Asymmetric synthesis of 1,3-dithiolane nucleoside analogues

Article abstract of DOI:10.1002/ejoc.200390040

We report the ready asymmetric synthesis of nucleoside analogues containing a 1,3-dithiolane ring that mimics the sugar moiety of natural nucleosides. The synthesis is accomplished in three main steps from benzoyloxyethanal 1,3-dithiolane, the key step being its conversion into a chiral monosulfoxide by a modified Sharpless sulfo-oxygenation reaction. The nucleoside analogues were obtained in good overall yields and with excellent enantiomeric excesses. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390040

FULL PAPER
Asymmetric Synthesis of 1,3-Dithiolane Nucleoside Analogues
Romualdo Caputo,[a] Annalisa Guaragna,*[a] Giovanni Palumbo,[a] and Silvana Pedatella[a]
Dedicated to Prof. L. Mangoni on his 70th birthday
Keywords: Nucleosides / Sulfur heterocycles / Chirality / Sulfoxides / Antiviral agents
We report the ready asymmetric synthesis of nucleoside ana-
logues containing a 1,3-dithiolane ring that mimics the sugar
moiety of natural nucleosides. The synthesis is accomplished
in three main steps from benzoyloxyethanal 1,3-dithiolane,
the key step being its conversion into a chiral monosulfoxide
by a modified Sharpless sulfo-oxygenation reaction. The nuc-
leoside analogues were obtained in good overall yields and
with excellent enantiomeric excesses.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
In this paper, we report a new asymmetric synthesis of
1,3-dithiolane nucleoside analogues, a class of thioribonu-
cleosides having a second sulfur atom replacing the 3Ј rib-
ose carbon atom. Synthetic paths leading to such com-
pounds are not very common and, to the best of our know-
ledge, so far only two synthetic routes have been re-
ported,[13,14] although both of them lead to racemic
products that need resolution by HPLC on chiral columns
to get enantiomerically pure compounds.
The discovery of modified nucleosides that are effective
in the treatment of Acquired Immunodeficiency Syn-
drome[1] (AIDS) has aroused a great interest in the synthesis
of such molecules during the last decade. Only a few nucle-
oside analogues, which act as reverse transcriptase inhib-
itors[2] (NRTI), have been approved so far for the treatment
of HIV-infected individuals, including AZT[3] (Zidovudine),
ddC[4] (Zalcitabine), ddI[5] (Didanosine), d4T[6] (Stavudine),
3TC[7] (Lamivudine), and the carbocyclic analogue ABC[8]
(Abacavir).
Results and Discussion
In general, nucleoside analogues having one or more het-
eroatoms replacing the ring atoms of the sugar moiety turn
out to be more potent,[9] possess improved selectivity to-
ward mutant viruses, and show enhanced cellular uptake.
The sugar configuration also seems to affect the biological
activity of the NRTIs;[10] in fact, β--(Ϫ)-2Ј-deoxy-3Ј-thia-
cytidine (lamivudine), which is the sole -nucleoside ana-
logue in use, is much less cytotoxic[11] than its -enantiomer
(BCH-189), although both of them are roughly equipotent
against the replication of HIV-1. All these considerations
have spurred chemical research towards the synthesis of
new -sugar-based nucleoside analogues as potential reverse
transcriptase inhibitors.
As a part of our current interest in the synthesis of modi-
fied sugars[15] for their incorporation into nucleoside ana-
logues, we have devised a new general approach to the
asymmetric synthesis of chiral 1,3-dithiolanyl nucleosides
(2,4-disubstituted 1,3-dithiolanes) with excellent enantiom-
eric excesses, in three main steps starting from benzoyloxye-
thanal 1,3-dithiolane.[16]
The key step of our approach is the preparation of the
chiral sulfoxides 2 (Scheme 1). 2-[(Phenylcarbonyloxy)me-
thyl]-1,3-dithiolane (1) was obtained in very high yield
(98%) by treatment of benzoyloxyethanal[17] (from mono-
benzoylglycerol) with ethanedithiol in the presence of
polystyryl diphenylphosphaneϪiodine complex, which acts
as both a Lewis acid and a dehydrating agent, according to
a procedure formerly developed in our laboratory[18].The
conversion of achiral 1 into the chiral sulfoxides 2 was then
performed by a Di FuriaϪModena oxidation[19] with tert-
butyl hydroperoxide and diethyl -tartrate in the presence
of TiIV isopropoxide as catalyst.
As a consequence, several methods are available in the
recent literature for the synthesis of various nucleoside ana-
logues,[12] although the real challenge is the difficulty in pre-
paring such compounds in optically pure forms.
[a]
`
Dipartimento di Chimica Organica e Biochimica, Universita di
Napoli Federico II
In order to avoid the double oxidation of 1 at both the
sulfur atoms (and overoxidation to the sulfone as well) we
used a 5:1 molar ratio of 1 and the oxidizing system
(tBuOOH/-DET/TiIV). Under such conditions, the oxida-
Via Cynthia, 4, 80126 Napoli, Italy
E-mail: guaragna@unina.it
[b]
Consorzio Interuniversitario Nazionale, La Chimica per
l’Ambiente
`
Via della Liberta, 5/12, 30175 Marghera (VE), Italy
346
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0102Ϫ0346 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 346Ϫ350

Asymmetric Synthesis of 1,3-Dithiolane Nucleoside Analogues
FULL PAPER
Scheme 1. Conversion of 1,3-dithiolane 1 into chiral sulfoxides 2
and 3; i. -DET/Ti(OiPr)4/tBuOOH in CH2Cl2, Ϫ20 °C, 16 h; ii.
same as i., but with -DET
tion of 1 led in high yield (90%) to a mixture of the diaster-
eoisomeric E and Z pairs (2) in a 96:4 ratio (Scheme 1).
After chromatographic separation, the more-abundant E
Figure 1. 1,3-Dithiolane nucleoside analogues from chiral sulfox-
ides 2 and 3
1
pair exhibited an ee of 92%, as determined by H NMR
spectroscopic analysis using Eu(hfc)3 (Aldrich) as the chiral
shift reagent.
ferent, and their melting points differ by more than 90 °C)
nor do they match our data for the same compounds.
Our new approach to the asymmetric synthesis of hetero-
substituted nucleoside analogues may represent a rapid
entry to optically pure materials and potentially is amenable
to the preparation of multi-gram quantities of these import-
ant compounds.
The replacement of diethyl -tartrate with its -enanti-
omer led also to a diastereoisomeric (E/Z ϭ 96:4) mixture
(3) in which the more-abundant E pair exhibited an ee of
1
94% (by H NMR spectroscopy). The (2R,SR) stereochem-
istry assigned to the sulfoxide (E)-3 was supported by X-
ray crystallographic analysis (85% confidence). The final
step of the synthesis consisted of the coupling of the more-
abundant chiral sulfoxides (E)-2 and (E)-3 with both N4-
acetylcytosine and 6-Cl-purine under modified Pummerer
rearrangement conditions;[20] i.e., by direct treatment of the
heterocyclic base silylated in situ with trimethylsilyl triflate
in the presence of triethylamine. The results obtained are
displayed in Figure 1. The cis/trans configurations were
assigned by NOE difference experiments (see Exp. Sect.).
Experimental Section
General: 1H and 13C NMR spectra: Varian Inova 500, Bruker
DRX-400, Varian Gemini 200 spectrometers, CDCl3 unless other-
wise specified, TMS internal standard. Optical rotations: Jasco P-
1010 (1.0 dm cell). Combustion analyses: PerkinϪElmer Series II
Treatment of the protected dithiolanyl nucleosides with 2400, CHNS analyzer. HPLC analyses: Gynkotek M480 chromato-
graph equipped with UVD 160S detector. Chiral columns: Cyclo-
bond I 2000 RSP 4.6 mm ID ϫ 250 mm (Astec) and DIACEL-
chiralcel-OD-R 4.6 mm ID ϫ 250 mm (JT Baker). TLC analyses:
silica gel Merck 60 F254 plates (0.2 mm layer thickness). Column
chromatography: Merck Kieselgel 60 (70Ϫ230 mesh). Dry solvents
were distilled immediately before use.
sodium methoxide in methanol afforded the corresponding
free cytosinyl nucleosides 5a, 5b, 9a, and 9b, and purinyl
nucleosides 7a and 7b in high yields.
This procedure for the synthesis of thiosugar-based nuc-
leoside analogues, via chiral sulfoxides, is an appealing one
for the preparation of such compounds belonging to both
 and  series, with excellent enantiomeric excesses, merely
by judicious choice of a suitable ligand to use as the chiral-
ity inductor in the asymmetric sulfo-oxygenation step.
While this work was in progress, we encountered a pa-
per[14] that describes the synthesis and separation on a
chiral HPLC column of two enantiomeric compounds
matching our products 5b and 9b. In our opinion, this re-
port is rather questionable and should be reconsidered since
Compound 1: A solution of benzoyloxyethanal (3.7 g, 22.6 mmol)
in dry MeCN (25 mL) was added with a syringe in one portion
to
a
magnetically
stirred
suspension
of
polystyryl
diphenylphosphaneϪiodine complex (22.6 mmol, prepared in situ)
in dry MeCN (150 mL), at room temperature and under an atmo-
sphere of dry N2. After 10 min, 1  ethanedithiol in the same sol-
vent (23 mL) was added in one portion. Benzoyloxyethanal was
fully consumed (TLC monitoring) within 2 h. Solid K2CO3 (excess)
was added, the suspension stirred for a couple of minutes, and then
filtered. The residual solid was washed with chloroform (3 ϫ
the physical data of those products are not those expected
1
for enantiomers (e.g., their H NMR spectra are quite dif- 100 mL), and then the combined filtrates were washed with 5  aq
Eur. J. Org. Chem. 2003, 346Ϫ350
347

R. Caputo, A. Guaragna, G. Palumbo, S. Pedatella
FULL PAPER
sodium thiosulfate (50 mL) and water until neutral. The solvents
were then evaporated under reduced pressure to leave a residue
Higher Rf product 4a (trans) (0.12 g), m.p. 194Ϫ196 °C (MeOH).
[α]2D5 ϭ ϩ78.0 (c ϭ 0.2, CHCl3). C17H17N3O4S2 (391.4): calcd. C
52.12, H 4.38; found C 52.26, H 4.37. H NMR (500 MHz): δ ϭ
1
consisting of practically pure 1 (5.3 g, 98%) as an oil. C11H12O2S2
1
(240.3): calcd. C 54.97, H 5.03; found C 55.13, H 5.04. H NMR 2.23 (s, 3 H, COCH3), 3.46 (dd, J5a,4 ϭ 1.3, J5a,5b ϭ 13.5 Hz, 1 H,
(200 MHz): δ ϭ 3.25 (s, 4 H, 4-H and 5-H), 4.35 (d, J6,2 ϭ 7.1 Hz,
5-Ha), 3.63 (dd, J5b,4 ϭ 4.6, J5b,5a ϭ 13.5 Hz, 1 H, 5-Hb), 4.37 (dd,
2 H, 6-H), 4.79 (t, J2,6 ϭ 7.1 Hz, 1 H, 2-H), 7.38Ϫ7.52 (m, 3 H, J6a,2 ϭ 7.2, J6a,6b ϭ 11.4 Hz, 1 H, 6-Ha), 4.49 (dd, J6b,2 ϭ 7.2,
para-H and meta-H), 8.03 (d, Jortho ϭ 7.9 Hz, 2 H, ortho-H). 13C J6b,6a ϭ 11.4 Hz, 1 H, 6-Hb), 5.02 (t, J2,6a ϭ J2,6b ϭ 7.2 Hz, 1 H,
NMR (200 MHz): δ ϭ 37.8 (C-4, C-5), 50.4 (C-2), 68.0 (C-6), 120.5 2-H), 6.78 (dd, J4,5a ϭ 1.3, J4,5b ϭ 4.6 Hz, 1 H, 4-H), 7.41 (d,
(C-arom), 128.2Ϫ132.9 (C-arom), 165.8 (CϭO).
J5Ј,6Ј ϭ 7.5 Hz, 1 H, H-5Ј), 7.45Ϫ7.48 (m, 2 H, meta-H), 7.60 (t,
Jortho ϭ 7.4 Hz, 1 H, para-H), 8.04 (d, Jortho ϭ 7.4 Hz, 2 H, ortho-
H), 8.24 (d, J6Ј,5Ј ϭ 7.5 Hz, 1 H, 6Ј-H), 8.42 (br. s, 1 H, NH); [2-
H, 4-H protons: no NOE effect]. 13C NMR (200 MHz): δ ϭ 24.7
(COCH3), 43.8 (C-5), 51.6 (C-2), 67.1 (C-4), 70.2 (C-6), 96.0 (C-
5Ј), 128.4, 129.1, 129.6, 133.3 (C-arom), 146.3 (C-6Ј), 155.2 (Cϭ
O), 162.9 (CϭN), 165.7 (CϭO), 171.1 (CϭO). HPLC (Cyclobond
Compound 2. Typical Procedure: Diethyl -tartrate (1.4 mL,
9.6 mmol) dissolved in dry CH2Cl2 (15 mL) was added under vigor-
ous magnetic stirring at room temperature to a solution of TiIV
isopropoxide (0.7 mL, 2.4 mmol) in dry CH2Cl2 (15 mL). After
10 min, the resulting yellow homogeneous solution was cooled to
Ϫ20 °C. tert-Butyl hydroperoxide (1.6 mL, 5.7 mmol) was then ad-
ded dropwise, followed after a few minutes by 1,3-dithiolane 1
(2.9 g, 12.1 mmol) dissolved in dry CH2Cl2 (20 mL). The reaction
mixture was maintained at Ϫ20 °C whilst stirring for 14 h, then
quenched with cold H2O (30 mL) and warmed up to room temper-
ature. The resulting emulsion was cleared by filtration through Cel-
ite and the organic layer was then separated. The aqueous phase
was extracted with CH2Cl2 (2 ϫ 50 mL) and the combined organic
phases were washed with 10% aq. sodium metabisulfite (100 mL),
5% aq. sodium hydroxide, and brine until neutral, then dried
(Na2SO4) and the solvents evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel
(CHCl3) and, in addition to the unreacted starting material (1.5 g,
6.2 mmol), two diastereoisomeric sulfoxides were separated (overall
yield 1.35 g, 90%). (E)-2 (1.29 g, 5.03 mmol), m.p. 82Ϫ83 °C (from
hexane). [α]2D5 ϭ Ϫ75.8 (c ϭ 0.7, CHCl3). C11H12O3S2 (256.3):
calcd. C 51.54, H 4.72; found C 51.67, H 4.70. 1H NMR
(400 MHz): δ ϭ 2.80Ϫ2.94 (m, 1 H, 5-Ha), 3.48Ϫ3.62 (m, 2 H, 4-
I 2000 RSP, 50% MeOH plus 0.1  NH4OAc in H2O): Rt
ϭ
25.98 min (96%), 29.09 min (4%).
Lower Rf product 4b (cis) (0.1 g), m.p. 148Ϫ150 °C (MeOH).
[α]2D5 ϭ Ϫ85.0 (c ϭ 0.2, CHCl3). C17H17N3O4S2 (391.4): calcd. C
1
52.16, H 4.38; found C 52.33, H 4.41. H NMR (500 MHz): δ ϭ
2.24 (s, 3 H, COCH3), 3.48 (dd, J5a,4 ϭ 2.6, J5a,5b ϭ 13.5 Hz, 1 H,
5-Ha), 3.62 (dd, J5b,4 ϭ 4.6, J5b,5a ϭ 13.5 Hz, 1 H, 5-Hb), 4.78 (dd,
J6a,2 ϭ 5.6, J6a,6b ϭ 11.8 Hz, 1 H, 6-Ha), 4.81 (dd, J6b,2 ϭ 5.6,
J6b,6a ϭ 11.8 Hz, 1 H, 6-Hb), 5.02 (t, J2,6a ϭ J2,6b ϭ 5.6 Hz, 1 H,
2-H), 6.71 (dd, J4,5a ϭ 2.6, J4,5b ϭ 4.6 Hz, 1 H, 4-H), 7.29 (d,
J5Ј,6Ј ϭ 7.5 Hz, 1 H, 5Ј-H), 7.49Ϫ7.53 (m, 2 H, meta-H), 7.64 (t,
Jortho ϭ 7.6 Hz, 1 H, para-H), 8.07 (d, Jortho ϭ 7.4 Hz, 2 H, ortho-
H), 8.51 (d, J6Ј,5Ј ϭ 7.5 Hz, 1 H, 6Ј-H); [2-H, 4-H protons: NOE
effect]. 13C NMR (200 MHz): δ ϭ 24.7 (CH3CO), 45.3 (C-5), 53.6
(C-2), 64.7 (C-4), 69.6 (C-6), 96.1 (C-5Ј), 128.5, 129.6, 130.8, 133.6
(C-arom), 146.3 (C-6Ј), 155.0 (CϭO), 162.7 (CϭN), 165.8 (CϭO),
171.0 (CϭO). HPLC (Cyclobond I 2000 RSP, 50% MeOH plus 0.1
 NH4OAc in H2O): Rt ϭ 13.37 min (96%), 15.76 min (4%).
H), 3.75Ϫ3.86 (m, 1 H, 5-Hb), 4.35 (dd, J6a,2 ϭ 9.3, J6a,6b
ϭ
12.4 Hz, 1 H, 6-Ha), 4.53 (dd, J6b,2 ϭ 4.9, J6b,6a ϭ 12.4 Hz, 1 H,
6-Hb), 4.59 (dd, J2,6b ϭ 4.9, J2,6a ϭ 9.3 Hz, 1 H, 2-H), 7.43Ϫ7.51
(m, 2 H, meta-H), 7.60 (t, Jortho ϭ 7.4 Hz, 1 H, para-H), 8.02 (d,
Jortho ϭ 7.4 Hz, 2 H, ortho-H). [The signal of the 2-H proton is
split by addition of Eu(hfc)3 from δ ϭ 4.59 (dd) to δ ϭ 5.06 (br. s,
96%) and δ ϭ 5.17 (br. s, 4%).] 13C NMR (400 MHz): δ ϭ 32.8
(C-4), 55.1 (C-5), 63.6 (C-6), 72.3 (C-2), 128.9, 129.0, 130.1, 133.9
(C-arom), 166.1 (CϭO). HPLC (DIACEL, 60% MeCN plus 0.01%
TFA in H2O): Rt ϭ 15.48 min (4%), 19.99 min (96%).
Under the same conditions the sulfoxides 3 [(E)-pair] afforded their
enantiomeric nucleosides (8a and 8b) in 72% yield, trans/cis ϭ
1.1:1.0):
8a (trans), m.p. 193Ϫ195 °C (MeOH). [α]2D5 ϭ Ϫ80.0 (c ϭ 0.2,
CHCl3). C17H17N3O4S2 (391.4): calcd. C 52.16, H 4.38; found C
52.21, H 4.38. 1H NMR and 13C NMR spectra superimposable on
those of 4a. HPLC (Cyclobond I 2000 RSP, 50% MeOH plus 0.1
 NH4OAc in H2O): Rt ϭ 27.40 min (97%), 29.45 min (3%).
(E)-3 was prepared (yield 90%) under the same conditions from 1
8b (cis), m.p. 149Ϫ151 °C (MeOH). [α]2D5 ϭ ϩ84 (c ϭ 0.2, CHCl3).
using diethyl -tartrate: m.p. 71Ϫ73 °C (from hexane). [α]2D5
ϭ
C17H17N3O4S2 (391.4): calcd. C 52.16, H 4.38; found C 52.25, H
ϩ74.9 (c ϭ 0.6, CHCl3). C11H12O3S2 (256.3): calcd. C 51.54, H
1
4.39. H NMR and 13C NMR spectra superimposable on those of
1
4.72; found C 51.41, H 4.73. H NMR and 13C NMR spectra su-
4b. HPLC (Cyclobond I 2000 RSP, 50% MeOH plus 0.1 
NH4OAc in H2O): Rt ϭ 13.74 min (3%), 16.32 min (97%).
perimposable on those of (E)-2. HPLC (DIACEL, 60% MeCN plus
0.01% TFA in H2O): Rt ϭ 15.48 min (97%), 19.99 min (3%).
Compounds 4a and 4b. Typical Procedure: Trimethylsilyl triflate
Compounds 6a and 6b: Trimethylsilyl triflate (TMSOTf) (0.44 mL,
(TMSOTf) (0.9 mL, 4.8 mmol) and triethylamine (0.6 mL, 2.4 mmol) and triethylamine (0.4 mL, 2.4 mmol) were added drop-
4.8 mmol) were added dropwise sequentially to a magnetically
wise sequentially to a magnetically stirred suspension of 6-chlorop-
urine (0.26 g, 1.6 mmol) in dry toluene (10 mL) at 0 °C under an N2
stirred suspension of N4-acetylcytosine (0.1 g, 1.2 mmol) in dry
toluene (15 mL), at 0 °C and under nitrogen atmosphere. After atmosphere. After 4 h a suspension of sulfoxide 2 [(E)-pair] (0.2 g,
20 min a suspension of sulfoxide 2 [(E)-pair] (0.2 g, 0.8 mmol) in
dry toluene (5 mL) was added and the resulting mixture was stirred
overnight. After partial evaporation of the solvent under reduced
pressure the residue was diluted with EtOAc (15 mL), washed with
0.8 mmol) and ZnI2 (0.08 g, 0.24 mmol) in the same solvent (5 mL)
was added and the resulting mixture was stirred overnight. After
partial evaporation of the solvent under reduced pressure, the res-
idue was redissolved in EtOAc (15 mL), washed with 5% aq
5% aq NaHCO3 (2 ϫ 10 mL) and water until neutral, dried NaHCO3 (2 ϫ 10 mL) and water until neutral, dried (Na2SO4),
(Na2SO4), and then the solvents were evaporated under reduced and then the solvents evaporated under reduced pressure. After
pressure. After purification by column chromatography on silica
gel (EtOAc/petroleum ether, 7:3) two diastereoisomeric cytosinyl
dithiolanes (overall yield 0.22 g, 70%) were obtained.
purification by column chromatography on silica gel (EtOAc/petro-
leum ether, 7:3) two diastereoisomeric purinyl dithiolanes 6a and
6b (0.4 g, yield 65%) were obtained.
348
Eur. J. Org. Chem. 2003, 346Ϫ350

Asymmetric Synthesis of 1,3-Dithiolane Nucleoside Analogues
FULL PAPER
Higher Rf product 6a (trans) (0.2 g), m.p. 156Ϫ157 °C (MeOH).
[α]2D5 ϭ ϩ43.3 (c ϭ 0.2, MeOH). C16H13ClN4O2S2 (392.9): calcd.
Compound 9a from 8a: 80% yield, m.p. 202 °C dec. (EtOAc). [α]2D5
Ϫ28.5 (c ϭ 0.7, MeOH). C8H11N3O2S2 (245.3): calcd. C 39.17, H
ϭ
C 48.91, H 3.34; found C 48.80, H 3.35. 1H NMR (500 MHz): δ ϭ 4.52; found C 39.29, H 4.51. H NMR and 13C NMR spectra su-
1
3.42 (dd, J5a,4 ϭ 1.5, J5a,5b ϭ 13.4 Hz, 1 H, 5-Ha), 3.79 (dd, J5b,4 ϭ
4.1, J5b,5a ϭ 13.4 Hz, 1 H, 5-Hb), 4.45 (dd, J6a,2 ϭ 7.3, J6a,6b
11.4 Hz, 1 H, 6-Ha), 4.56 (dd, J6b,2 ϭ 7.3, J6b,6a ϭ 11.4 Hz, 1 H,
6-Hb), 5.15 (t, J2,6a ϭ J2,6b ϭ 7.3 Hz, 1 H, 2-H), 7.12 (dd, J4,5a
1.5, J4,5b ϭ 4.1 Hz, 1 H, 4-H), 7.50 (t, Jortho ϭ 7.3 Hz, 2 H, meta-
H), 7.62 (t, Jortho ϭ 7.3 Hz, 1 H, para-H), 8.07 (d, J ϭ 7.3 Hz, 2
H, ortho-H), 8.82 (s, 1 H, 2Ј-H), 8.91 (s, 1 H, 8Ј-H); [2-H, 4-H
protons: no NOE effect]. 13C NMR (200 MHz): δ ϭ 45.0 (C-5),
51.8 (C-2), 66.8 (C-4), 69.4 (C-6), 121.7 (C-5Ј), 128.6, 129.2, 130.8,
133.6 (C-arom), 142.4 (C-4Ј), 148.5 (C-8Ј), 152.8 (C-2Ј), 162.8 (C-
6Ј),165.9 (CϭO).
perimposable on those of 5a. HPLC (50% MeOH plus 0.1 
NH4OAc in H2O): Rt ϭ 9.70 min (97%), 10.65 min (3%).
ϭ
Compound 9b from 8b: 78% yield, m.p. 108Ϫ110 °C (EtOAc).
[α]2D5 ϭ Ϫ20.5 (c ϭ 0.1, MeOH). C8H11N3O2S2 (245.3): calcd. C
39.17, H 4.52; found C 39.22, H 4.52. 1H NMR and 13C NMR
spectra superimposable on those of 5b. HPLC (50% MeOH plus
0.1  NH4OAc in H2O): Rt ϭ 9.75 min (97%), 10.79 min (3%).
ϭ
Compound 7a from 6a: 94% yield, m.p. 192Ϫ194 °C (MeOH).
[α]2D5 ϭ ϩ25.8 (c ϭ 0.34, MeOH). C9H9ClN4OS2 (288.8): calcd. C
1
37.43, H 3.14; found C 37.36, H 3.12. H NMR (500 MHz): δ ϭ
3.39 (dd, J5a,4 ϭ 1.5, J5a,5b ϭ 13.2 Hz, 1 H, 5-Ha), 3.64 (dd, J5b,4 ϭ
4.2, J5b,5a ϭ 13.2 Hz, 1 H, 5-Hb), 3.72Ϫ3.78 (m, 2 H, 6-H), 4.87 (t,
Lower Rf product 6b (cis) (0.2 g), amorphous. [α]2D5 ϭ Ϫ34.4 (c ϭ
0.2, MeOH). C16H13ClN4O2S2 (392.9): calcd. C 48.91, H 3.34;
found C 48.83, H 3.33. 1H NMR (500 MHz): δ ϭ 3.65 (dd, J5a,4 ϭ
J
2,6 ϭ 6.6 Hz, 1 H, 2-H), 6.85 (dd, J4,5a ϭ 1.5, J4,5b ϭ 4.2 Hz, 1 H,
4-H), 8.61 (s, 1 H, 2Ј-H), 8.64 (s, 1 H, 8Ј-H). 13C NMR (500 MHz):
δ ϭ 44.5 (C-5), 54.3 (C-2), 66.2 (C-4), 69.5 (C-6), 112.0 (C-5Ј),
144.9 (C-8Ј), 152.3 (C-8Ј), 156.7 (C-4Ј), 161.9 (C-5Ј).
2.5, J5a,5b ϭ 13.4 Hz, 1 H, 5-Ha), 3.81 (dd, J5b,4 ϭ 4.4, J5b,5a
ϭ
13.4 Hz, 1 H, 5-Hb), 4.73 (dd, J6a,2 ϭ 6.4, J6a,6b ϭ 11.7 Hz, 1 H,
6-Ha), 4.79 (dd, J6b,2 ϭ 6.4, J6b,6a ϭ 11.7 Hz, 1 H, 6-Hb), 5.17 (t,
Compound 7b from 6b: 95% yield, amorphous. [α]2D5 ϭ Ϫ32.7 (c ϭ
J2,6a ϭ J2,6b ϭ 6.4 Hz, 1 H, 2-H), 7.06 (dd, J4,5a ϭ 2.5, J4,5b
ϭ
0.34, MeOH). C9H9ClN4OS2 (288.8): calcd. C 37.43, H 3.14; found
4.4 Hz, 1 H, 4-H), 7.49 (t, Jortho ϭ 7.3 Hz, 2 H, meta-H), 7.62 (t,
Jortho ϭ 7.3 Hz, 1 H, para-H), 8.04 (d, J ϭ 7.3 Hz, 2 H, ortho-H),
8.92 (s, 1 H, 2Ј-H), 9.02 (s, 1 H, 8Ј-H); [2-H, 4-H protons: NOE
effect]. 13C NMR (200 MHz): δ ϭ 46.3 (C-5), 53.4 (C-2), 65.5 (C-
4), 68.7 (C-6), 120.5, (C-5Ј), 128.0, 129.1, 133.6 (C-arom), 142.1
(C-4Ј), 148.2 (C-8Ј), 152.7 (C-2Ј), 162.6 (C-6Ј), 165.8 (CϭO).
1
C 37.35, H 3.15. H NMR (500 MHz): δ ϭ 3.53 (dd, J5a,4 ϭ 2.9,
J5a,5b ϭ 13.1 Hz, 1 H, 5-Ha), 3.72 (dd, J5b,4 ϭ 4.4, J5b,5a ϭ 13.1 Hz,
1 H, 5-Hb), 3.74Ϫ3.81 (m, 2 H, 6-H), 4.91 (t, J2,6 ϭ 5.6 Hz, 1 H,
2-H), 6.78 (dd, J4,5a ϭ 2.9, J4,5b ϭ 4.4 Hz, 1 H, 4-H), 8.65 (s, 1 H,
2Ј-H), 8.84 (s, 1 H, 8Ј-H). 13C NMR (500 MHz): δ ϭ 46.2 (C-5),
56.9 (C-2), 65.5 (C-4), 69.1 (C-6), 111.5 (C-5Ј), 144.5 (C-8Ј), 152.3
(C-2Ј), 156.0 (C-4Ј), 160.2 (C-6Ј).
Typical Deprotection Procedure. Compound 5a: NaOMe (5.4 mg,
0.1 mmol) was added at room temperature to a stirring solution of
4a (0.04 g, 0.1 mmol) in MeOH (5 mL) under an N2 atmosphere.
After 6 h the reaction mixture was quenched with glacial acetic
acid (excess), the MeOH was removed under reduced pressure, and
the crude residue chromatographed on silica gel (CHCl3/MeOH,
9:1) to give pure 5a (0.02 g, yield 81%), m.p. 205 °C dec. (EtOAc).
[α]2D5 ϭ ϩ26.5 (c ϭ 0.7, MeOH). C8H11N3O2S2 (245.3): calcd. C
39.17, H 4.52; found C 39.06, H 4.55. 1H NMR (400 MHz,
[D6]DMSO): δ ϭ 3.32Ϫ3.58 (m, 4 H, 5-H and 6-H), 4.72 (t, J2,6 ϭ
6.9 Hz, 1 H, 2-H), 5.35 (t, JOH,6 ϭ 5.6 Hz, 1 H, OH), 5.71 (d,
J5Ј,6Ј ϭ 7.6 Hz, 1 H, 5Ј-H), 6.48 (dd, J4,5a ϭ 1.2, J4,5b ϭ 4.6 Hz, 1
H, H-4), 7.22 (br. d, 2 H, NH2), 7.88 (d, J6Ј,5Ј ϭ 7.6 Hz, 1 H, 6Ј-
H). 13C NMR (500 MHz, [D6]DMSO): δ ϭ 42.6 (C-5), 55.1 (C-2),
65.9 (C-4), 68.0 (C-6), 93.2 (C-5Ј), 142.5 (C-6Ј), 155.1 (CϭO), 165.6
(CϭN). HPLC (Cyclobond I 2000 RSP, 50% MeOH plus 0.1 
NH4OAc in H2O): Rt ϭ 9.68 min (4%), 10.63 min (96%).
Acknowledgments
Work supported by Regione Campania (L. 41/94) and Consorzio
Interuniversitario Nazionale La Chimica per lЈAmbiente
(M.I.U.R., L. 488/92, Cluster 11-A). 1H and 13C NMR spectra
were recorded at Centro Interdipartimentale di Metodologie Chim-
`
ico-Fisiche, Universita di Napoli Federico II. The authors are
gratefully indebted to Prof. F. Giordano (Dip. di Chimica, Univer-
`
sita di Napoli Federico II) for the X-ray crystallographic analysis
of the chiral sulfoxide (E)-3.
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