Acid (()-22 and (()-23. To
a solution of the above mixture of (()-11 and (()-14 (3.70 g, 11.3
mmol) in MeOH (50 mL) was added 85% KOH (1.49 g, 22.6 mmol,
2 equiv), and the mixture was heated under reflux for 3 h. The
organic solvent was evaporated in vacuo, water (100 mL) was added
and the mixture was washed with AcOEt (100 mL). The aqueous
phase was made acidic with aqueous 1 N HCl (20 mL) till pH 4
and was extracted with AcOEt (3 × 100 mL). The combined
organic phases were dried with anhydrous Na2SO4, filtered and
concentrated in vacuo to give a mixture of (()-22 and (()-23 (3.10
g, 88% yield) as a yellow oil, which was used in the next step
without further purification; Rf 0.08 (hexane/AcOEt 1:2); IR (NaCl)
ν 3700-2100 (max at 3288, 3060, 3031, 2958, 2850), 1651, 1614
(CdO st), 1581, 1495, 1478, 1455, 1439, 1407, 1374, 1306, 1194,
5.28 (s, 1H, 3′-H), 7.17 (tm, JHpara/Hmeta ≈ 7.2 Hz, JHpara/Hortho
)
1.2 Hz, 1H, Ar-Hpara N-phenyl), 7.28-7.46 (complex signal, 10H,
Ar-Hmeta N-phenyl, Ar-Hmeta S-phenyl, Ar-Hpara S-phenyl and Ar-H
C-phenyl), 7.61 (m, 2H, Ar-Hortho N-phenyl), 7.78 (m, 2H, Ar-Hortho
S-phenyl); 13C NMR (CDCl3, 75.4 MHz) δ 21.0 (CH3, 4′R-CH3),
24.5 (CH3, 4′ꢀ-CH3), 37.3 (C, C4′), 43.2 (CH3, N-CH3), 51.1 (CH2,
C4), 57.7 (CH2, C5′), 72.5 (CH, C3), 79.4 (CH, C3′), 91.5 (C, C5),
119.5 (CH, Ar-Cortho N-phenyl), 124.9 (CH, Ar-Cpara N-phenyl), 128.0
(CH, Ar-Cmeta C-phenyl), 128.3 (CH, Ar-Cpara C-phenyl), 128.6 (CH,
Ar-Cmeta N-phenyl), 128.7 (CH, Ar-Cmeta S-phenyl), 128.9 (CH, Ar-
Cortho C-phenyl), 129.0 (CH, Ar-Cpara S-phenyl), 131.5 (C, Ar-Cipso
S-phenyl), 135.6 (CH, Ar-Cortho S-phenyl), 136.8 (C, Ar-Cipso C-
phenyl), 138.9 (C, Ar-Cipso N-phenyl), 167.9 (C) and 168.0 (C) (COO
and C2′). Anal. Calcd for C29H30N2O4S: C, 69.30; H, 6.02; N, 5.57;
S 6.38. Found: C, 69.14; H, 6.07; N, 5.55; S 6.11.
(3S,5S,3′R)- and (3R,5R,3′R)-4,4-Dimethyl-2-oxo-1-phenylpyr-
rolidin-3-yl 2-Methyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1-
pyrimidinyl)-3-phenylisoxazolidine-5-carboxylate 20 and 21. To a
solution of the diastereomeric mixture of esters 24-27 (6.00 g,
11.9 mmol) in anhydrous CH2Cl2 (110 mL) were added 17 (6.50
g, 23.9 mmol, 2 equiv) and 4 Å molecular sieves (5 g) under argon
and the reaction mixture was stirred at room temperature for 20
min. Then, NBS (2.32 g, 13.1 mmol, 1.1 equiv) was added and the
reaction mixture was stirred at room temperature for 1 h. The
resulting mixture was treated with 10% aqueous Na2S2O3 (250 mL),
the organic phase was separated and the aqueous one was extracted
with CH2Cl2 (3 × 200 mL). The combined organic phases were
dried with anhydrous Na2SO4, filtered and concentrated in vacuo
to give a residue (8.2 g), which was subjected to column
chromatography [silica gel (250 g), hexane/AcOEt mixtures]. On
elution with a mixture of hexane/AcOEt 1:1, a diastereomeric
mixture of 20 and 21 at an approximate ratio of 1:1 (4.50 g, 73%
yield) was obtained as a white foam. Column chromatography of
this mixture [silica gel (250 g), CH2Cl2/AcOEt mixtures] gave 20
(320 mg, dr >98:2, by 1H NMR) and a mixture of 20 and 21 (2.68
g), on elution with a mixture CH2Cl2/AcOEt 13:1; and 21 (640
1158, 1024, 979, 746, 700 cm-1
NMR Data of the Main Diastereoisomer (()-22. 1H NMR
(CDCl3, 300 MHz) δ 2.69 (s, 3H, N-CH3), 2.89 (dd, J4-HR/4-Hꢀ
.
)
14.1 Hz, J3-H/4-Hꢀ ) 8.1 Hz, 1H, 4-Hꢀ), 3.05 (dd, J4-HR/4-Hꢀ ) 14.1
Hz, J3-H/4-HR ) 9.6 Hz, 1H, 4-HR), 3.46 (m, 1H, 3-H), 7.21-7.45
(complex signal, 8H, Ar-Hmeta, Ar-Hpara S-phenyl and Ar-H
C-phenyl), 7.66-7.70 (m, 2H, Ar-Hortho S-phenyl), 8.1-8.6 (broad
signal, 1H, COOH); 13C NMR (CDCl3, 75.4 MHz) δ 42.7 (CH3,
N-CH3), 48.8 (CH2, C4), 73.3 (CH, C3), 90.5 (C, C5), 127.7 (CH,
Ar-Cmeta C-phenyl), 128.7 (CH, Ar-Cmeta S-phenyl), 128.8 (CH, Ar-
1
mg, dr >98:2, by H NMR), on elution with a mixture CH2Cl2/
AcOEt 6:1. The fraction mixture of 20 and 21 was subjected to a
J. Org. Chem. Vol. 73, No. 17, 2008 6663

Camps et al.
new column chromatography [silica gel (250 g), hexane/AcOEt
6:1)] to give 20 (1.52 g, dr >98:2), a mixture of 20 and 21 (0.61
g), and 21 (400 mg, dr >98:2). Altogether, 20 (1.84 g, 30% total
yield, dr >98:2) and 21 (1.04 g, 17% total yield, dr >98:2) were
obtained as white foams.
>99% ee, by chiral HPLC) as a white solid and (-)-18 (62 mg,
75% yield, 98.6% ee, by chiral HPLC) as a white foam were
isolated.
(-)-18: Rf 0.48 (hexane/AcOEt 1:1); [R]20 -43.1 (c 0.26,
D
AcOEt); chiral HPLC (conditions A) tR 16.99 min, k2′ ) 2.19, R
) 1.18, Res ) 1.28; IR (NaCl) ν 3178, 3035, 2962, 2927, 2854,
1758 and 1690 (CdO st), 1457, 1437, 1365, 1320, 1283, 1201,
1121, 1085, 1068, 996, 850, 790, 767, 700 cm-1; 1H NMR (C6D6,
300 MHz) δ 1.77 (d, J5-CH3/6-H ) 1.2 Hz, 3H, pyrimidinedione
5-CH3), 2.38 (s, 3H, N-CH3), 2.62 (dd, J4-HR/4-Hꢀ ) 13.8 Hz, J3-H/
20: mp 121-123 °C (CH2Cl2/AcOEt 6:1); Rf 0.18 (CH2Cl2/
AcOEt 6:1); [R]20D -67.0 (c 0.25, AcOEt); IR (KBr) ν 3184 (N-H
st), 3063, 2966, 2929, 2876, 1767 and 1706 and 1690 (CdO st),
1598, 1500, 1458, 1410, 1386, 1372, 1325, 1270, 1188, 1122, 1087,
1071, 991, 762, 693 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.00 (s,
3H, 4′R-CH3), 1.28 (s, 3H, 4′ꢀ-CH3), 2.02 (d, J5-CH3/6-H ) 1.2 Hz,
3H, pyrimidinedione 5-CH3), 2.65 (dd, J4-HR/4-Hꢀ ) 12.6 Hz, J3-H/
4-Hꢀ ) 9.0 Hz, 1H, 4-Hꢀ), 2.79 (s, 3H, N-CH3), 3.47 (d, J5′R-H/5′ꢀ-H
) 9.6 Hz, 1H, 5′R-H), 3.61 (d, J5′R-H/5′ꢀ-H ) 9.6 Hz, 1H, 5′ꢀ-H),
3.96 (dd, J3-H/4-Hꢀ ) 9.0 Hz, J3-H/4-HR ) 7.2 Hz, 1H, 3-H), 4.03 (dd,
J4-HR/4-Hꢀ ) 12.6 Hz, J3-H/4-HR ) 7.2 Hz, 1H, 4-HR), 5.45 (s, 1H,
3′-H), 7.17 (tm, JHpara/Hmeta ≈ 7.2 Hz, 1H, Ar-Hpara N-phenyl),
7.28-7.40 (complex signal, 7H, Ar-Hmeta N-phenyl and Ar-H
4-Hꢀ ) 10.2 Hz, 1H, 4-Hꢀ), 3.38 (s, 3H, CO2CH3), 3.75 (dd, J
3-H/
4-Hꢀ ) 10.2 Hz, J3-H/4-HR ) 7.2 Hz, 1H, 3-H), 4.13 (dd, J4-HR/4-Hꢀ
)
13.8 Hz, J3-H/4-HR ) 7.2 Hz, 1H, 4-HR), 7.03 (s, 5H, Ar-H), 7.63
(q, J5-CH3/6-H ≈ 1.2 Hz, 1H, pyrimidinedione 6-H), 10.7 (broad
signal, 1H, NH); 13C NMR (C6D6, 75.4 MHz) δ 12.8 (CH3,
pyrimidinedione 5-CH3), 42.9 (CH3, N-CH3), 52.1 (CH2, C4), 53.3
(CH3, CO2CH3), 74.3 (CH, C3), 93.2 (C, C5), 109.7 (C, pyrim-
idinedione C5), 127.8 (CH, Ar-Cmeta phenyl), 128.5 (CH, Ar-Cpara
phenyl), 128.9 (CH, Ar-Hortho phenyl), 134.2 (CH, pyrimidinedione
C6), 136.3 (C, Ar-Cipso phenyl), 151.2 (C, pyrimidinedione C2),
164.7 (C, pyrimidinedione C4), 166.3 (C, COO); HRMS calcd for
[C17H19N3O5]•+ 345.1325, found 345.1337. Anal. Calcd for
C17H19N3O5 ·0.6H2O: C, 57.33; H, 5.72; N, 11.80. Found: C, 57.59;
H, 5.68; N, 11.31.
C-phenyl), 7.62 (m, 2H, Ar-Hortho N-phenyl), 7.79 (q, J5-CH3/6-H
)
1.2 Hz, 1H, pyrimidinedione 6-H), 8.3-8.4 (broad signal, 1H, NH);
13C NMR (CDCl3, 75.4 MHz) δ 12.8 (CH3, pyrimidinedione
5-CH3), 20.9 (CH3, 4′R-CH3), 24.4 (CH3, 4′ꢀ-CH3), 37.5 (C, C4′),
43.4 (CH3, N-CH3), 51.9 (CH2, C4), 57.4 (CH2, C5′), 73.9 (CH,
C3), 79.8 (CH, C3′), 92.9 (C, C5), 109.5 (C, pyrimidinedione C5),
119.3 (CH, Ar-Cortho N-phenyl), 124.9 (CH, Ar-Cpara N-phenyl),
127.6 (CH, Ar-Cmeta C-phenyl), 128.6 (CH, Ar-Cpara C-phenyl),
128.8 (CH, Ar-Cmeta N-phenyl and Ar-Hortho C-phenyl), 134.8 (CH,
pyrimidinedione C6), 135.7 (C, Ar-Cipso C-phenyl), 138.8 (C, Ar-
Cipso N-phenyl), 150.4 (C, pyrimidinedione C2), 164.1 (C, pyrim-
idinedione C4), 164.8 (C, COO), 167.6 (C, C2′). Anal. Calcd for
C28H30N4O6 ·0.3H2O: C, 64.18; H, 5.89; N, 10.69. Found: C, 64.17;
H, 5.72; N, 10.63.
Methyl (3R,5R)-(+)-2-Methyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tet-
rahydro-1-pyrimidinyl)-3-phenylisoxazolidine-5-carboxylate (+)-
18. To a solution of 21 (820 mg, 1.55 mmol, >98:2 dr) in MeOH
(16.5 mL) was added K2CO3 (433 mg, 3.12 mmol, 2 equiv) and
the mixture was stirred under argon at room temperature for 3 h.
The organic solvent was eliminated in vacuo and the residue (1.3
g) was subjected to column chromatography [silica gel (5 g),
hexane/AcOEt 7:3]. In order of elution, (R)-1 (320 mg, quantitative
yield, >99% ee, by chiral HPLC) as a white solid and (+)-18 (370
mg, 69% yield, 96% ee, by chiral HPLC) as a white foam were
isolated.
21: mp 121-123 °C (CH2Cl2/AcOEt 6:1); Rf 0.12 (CH2Cl2/
AcOEt 6:1); [R]20D +1.1 (c 0.19, AcOEt); IR (KBr) ν 3185 (N-H
st), 3064, 2966, 2929, 2877, 1764 and 1702 and 1686 (CdO st),
1598, 1500, 1458, 1411, 1386, 1373, 1325, 1279, 1190, 1143, 1120,
1087, 1070, 991, 788, 761, 693 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.22 (s, 3H, 4′R-CH3), 1.35 (s, 3H, 4′ꢀ-CH3), 2.02 (d, J5-CH3/6-H
) 1.2 Hz, 3H, pyrimidinedione 5-CH3), 2.69 (dd, J4-HR/4-Hꢀ ) 13.8
Hz, J3-H/4-Hꢀ ) 10.2 Hz, 1H, 4-Hꢀ), 2.79 (s, 3H, N-CH3), 3.56 (d,
J5′R-H/5′ꢀ-H ) 9.9 Hz, 1H, 5′R-H), 3.64 (d, J5′R-H/5′ꢀ-H ) 9.9 Hz, 1H,
5′ꢀ-H), 3.93 (dd, J4-HR/4-Hꢀ ) 13.8 Hz, J3-H/4-HR ) 6.9 Hz, 1H, 4-HR),
4.04 (dd, J3-H/4-Hꢀ ) 10.2 Hz, J3-H/4-HR ) 6.9 Hz, 1H, 3-H), 5.42 (s,
1H, 3′-H), 7.19 (tm, JHpara/Hmeta ≈ 7.2 Hz, 1H, Ar-Hpara N-phenyl),
7.26-7.43 (complex signal, 7H, Ar-Hmeta N-phenyl and Ar-H
(+)-18: Rf 0.48 (hexane/AcOEt 1:1); [R]20 +44.3 (c 0.30,
D
AcOEt); chiral HPLC (conditions A) tR 15.36 min, k1′ ) 1.86);
the IR and NMR data coincide with those described before for (-)-
18; HRMS calcd for [C17H19N3O5]•+ 345.1325, found 345.1334.
Anal. Calcd for C17H19N3O5 ·0.15H2O: C, 58.66; H, 5.59; N, 12.07.
Found: C, 58.90; H, 5.75; N, 11.71.
(3S,5S)-(-)-[2-Methyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
1-pyrimidinyl)-3-phenylisoxazolidin-5-yl]methanol (-)-32. To a
cold (0 °C) solution of (-)-18 (377 mg, 1.09 mmol) in anhydrous
toluene (12 mL) was added Red-Al (1.1 mL, 1.06 g, 3.27 mmol, 3
equiv) dropwise and the mixture was stirred at room temperature
for 1 h. The mixture was cooled to 0 °C, water (5 mL) was added
dropwise, and then the mixture was made acidic till pH 6 with
aqueous 1 N HCl (10 mL). The precipitated solid was filtered off
and washed with CH2Cl2 (3 × 15 mL) and the combined filtrate
and washings were concentrated in vacuo to give alcohol (-)-32
(201 mg, 58% yield) as a white solid. Part of this solid (168 mg)
was crystallized from AcOEt (5 mL) to give the analytical sample
of (-)-32 (94 mg, >99% ee) as a white solid; the mp, Rf, IR and
C-phenyl), 7.64 (m, 2H, Ar-Hortho N-phenyl), 7.71 (q, J5-CH3/6-H
)
1.2 Hz, 1H, pyrimidinedione 6-H), 8.46 (br signal, 1H, NH); 13C
NMR (CDCl3, 75.4 MHz) δ 12.8 (CH3, pyrimidinedione 5-CH3),
21.1 (CH3, 4′R-CH3), 24.8 (CH3, 4′ꢀ-CH3), 37.9 (C, C4′), 43.4
(CH3, N-CH3), 51.3 (CH2, C4), 57.7 (CH2, C5′), 73.9 (CH, C3),
80.2 (CH, C3′), 92.8 (C, C5), 109.5 (C, pyrimidinedione C5), 119.5
(CH, Ar-Cortho N-phenyl), 125.0 (CH, Ar-Cpara N-phenyl), 127.7
(CH, Ar-Cmeta C-phenyl), 128.6 (CH, Ar-Cpara C-phenyl), 128.8
(CH) and 128.9 (CH) (Ar-Cmeta N-phenyl and Ar-Hortho C-phenyl),
134.4 (CH, pyrimidinedione C6), 135.5 (C, Ar-Cipso C-phenyl),
138.8 (C, Ar-Cipso N-phenyl), 150.5 (C, pyrimidinedione C2), 164.0
(C, pyrimidinedione C4), 164.9 (C, COO), 167.6 (C, C2′). Anal.
Calcd for C28H30N4O6 ·0.2H2O: C, 64.41; H, 5.87; N, 10.73. Found:
C, 64.41; H, 5.96; N 10.64.
NMR data of this compound coincide with those of (+)-32; [R]20
D
-132.6 (c 0.94, CH2Cl2); chiral HPLC (conditions A) tR 18.97 min,
k1′
) 1.24, R ) 1.18, Res ) 1.39). Anal. Calcd for
C16H19N3O4 ·0.1H2O: C, 60.22; H, 6.06; N, 13.17. Found: C, 60.07;
H, 6.14; N, 13.04.
(3R,5R)-(+)-[2-Methyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
1-pyrimidinyl)-3-phenylisoxazolidin-5-yl]methanol (+)-32. To a
cold (0 °C) solution of (+)-18 (292 mg, 0.85 mmol) in anhydrous
toluene (10 mL) was added dropwise Red-Al (0.8 mL, 0.77 g, 2.55
mmol, 3 equiv) and the mixture was stirred at room temperature
for 1 h. The mixture was cooled to 0 °C, water (5 mL) was added
dropwise, and then the mixture was made acidic till pH 6 with
aqueous 1 N HCl. The precipitated solid was filtered off and washed
with CH2Cl2 (3 × 15 mL) and the combined filtrate and washings
were concentrated in vacuo to give alcohol (+)-32 (184 mg, 68%
Methyl (3S,5S)-(-)-2-Methyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tet-
rahydro-1-pyrimidinyl)-3-phenylisoxazolidine-5-carboxylate (-)-
18. To a solution of 20 (125 mg, 0.24 mmol, dr >98:2) in MeOH
(3 mL) was added K2CO3 (66 mg, 0.47 mmol, 2 equiv) and the
mixture was stirred under argon at room temperature for 3 h. The
organic solvent was eliminated in vacuo and the residue (196 mg)
was subjected to column chromatography [silica gel (10 g), hexane/
AcOEt 7:3]. In order of elution, (R)-1, (49 mg, quantitative yield,
6664 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis and Absolute Configuration of NoVel N,O-Psiconucleosides
yield) as a white solid. Part of this solid (165 mg) was crystallized
from AcOEt (5 mL) to give the analytical sample of (+)-32 (96
mg, >99% ee) as a white solid; mp 194-195 °C (AcOEt); Rf 0.53
(AcOEt/MeOH 10:1); [R]20D +131.1 (c 0.64, CH2Cl2); chiral HPLC
(conditions A) tR 21.47 min, k2′ ) 2.93); IR (KBr) ν 3700-2800
(max at 3523, 3312, 3182, 3085, 3060, 3039, 2961, 2925 and 2877),
1706, 1685, 1670, and 1647 (CdO st), 1467, 1455, 1306, 1293,
Acknowledgment. Financial support from Direccio´n General
de Investigacio´n of Ministerio de Ciencia y Tecnolog´ıa and
FEDER (project CTQ2005-02192/BQU) and Comissionat per
a Universitats i Recerca of the Generalitat de Catalunya (project
2005-SGR00180) is gratefully acknowledged. We also thank
the Serveis Cient´ıfico-Te`cnics of the University of Barcelona
for NMR facilities and Ms. P. Dome`nech from the IIQAB
(CSIC, Barcelona, Spain) for carrying out the elemental
analyses. We are indebted to Leentje Persoons, Frieda De
Meyer, and Vicky Broeckx for excellent technical assistance
and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen
(project No. G.0188.07) and the International Consortium on
Anti-Virals (ICAV) for financial support.
1
1276, 1124, 1114, 1084, 1058, 766, 703 cm-1; H NMR (CDCl3,
300 MHz) δ 1.86 (d, J5-CH3/6-H ≈ 1.2 Hz, 3H, pyrimidinedione
5-CH3), 2.69 (s, 3H, N-CH3), 2.89 (dd, J4-HR/4-Hꢀ ) 14.4 Hz, J3-H/
4-Hꢀ ) 9.9 Hz, 1H, 4-Hꢀ), 3.05 (dd, J4-HR/4-Hꢀ )14.4 Hz, J3-H/4-HR
)
7.5 Hz, 1H, 4-HR), 3.67 (dd, J3-H/4-Hꢀ ) 9.9 Hz, J3-H/4-HR ) 7.5 Hz,
1H, 3-H), 3.84 (dd, 1H, JHa/Hb ) 12.3 Hz, JHa/OH ) 7.8 Hz, CHa-
O), 4.37 (br signal, 1H, OH), 4.49 (dd, 1H, JHa/Hb ) 12.3 Hz, JHb/
OH ) 5.4 Hz, CHb-O), 7.21-7.30 (complex signal, 5H, Ar-H), 7.78
(q, J5-CH3/6-H ) 1.2 Hz, 1H, pyrimidinedione 6-H), 10.37 (br signal,
1H, NH); 13C NMR (CDCl3, 75.4 MHz) δ 12.8 (CH3, pyrimidinedi-
one 5-CH3), 43.1 (CH3, N-CH3), 49.0 (CH2, C4), 64.6 (CH2,
CH2OH), 73.8 (CH, C3), 97.0 (C, C5), 107.8 (C, pyrimidinedione
C5), 127.6 (CH, Ar-Cmeta phenyl), 128.3 (CH, Ar-Cpara phenyl),
128.7 (CH, Ar-Hortho phenyl), 136.7 (C, Ar-Cipso phenyl), 138.2 (CH,
pyrimidinedione C6), 150.8 (C, pyrimidinedione C2), 165.9 (C,
pyrimidinedione C4). Anal. Calcd for C16H19N3O4: C, 60.56; H,
6.03; N, 13.24. Found: C, 60.72; H, 6.09; N 13.30.
Supporting Information Available: Experimental details for
compounds 4, 7, (()-9, (()-12/(()-13/(()-15/(()-16, (()-18,
(()-19, 29, 30, (-)-31, (+)-31, (-)-33, (+)-33, (()-39, 40, 41,
(-)-39, (+)-39, (-)-37, (+)-37, (-)-35, (+)-35, (-)-36, (+)-
36, (+)-34, (-)-34, and complementary procedures for (+)-36
from (-)-18 and 29, and (-)-36 from 21 and 30. Crystal-
lographic data and CIF file for compound 40. 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Antiviral Activity Assays. Antiviral activity was determined on
the basis of inhibition of virus-induced cytopathic effects (CPE),
essentially as described previously.35,36
JO800769M
(35) De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.; Jones, A. S.;
Torrence, P. F.; Shugar, D. J. Infect. Dis. 1981, 141, 563–574.
(36) De Clercq, E. Antimicrob. Agents Chemother. 1985, 28, 84–89.
J. Org. Chem. Vol. 73, No. 17, 2008 6665