Enantioselective synthesis of (+)-neplanocin F

Article abstract of DOI:10.1016/S0040-4020(02)00287-9

(+)-Neplanocin F ((+)-5), a minor component of the neplanocin family of antibiotics was enantioselectively synthesized starting from D-ribono-1,4-lactone via a convergent approach in 14 steps. This synthetic approach employed a regioselective protection of a secondary allylic hydroxyl group over a homoallylic one as key step.

Full text of DOI:10.1016/S0040-4020(02)00287-9

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3129±3136
Enantioselective synthesis of (1)-neplanocin F
p
 Â
Marõa J. Comin, Julieta Leitofuter and Juan B. Rodrõguez
  Â
Departamento de Quõmica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2,
Ciudad Universitaria, 1428 Buenos Aires, Argentina
Received 8 January 2002; accepted 11 March 2002
AbstractÐ(1)-Neplanocin F ((1)-5), a minor component of the neplanocin family of antibiotics was enantioselectively synthesized
starting from d-ribono-1,4-lactone via a convergent approach in 14 steps. This synthetic approach employed a regioselective protection
of a secondary allylic hydroxyl groupover a homoallylic one as key step. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
either at the base or at the pseudosugar moiety could result
in biological activity.
The term carbanucleoside refers to a nucleoside analogue in
which a methylene grouphas replaced the oxygen atom of
the furanose ring.1±4 Due to this surrogate, these analogues
have potent metabolic stability because they are unaffected
by phosphorylases and hydrolases that cleave the glycosidic
bond of natural nucleosides. Remarkably, they are
recognized by the same enzymes that recognize normal
nucleosides displaying, correspondingly, a wide range of
pharmacological responses mainly as antiviral and anti-
tumor agents.5,6 The neplanocin family is an important
class of natural carbocyclic nucleosides isolated from
Ampullariella regularis as fermentation products.7 Of the
neplanocins, that include at least ®ve components, such as
neplanocin C ((2)-1), neplanocin A ((2)-2), neplanocin B
((2)-3), neplanocin D ((2)-4), and neplanocin F ((2)-5),
only 1 and 2 have received extensive consideration (Fig. 1).
Neplanocin C is a notable model of conformationally locked
nucleoside analogue that led to the development of several
carbocyclic nucleosides either in the Northern or Southern
hemisphere. All of them were designed either as building
block for the synthesis of oligonucleotides8 or as antiviral
agents.9 Neplanocin A has received much attention due to
its interesting biological properties. In fact, a signi®cant
number of syntheses of neplanocin A10,11 as well as of its
analogues have been reported.12 On the other hand, neplano-
cin F is a minor member of the neplanocin family, and
presently, only one synthetic approach for the total synthesis
of (^)-5 has been reported.13 Although neplanocin F is
devoid of antiviral activity, it would be very important to
have a general enantioselective method to make this
compound and other closely related carbanucleosides
available bearing in mind that small structural variations
2. Results and discussion
A straightforward synthesis of the unnatural isomer of
neplanocin
F was enantioselectively achieved from
d-ribono-1,4-lactone through the known cyclopentenol 6
in 14 steps.11e,14±16 We recently described an improved
procedure for the synthesis of this important advanced
Figure 1. Chemical structures of the neplanocin family of naturally occur-
ring carbanucleosides.
Keywords: neplanocin; Ampullariella regularis; nucleoside; carbocyclic.
Corresponding author. Tel.: 154-11-4-576-3346; fax: 154-11-4-804-
1692; e-mail: jbr@qo.fcen.uba.ar
p
Scheme 1. Retrosynthetic analysis for the preparation of neplanocin F.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00287-9

3130
M. J. Comin et al. / Tetrahedron 58 (2002) 3129±3136
led to the tetra-O-benzyl derivative 10 and to the recovered
unreacted starting material in all cases (Scheme 2).
A straightforward synthesis of (1)-neplanocin F was
performed employing the second approach. Therefore,
cyclopentenol 6 reacted with benzyl bromide in N,N-di-
methylformamide at 08C19 to afford the corresponding
benzyl ether 11 in good yield, which after treatment with
acetic acid at 608C20 gave rise to compound 12 in almost
theoretical yield.
The selective monoprotection of the resulting diol would be
the key stepfor the synthesis of the target molecule.
This strategy, although simpler than the former one, was
challenging and not trivial at the beginning. In fact, both
secondary hydroxyl groups of the glycol unit exhibited
minor different electronic and steric environment. This
approach was ®rst attempted by treatment of 12 with
1 equiv. of benzyl bromide. Unfortunately, no regio-
selectivity was observed, on the contrary, a 2:3 mixture of
4-O-benzyl and 5-O-benzyl ethers were isolated (com-
pounds 13 and 14, respectively). Each compound was
unambiguously characterized from the analysis of the
proton NMR spectra of compounds 13 and 14 and the
changing of indicative chemical shifts of their respective
acetyl derivatives 15 and 16, respectively. The H-5 signal
of 13 was quite diagnostic to differentiate both regio-
isomers. This signal was observed as a triplet centred at
4.33 ppm with a coupling constant of 5.2 Hz after deuterium
oxide exchange employing methyl sulfoxide-d6 as a solvent.
The multiplicity shown by H-5 can be justi®ed by the
presence of the two vicinal hydrogen atoms with similar
Scheme 2. Reagents and conditions: (a) 60% AcOH, 508C, 24 h, 96% for 8,
100% for 12; (b) BnBr, 50% NaH, DMF, 08C, 63% for 10, 85% for 11, 30%
for 13, 33% for 14; (c) Ac2O, py, room temperature, 24 h, 80% for 15, 80%
for 16.
synthetic intermediate with an accurate determination of the
enatiomeric excess (77% from the 1H NMR analysis of the
Mosher's ester of 6).14 The loss of optical purity when
employed an intramolecular Wittig-type reaction as key
stepfor the synthesis of 6 and other closely related carbo-
cyclic rings has been noticed by us and other authors.11e,15±17
The general approach for the synthesis of neplanocin F is
outlined in the retrosynthetic analysis presented in Scheme
1. Compound numbering for all carbocyclic rings was kept
for clarity as illustrated for the cyclopentenyl alcohol 6. The
same consideration must be considered once the hetero-
cyclic base was introduced (compounds (1)-5, 19, 20 and
21). A critical step for obtaining optically pure neplanocin F
was the coupling of the heterocyclic base via a Mitsunobu-
type reaction with the corresponding glycon 7, in which the
hydroxyl groupat C-5 was not protected, while the rest of
the hydroxyl groups (C-1, C-4 and C-6) remained protected.
The selective monoprotection of polyhydroxylated com-
pounds has been subject of research for many years because
of its importance in organic synthesis.18 In order to obtain
the carbocyclic ring with this C-5 position free, there were
two ways to follow starting from 6: (a) selective protection
of both allylic hydroxyl groups on triol 8 over the homo-
allylic position, which would be less favoured to carry out a
SN2 reaction due to electronic effect and also to the resultant
steric effects produced once each protecting groups are
being incorporated in either allylic sites, C-1 and C-4,
respectively; (b) sequential protection, ®rst blocking the
free alcohol at C-1, followed by cleavage of the isopropyl-
idene group, and ®nally selective protection of the allylic
hydroxyl position of the resulting diol 9 with an appropriate
protecting group. Once the required synthetic intermediate 7
were at hand, a convergent approach would lead to the
target molecule by introducing the base via a Mitsunobu-
type reaction and further removal of the corresponding
protecting groups.
1
coupling constant values. The complete assignment of H
and 13C NMR spectra was conducted employing homo-
nuclear and heteronuclear correlated spectroscopy. The
H-5 of the acetylated product 15 shifted down®eld
1.2 ppm compared to the same signal of 13 indicating that
the C-4 position had been benzylated. On the other hand, the
monobenzylation at the C-5 position of compound 12 to
give 14 was also determined by NMR spectroscopy. The
1H NMR spectrum corresponding to this compound was
thoroughly assigned by 2D NMR techniques as well. The
typical signals for this compound were a triplet centred at
4.01 ppm with a coupling constant of 5.3 Hz, a double of
doublets centred at 4.39 ppm and coupling constants of 5.0
and 1.8 Hz corresponding to H-5 and H-1, respectively, and
a doublet peak at 4.36 ppm with a coupling constant of
6.2 Hz from the unprotected hydroxyl group at H-4. This
signal shifted down®eld to 5.63 ppm keeping a similar
coupling constant (5.7 Hz) when 14 was acetylated to afford
16.
As the benzylation reaction favoured the undesired product
14, it was decided to replace the benzyl functionality by
other protecting group that could be introduced discrimi-
nating between these two positions. Regioselective intro-
duction of the methoxymethyl (MOM) protecting group
seemed to be appropriate to differentiate between allylic
and homoallylic secondary alcohols. Actually, Friesen and
Vanderwal have reported a high regioselective method for
introducing a MOM moiety onto the less sterically hindered
hydroxyl groupof a glycol. 21 This approach is based on the
formation of an orthoester intermediate prepared from the
The former route was primarily attempted taking advantage
of the reactivity of the allylic alcohols, but the treatment of 8
with 2 equiv. of benzyl bromide under different conditions

M. J. Comin et al. / Tetrahedron 58 (2002) 3129±3136
3131
trichloride25 in methylene chloride at 2788C on this
substrate gave rise to the target molecule (1)-neplanocin
F (Scheme 3). The N-9 alkylated position was unam-
biguously established by UV spectroscopy of the target
molecule (1)-5 showing a maximum peak at 260 nm,
typical of this pattern.9a,b In addition, the 1H NMR spectrum
perfectly agreed with that previously described for the
synthetic racemic product.13 Moreover, the melting point
matched the described for the natural product, while the
optical rotation presented almost the same absolute value
with the opposite sign.26
In conclusion, the ®rst enantioselective synthesis of
(1)-neplanocin F was achieved providing a general
methodology for the preparation of closely related carbo-
cyclic nucleosides, which belong to the neplanocin family
of antibiotics. This synthetic approach was more ef®cient
than the previously reported racemic preparation in 17
synthetic steps from the same starting material.
Scheme 3. Reagents and conditions: (a) (i) trimethyl orthoformate, CH2Cl2,
CAN, room temperature, 2 h, (ii) DIBAL, 2788C 1 h !08C 10 min, 66%;
(b) BnBr, 50% NaH, DMF, 08C, 90%; (c) 6-chloropurine, DEAD, PPh3,
THF, room temperature, 16 h, 57%; (d) CF3COOH, CH2Cl2, room tempera-
ture, 16 h, 70% for 14, 76% for 20; (e) MeOH/NH3, 708C, 5 h, 77%;
(f) (i) BCl3, CH2Cl2, 2788C, (ii) MeOH, 2788C, 85%.
3. Experimental
3.1. General
corresponding diol on reaction with trimethyl orthoformate
followed by in situ reductive cleavage by treatment with
DIBAL in methylene chloride at low temperature. Contrary
to these ®ndings, Yamamoto had previously described a
similar method to protect a secondary alcohol with MOM
groups in the presence of a primary alcohol.22 The regio-
selectivity of this one pot reaction is strongly modulated by
the electronegativity and steric bulk of the substituents in
the vicinity of the glycol group. Therefore, it was decided to
explore its scope in our speci®c problem. Therefore, glycol
12 was treated with trimethyl orthoformate in the presence
of ceric ammonium nitrate as catalyst. The resulting ortho-
ester was treated in situ with DIBAL-H at 2788C to give
rise to the monoprotected MOM derivative at the allylic
position exclusively (compound 17) in good yields. Sur-
prisingly, when the commonly described camphorsulfonic
acid21,22 was used as catalyst instead of ceric ammonium
nitrate, simply unreacted starting material was isolated. In
order to con®rm the formation of the desired product,
compound 17 was treated with benzyl bromide followed
by MOM cleavage by reaction with tri¯uoroacetic acid
in methylene chloride to produce the above described
O-benzyl derivative 14 exclusively. The regioselectivity
observed in the introduction of a single protecting group
at the allylic hydroxyl groupin 12 was very encouraging.
This approach allowed us to have an advanced synthetic
intermediate with the alcohol free at the required position
with the appropriate absolute stereochemistry. The oxidant
ceric ammonium nitrate constitutes a novel catalyst in this
MOM-monoprotection methodology. Further studies on this
matter are currently being pursued in our laboratory
(Scheme 3).
The glassware used in air and/or moisture sensitive reac-
tions were ¯ame-dried and carried out under a dry argon
atmosphere. Unless otherwise noted, chemicals were
commercially available and used without further puri®-
cation. Solvents were distilled before use. Tetrahydrofuran
was distilled from sodium/benzophenone ketyl, methylene
chloride was distilled from phosphorus pentoxide and
Ê
stored over freshly activated 4 A molecular sieves.
Anhydrous N,N-dimethylformamide was used as supplied
from Aldrich.
Nuclear magnetic resonance spectra were recorded using a
Bruker AC-200 MHz or a Bruker AM-500 MHz spectro-
meters. Chemical shifts are reported in parts per million
1
(d) relative to tetramethylsilane. The H NMR spectra are
referenced with respect to the residual CHCl3 proton of the
solvent CDCl3 at 7.26 ppm. Coupling constants are reported
in Hertz. 13C NMR spectra were fully decoupled and are
referenced to the middle peak of the solvent CDCl3 at
77.0 ppm. Splitting patterns are designated as s, singlet; d,
doublet; t, triplet; q, quartet.
Melting points were determined using a Fisher±Johns
apparatus and are uncorrected. IR spectra were recorded
using a Nicolet Magna 550 spectrometer.
Low-resolution mass spectra were obtained on a VG TRIO 2
instrument at 70 eV (direct inlet). Accurate mass analysis
for the ®nal product was conducted at a resolution of 2700
(10% valley) in the molecular ion region. Glycerol was used
as a FAB matrix and ionization was effected by an atom
beam generated from charge-exchanged xenon ions. The
glycerol peaks at m/z 185 (Gly2H1) and 277 (Gly3H1)
were used as reference ions and the VG-7070-EHF mass
spectrometer was voltage scanned under control of a
Maspec-II data system. Standard data system software was
used to assign and calculate masses of the reference and
sample ions, respectively.
Therefore, the heterocyclic base (6-chloropurine) was
coupled with 17 via a Mitsunobu-type reaction to produce
solely the N-9 alkylated product (compound 19).23 The
presence of the undesired N-7 isomer was not detected.
On treatment with tri¯uoroacetic acid,24 19 was converted
into 20, which after reaction with methanolic ammonia gave
the purine derivative 21 in good yield. Removal of the
remaining two benzyl ethers by treatment with boron

3132
M. J. Comin et al. / Tetrahedron 58 (2002) 3129±3136
Column chromatography was performed with E. Merck
silica gel (Kieselgel 60, 230±400 mesh). Analytical thin
layer chromatography was performed employing 0.2 mm
coated commercial silica gel plates (E. Merck, DC-Alu-
minum sheets, Kieselgel 60 F254) and was visualized by
254 nm UV or by immersion into an ethanolic solution of
5% H2SO4.
tained at 08C. The reaction mixture was stirred at 08C for
40 min. The reaction was quenched by addition of an
aqueous saturated solution of ammonium chloride
(20 mL). The mixture was extracted with methylene
chloride (3£30 mL), and the combined organic layers
were washed with brine (2£10 mL), dried (Na2SO4), and
the solvent was evaporated. The residue was puri®ed by
column chromatography (silica gel) using hexane±EtOAc
Elemental analyses were conducted by Atlantic Microlab
Inc., Norcross, Georgia. The results were within ^0.4% of
the theoretical values except where otherwise stated.
(19:1) as eluant to give 1.120 g (85% yield) of pure 11 as a
yellow pale oil: Rf 0.46 (hexane±EtOAc, 4:1); [a]D
24
ˆ
1
23.88 (c 1.21, CHCl3); H NMR (500 MHz, CDCl3) d
1.40 (s, 3H, CH3), 1.45 (s, 3H CH3), 4.17 (m, 2H, H-6),
4.39 (dq, Jˆ5.0, 2.0 Hz, 1H, H-1), 4.55 (dAB, Jˆ20.1 Hz,
2H, OCH2Ph), 4.61 (d, Jˆ12.1 Hz, 1H, OCHaHPh), 4.80 (t,
Jˆ5.5 Hz, 1H, H-5), 4.81 (d, Jˆ12.1 Hz, 1H, OCHHbPh),
4.91 (d, Jˆ5.7 Hz, 1H, H-4), 5.80 (d, Jˆ0.7 Hz, 1H, H-2),
7.32 (m, 10H, Ph); 13C NMR (50 MHz, CDCl3) d 26.8
(CH3), 27.6 (CH3), 66.4 (C-6), 71.8 (OCH2Ph), 72.9
(OCH2Ph), 78.0 (C-5), 79.8 (C-1), 82.9 (C-4), 112.5
(C(CH3)2), 127.6 (Ph), 127.6 (Ph), 128.0 (Ph), 128.3 (Ph),
128.4 (Ph), 128.8 (C-2), 138.1 (Ph), 138.4 (Ph), 143.1 (C-3).
3.1.1. (1S,4R,5S)-3-(Benzyloxy)methyl-cyclopent-2-ene-
1,4,5-triol (8). Compound 6 (100 mg; 0.36 mmol) was
dissolved in 60% acetic acid (5 mL) and the mixture was
stirred at 508C for 24 h. The solvent was evaporated and the
residue was puri®ed by column chromatography (silica gel)
using a mixture of hexane±EtOAc (1:4) as eluant to afford
82 mg (96% yield) of pure compound 8 as a colorless oil:
Rf 0.22 (hexane±EtOAc, 3:7); 1H NMR (200 MHz, CDCl3)
d 4.07 (t, Jˆ5.5 Hz, 1H, H-5), 4.18 (m, 2H, CH2OBn),
4.36±4.42 (m, 2H, H-1, H-4), 4.53 (m, 2H, OCH2Ph),
5.94 (d, Jˆ1.1 Hz, 1H, H-2), 7.32 (m, 5H, Ph); 13C NMR
(50 MHz, CDCl3) d 66.9 (C-6), 71.4 (C-5), 72.8 (OCH2Ph),
73.2 (C-1)p, 73.6 (C-4)p, 127.7 (Ph), 128.3 (Ph), 130.2 (C-2),
3.1.4. (1S,4S,5R)-1-Benzyloxy-3-[(benzyloxy)methyl]-2-
cyclopentene-4,5-diol (12). Compound 11 (1.00 g,
2.38 mmol) was dissolved in 60% acetic acid (10 mL) and
the mixture was stirred at 508C for 24 h. The solvent was
evaporated under vacuum to give 775 mg of nearly pure
compound 12 (100% yield) as a white solid, which was
used as such in the next step. An analytical sample was
puri®ed by column chromatography (silica gel) using a
mixture of hexane±EtOAc (7:3) as eluant: Rf 0.26 (hexane±
p
137.8 (Ph), 145.5 (C-3). Signal assignment may be inter-
changed.
3.1.2.
(1S,4R,5S)-1,4,5-Tribenzyloxy-3-(benzyloxy)-
methyl-2-cyclopentene (10). A solution of alcohol 8
(18 mg; 0.008 mmol) in anhydrous N,N-dimethylforma-
mide (1 mL) cooled at 08C was treated with benzyl bromide
(20 mL, 0.016 mmol). Then, a 50% sodium hydride disper-
sion (4 mg, 0.016 mmol) was added while the temperature
was maintained at 08C. The reaction mixture was stirred at
08C for 40 min. The reaction was quenched by addition of a
saturated aqueous solution of ammonium chloride (1 mL).
The mixture was extracted with methylene chloride
(3£2 mL), and the combined organic layers were washed
with brine (2£2 mL), dried (Na2SO4), and the solvent was
evaporated. The residue was puri®ed by column chroma-
tography (silica gel) using hexane±EtOAc (19:1) as eluant
to give 19.6 g of pure 10 (63% yield) as the main product: Rf
24
EtOAc, 3:2); mp57±58 8C; [a]D ˆ115.38 (c 1.7, CHCl3);
1H NMR (200 MHz, CDCl3) d 4.20 (m, 2H, H-6), 4.21±
4.40 (m, 3H, H-1, H-4, H-5), 4.55 (mAB, 2H, OCH2Ph),
4.63 (d, Jˆ11.7 Hz, 1H, OCHaHPh), 4.71 (d, Jˆ11.7 Hz,
1H, OCHHbPh), 5.89 (s, 1H, H-2), 7.34 (m, 10H, Ph); 13C
NMR (50 MHz, CDCl3) d 66.8 (C-6), 70.6 (C-5), 72.1
(OCH2Ph), 72.9 (OCH2Ph), 74.2 (C-4), 79.9 (C-1), 126.7
(C-2), 127.6 (Ph), 127.8 (Ph), 127.9 (Ph), 128.3 (Ph),
128.5 (Ph), 137.6 (Ph), 137.9 (Ph), 146.9 (C-3). Anal.
calcd for C20H22O4: C 73.60, H 6.79. Found: C 73.65, H
6.76.
1
0.45 (hexane±EtOAc, 4:1); H NMR (200 MHz, CDCl3) d
3.1.5. (1S,4R,5S)-1,4-Di(benzyloxy)-3-[(benzyloxy)methyl]-
cyclopent-3-en-5-ol (13) and (1S,4R,5S)-1,5-di(benzyl-
4.12 (t, Jˆ5.7 Hz, 1H, H-5), 4.13 (m, 2H, CH2OBn), 4.41
(m, 1H, H-4), 4.45 (d, Jˆ11.8 Hz, 1H, OCHaHPh), 4.50
(d, Jˆ12.1 Hz, 1H, OCHHbPh), 4.66±4.79 (m, 6H,
3-OCH2Ph), 6.02 (s, 1H, H-2), 7.24±7.28 (m, 15H, Ph);
13C NMR (50 MHz, CDCl3) d 67.0 (C-6), 71.1 (OCH2Ph),
71.6 (OCH2Ph), 72.1 (OCH2Ph), 72.9 (OCH2Ph), 78.7
(C-5)p, 78.7 (C-1)p, 78.9 (C-4)p, 127.3 (Ph), 127.4 (Ph),
127.5 (Ph), 127.6 (Ph), 127.7 (Ph), 127.9 (Ph), 127.9 (Ph),
128.0 (Ph), 128.2 (Ph), 128.2 (Ph), 128.3 (Ph), 128.4 (Ph),
128.8 (C-2), 138.1 (Ph), 138.6 (Ph), 139.0 (Ph), 139.1 (Ph),
oxy)-3-[(benzyloxy)methyl]-cyclopent-3-en-4-ol
(14).
Method a. To a solution of diol 12 (52 mg, 0.159 mmol)
in anhydrous N,N-dimethylformamide (2 mL) was cooled
at 08C were added benzyl bromide (21 mL; 0.175 mmol)
and a 50% sodium hydride dispersion (10 mg, 0.19
mmol). The mixture was stirred at 08C for 30 min. The
reaction was quenched by addition of a saturated aqueous
solution of ammonium chloride (2 mL). The mixture was
extracted with methylene chloride (3£10 mL), and
the combined organic layers were washed with brine
(2£5 mL), dried (Na2SO4), and the solvent was evaporated.
The residue was puri®ed by column chromatography (silica
gel) using hexane±EtOAc (9:1) as eluant to give 20 mg of
13 and 28 mg of the regioisomer 14 (73% overall yield) as
colorless oils. Compound 13: Rf 0.58 (hexane±EtOAc, 7:3);
1H NMR (500 MHz, DMSO-d6) d 4.06 (m, 2H, CH2OBn),
4.17 (d, Jˆ4.8 Hz, 1H, H-4), 4.21 (d, Jˆ5.0 Hz, 1H, H-1),
4.33 (t, Jˆ5.2 Hz, 1H, H-5), 4.43 (d, Jˆ12.1 Hz, 1H,
p
144.3 (C-3). Signal assignment may be interchanged.
3.1.3.
(1S,4R,5S)-1-Benzyloxy-3-[(benzyloxy)methyl]-
4,5-(isopropylidenedioxy)-2-cyclopentene (11). A solu-
tion of alcohol 6 (966 mg; 3.5 mmol) in anhydrous
N,N-dimethylformamide (7 mL) cooled at 08C was treated
with benzyl bromide (0.46 mL, 3.9 mmol). Then, a 50%
sodium hydride dispersion (185 mg, 3.9 mmol) was added
portionwise over 15 min while the temperature was main-

M. J. Comin et al. / Tetrahedron 58 (2002) 3129±3136
3133
OCHaHPh), 4.47 (d, Jˆ12.3 Hz, 1H, OCHHbPh), 4.50 (d,
Jˆ12.3 Hz, 1H, OCHaHPh), 4.53 (d, Jˆ12.1 Hz, 1H,
OCHaHPh), 4.68 (d, Jˆ12.1 Hz, 1H, OCHHbPh), 4.72 (d,
Jˆ11.9 Hz, 1H, OCHHbPh), 5.84 (s, 1H, H-2), 7.26±7.34
(m, 15H, Ph); 13C NMR (50.3 MHz, CDCl3) d 66.9 (C-6),
71.2 (C-5), 72.0 (OCH2Ph), 72.8 (OCH2Ph), 73.0
(OCH2Ph), 79.8 (C-1), 80.1 (C-4), 127.7 (Ph), 127.8 (Ph),
128.0 (Ph), 128.4 (C-2), 128.6 (Ph), 138.1 (Ph), 138.3 (Ph),
144.8 (C-3). Compound 14: Rf 0.48 (hexane±EtOAc, 7:3);
1H NMR (500 MHz, DMSO-d6) d 4.01 (t, Jˆ5.3 Hz, 1H,
H-5), 4.13 (mAB, 2H, CH2OBn), 4.36 (d, Jˆ6.2 Hz, 1H,
H-4), 4.39 (dd, Jˆ5.0, 1.8 Hz, 1H, H-1), 4.49 (mAB, 2H,
OCH2Ph), 4.54±4.56 (m, 3H, OCH2Ph, OH), 4.62 (d, Jˆ
11.6 Hz, 1H, OCHaHPh), 4.73 (d, Jˆ11.6 Hz, 1H,
OCHHbPh), 5.84 (s, 1H, H-2), 7.25±7.32 (m, 15H, Ph);
13C NMR (50 MHz, CDCl3) d 67.1 (C-6), 71.8 (OCH2Ph),
72.4 (OCH2Ph), 72.7 (C-4), 72.9 (OCH2Ph), 78.7 (C-5),
79.7 (C-1), 127.5 (C-2), 127.6 (Ph), 127.7 (Ph), 127.8
(Ph), 128.0 (Ph), 128.3 (Ph), 128.4 (Ph), 138.0 (Ph), 138.1
(Ph), 138.6 (Ph), 147.6 (C-3).
of compound 14 (9 mg; 0.022 mmol) in pyridine (1 mL)
was added acetic anhydride (0.5 mL). The solution was
stirred at room temperature for 24 h. The reaction was
worked upas depicted for 15. The residue was puri®ed by
preparative TLC (silica gel) employing hexane±EtOAc
(4:1) as eluant to afford 8 mg (80% yield) of pure compound
16 as a colorless oil: Rf 0.36 (hexane±EtOAc, 4:1); 1H NMR
(500 MHz, CDCl3) d 2.05 (s, 3H, CH3), 4.10 (s, 3H,
CH2OBn, H-5), 4.39 (dd, Jˆ5.5, 1.3 Hz, 1H, H-1), 4.48
(d, Jˆ11.8 Hz, 1H, OCHaHPh), 4.53 (d, Jˆ12.1 Hz, 1H,
OCHHbPh), 4.64 (d, Jˆ11.8 Hz, 1H, OCHaHPh), 4.65 (d,
Jˆ11.9 Hz, 1H, OCHaHPh), 4.67 (d, Jˆ12.1 Hz, 1H,
OCHHbPh), 4.71 (d, Jˆ12.1 Hz, 1H, OCHHbPh), 5.63 (d,
Jˆ5.7 Hz, 1H, H-4), 6.01 (d, Jˆ0.7 Hz, H-2), 7.31 (m, 15H,
Ph); 13C NMR (125 MHz, CDCl3) d 21.1 (CH3), 66.7 (C-6),
71.3 (OCH2Ph), 72.8 (OCH2Ph), 72.9 (OCH2Ph), 73.3
(C-5), 77.9 (C-4), 78.8 (C-1), 127.5 (Ph), 127.6 (Ph),
127.7 (Ph), 127.7 (Ph), 127.7 (Ph), 127.9 (Ph), 128.3 (Ph),
128.3 (Ph), 128.4 (Ph), 130.7 (C-2), 137.9 (Ph), 138.3 (Ph),
138.8 (Ph), 142.6 (C-3), 170.9 (COCH3).
Method b (MOM cleavage from compound 18). To a solu-
tion of compound 18 (13 mg, 0.03 mmol) in methylene
chloride (2 mL) was added tri¯uoroacetic acid (200 mL).
The reaction mixture was stirred at room temperature
overnight. The mixture was treated with an aqueous
saturated solution of sodium bicarbonate (2 mL) and was
extracted with CH2Cl2 (3£3 mL). The organic phase was
dried (MgSO4) and the solvent was evaporated. The residue
was puri®ed by column chromatography (silica gel) to
afford 9 mg (70% yield) of compound 14 as a colorless oil.
3.1.8. (1S,4R,5S)-1-Benzyloxy-3-[(benzyloxy)methyl]-4-
[(methoxy)methoxy]-cyclopent-3-en-5-ol (17). A solution
of diol 12 (178 mg; 0.54 mmol) in anhydrous methylene
chloride (10 mL) was treated with trimethyl orthoformate
(120 mL, 1.08 mmol) in the presence of ceric ammonium
nitrate CAN (20 mg) as catalyst under argon atmosphere.
The reaction mixture was stirred at room temperature for
2 h. The solution was cooled at 2788C, and neat DIBAL-H
(1.0 mL, 5.40 mmol) was added. The mixture was stirred at
this temperature for 1 h and then placed in an ice bath. After
10 min, an aqueous 1.0N solution of hydrochloric acid
(2 mL) and an aqueous saturated solution of sodium and
potassium tartrate (10 mL) were added and the mixture
was extracted with methylene chloride (3£15 mL). The
combined organic layers were washed with brine
(2£50 mL), dried (Na2SO4), and the solvent was evapo-
rated. The residue was puri®ed by column chromatography
(silica gel) using a mixture of hexane±EtOAc (17:3) as
3.1.6.
(1S,4R,5S)-1,4-Di(benzyloxy)-3-[(benzyloxy)-
methyl]-5-(acetyloxy)-2-cyclopentene (15). A solution of
compound 13 (10 mg; 0.028 mmol) in pyridine (1 mL) was
treated with acetic anhydride (0.5 mL). The solution was
stirred at room temperature for 24 h. Then the mixture
was quenched with 5% hydrochloric acid (0.5 mL) and
stirred for additional 30 min. The mixture was extracted
with methylene chloride (3£2 mL). The combined organic
phases were washed with a saturated aqueous solution of
sodium bicarbonate (2£1 mL), brine (2 mL), and dried
(Na2SO4). The solvent was removed by distillation under
reduced pressure and the residue was puri®ed by preparative
TLC (silica gel) employing hexane±EtOAc (4:1) as eluant
to afford 10 mg (80% yield) of pure compound 15 as a
colorless oil: Rf 0.38 (hexane±EtOAc, 4:1); 1H NMR
(500 MHz, CDCl3) d 2.07 (s, 3H, CH3), 4.13 (s, 2H,
CH2OBn), 4.43 (m, 2H, H-1, H-4), 4.47 (d, Jˆ11.9 Hz,
1H, OCHaHPh), 4.51 (d, Jˆ11.9 Hz, 1H, OCHHbPh), 4.52
(d, Jˆ11.9 Hz, 1H, OCHaHPh), 4.55 (d, Jˆ12.1 Hz, 1H,
OCHaHPh), 4.62 (d, Jˆ12.1 Hz, 1H, OCHHbPh), 4.63 (d,
Jˆ11.9 Hz, 1H, OCHHbPh), 5.52 (t, Jˆ5.5 Hz, 1H, H-5),
5.93 (s, 1H, H-2), 7.31 (m, 15H, Ph); 13C NMR (50.3 MHz,
CDCl3) d 21.0 (CH3), 66.5 (C-6), 71.8 (OCH2Ph), 72.5
(OCH2Ph), 72.6 (OCH2Ph), 72.9 (C-5), 79.0 (C-4)p, 79.4
(C-1)p, 127.6 (C-2), 127.7 (Ph), 127.7 (Ph), 127.7 (Ph),
127.9 (Ph), 128.3 (Ph), 128.3 (Ph), 128.4 (Ph), 128.4 (Ph),
138.0 (Ph), 138.3 (Ph), 138.4 (Ph), 143.7 (C-3), 171.0
(COCH3).
eluant to give 131 mg (66% yield) of pure compound 17
ˆ
24
as a colorless oil: Rf 0.41 (hexane±EtOAc, 3:2); [a]D
131.48 (c 1.8, CHCl3); IR (®lm, cm21) 3277, 2930, 2862,
1746, 1257, 1108; H NMR (200 MHz, CDCl3) d 3.39 (s,
1
3H, OCH3), 4.17 (m, 2H, H-6), 4.20±4.27 (m, 2H, H-1,
H-4), 4.37 (m, 1H, H-5), 4.52 (m, 2H, OCH2Ph), 4.65 (d,
Jˆ12.1 Hz, 1H, OCHaHPh), 4.69 (d, Jˆ6.9 Hz, 1H,
CHaHOCH3), 4.75 (d, Jˆ12.4 Hz, 1H, OCHHbPh), 4.82
(d, Jˆ6.6 Hz, 1H, CHHbOCH3), 5.96 (s, 1H, H-2), 7.32
(m, 10H, Ph); 13C NMR (50 MHz, CDCl3) d 55.8 (OCH3),
66.9 (C-6), 71.3 (C-5), 72.2 (OCH2Ph), 72.8 (OCH2Ph),
78.7 (C-4), 79.6 (C-1), 96.7 (CH2OCH3), 127.7 (C-2, Ph),
127.8 (Ph), 127.9 (Ph), 128.4 (Ph), 128.8 (Ph), 138.0 (Ph),
138.2 (Ph), 144.9 (C-3). Anal. calcd for C22H26O5: C 71.33,
H 7.07. Found: C 71.29, H 6.98.
3.1.9. (1S,4R,5S)-1,5-Dibenzyloxy-3-[(benzyloxy)methyl]-
4-[(methoxy)methoxy]-cyclopent-3-en-5-ol (18). A solu-
tion of alcohol 17 (62 mg; 0.17 mmol) in anhydrous
N,N-dimethylformamide (2 mL) cooled at 08C was treated
with benzyl bromide (24 mL, 0.20 mmol) under argon
atmosphere. Then, a 50% sodium hydride dispersion
(10 mg; 0.20 mmol) was added while the temperature was
maintained at 08C. The reaction mixture was stirred at 08C
3.1.7. (1S,4R,5S)-1,5-Bis(benzyloxy)-3-[(benzyloxy)-
methyl]-4-(acetyloxy)-2-cyclopentene (16). To a solution

3134
M. J. Comin et al. / Tetrahedron 58 (2002) 3129±3136
for 1 h. The reaction was quenched by addition of an
aqueous saturated solution of ammonium chloride (2 mL).
The mixture was extracted with methylene chloride
(3£3 mL), and the combined organic layers were washed
with brine (2£3 mL), dried (Na2SO4), and the solvent was
evaporated. The residue was puri®ed by column chroma-
tography (silica gel) using hexane±EtOAc (17:3) as eluant
to afford 68 mg (90% yield) of pure compound 18 as a
colorless oil: Rf 0.62 (hexane±EtOAc, 7:3); 1H NMR
(500 MHz, CDCl3) d 3.35 (s, 3H, OCH3), 3.98 (t,
Jˆ5.6 Hz, 1H, H-5); 4.19 (m, 2H, H-6), 4.35 (d, Jˆ
4.3 Hz, 1H, H-1), 4.47 (d, Jˆ5.7 Hz, 1H, H-4), 4.50 (d,
Jˆ11.9 Hz, 1H, OCHaHPh), 4.53 (d, Jˆ11.9 Hz, 1H,
OCHHbPh); 4.65 (d, Jˆ12.1 Hz, 1H, OCHaHPh), 4.66 (d,
Jˆ12.1 Hz, 1H, OCHaHPh), 4.70 (d, Jˆ12.3 Hz, 1H,
OCHHbPh), 4.75 (d, Jˆ6.4 Hz, 1H, OCHaHOCH3), 4.76
(d, Jˆ11.4 Hz, 1H, OCHHbPh), 4.85 (d, Jˆ6.8 Hz, 1H,
OCHHbCH3), 6.00 (s, 1H, H-2), 7.31 (m, 15H, Ph); 13C
NMR (125 MHz, CDCl3) d 55.6 (OCH3), 67.0 (C-6), 70.9
(OCH2Ph), 71.9 (OCH2Ph), 72.8 (OCH2Ph), 76.8 (C-5),
78.2 (C-4)p, 78.4 (C-1)p, 96.4 (OCH2O), 127.4 (Ph), 127.5
(Ph), 127.7 (C-2), 127.7 (Ph), 127.7 (Ph), 128.0 (Ph), 128.2
(Ph), 128.3 (Ph), 128.8 (Ph), 138.0 (Ph), 138.5 (Ph), 138.9
(Ph), 144.8 (C-3). pSignal attributions may be interchanged.
(200 mL). The reaction mixture was stirred at room
temperature 48 h. The mixture was extracted with an
aqueous saturated solution of sodium bicarbonate (2 mL)
and was extracted with CH2Cl2 (3£3 mL). The organic
phase was dried (MgSO4) and the solvent was evaporated.
The residue was puri®ed by column chromatography (silica
gel) to afford 50 mg (76% yield) of compound 20 as a
colorless oil: Rf 0.18 (hexane±EtOAc, 3:2); [a]D
24
ˆ
1
132.48 (c 0.9, CHCl3); H NMR (500 MHz, CDCl3) d
4.20±4.35 (m, 3H, H-60, H-10), 4.41 (d, Jˆ12.3 Hz, 1H,
OCHaHPh), 4.50±4.63 (m, 3H, OCH2Ph, H-20), 4.66 (d,
Jˆ11.8 Hz, 1H, OCHHbPh), 5.06 (dt, Jˆ6.5, 1.5 Hz, 1H,
H-50), 5.09 (m, 1H, H-20), 6.08 (s, 1H, H-40), 7.18 (m, 5H,
Ph), 7.34 (m, 5H, Ph), 7.99 (s, 1H, H-8), 8.61 (s, 1H, H-2);
13C NMR (125 MHz, CDCl3) d 66.6 (C-60), 71.7 (C-10),
72.4 (OCH2Ph), 73.2 (OCH2Ph), 76.4 (C-20), 80.8 (C-50),
126.5 (C-40) 127.8 (Ph), 127.9 (Ph), 128.1 (Ph), 128.4 (Ph),
128.5 (Ph), 137.1 (Ph), 137.6 (Ph), 143.6 (C-30, 145.3 (C-8),
151.3 (C-2); MS (m/z, relative intensity) 463 ([M11]1, 1),
271 (3), 354 (8), 155 (13), 91 (100)
3.1.12.
(1)-9-[(1R,2R,5S)-5-Benzyloxy-3-(benzyloxy)-
methyl-2-hydroxy-cyclopent-3-en-1-yl]-6-aminopurine
(21). Compound 20 (30 mg, 0.06 mmol) was treated with
methanolic ammonia (1 mL, saturated at 2788C) and heated
in a sealed tube at 708C for 5 h. The mixture was cooled to
room temperature and the solvent was evaporated. The
residue was puri®ed by column chromatography (silica
gel) using ethyl acetate as eluant to afford 22 mg (77%
yield) of pure 21 as a white solid: Rf 0.25 (EtOAc); mp
3.1.10.
(1)-9-[(1R,2R,5S)-5-Benzyloxy-3-(benzyloxy)-
methyl-2-(methoxy)methoy-cyclopent-3-en-1-yl]-6-chloro-
purine (19). A suspension of 6-chloropurine (88 mg,
0.56 mmol) and triphenylphosphine (399 mg, 1.52 mmol)
in anhydrous tetrahydrofuran (5 mL) was treated with
diethylazodicarboxylate (206 mg, 0.56 mmol) under argon
atmosphere. The resulting mixture was vigorously stirred
for 10 min, then a solution of alcohol 17 (100 mg,
0.27 mmol) in tetrahydrofuran (2 mL) was added in one
portion. The reaction mixture was stirred at room tempera-
ture overnight. The solvent was evaporated and the residue
was adsorbed on silica gel and puri®ed by column chroma-
tography (silica gel) using hexane±EtOAc (4:1) as eluant to
afford 80 mg (57% yield) of compound 19 as a colorless oil:
24
157±1588C; [a]D ˆ142.28 (c 0.8, CHCl3); 1H NMR
(500 MHz, CD3OD) d 4.18 (dq, Jˆ13.9, 0.9 Hz, 1H,
H-60a), 4.23 (dt, Jˆ16.1, 2.3 Hz, 1H, H-60 ), 4.41 (d, Jˆ
b
12.3 Hz, 1H, OCHaHPh), 4.54 (d, Jˆ12.3 Hz, 1H,
OCHHbPh), 4.56 (d, Jˆ11.7 Hz, 1H, OCHaHPh), 4.60 (t,
Jˆ6.3 Hz, 1H, H-1), 4.61 Jˆ11.9 Hz, 1H, OCHHbPh),
5.03 (dt, Jˆ6.2, 1.5 Hz, 1H, H-10), 5.09 (d, Jˆ6.5 Hz, 1H,
H-20), 6.02 (p, Jˆ1.4 Hz, 1H, H-40), 7.05 (m, 5H, Ph), 7.34
(m, 5H, Ph), 8.06 (s, 1H, H-8), 8.07 (s, 1H, H-2); 13C NMR
(125 MHz, CD3OD) d 67.2 (C-60), 72.6 (OCH2Ph), 73.5
(C-10), 73.7 (OCH2Ph), 77.3 (C-20), 82.6 (C-50), 120.9
(C-5), 128.0 (C-40), 128.7 (Ph), 128.7 (Ph), 128.8 (Ph),
129.0 (Ph), 129.1 (Ph), 129.4 (Ph), 139.2 (Ph), 139.6 (Ph),
142.7 (C-8), 145.8 (C-30), 150.8 (C-4), 153.3 (C-2), 157.3
(C-6). Anal. calcd for C25H25N5O3´1.35EtOAc: C 64.92, H
6.42, N 12.45. Found: C 65.32; H, 6.50; N, 12.08.
24
Rf 0.36 (hexane±EtOAc, 3:2); [a]D ˆ112.88 (c 0.8,
CHCl3); IR (®lm, cm21) 3067, 3036, 2936, 2862, 1740,
1560, 1040; H NMR (500 MHz, CDCl3) d 3.06 (s, 3H,
1
OCH3), 4.17 (d, Jˆ13.4 Hz, 1H, H-60a), 4.21 (d, Jˆ
13.9 Hz, 1H, H-60 ), 4.36 (d, Jˆ12.1 Hz, 1H, OCHaHPh),
b
4.44 (mAB, 2H, OCH2Ph), 4.54 (d, Jˆ11.8 Hz, 1H,
CHaHOCH3), 4.56 (d, Jˆ11.4 Hz, 1H, OCHHbPh), 4.61
(d, Jˆ11.8 Hz, 1H, CHHbOCH3), 4.72 (t, Jˆ6.0 Hz, 1H,
H-10), 5.01 (m, 1H, H-50), 5.12 (d, Jˆ5.9 Hz, 1H, H-20),
6.10 (s, 1H, H-40), 7.02 (m, 2H, Ph), 7.11 (m, 3H, Ph),
7.34 (m, 5H, Ph), 7.95 (s, 1H, H-8), 8.61 (s, 1H, H-2). 13C
NMR (125 MHz, CDCl3) d 55.5 (OCH3), 65.9 (C-60), 71.2
(C-10), 72.0 (OCH2Ph), 72.8 (OCH2Ph), 81.6 (C-50), 82.5
(C-20), 97.0 (OCH2OCH3), 127.6 (C-40, Ph), 127.7 (Ph),
127.8 (Ph), 127.9 (Ph), 128.0 (Ph), 128.2 (Ph), 128.4 (Ph),
128.9 (Ph), 132.3 (C-5), 137.3 (Ph), 137.8 (Ph), 143.0
(C-30), 145.8 (C-8), 151.1 (C-4), 151.3 (C-6), 151.4 (C-2);
MS (m/z, relative intensity) 506 ([M11]1, 1), 429 (2), 338
(4), 247 (3), 171 (16), 157 (18), 105 (25), 91 (100).
3.1.13. (1)-9-[(1R,2R,5S)-2,5-Dihydroxy-3-(hydroxy)-
methyl-cyclopent-3-en-1-yl]-6-aminopurine (5), (1)-nep-
lanocin F. A solution of compound 21 (22 mg; 0.05 mmol)
in anhydrous methylene chloride (4 mL), cooled at 2788C,
was treated with a 1.0 M solution of boron trichloride in
methylene chloride 400 mL) under argon atmosphere. The
reaction mixture was stirred at 2788C for 5 h, and then for
1 h at 2458C. The mixture was cooled again to 2788C then
methanol (1.0 mL) was added, and the mixture was stirred at
2788C for an additional 1 h. The reaction mixture was
allowed to warm upto room temperature and the solvent
was evaporated. Methanol (6£5 mL) was added and evapo-
rated after each addition. The residue was puri®ed by
reverse phase column chromatography using a cartridge
(C-18 octadecyl) and eluting with water to afford after
lyophylisation 11 mg (85%) of pure neplanocin F as a
3.1.11.
(1)-9-[(1R,2R,5S)-5-Benzyloxy-3-(benzyloxy)-
methyl-2-hydroxy-cyclopent-3-en-1-yl]-6-chloropurine
(20). To a solution of compound 19 (72 mg; 0.14 mmol) in
methylene chloride (3 mL) was added tri¯uoroacetic acid

M. J. Comin et al. / Tetrahedron 58 (2002) 3129±3136
3135
George, C.; Nicklaus, M. C.; Dai, F.; Ford, Jr., H. Nucleosides
Nucleotides 1999, 18, 521±530. (f) Jeong, L. S.; Marquez,
V. E.; Yuan, C.-S.; Borchardt, R. T. Heterocycles 1995, 41,
2651±2656. (g) Ezzitouni, A.; Marquez, V. E. J. Chem. Soc.,
Perkin Trans. 1 1997, 1073±1078. (h) Ezzitouni, A.; Russ, P.;
Marquez, V. E. J. Org. Chem. 1997, 62, 4870±4873.
(i) Ezzitouni, A.; Barchi, Jr., J. J.; Marquez, V. E. J. Chem.
Soc., Chem Commun. 1995, 1345±1346.
white solid: Rf 0.05 (EtOAc±MeOH, 9:1); mp220 8C (d),
24
lit.26 2238C for the natural isomer; [a]D ˆ16.38 (c 0.53,
H2O), lit.26 [a]D ˆ26.68 (c 0.8, H2O) for the natural
24
isomer; UV (H2O) lmax 260 nm; 1H NMR (500 MHz,
DMSO-d6) d 3.88 (d, Jˆ15.6 Hz, 1H, H-60a), 3.99 (d, Jˆ
15.6 Hz, 1H, H60b), 4.29 (t, Jˆ6.7 Hz, 1H, H-10), 4.79±4.81
(m, 2H, H-50, H-20), 5.54 (s, 1H, H-40), 8.20 (s, 1H, H-8),
8.37 (s, 1H, H-2); 13C NMR (125 MHz, D2O) d 58.7
(CH2OH), 74.0 (C-10), 76.3 (C-20), 77.3 (C-50), 119.8
(C-5), 128.3 (C-40), 144.8 (C-8), 145.7 (C-30), 146.5
(C-2), 149.8 (C-4), 151.3 (C-6); HRMS (FAB) Calcd for
C11H14N5O3 (MH1) 264.1097, found 264.1096.
10. (a) Hegedus, L. S.; Geisler, L. J. Org. Chem. 2000, 65, 4200±
4203. (b) Shin, D. H.; Lee, H. W.; Park, S. S.; Kim, J. H.;
Jeong, L. S.; Chun, M. W. Arch. Pharm. Res. 2000, 23,
302±309. (c) Yoshida, N.; Kamikubo, T.; Ogasawara, K.
Tetrahedron Lett. 1998, 39, 4677±4678. (d) Ohira, S.;
Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995, 36,
1537±1538.
Acknowledgements
11. (a) Marquez, V. E.; Lim, M.; Tseng, C. K.-H.; Markovac, A.;
Priest, M. A.; Khan, M. S.; Kaskar, B. J. Org. Chem. 1988, 53,
5709±5714. (b) Bestmann, H. J.; Roth, D. Angew. Chem., Int.
Ed. Eng. 1990, 29, 99±100. (c) Trost, B. M.; Madsen, R.;
Guile, S. D. Tetrahedron Lett. 1997, 38, 1707±1710.
Thanks are owed to the National Research Council of
Argentina (Grant PIP 635/98) and the Universidad de
Buenos Aires (Grant X-080) for partial ®nancial support.
We also thank Dr James A. Kelley, Laboratory of Medicinal
Chemistry, National Cancer Institute, NIH for accurate
mass determination.
12. (a) Shuto, S.; Niizuma, S.; Matsuda, A. J. Org. Chem. 1998,
63, 4489±4493. (b) Niizuma, S.; Shuto, S.; Matsuda, A.
Tetrahedron 1997, 53, 13621±13632. (c) Obara, T.; Shuto,
S.; Saito, Y.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq,
E.; Matsuda, A. J. Med. Chem. 1996, 39, 3847±3852.
(d) Shuto, S.; Obara, T.; Saito, Y.; Yamashita, K.; Tanaka,
M.; Sasaki, T.; Andrei, G.; Snoeck, R.; Neyts, J.; Padalko, E.;
Balzarini, J.; De Clercq, E.; Matsuda, A. Chem. Pharm. Bull.
1997, 45, 1163±1168. (e) Shuto, S.; Obara, T.; Saito, Y.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Matsuda, A. J. Med.
Chem. 1996, 39, 2392±2399. (f) Wolfe, M. S.; Lee, Y.;
Bartlett, W. J.; Borcherding, D. R.; Borchardt, R. T. J. Med.
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