Enantiomeric d4T analogues and their structural determination

Article abstract of DOI:10.1016/S0957-4166(02)00106-4

Asymmetric synthesis of d4T analogues having a benzo[c]furan moiety with two asymmetric carbon atoms was realized using Sharpless asymmetric dihydroxylation as the key step in a synthesis starting from o-phthalaldehyde. Enantiomeric purities were determin

Full text of DOI:10.1016/S0957-4166(02)00106-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 407–413
Enantiomeric d4T analogues and their structural determination
Abdelmajid Selouane,a,b Claude Vaccher,c Pierre Villa,a Denis Postela and Christophe Lena,*
aLaboratoire des Glucides, Universite´ de Picardie, Jules Verne, F-80039 Amiens, France
bUniversite´ IBN Tofail, Ke´nitra, Morocco
cLaboratoire de Chimie Analytique, Faculte´ des Sciences Pharmaceutiques et Biologiques, Universite´ de Lille 2,
F-59006 Lille, France
Received 6 February 2002; accepted 28 February 2002
Abstract—Asymmetric synthesis of d4T analogues having a benzo[c]furan moiety with two asymmetric carbon atoms was realized
using Sharpless asymmetric dihydroxylation as the key step in a synthesis starting from o-phthalaldehyde. Enantiomeric purities
were determined by analytical chiral HPLC with an amylose-derived stationary phase, while the absolute configurations were
established by X-ray crystallography. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Hivid),7 didanosine (ddI, Videx),8 lamivudine (3TC,
Epivir)9 and abacavir (ABC, 1592U89, Ziagen).10 d4T
shows selective anti-HIV activity comparable to that of
AZT in vitro.11 However, d4T is less toxic and less
inhibitory to mitochondrial DNA replication than
AZT.12 Novel nucleoside analogues based on a 1,3-
dihydrobenzo[c]furan glycone and 1-phenylethan-1,2-
diol, as exemplified by 1–5, have been described as
thymine analogues of d4T13–15 (Fig. 1).
2%,3%-Dideoxynucleosides (ddNs) are the most important
class of compounds active against HIV.1–3 They act as
DNA chain terminators and competitive inhibitors of
viral reverse transcriptase (RT).4 Currently, six drugs
belonging to the ddNs family are approved by the FDA
and are commercially available: zidovudine (AZT,
Retrovir),5 stavudine (d4T, Zerit),6 zalcitabine (ddC,
O
O
NH
NH
O
N
O
O
N
O
HO
HO
d4T
1
O
N
O
N
O
O
N
NH
NH
NH
NH
O
O
O
O
O
O
N
O
O
HO
HO
HO
HO
2
3
4
5
Figure 1.
* Corresponding author. E-mail: christophe.len@sc.u-picardie.fr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00106-4

408
A. Selouane et al. / Tetrahedron: Asymmetry 13 (2002) 407–413
mechanic models have been completed and permit
rationalization of the Sharpless’ model.19 To confirm
the modeling part, NMR and X-ray studies have been
developed which determine the absolute configuration
of the two stereogenic centers of the nucleoside
analogues.
Various routes to the nucleosides 2–5 have been pub-
lished starting in all cases from o-phthalaldehyde.14,15
Two stereogenic carbon centers are created in the for-
mation of the nucleosides leading to four stereoisomers
in a racemic synthesis14 or four diastereomerically pure
stereoisomers via asymmetric synthesis.15 The
diastereomerically pure nucleosides have been prepared
by application of the Sharpless asymmetric dihydroxy-
lation (AD) methodology.16 Starting from o-phthal-
aldehyde, the diols (S)-7 and (R)-7 having one stereo-
genic center were obtained using AD-mix a and AD-
mix b, respectively. For the first time the absolute
configuration of the carbon was assigned using the
mnemonic device.17 However, the literature18,19 has
shown that the enantioselectivity was opposite to that
expected. Modeling studies based on molecular
2. Results and discussion
Synthesis of the diols (S)-7 and (R)-7 have been
reported previously.15 Selective protection of one alde-
hyde function of o-phthalaldehyde using propan-1,3-
diol in the presence of p-TSA followed by
homologation using classical Wittig chemistry gave the
styrene derivative 6 in two steps in 58% yield overall
(Scheme 1).
O
O
O
i, ii
O
6
iv
iii
RO
OH
RO
OH
O
O
O
O
7S, R = H
7R, R = H
v
iv
8S, R = Piv
8R, R = Piv
vi
vi
O
O
O
O
OMe
OMe
OMe
OMe
PivO
PivO
PivO
+
PivO
+
9
15
10
16
vii
vii
O
O
O
O
NH
O
NH
NH
NH
O
O
O
O
N
N
O
N
O
N
O
RO
RO
RO
+
RO
+
11, R = Piv
13, R = H
12, R = Piv
14, R = H
17, R = Piv
19, R = H
18, R = Piv
20, R = H
viii
viii
viii
viii
Scheme 1. Reagents and conditions: (i) propan-1,3-diol, p-TSA, toluene; (ii) MePPh3Br, n-BuLi, THF, rt; (iii) AD mix a, t-BuOH,
H2O; (iv) AD mix b, t-BuOH, H2O; (v) PivCl, N(C2H5)3, toluene; (vi) MeOH/HCl (1%); (vii) silylated uracil, SnCl4, C2H4Cl2;
(viii) NaOH, H2O, dioxane.

A. Selouane et al. / Tetrahedron: Asymmetry 13 (2002) 407–413
409
Asymmetric dihydroxylation of 6 with AD mix a and
AD mix b afforded the diols (S)-7 and (R)-7 in 85 and
78% yields, respectively. Deprotection of the aldehyde
group of diol (S)-7 afforded a mixture of four com-
pounds namely 3-hydroxymethyl-1-methoxy-1,3-dihy-
drobenzo[c]furan 7a and the 4-hydroxy-1-methoxy-
isochromane 7b in 38 and 4% yields, respectively with
an epimeric mixture of 7a and 7b (1:1) (Scheme 2).
Table 1 shows the chromatographic data: retention,
selectivity and resolution factors for the stereoisomers
11, 12, 17 and 18 using different mobile phases by
changing the nature of the alcohol (ethanol or 2-
propanol) and the percentage (10 or 20%) with the
amylose-derived CSP Chiralpak AS. The alcohol
modifier can affect the retention of the solutes in differ-
ent ways: (i) by improving solvation in the mobile
phase and/or (ii) by competing for the H-bonding sites
in the stationary phase. We observed an increase in the
retention factors k% of all compounds by changing the
modifier from ethanol to 2-propanol, as generally
expected, due to the higher polarity of the ethanol. The
nucleosides 11, 12, 17 and 18 having a pivaloyl group
showed significantly lower k% values than those when
the pivaloyl group was changed to a benzyl or a
benzoyl group.21 This may support a possible role in
the retention mechanism of p–p interactions between
the phenyl groups of the stationary phases and the
aromatic group of the R substituent of the solute.21,22
The protection of the primary hydroxyl group of (S)-7
with pivaloyl chloride in a mixture of toluene and
triethylamine gave (S)-8 in 78% yield. The aldehyde
functionality of (S)-8 was selectively deprotected with
HCl in methanol to afford the cyclic acetals 9 and 10 in
72% yield. The mixture 9 and 10 was condensed with
silylated uracil and the two epimeric nucleoside prod-
ucts were separated by column chromatography to
afford 11 and 12 in 35 and 38% yields, respectively.
Deprotection of the pivaloyl group of 11 and 12 with
1N NaOH in dioxane then afforded the nucleosides 13
and 14 in 93% yield. Starting from the diol (R)-7 the
above strategy gave the derivatives (R)-8, 15–20 with
similar yields. Because the AD reactions of the styrene
derivative 6 with AD-mix a and AD-mix b were key
reactions in the synthesis of the nucleosides 11–14 and
17–20, a reliable method for the determination of the
enantiomeric excess of the products was required.
On this class of CSP the type and concentration of
alcohol did not influence the elution order. It is note-
worthy that the same elution order was observed
between the diastereomers 17 (first eluted) and 18 (sec-
ond eluted) corresponding to the (3%R) series in one
part and between 12 (first eluted) and 11 (second
eluted) corresponding to the (3%S) series in the other
one. The same elution order was observed between the
enantiomers 17 (first eluted) and 12 (second eluted)
corresponding to the trans isomers in one part and
between 18 (first eluted) and 11 (second eluted) corre-
sponding to the cis isomers in the other one (Fig. 2).
The good separation of the diastereomers makes this
chromatographic method suitable to quantify their
Separation of enantiomers by chiral analytical HPLC is
now an established preparative and analytical tool, with
over 50 different chiral stationary phases (CSPs) com-
mercially available. Among them cellulose and amylose
ester and carbamate derivatives coated onto large pore
silica gel supports had proven useful stationary phases
when used in normal-phase mode.20
O
O
OMe
HO
OH
O
HO
OMe
O
HO
+
7S
7a
7b
Scheme 2. Reagents and conditions: MeOH/HCl (1%).
Table 1. Chromatographic resolution on the amylose-derived column (Chiralpak AS): retention factors (k%) separation factor
(a) and resolution (Rs) of diastereomers 11, 12 17 and 18
Compounds
Eluent
k%
1
k%
2
a
Rs
17, 18 (3%R)
A
B
C
D
A
B
1.83 (1%R,3%R)-17
4.52 (1%R,3%R)-17
2.90 (1%R,3%R)-17
8.10 (1%R,3%R)-17
2.94 (1%S,3%S)-12
7.45 (1%S,3%S)-12
3.47 (1%S,3%S)-12
1.03 (1%S,3%S)-12
2.23 (1%S,3%R)-18
5.16 (1%S,3%R)-18
3.65 (1%S,3%R)-18
9.15 (1%S,3%R)-18
3.59 (1%R,3%S)-11
8.53 (1%R,3%S)-11
6.06 (1%R,3%S)-11
1.54 (1%R,3%S)-11
1.28
1.14
1.26
1.13
1.22
1.14
1.74
1.49
1.92
1.79
2.51
1.47
1.92
2.16
5.89
5.09
11, 12 (3%S)
C
D
Eluents A: n-hexane/ethanol: 80/20; B: n-hexane/ethanol: 90/10; C: n-hexane/2-propanol: 80/20; D: n-hexane/2-propanol: 90/10.

410
A. Selouane et al. / Tetrahedron: Asymmetry 13 (2002) 407–413
Figure 2. Stacking plot for the separations of (1%R,3%R)-17, (1%S,3%R)-18, (1%S,3%S)-12 and (1%R,3%S)-11 on Chiralpak AS at l=200
nm with 20% ethanol (eluent A).
purity which was greater than 99% (Fig. 2) and permit-
ted to determine the enantiomeric excess (e.e. >99%) of
the AD products (S)-7 and (R)-7.
J1%3% was not accessible for the cis configuration and the
J1%3% of 2.5 Hz in the trans configuration.
The absolute configuration of the C(3%) carbon atoms
was determined by X-ray spectroscopy. The 3,5-O-
The absolute configuration of the carbon atoms C(1%)
and C(3%) of the nucleoside analogues 11–14 and 17–20
was determined using NMR and X-ray spectroscopies.
The NMR spectroscopy showed an NOE interaction
between the C(1%)H and C(3%)H for compounds 11 and
18 confirming the cis configuration (1%R,3%S) or
(1%S,3%R) and no interaction for the trans compounds
12 and 17 (1%S,3%S) or (1%R,3%R). It was notable that the
[2-((S)-oxiranyl)benzylidene]-1,2-O-isopropylidene-a-D-
xylofuranose 2123 was an intermediate in the synthesis
of benzo[c]furan derivatives and afforded unequivocally
the nucleosides 2 and 3 having (3%S)-configuration
(Scheme 3). The specific rotations of nucleosides 2 and
3 were identical starting from both the chiral oxirane 21
and the diol (S)-7. These results confirmed the stereo-

A. Selouane et al. / Tetrahedron: Asymmetry 13 (2002) 407–413
411
O
O
N
O
O
O
NH
NH
O
O
O
O
+
O
N
O
O
HO
HO
21
13
14
Scheme 3.
chemistry of the nucleosides 11–14 and 17–20 obtained
chiral shift reagent) [h]2D2 +32.8 (c 3.86 in CHCl3),
AD-mix b gave the R-enantiomer (R)-7, (2.5 g, 78%),
(e.e. >99% by comparison of NMR spectra with added
chiral shift reagent), [h]2D2 −33.6 (c 3.42 in CHCl3); both
enantiomers had Rf 0.1 (hexane:ethyl acetate, 3:7); lH
(CDCl3): 1.46, 2.25 (2H, m, CH2 dioxanyl), 2.7, 3.2
(2H, two br s, OH), 3.75 (2H, m, OCH2), 3.89, 4.25
(4H, m, OCH2 dioxanyl), 5.24 (1H, m, OCH), 5.81 (1H,
s, dioxanyl), 7.40–7.65 (4H, m, aromatic H); lC
(CDCl3) 25.6 (1C, CH2 dioxanyl), 67.2, 67.6 (1C, OCH2
dioxanyl), 67.2 (1C, OCH), 70.5 (1C, OCH2), 101.0
(1C, CH dioxanyl), 126.7, 126.9, 127.8, 129.3, 135.6,
139.0 (6C, aromatic C).
with the present strategy.
The synthesis of benzo[c]furan nucleoside analogues
was developed starting from styrene derivative 6 using
an AD with high enantiomeric excess (e.e. >99%). The
determination of the configuration of the two stereo-
genic carbon atoms was realized by NMR study and
X-ray crystallography.
3. Experimental
3.1. General procedures
3.2.2. (S)- and (R)-1-O-Pivaloyl-1-(2-(1,3-dioxan-2-
yl)phenyl)ethan-1,2-diols, (S)-8 and (R)-8. Pivaloyl chlo-
ride (4.90 mL, 40.13 mmol) was added to the diol (S)-7
or (R)-7 (7.5 g, 33.44 mmol) in a mixture of toluene (9
mL) and triethylamine (3.5 mL) at –20°C and the
mixture stirred overnight at –10°C. Ice-water was added
and the mixture stirred for 30 min and then extracted
with toluene. This extract was worked up and the crude
product purified by column chromatography (hex-
ane:ethyl acetate, 7:3) to afford the protected diols
(S)-8 or (R)-8 as an oil, (8.1 g, 78%). (Found: C, 66.21;
H, 7.84, calcd for C17H24O5: C, 66.15; H, 7.91%);
S-enantiomer (S)-8 [h]2D2 +35.0 (c 1.0 in CHCl3), (R)-
enantiomer (R)-8 [h]2D2 –34.7 (c 1.0 in CHCl3); both
enantiomers had Rf 0.6 (hexane:ethyl acetate, 7:3); lH
(CDCl3) 1.22 (9H, s, CH3), 1.45, 2.20 (2H, m, CH2
dioxanyl), 4.01, 4.26 (4H, m, CH2 dioxanyl), 3.1 (1H,
m, OH), 4.20 (1H, dd, J=3.7, J=11.4, OCH2), 4.43
(1H, dd, J=8.0, OCH2), 5.41 (1H, m, OCH), 5.71 (1H,
s, dioxanyl), 7.35–7.57 (4H, m, aromatic H); lC
(CDCl3) 26.0 (CH2, dioxanyl), 27.6 (3C, CH3), 39.2
(1C, C(CH3)3), 67.8 (2C, OCH2, dioxanyl), 68.9 (1C,
CH2O), 69.0 (1C, CHOH), 101.1 (1C, dioxanyl), 127.2,
128.4, 129.6, 136.0, 138.6 (6C, aromatic C), 179.1 (CO).
NMR spectra were recorded with a Lambda 400 spec-
trometer using standard conditions with a data point
1
resolution of ca. 0.1 Hz. H Chemical shifts were mea-
sured relative to Me4Si and 13C chemical shifts relative
to CDCl3 (77.0 ppm) or (CD3)2SO (39.5 ppm). All
coupling constants are given in hertz. Assignments of
1
the H spectra were made by detailed analysis using
decoupling or correlation techniques where appropri-
ate. Diastereoisomer ratios were determined from the
integration of suitable peaks. Column chromatography
was performed on silica gel (230–400 mesh; Prolabo)
and TLC on silica gel 60, F254 (Merck) with detection
by UV absorbance or phosphomolybdic acid. Optical
rotation values are given in 10−1 deg cm2 g−1.
3.2. Syntheses
3.2.1. (S)- and (R)-1-(2-(1,3-Dioxan-2-yl)phenyl)ethan-
1,2-diols, (S)-7 and (R)-7. AD-mix a or AD-mix b
(19.98 g) in a mixture of tert-butyl alcohol (71.35 mL)
and water (71.35 mL) was stirred at room temperature
until both phases were clear. The mixture was cooled to
0°C and (2-(1,3-dioxan-2-yl)phenyl)ethene (2.71 g,
14.27 mmol) was added to the mixture at –10°C. The
resulting slurry was stirred vigorously at 0°C for 1 h.
Sodium sulfite (21.4 g) was added and the mixture
stirred at 20°C for 30 min, then diluted with water (80
mL) and extracted with dichloromethane. This extract
was worked up and the crude product purified by
column chromatography (gradient of hexane:EtOAc,
3:7; then 2:8, then 1:9, then pure EtOAc) to give the
diol as an oil. (Found: C, 63.03; H, 7.35, calcd for
C12H16O4·0.25 H2O: C, 63.00; H, 7.27%); AD-mix a
reagent gave the (S)-enantiomer (S)-7, (2.7 g, 85%),
(e.e. >99% by comparison of NMR spectra with added
3.2.3. (3S)- and (3R)-3-Pivaloyloxymethyl-1,3-dihydro-
1-methoxybenzo[c]furans: 9, 10, 15, 16. To compound
(S)-8 or (R)-8 (4.2 g, 13.6 mmol) was added a solution
of methanolic HCl (1%, 90 mL) at 20°C for 1 h. The
solution was concentrated to about 10 mL and the
precipitate collected to give the 1,3-dihydro-1-methoxy-
benzo[c]furans 9, 10 or 15, 16 as oils, (2.6 g, 72%); Rf
0.2 (hexane:diethyl ether, 5:5). (Found: C, 68.53; H,
7.60, calcd for C15H20O4: C, 68.16; H, 7.63%); (1R,3S)-
isomer 9 and (1S,3R)-enantiomer 16 lH (CDCl3) 1.18
(9H, s, CH3), 3.50 (3H, s, OCH3), 4.30 (1H, dd, J=4.4,
J=11.5, OCH2), 4.40 (1H, dd, J=6.1, OCH2), 5.34

412
A. Selouane et al. / Tetrahedron: Asymmetry 13 (2002) 407–413
(1H, m, H-3), 6.12 (1H, s, H-1), 7.28-7.41 (4H, m,
aromatic H); lC (CDCl3) 27.4 (CH3), 39.2 (C(CH3)3),
55.3 (OCH3), 67.5 (C-8), 81.7 (C-3), 107.5 (C-1), 122.0,
123.4, 128.9, 129.7, 138.6, 139.7 (6C, aromatic C), 178.5
(CO); (1S,3S)-enantiomer 10 and (1R,3R)-enantiomers
15 lH (CDCl3) 1.07 (9H, s, CH3), 3.45 (3H, s, OCH3),
4.33 (1H, dd, J=3.6, J=11.8, OCH2), 4.50 (1H, dd,
J=4.6, OCH2), 5.55 (1H, m, H-3), 6.24 (1H, s, H-1),
7.28–7.41 (4H, m, aromatic H); lC (CDCl3) 27.4 (CH3),
39.2 (C(CH3)3), 54.8 (OCH3), 66.0 (C-8), 81.7 (C-3), 107.5
(C-1), 122.0, 123.4, 128.9, 129.7, 138.6, 139.7 (6C, aro-
matic C), 178.5 (CO).
dioxane (36 mL) and aqueous NaOH 1N (36 mL) and
the mixture stirred for 2 h. After addition of acetic acid
(pH 7) the evaporation of the solvent and column
chromatography (CHCl3:MeOH, 9:1) gave the
nucleosides 13, 14, 19 or 20 (503 mg, 93%). In all cases
the NMR data and the physical data were identical to
those reported in a previous paper.15
3.3. General procedure for HPLC
Chromatography was carried out on a Chiralpak AS
column (amylose tris-(S)-1-phenylethylcarbamate; 250×
4.6 mm i.d.; 10 mm) (Daicel Chemical Industries, Baker
France) using a gradient Waters 600E metering pump
model equipped with a Waters 996 photodiode array
spectrophotometer. Chromatographic data were col-
lected and processed on a Digital computer running with
Millennium 2010. The column eluate was monitored at
200; 254 nm. The sample loop was 20 mL (Rheodyne 7125
injector). Mobile phase elution was made isocratically
using n-hexane and a modifier (ethanol or 2-propanol)
at various percentages. The flow-rate was 1.0 mL min−1.
The peak of the solvent front was considered to be equal
to the dead time (to=3.5 min) and was taken from each
particular run. Retention times were mean values of two
replicate determinations. All separations were carried out
at 30°C. The separation factor (h) was calculated as k%/k%
3.2.4. (1R,3S)-, (1S,3S)-, (1R,3R)- and (1S,3R)-1-(3-
Pivaloyloxymethyl-1,3-dihydrobenzo[c]furan-1-yl)uracils
11, 12, 17 and 18. A suspension of uracil (1.1 g, 9.46
mmol) in hexamethyldisilazane (19 mL) and ammonium
sulfate were refluxed with exclusion of moisture until a
clear solution was obtained (3 h). Volatiles were removed
by repeated co-evaporation with toluene to leave syrup.
This syrup and the 1,3-dihydrobenzo[c]furan 9, 10 or 15,
16 (1.0 g, 3.78 mmol) were taken up in dry dichloroethane
(24 mL) and SnCl4 (890 mL, 9.46 mmol) added at –15°C.
After stirring for 2 h at 0°C sat. NaHCO3 solution (20
mL) was added, the mixture was stirred for 30 min and
then extracted with CH2Cl2. This extract was worked up
and the diastereoisomers 11, 12 or 17, 18 were separated
by column chromatography (hexane:EtOAc, 7:3); the
compound eluting first was the cis isomer (11 or 18), 460
mg (35%), mp 178°C (EtOH), Rf 0.56, (hexane:EtOAc,
1:1), isomer 11. (Found: C, 62.65; H, 5.94; N, 8.16, calcd
for C18H20N2O5: C, 62.78; H, 5.85; N, 8.13%); [h]2D2 +24.0
(c 1.0 in CHCl3), enantiomer 18 (Found: C, 62.58; H,
5.85; N, 8.11, calcd for C18H20N2O5: C, 62.78; H, 5.85;
N, 8.13%); [h]2D2 –23.8 (c 1.0 in CHCl3); lH (CDCl3): 1.07
(9H, s, CH3), 4.37 (1H, m, J=2.9, J=12.6, CH2O), 4.79
(1H, m, J=4.5, H-8b), 5.68 (1H, d, J 8.1, H-5), 5.51 (1H,
J=2.7, H-3), 7.18 (1H, d, H-6), 7.47 (1H, d, H-1),
7.31–7.52 (4H, m, aromatic H); lC (CDCl3) 27.4 (CH3),
39.1 (C(CH3)3), 65.4 (C-8), 82.4 (C-3), 87.9 (C-1), 103.5
(C-5 uracil), 122.4, 123.3, 130.0, 130.6, 136.5, 138.9 (6C,
aromatic C), 140.6 (C-6 uracil), 151.3 (C-2 uracil), 162.8
(C-4 uracil), 178.2 (CO). trans Isomer (12 or 17), 485 mg
(38%), mp 121–122 °C (EtOH), Rf 0.47, (hexane:EtOAc,
1:1), enantiomer 12. (Found: C, 62.77; H, 5.83; N, 8.16,
calcd for C18H20N2O5: C, 62.78; H, 5.85; N, 8.13%); [h]D22
–104.2 (c 1.0 in CHCl3), enantiomer 17. (Found: C, 62.79;
H, 5.93; N, 8.10, calcd for C18H20N2O5: C, 62.78; H, 5.85;
N, 8.13%); [h]2D2 +104.6 (c 1.0 in CHCl3); lH (CDCl3): 1.09
(9H, s, CH3), 4.33 (1H, m, J=3.3, J=12.0, CH2O), 4.53
(1H, m, J=4.4, H-8b), 5.67 (1H, d, J 8.1, H-5), 5.70 (1H,
J=2.7, H-3), 6.81 (1H, d, H-6), 7.54 (1H, d, H-1),
7.28–7.52 (4H, m, aromatic H), 9.13 (1H, br s, NH); lC
(CDCl3) 27.4 (CH3), 39.3 (C(CH3)3), 65.9 (C-8), 83.2
(C-3), 88.8 (C-1), 103.7 (C-5 uracil), 122.6, 123.3, 130.1,
130.7, 136.5, 139.2 (6C, aromatic C), 140.2 (C-6 uracil),
150.8 (C-2 uracil), 162.8 (C-4 uracil), 178.2 (CO).
2
1
and retention factors (k%) as k%=(t1–t0)/t0 and k%=(t2–
1
2
t0)/t0 where t1, t2 refer to the retention times of the first
and second enantiomers, respectively. The resolution
factor (RS) was calculated by the formula RS=2 (t2–t1)/
(w1+w2) where w1 and w2 are the peak widths for the first
and second eluting enantiomer peaks, respectively.
Reagents: ethanol, 2-propanol and n-hexane were HPLC
grade from Merck or Baker. All the solutions were
filtered (0.45 mm), degassed with a Waters in-line degasser
apparatus. The mobile phases used were A: n-hexane/
ethanol: 80/20; B: n-hexane/ethanol: 90/10; C: n-hexane/
2-propanol: 80/20; D: n-hexane/2-propanol: 90/10.
Compounds were chromatographed by dissolving them
in the corresponding alcohol to a concentration of about
0.75 mM (which corresponds to 15 nmoles injected) and
passed through a 0.45 mm membrane filter prior to
loading the column.
Acknowledgements
We thank «Le conseil Re´gional de Picardie» for financial
support.
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