First synthesis of (-)-neplanocin C

Article abstract of DOI:10.1016/S0040-4020(00)00379-3

(-)-Neplanocin C (4), a minor component of the neplanocin family of antibiotics and a lead drug for the design of several conformationally constrained nucleosides analogues, was enantioselectively synthesized starting from D-ribono-1,4-lactone via a convergent approach in twelve steps. The proton NMR spectrum of 4 was in agreement with the corresponding natural product. Calculated coupling constants obtained from ab initio molecular modeling studies and from previously published X-ray structure of neplanocin C also corresponded to the spectroscopic data. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00379-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4639±4649
First Synthesis of (2)-Neplanocin C
*
Â
Marõa J. Comin and Juan B. Rodriguez
  Â
Departamento de Quõmica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2,
Ciudad Universitaria RA-1428 Buenos Aires, Argentina
Received 13 March 2000; accepted 1 May 2000
AbstractÐ(2)-Neplanocin C (4), a minor component of the neplanocin family of antibiotics and a lead drug for the design of several
conformationally constrained nucleosides analogues, was enantioselectively synthesized starting from d-ribono-1,4-lactone via a convergent
approach in twelve steps. The proton NMR spectrum of 4 was in agreement with the corresponding natural product. Calculated coupling
constants obtained from ab initio molecular modeling studies and from previously published X-ray structure of neplanocin C also
corresponded to the spectroscopic data. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
It has been reported that a cyclopropane or epoxide ring can
confer a remarkable rigidity to the sugar moiety of nucleo-
sides in such a way that the solution conformation is
identical to that found in the crystalline structure and, for
that reason, the equilibrium N,S is unobserved.6
Compounds 1, 2 and 3 were the ®rst examples of conforma-
tionally rigid nucleosides in which a [3.1.0]-fused hexane
system was used as sugar unit. However, the ®xed confor-
mations found in each compound with a 20,30-epoxy group
oriented a and b, respectively, not only differ sharply from
those typical for common nucleosides but also present an
unusual ¯at ring puckering (nmax). This effect is more
noticeable in the case of compounds 1 or 2 when this ring
puckering is practically eliminated with nmax values below
108 (Scheme 1).6
The biological properties of nucleosides have been exten-
sively studied, especially as antiviral and antitumor agents.1
The term carbanucleoside refers to a nucleoside analogue in
which a methylene group has replaced the oxygen atom of
the furanose ring.2 These analogues have potent metabolic
stability because they are unaffected by phosphorilases and
hydrolases that cleave the glycosidic bond of natural nucleo-
sides. Interestingly, they are also recognized by the same
enzymes that recognize normal nucleosides displaying,
correspondingly, a wide range of biological properties.3
On the other hand, the conformation and puckering of the
glycon moiety of nucleosides play a critical role in modu-
lating biological activity.4 It is known that in solution, this
ribose unit exits in a rapid dynamic equilibrium between the
northern-type (N) geometry (20-exo/30-endo) and the facing
southern-type (S) geometry (20-endo/30-exo) according to
the concept of the pseudorotational cycle de®ned by Altona
and Sundaralingman.5 On the contrary, only one of these
conformers is found in the crystalline structure, and the
Northern or Southern conformer are solely responsible for
molecular recognition of a determined enzyme, such as the
activation sequence that leads to active triphosphates,
which, in turn, are further recognized by other speci®c target
enzymes. However, as the ribose ring is very ¯exible and the
conformation in solution may be unlike that found in the
solid state, any attempt to correlate sugar conformation with
a preferred conformation requirement of a speci®c enzyme
for binding, would be ¯awed unless the crystalline structure
and the solution conformation are the same.
On the other hand, neplanocin C (4), a naturally occurring
carbocyclic nucleoside, is a good prototype of a conforma-
tionally locked nucleoside analogue.7 This compound was
isolated from Ampullariela regularis and is a minor compo-
nent of the neplanocin family, which is composed of at least
®ve components: neplanocin C (4), A (5), B (6), D (7), and F
(8) (Scheme 2).7 Certainly, this nucleoside analogue, also
built on a [3.1.0]-bicyclic system, exhibits the typical
northern-type (N) geometry as determined by the P value
of the pseudorotational cycle. The calculated
P
Keywords: carbohydrates; nucleosides; purines; enantiomeric purity.
* Corresponding author. Tel.: 154-11-4-576-3385; fax: 154-11-4-576-
3346; e-mail: jbr@qo.fcen.uba.ar
Scheme 1. Chemical structures of representative [3.1.0]-fused nucleosides
analogues.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00379-3

4640
M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
derivative (N)-methanocarba-20-desoxyadenosine (14) is a
substrate of adenosine deaminase (ADA), the enzyme
responsible for catalyzing deamination of adenosine to
inosine, this compound is deaminated 100 times faster
than its antipodal rigid conformer 15, (S)-methanocarba-
20-deoxyadenosine10h (Scheme 3). In conclusion, some of
the Northern analogues proved to be extremely potent anti-
viral agents while the Southern derivatives exhibited
vanishing inhibitory action.10
Although 50-nor-dideoxycarbanucleosides employing an
oxabicyclic [3.1.0]hexane system as carbocyclic ring have
been prepared,9 to date the synthesis of neplanocin C has not
been accomplished. Bearing in mind the potential useful-
ness of carbocyclic nucleosides built onto a rigid pseudo-
sugar template, the preparation of this important carbocyclic
nucleoside was encouraged.
Scheme 2. Chemical structures of the neplanocin family of naturally occur-
ring carbanucleosides.
valueˆ338.038 and nmaxˆ21.898 from the solved X-ray
structure8 indicates that this nucleoside analogue is in the
predicted northern geometry, speci®cally, in the E con-
2
formation that is very close to a pure 3T2 (Pˆ08) geometry,
which is the usual conformation found in normal nucleo-
sides. It has been demonstrated by ab initio molecular
orbital calculations that the boat like conformation in an
oxabicyclo[3.1.0]hexane system is more stable than the
pseudochair conformation.9
Results and Discussion
The enantioselective preparation of (2)-neplanocin C was
successfully carried out using 1,4-ribonolactone as chiral
starting material via the known cyclopentenol intermediate
16.11 The protection of both secondary hydroxyl groups as
an isopropylidene unit to form (2)-2,3-O-isopropylidene-d-
ribono-1,4-lactone (17) was conducted according to
previously published procedures.12±14 Several attempts to
protect the free primary hydroxyl group of 17 as a benzyl
ether were made such as in situ generation of benzyl iodide
by treatment with sodium hydride, benzyl bromide and
tetrabutyl ammonium iodide in tetrahydrofuran,15 or silver
oxide/benzyl bromide.16 However, all of these methods
failed in terms of the yield without recovering the starting
material, probably due to ring opening of the lactone deri-
vative 17. Therefore, it was decided to change the oxidation
state of carbon-1 to avoid ring opening. The lactol group
might be resistant to the basic medium required for the
introduction of the benzyl moiety. On treatment with
lithium dimethyl methylphosphonate, lactone 17 was
converted into lactol 18 in very good yield and with high
diastereoselectivity, which after reaction with benzyl
bromide in the presence of sodium hydride afforded the
benzyl ether derivative 19 in excellent yield. The stereo-
chemistry of lactol 18 may be explained by nucleophilic
attack from the less hindered b-face of the molecule, modu-
lated by the presence of the isopropylidene group, the
presence of its epimer (a-nucleophilic attack) was not
detected. 1H and 13C NMR spectra agreed with the presence
of a unique diastereomer. Once compound 19 was in hand, a
similar synthetic route to that reported for the synthesis of
neplanocin A was followed to obtain the cyclopentenol 16.11
Thus, hydrolysis of this compound with methanolic potas-
sium hydroxide gave rise to 2011 as the main product and 21
as a side product. Compound 20 reacted with Collins
reagent to give the diketo derivative 22 in good yield.11
Although other mild oxidizing agents were employed like
oxalylchloride/methyl sulfoxide17 or tetra-n-propyl ammo-
nium perruthenate,18 they were not able to produce the
desired compound, on the contrary, a complex mixture of
products was observed in each case. The preparation of 22
was ®rst attempted by another way: reductive ring opening
with sodium borohydride19 of 19 to form the diastereomic
Several conformationally constrained carbocyclic nucleo-
sides displaying a wide range of biological properties
have been prepared taking the chemical structure of
neplanocin C as lead drug. For example, adenosine deriva-
tive of 20,30-dideoxycarbanucleosides locked in the N
geometry (9) is moderately active against HIV;10a,b the 50-
triphosphate of conformationally restricted carbocyclic
analogues of AZT locked in the Northern conformation
(10) is exclusively responsible for reverse transcriptase
(RT) inhibition,10c while the 50-triphosphate of its isomer
rigid in the S geometry 11 ((S)-methanocarba-AZT) was
devoid of activity against RT;10c (N)-methanocarbathy-
midine (12) is an extremely potent drug against herpes
simplex virus 1 and 2 (HSV1 and HSV2) and even more
active than well known antiherpetic agents like gancyclovir
and acyclovir;10d,e (N)-methanocarbathymidine and (S)-
methanocarbathymidine (13) present antisense activity, in
fact, when 12 replaces thymidine in DNA/RNA hetero-
duplexes an increment of thermodynamic stability is
observed, while 13, which is locked in the S geometry,
produces an opposite destabilizing effect;10f,g adenosine
Scheme 3. Chemical structures of biologically active carbanucleosides
built on a rigid [3.1.0]hexane system.

M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
4641
Scheme 4. Reagents and conditions: (a) (MeO)2P(O)CH3, n-BuLi, THF, 2788C!rt, 1 h, 78%; (b) 50% NaH, BnBr, DMF, 08C, 30 min, 92%; (c) KOH, MeOH,
rt, 20 h, 77%; (d) Collins, CH2Cl2, rt, overnight, 80%; (e) K2CO3, PhH, 18-crown-6, 568C, 40 min, 35%; (f) NaBH4, CeCl3, MeOH, 08C, 15 min, 100%;
(g) R-O-acetylmandelic acid, dicyclohexylcarbodiimide, 4-DMAP, CH2Cl2, 08C, 77%; (h) NaBH4, THF, 08C, 25% for 23 and 25% for 24.
mixture of diols 23 and 24 and successive oxidation of either
diol. However, all the oxidation methods employed on each
diol (23 or 24) failed, giving rise not only to the desired
compound 22 but also to partially oxidized product such as
20 and 5-keto derivatives. The cyclization reaction was a
critical point for the preparation of the carbocyclic ring. In
spite of higher yield having been reported (close to 50%),11
we were able to obtain the cyclopentenone 25 in only 35%
yield on reaction of the diketo derivative 21 with potassium
carbonate in benzene in the presence of 18-crown-6 as trans-
fer catalyst. In addition, some other closely related methods
for this intramolecular Wittig-type reaction were attempted.
For example, the use of sodium hydride as a base in
diglyme19 or in tetrahydrofuran at 658C did not result in
an increase of the yield. Contrarily, several undesired
products were formed, and even the starting material
could not be recovered. Reduction of the cyclopentenone
25 with sodium borohydride in the presence of cerium
chloride afforded the allylic cyclopentenol 16 with high
diastereoselectivity.11 Formation of the diastereomeric b
alcohol was not detected (Scheme 4).
It has been demonstrated that compound 22 and other
closely related 1,4-diketo-2,3-O-isopropylidene derivatives
are able to undergo partial racemization.11,12,20 Then, as the
tendency of racemization for 22 under the basic medium of
the Wittig-type reaction to form cyclopentenone 25
increases, it was quite important to analyze any loss of
optical purity. It was thought that the cyclopentenol 16
could be a suitable substrate to prepare the O-acetylmande-
late derivatives and, in fact, compound 16 reacted with
O-acetylmandelic acid in the presence of dicyclohexyl-
carbodiimide21 to produce the corresponding ester 26.
From the analysis of the proton NMR spectrum and high
performance liquid chromatography of O-acetylmandelic
ester 26, the enantiomeric excess of cyclopentenol 16 was
found to be 77%.
In order to prepare the target molecule 4, two synthetic
strategies were considered according to the retrosynthetic
analysis shown in Scheme 5: (a) diastereoselective epoxida-
tion of the advanced cyclopentenol intermediate (compound
16) would be directed by the free hydroxyl group to produce
Scheme 5. Retrosynthetic analysis for the preparation of neplanocin C.

4642
M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
the epoxyalcohol 27 as anticipated by the Hembest rule.22
Coupling of 27 with 6-chloropurine under Mitsunobu type
conditions23 would lead to the carbanucleoside 28.
Ammonolysis of the chloropurine intermediate followed
by cleavage of the isopropylidene and benzyl protective
groups would form the desired target molecule. (b)
Coupling of the cyclopentenyl alcohol 16 with 6-chloro-
purine followed by removal of the isopropylidene protective
group would give rise to carbocyclic nucleoside precursor
29. Hydroxyl-directed epoxidation would lead to the
carbanucleoside intermediate built on a rigid [3.1.0]oxa-
bicyclic hexane system (compound 30). Ammonolysis of
30 followed by deprotection of the benzyl ether would
produce the desired molecule of neplanocin C. Although
the former synthetic approach seems to be very attractive,
one critical point was the removal of the isopropylidene
group in the presence of a labile epoxy functionality. The
use of 60% acetic acid at 508C is a mild method described24
for the deprotection of isopropylidene groups. In order to
study the stability of the epoxy group under these reaction
conditions, carbanucleoside 31 taken as a simple model was
employed.9 This compound, built on an oxabicyclo[3.1.0]-
hexane system similar to 28, underwent ring opening to
afford diol 32 in less than one hour when treated with
60% acetic acid, while elimination of the isopropylidene
group required 24 h for completion (Scheme 6). Other
mild methods for acetonide cleavage were tested like treat-
ment of pyridinium 4-toluenesulfonate in methanol at
658C25 or Dowex 50W (H1) in water at 708C,26 however,
both of these reaction conditions produced ring opening of
the epoxy group. The rest of the known methodologies to
carry out this transformation need stronger acid media
making them incompatible with the presence of epoxy
groups. In the second strategy, epoxidation of the cyclo-
pentenyl pseudosugar in compound 29 could lead to some
dif®culties due to the propensity of oxidation at the N-1
position.27 For that reason, the reaction of a simple model
(compound 33) was investigated when this substrate reacted
with m-chloroperoxybenzoic acid. Surprisingly, no nitrogen
of the base underwent oxidation to form the corresponding
N-oxides, only the epoxy derivative 34 was isolated.
Scheme 6. Reagents and conditions: (a) 60% AcOH, 508C, 24 h, 92%; (b)
6-chloropurine, Ph3P, DEAD, THF, rt, 28%; (c) m-CPBA, Cl2CH2, 08C!rt,
24 h, 69%.
For the above reasons, it was decided to use the latter
synthetic strategy. Therefore, cyclopentenol 16 was coupled
with 6-chloropurine under Mitsunobu conditions23 to give
the N-9 alkylated compound (carbanucleoside 35) as the
main product, and a small amount of the undesired N-7
isomer (compound 36). On treatment with 60% acetic acid
at 508C for 24 h, 35 was converted into diol 37 in 40%
overall yield starting from 16 (Scheme 7).
Then, 37 reacted with m-chloroperbenzoic acid at room
temperature to give a mixture of the precursor of neplanocin
C (compound 38) and the precursor of its diastereomer
(compound 39) in a 1:1 ratio, which was easily puri®ed by
column chromatography. The reaction needed ten days for
completion. The proton NMR spectrum was quite diagnos-
tic, it unambiguously established the structure of compound
38. The pseudoanomeric signal corresponding to compound
38 appeared as a singlet centered at 5.06 ppm while the
pseudoanomeric signal for 39 was observed as a doublet
of doublets centered at 5.02 ppm with coupling constants
of 6.6 and 1.1, respectively. These NMR data showed that
Scheme 7. Reagents and conditions: (a) 6-chloropurine, PPh3, DEAD,
THF, rt, 1 h; (b) AcOH, 508C, 24 h, 40% from 16; (c) m-CPBA, CH2Cl2,
08C!rt, 10 days, (d) NH3/MeOH, 708C, 5 h, 75% for 40, 63% for 41; (e)
H2, 10% Pd/C, MeOH, 3 atm, 88% for 4, 72% for 42.

M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
4643
Table 1.
0
0
0
fH3 ±C3 ±C4 ±H4
0
0
0
0
J Calcd J Obs fH2 ±C2 ±C3 ±H3
0
0
0
0
J Obs fH4 ±C4 ±C5 ±H5
0
Compound E (kcal/mol)
DE
1.58
25.9
J Calcd
J Calcd
J Obs
a
a
a
4 (anti)
2624884.15
2624885.73
2746458.61
2746452.74
290.0
294.3
99.6
144.8
155.0
0.0
0.63
0.8
235.6
234.9
25.6
218.1
232.8
5.3
5.4
6.1
6.8
7.3
7.3
5.1
5.1
m
69.5
73.1
250.9
272.1
254.5
2.3
1.9
4.2
3.0
a
4 (syn)
37 (anti)b
37 (syn)b
42 (anti)
2.2
2.2
7.5
br s
br s
br s
5.8
7.9
5.64
2.69
a Not observed.
b Neplanocin C numbering was employed for simplicity.
the locked conformations of 38 and 39 perfectly agreed with
the published X-ray structure of neplanocin C8 and the
calculated lowest energy conformers for this compound
and its diastereomer 39. Bearing in mind the rigidity of
the pseudosugar moiety in this oxabicyclic system, it can
be postulated that the dihedral angles of the carbocyclic ring
of all synthetic intermediates that lead to the target molecule
should be almost identical providing quite similar proton
NMR spectra. Therefore, the optimized energy conformer
of 38 (base in the anti position) presented torsion
achieved providing a general methodology for the prepara-
tion of this important class of conformationally rigid nucleo-
side analogues built on a oxabicyclo[3.1.0]hexane system as
pseudosugar moiety.
Experimental
The glassware used in air and/or moisture sensitive reac-
tions was ¯ame-dried and reactions were 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. Benzene and
tetrahydrofuran were distilled from sodium/benzophenone
ketyl, methylene chloride was distilled from phosphorus
0
0
0
0
0
0
0
0
angles fH3 ±C3 ±C4 ±H4 ˆ2908, fH2 ±C2 ±C3 ±H3 ˆ235.68
0
0
0
0
and fH4 ±C4 ±C5 ±H5 ˆ69.458 and calculated coupling
constants of 0.0, 5.3, and 2.3 Hz, respectively. The
calculated torsion angles for 39 (base in the anti position)
0
0
0
0
0
0
0
0
were fH3 ±C3 ±C4 ±H4 ˆ1558, fH2 ±C2 ±C3 ±H3 ˆ2338 and
0
0
0
0
fH4 ±C4 ±C5 ±H5 ˆ2558 with estimated coupling constants
of 7.9, 5.6 and 2.7 Hz, respectively. These data were quite
in agreement with the observed NMR spectra (see Table 1).
Moreover, the unusual stereochemical course of the epoxi-
dation reaction can be explained bearing in mind that the
base in the anti position in 37 is almost 6 kcal/mol more
stable that the syn conformer. Then, the electrophilic epoxi-
dizing agent can also coordinate with the N-3 rather than
exclusively with the hydroxyl groups affording equal
amounts of 38 and 39.
Ê
pentoxide and 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.
Treatment of 38 with methanolic ammonia gave the purine
derivative 40 in good yield, which after catalytic hydro-
genation gave rise to (2)-neplanocin C. The remarkable
stability of the epoxy functionality under methanolic
ammonia at high temperature had already been described
by us.9 The proton NMR spectrum of the synthetic product
was identical to that previously described.7f In a similar
way, compound 39 was transformed into 41, which was
additionally converted into carbanucleoside 42 in a compar-
able overall yield.
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). Positive ion fast atom
bombardment mass spectra (FABMS) were obtained on a
VG ZAB BEqQ spectrometer at an accelerating voltage of
8 kV and a resolution of 500. Thioglycerol was used as the
sample matrix, and ionization was effected by a beam of
cesium atoms. Accurate mass analysis for the ®nal products
was conducted at a resolution of 2850 (10% valley) in the
molecular ion region using charge-exchanged xenon atoms
and glycerol as a matrix. The glycerol peaks at m/z 277
(Gly3H1) and 369 (Gly4H1) were used as reference ions
and the VG-7070-EHF mass spectrometer was voltage
scanned under computer control. The standard VG peak
centroiding software of the 11/250 data system was used
to assign and calculate masses for the reference and sample
ions, respectively. High resolution FAB mass spectrometry
for the rest of the compound was performed with a JEOL
The ab initio energy calculations of optimized conformers
were performed with the program Gaussian 98W employ-
ing a HF/6-31Gdp basis set.28 All geometries were initially
pre-optimized by the molecular mechanics method (MM1),
and also by semiempirical methods such as PM3 or AM1
employing the HyperChem program. The initial semi-
empirical calculations were not acceptable due to some
divergences with the experimental data.
Compound 42 was devoid of activity against Herpes
Simplex virus type 1 (HSV-1) strain F, Human Cyto-
megalovirus (HCMV) strain Davis Polio virus type 3,
Vesicular Stomatitis virus (VSV) and Junin virus strain IV.
In summary, the ®rst synthesis of neplanocin C was

4644
M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
SX102 spectrometer using 6 kV Xe atoms following
desorption from a glycerol matrix.
Jˆ5.9 Hz, 1H, H-3), 7.32 (m, 5H, aromatic protons);
13C NMR (CDCl3) d 25.1 (CH3), 26.5 (CH3), 31.3 (d,
JC±Pˆ6.8 Hz, C-1), 51.9 (d, JC±Pˆ6.7 Hz, P(OCH3)a), 53.4
(d, JC±Pˆ6.7 Hz, P(OCH3)b), 71.3 (C-6), 73.4 (OCH2Ph),
82.8 (C-5), 84.8 (C-4), 86.5 (d, JC±Pˆ8.3 Hz, C-3), 105.3
(d, JC±Pˆ6.8 Hz, C-2), 112.7 (C(CH3)2), 127.7 (Ph), 128.4
(Ph), 137.5 (Ph); MS (m/z, relative intensity) 403 (2), 295
(2), 241 (8), 219 (2), 213 (2), 151 (3), 91 (100).
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-Alumi-
num sheets, Kieselgel 60 F254) and was visualized by
254 nm UV or by immersion into an ethanolic solution of
5% H2SO4.
(2)-6-O-Benzyl-1-deoxy-1-(dimethylphosphono)-3,4-O-
isopropylidene-d-ribo-hexulose (20); (2)-5,6-O-di-
benzyl-1-deoxy-1-(dimethylphosphono)-3,4-O-isopropy-
lidene-d-ribo-hexulose (21). To a solution of 19 (6.40 g,
16.0 mmol) in methanol (50 mL) was added potassium
hydroxide (1.80 g, 32.0 mmol). The reaction mixture was
stirred at room temperature for 20 h. The mixture was
neutralized with an aqueous saturated solution of ammo-
nium chloride and was extracted with methylene chloride
(3£50 mL). The combined organic phases were washed
with brine (2£70 mL), dried (Na2SO4), and the solvent
was evaporated. The product was puri®ed by column chro-
matography (silica gel) using hexane±EtOAc (1:1) as eluant
to afford 4.91 g of pure compound 20 (77% yield) as a
yellow syrup and 0.79 g (12% yield) of compound 21 as a
yellow syrup. Compound 20: [a]2D4ˆ28.38 (c 1.05, CHCl3),
lit.11 [a]D24ˆ28.28 (c 1.02, CHCl3); IR (®lm, cm21) 3350,
2959, 2924, 2852, 2360, 2339, 1733, 1348, 1041, 870, 742,
706; 1H NMR (500 MHz, CDCl3) d 1.37 (s, 3H, CH3), 1.45
(s, 3H, CH3), 3.33 (dd, Jˆ22.3, 14.3 Hz, 1H, H-1a), 3.46
(dd, Jˆ22.3, 14.3 Hz, 1H, H-1b), 3.56 (dd, Jˆ9.8, 6.2 Hz,
1H, H-6a), 3.70 (dd, Jˆ9.8, 3.2 Hz, 1H, H-6b), 3.69 (d,
Jˆ11.4 Hz, 3H, P(OCH3)a), 3.70 (d, Jˆ11.4 Hz, 3H,
P(OCH3)b), 3.90 (m, 1H, H-5), 4.24 (t, Jˆ6.4 Hz, 1H,
H-4), 4.57 (mAB, 2H, OCH2Ph), 4.62 (d, Jˆ6.2 Hz, 1H,
H-3), 7.33 (m, 5H, aromatic protons); 13C NMR (CDCl3)
d 26.0 (CH3), 26.9 (CH3), 37.2 (d, JC±Pˆ131.0 Hz, C-1),
53.1 (d, JC±Pˆ6.8 Hz, P(OCH3)2), 70.9 (C-6), 71.6 (C-5),
73.5 (OCH2Ph), 77.5 (C-4), 82.7 (C-3), 111.3 (C(CH3)2),
127.7 (Ph), 128.4 (Ph), 137.9 (Ph), 199.5 (C-2); MS (m/z,
relative intensity) 403(4), 345 (5), 327 (7), 223 (17), 151
(31), 124 (37), 91 (100). Compound 21: 1H NMR
(500 MHz, CDCl3) d 1.35 (s, 3H, CH3), 1.45 (s, 3H,
CH3), 3.23 (dd, Jˆ22.1, 14.4 Hz, 1H, H-1a), 3.41 (dd,
Jˆ22.3, 14.4 Hz, 1H, H-1b), 3.60 (dd, Jˆ10.3, 5.6 Hz, 1H,
H-6a), 3.73 (d, Jˆ11.2 Hz, 3H, P(OCH3)a), 3.74 (d,
Jˆ11.4 Hz, 3H, P(OCH3)a), 3.84 (m, 1H, H-5), 4.40 (t,
Jˆ5.8 Hz, 1H, H-4), 4.53 (mAB, 2H, OCH2Ph), 4.62 (d,
Jˆ6.4 Hz, 1H, H-3), 4.70 (d, Jˆ11.6 Hz, 1H, OCHaPh),
4.77 (d, Jˆ11.6 Hz, 1H, OCHbPh), 7.27±7.35 (m, 10H,
aromatic protons); 13C NMR (125 MHz, CDCl3) d 25.8
(CH3), 26.7 (CH3), 36.7 (d, JC±Pˆ131.6 Hz, C-1), 52.7 (d,
JC±Pˆ6.8 Hz, P(OCH3)2), 69.6 (C-6), 72.9 (OCH2Ph), 73.2
(OCH2Ph), 77.3 (C-5), 78.0 (C-4), 81.7 (d, JC±Pˆ2.7 Hz,
C-2), 110.9 (C(CH3)2), 127.5 (Ph), 127.7 (Ph), 128.1 (Ph),
137.9 (Ph), 138.0 (Ph), 201.3 (C-2).
(2)-1-Deoxy-1-(dimethylphosphono)-3,4-O-isopropyli-
dene-d-ribo-hexofuranose (18). To a solution of dimethyl
methylphosphonate (15.0 mL, 136 mmol) in anhydrous
tetrahydrofuran (150 mL) cooled at 2788C under a nitrogen
atmosphere was added n-butyllithium (82 mL, 119 mmol,
1.5 M solution in hexane) dropwise over a 10 min period.
Then, a solution of 17 (6.1 g, 32 mmol) in anhydrous tetra-
hydrofuran (30 mL) was added dropwise to the resulting
mixture. After the addition was completed, the reaction
mixture was allowed to warm to room temperature and
the mixture was stirred for an additional hour. The reaction
mixture was neutralized by addition of glacial acetic acid,
and partitioned between brine (150 mL) and methylene
chloride (100 mL). The organic layer was dried (Na2SO4),
and the solvent was evaporated. The residue was puri®ed by
column chromatography (silica gel) employing hexane±
EtOAc (3:2) as eluant to give 7.91 g (78% yield) of pure
18 as a white solid: mp 98±998C; [a]2D4ˆ27.08 (c 1.0,
CHCl3); IR (®lm, KBr) 3398, 2998, 2956, 2851, 1653,
1
1471, 1280, 1212, 1037, 876, 834; H NMR (CDCl3) d
1.33 (s, 3H, CH3), 1.49 (s, 3H, CH3), 2.34 (m, 2H, H-1),
3.73 (m, 2H, H-6a,b), 3.76 (d, Jˆ11.3, Hz, 3H, P(OCH3)a),
3.83 (d, Jˆ11.1 Hz, 3H, P(OCH3)b), 4.35 (t, Jˆ6.0 Hz, 1H,
H-4), 4.53 (d, Jˆ5.8 Hz, 1H, H-5), 4.94 (d, Jˆ5.8 Hz, 1H,
H-3), 6.51 (br s, 1H, ±OH); 13C NMR (CDCl3) d 24.7
(CH3), 26.3 (CH3), 31.2 (d, JC±Pˆ137 Hz, C-1), 53.5 (d,
JC±Pˆ6.8 Hz, P(OCH3)a), 54.0 (d, JC±Pˆ6.8 Hz,
P(OCH3)b), 63.9 (C-6), 81.9 (C-5), 86.9 (C-4), 87.5 (C-3),
105.0 (d, JC±Pˆ7 Hz, C-2), 112.5 (C(CH3)2).
(2)-6-O-Benzyl-1-deoxy-1-(dimethylphosphono)-3,4-O-
isopropylidene-d-ribo-hexofuranose (19). A solution of
compound 18 (5.8 g, 18.5 mmol) in anhydrous N,N-
dimethylformamide (15 mL) cooled at 08C was treated
with benzyl bromide (2.64 mL, 22.2 mmol). Then, a 50%
sodium hydride dispersion (2.00 g, 40.7 mmol) was added
portionwise over 15 min while the temperature was main-
tained at 08C. The reaction mixture was stirred at 08C for
30 min. The reaction was quenched by addition of a satu-
rated aqueous solution of ammonium chloride (100 mL).
The mixture was extracted with methylene chloride
(2£50 mL), and the combined organic layers were washed
with brine (5£50 mL), dried (Na2SO4), and the solvent was
evaporated. The residue was puri®ed by column chromato-
graphy (silica gel) using hexane±EtOAc (4:1) as eluant to
give 6.80 g of pure 19 (92% yield) as a yellow pale oil:
[a]D24ˆ212.88 (c 1.5, CHCl3), lit.11 [a]2D4ˆ214.08 (c 0.93,
CHCl3); 1H NMR (CDCl3) d 1.32 (s, 3H, CH3), 1.48 (s, 3H,
CH3), 2.40 (m, 2H, H-1), 3.65 (m, 2H, H-6), 3.73 (d,
Jˆ11.0 Hz, 3H, P(OCH3)a), 3.83 (d, Jˆ11.0 Hz, 3H,
P(OCH3)b), 4.30 (t, Jˆ5.9 Hz, 1H, H-4), 4.51 (d,
Jˆ5.8 Hz, 1H, H-5), 4.57 (m, 2H, OCH2Ph), 4.78 (d,
(2)-6-O-Benzyl-1-deoxy-1-(dimethylphosphono)-3,4-O-
isopropylidene-d-erythro-2,5-hexodiulose (22). To
a
magnetically stirred solution of pyridine (6.8 mL,
83.6 mmol) in anhydrous methylene chloride (100 mL)
cooled at 08C was added powdered chromium trioxide
(4.18 g, 41.8 mmol) under argon atmosphere. Then, a
solution of the hydroxy ketone 20 (2.8 g, 7.0 mmol) in

M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
4645
anhydrous methylene chloride (10 mL) was added and the
reaction mixture was allowed to warm to room temperature
and was stirred overnight. The mixture was then ®ltered
through a silica gel pad eluting with EtOAc±acetone (2:1)
and the solvent was evaporated to afford 2.14 g (80% yield)
of the diketone 22 as a yellow pale oil that was used in the
next step without further puri®cation: [a]2D4ˆ213.48 (c 1.2,
3451, 1733, 1640, 1262, 1041; 1H NMR (500 MHz, CDCl3)
d 1.40 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.25 (dd, Jˆ22.8,
14.1 Hz, 1H, H-1a), 3.49 (dd, Jˆ22.5, 14.1 Hz, 1H, H-1b),
3.78 (d, Jˆ11.2 Hz, 3H, P(OCH3)a), 3.80 (d, Jˆ11.2 Hz,
3H, P(OCH3)b), 4.39 (d, Jˆ18.2 Hz, 1H, H-6a), 4.48 (d,
Jˆ18.5 Hz, 1H, H-6b), 4.62 (s, 2H, OCH2Ph), 4.79 (d,
Jˆ5.7 Hz, 1H, H-3), 4.82 (d, Jˆ5.9 Hz, 1H, H-4), 7.35
(m, 5H, aromatic protons); 13C NMR (CDCl3) d 25.9
(CH3), 26.1 (CH3), 37.0 (d, JC±Pˆ130.3 Hz, C-1), 53.1 (d,
JC±Pˆ4.5 Hz, P(OCH3)2), 72.6 (C-6), 73.4 (OCH2Ph), 79.4
(C-4), 81.5 (d, JC±Pˆ2.5 Hz, C-3), 113.0 (C(CH3)2),
127.7 (Ph), 128.0 (Ph), 128.5 (Ph), 136.9 (Ph), 199.6 (d,
JC±Pˆ7.5 Hz, C-2), 204.7 (C-5).
1.75 mmol) in anhydrous benzene (20 mL) at 568C under
argon atmosphere. The reaction mixture was stirred at this
temperature for 40 min. Then, the mixture was allowed to
cool to room temperature, was ®ltered and the ®ltrate was
poured into ethyl ether (30 mL). The resulting mixture was
washed with brine (3£15 mL), dried (Na2SO4) and the
solvent was evaporated. The product was puri®ed by
column chromatography (silica gel) employing hexane±
EtOAc (9:1) as eluant to afford 240 mg (35% yield) of
pure 25 as a colorless oil: [a]2D4ˆ27.98 (c 0.6, CHCl3),
lit.11 [a]D24ˆ27.28 (c 1.02, CHCl3); IR (®lm, cm21) 2986,
2939, 2852, 1730, 1629, 1382, 1215, 1148, 1082, 868, 741,
CHCl3), lit.11 [a]D24ˆ214.18 (c 1.0, CHCl3); IR (®lm, cm21
)
1
701; H NMR (CDCl3) d 1.39 (s, 6H, C(CH3)2), 4.33 (dd,
Jˆ17.3, 1.1 Hz, 1H, H-6a), 4.49 (d, Jˆ5.6 Hz, 1H, H-4),
4.49 (dd, Jˆ17.3, 1.6 Hz, 1H, H-6b), 4.64 (s, 2H,
OCH2Ph), 5.08 (d, Jˆ5.6 Hz, 1H, H-5), 5.20 (t, Jˆ1.7 Hz,
1H, H-2), 7.29 (m, 5H, aromatic protons); 13C NMR
(CDCl3) d 26.1 (CH3), 27.3 (CH3), 67.4 (C-6), 73.3
(OCH2Ph), 77.6 (C-4)p, 77.9 (C-5)p, 115.4 (C(CH3)2),
127.6 (Ph), 128.3 (C-2), 128.4 (Ph), 137.2 (Ph), 173.6
(C-3), 201.5 (C-1); MS (m/z, relative intensity) 259 (1),
p
168 (25), 110 (40), 91 (100). Signal assignment may be
interchanged.
6-O-Benzyl-1-deoxy-1-dimethylphosphono-3,4-O-iso-
propylidene-d-allose (23); 6-O-benzyl 1-deoxy-3,4-O-
isopropylidene-d-altrose (24). A solution of lactol 19
(780 mg, 1.95 mmol) in tetrahydrofuran (20 mL) was
treated with sodium borohydride (265 mg, 7.0 mmol) at
08C. The reaction mixture was stirred at room temperature
for 2 h, then an aqueous saturated solution of ammonium
chloride (100 mL) was added. The mixture was extracted
with ether (3£50 mL). The combined organic layers were
washed with brine (3£50 mL), dried (MgSO4), and the
solvent was evaporated. The residue was puri®ed by column
chromatography (silica gel) eluting with hexane±EtOAc
(2:3) to afford 198 mg (25% yield) of compound 23 as a
white solid and 210 mg (25% yield) of compound 24 as a
white solid: Compound 23: 1H NMR (CDCl3) d 1.31 (s, 3H,
CH3), 1.34 (s, 3H, CH3), 1.81±2.01 (m, 2H, H-1), 3.59 (dd,
Jˆ9.9, 6.3 Hz, 1H, H-6a), 3.77 (d, Jˆ10.9 Hz, 6H,
P(OCH3)2), 4.61 (mAB, 2H, OCH2Ph), 7.34 (m, 5H,
aromatic protons); 13C NMR (CDCl3) d 25.4 (CH3), 27.9
(CH3), 29.4 (d, JC±Pˆ140.3 Hz, C-1), 65.3 (d, JC±Pˆ5.7 Hz,
C-3), 68.6 (C-5), 71.7 (C-6), 73.5 (OCH2Ph), 77.3 (C-4),
80.3 (d, JC±Pˆ16.0 Hz, C-2), 108.8 (C(CH3)2), 127.7 (Ph),
128.4 (Ph), 138.1 (Ph). Compound 24: 1H NMR (CDCl3) d
1.34 (s, 3H, CH3), 1.45 (s, 3H, CH3), 2.17 (dd, Jˆ18.3,
6.3 Hz, 2H, H-1), 3.24 (s, 1H, ±OH), 3.56 (dd, Jˆ9.8,
5.7 Hz, 1H, H-6a), 3.74 (d, Jˆ10.9 Hz, 3H, P(OCH3)a),
3.75 (d, Jˆ11.0 Hz, 3H, P(OCH3)b), 4.06±4.15 (m, 3H),
4.43 (m, 1H), 4.57 (mAB, 2H, OCH2Ph) 7.33 (m, 5H,
aromatic protons); 13C NMR (CDCl3) d 25.5 (CH3), 27.5
(CH3), 30.5 (d, JC±Pˆ140.1 Hz, C-1), 52.6 (d, JC±Pˆ7.4 Hz,
P(OCH3)2), 65.0 (d, JC±Pˆ4.0 Hz, C-3), 68.6 (C-5),
72.1 (C-6), 73.7 (OCH2Ph), 77.9 (C-4), 80.1 (d,
JC±Pˆ16.1 Hz, C-2), 108.9 (C(CH3)2), 128.0 (Ph), 128.7
(Ph), 138.3 (Ph).
(1S,4R,5S)-(1)-3-[(Benzyloxy)methyl]-4,5-O-isopropyl-
idene-2-cyclopenten-1-ol (16). To a solution of 25
(729 mg, 2.66 mmol) and cerium(III) chloride heptahydrate
(834 mg, 2.24 mmol) in methanol (20 mL) cooled at 08C,
sodium borohydride (156 mg, 4.12 mmol) was added
portionwise while the temperature was maintained between
0 and 58C. After 15 min the pH was adjusted to 7 with acetic
acid. Water (10 mL) was added and the mixture was
extracted with ethyl ether (3£20 mL). The organic phase
was washed with brine (3£30 mL), dried (Na2SO4), and
the solvent was evaporated to give 734 mg (100%) of the
desired alcohol 16 as a colorless oil: [a]2D4ˆ125.18 (c 1.12,
CHCl3), lit.29 [a]D24ˆ141.6 (no solvent informed); 1H NMR
(500 MHz, CDCl3) d 1.40 (s, 3H, CH3), 1.42 (s, 3H, CH3),
2.70 (d, Jˆ9.8 Hz, 1H, H-1), 4.16 (m, 2H, H-6), 4.56 (s, 2H,
±OCH2Ph), 4.76 (t, Jˆ5.5 Hz, 1H, H-5), 5.80 (m, 1H, H-2),
7.29 (m, 5H, aromatic protons); 13C NMR (CDCl3) d 26.6
(CH3), 27.6 (CH3), 66.3 (C-6), 72.9 (OCH2Ph), 73.3 (C-1),
77.8 (C-5), 83.0 (C-4), 112.6 (C(CH3)2), 127.6 (Ph), 128.4
(Ph), 131.4 (C-2), 138.0 (Ph), 143.6 (C-3).
(1S,4R,5S)-(2)-3-[(Benzyloxy)methyl]-4,5-O-isopropyl-
idene-2-cyclopenten-1-yl (R)-O-acetylmandelate (26). A
solution of dicyclohexylcarbodiimide (52 mg, 0.25 mmol)
in anhydrous methylene chloride (2 mL) was added drop-
wise to a stirred solution of (R)-(2)-O-acetylmandelic acid
(44 mg, 0.23 mmol), alcohol 16 (62 mg, 0.23 mmol) and
4-(dimethylamino)pyridine (10 mg) in anhydrous methyl-
ene chloride (5 mL) at 08C. A white precipitate of dicyclo-
hexylurea was observed in the reaction medium before the
addition was completed. The reaction mixture was stirred at
room temperature for an additional 24 h. The dicyclohexyl-
urea was removed by ®ltration, and the resulting ®ltrate was
washed successively with an aqueous 0.5 M solution of HCl
(3£5 mL), an aqueous 1 M solution of Na2CO3 (2£10 mL)
and brine (3£10 mL). The organic layer was dried
(Na2SO4), and the solvent was evaporated. The residue
was puri®ed by column chromatography (silica gel) eluting
with hexane±EtOAc (9:1) to afford 76 mg (77% yield) of
(4R,5R)-(2)-3-[(Benzyloxy)methyl]-4,5-O-isopropylidene-
2-cyclopentenone (25). A solution of diketone 22 (1.00 g,
2.5 mmol), previously azeotroped with benzene (2£10 mL),
dissolved in anhydrous benzene (5 mL), was added to a
stirred suspension of powered potassium carbonate
(415 mg, 3.00 mmol) and 18-crown-6 ether (463 mg,

4646
M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
p
ester 26 (diastereomeric mixture) as a white solid: de 77%
(corresponds to ee 77% for 16) determinated by HPLC
(Alltech Ultrasphere ODS-2 5 mm, 250£10 mm column;
4.0 mL/min; MeOH±H2O 85:15; lˆ270 nm) tr1ˆ
9.12 min, tr2ˆ9.97 min; 1H NMR (500 MHz, CDCl3) d
1.17 (s, 3H, CH3), 1.26 (s, 3H, CH3), 1.35 (s, 3H, CH3),
2.19 (s, 3H, CH3CO), 4.10 (d, Jˆ13.9 Hz, 1H, H-6a), 4.16
(d, Jˆ13.9 Hz, 1H, H-6b), 4.55 (s, 2H, OCH2Ph), 4.80±5.00
(m, 1H, H-1), 4.88 (s, 1H, AcOCH), 5.23 (br s, 1H, H-5),
5.35 (br s, 1H, H-4), 6.07 (d, 1H, Jˆ10.3 Hz, H-2), 7.30±
7.60 (m, 10H, aromatic protons); 13C NMR (125 MHz,
CDCl3) d 20.6 (COCH3), 20.8 (COCH3), 26.9 (CH3), 27.2
(CH3), 27.3 (CH3), 66.4 (C-6), 73.0 (OCH2Ph), 74.2
(AcOCH), 75.3 (C-5), 76.5 (C-1), 76.9 (C-1), 83.0 (C-4),
112.9 (C(CH3)2), 125.7 (Ph), 127.7 (Ph), 127.8 (Ph), 128.4
(Ph), 128.5 (Ph), 128.7 (Ph), 129.2 (Ph), 133.3 (C-2), 133.5
(C-2), 137.9 (Ph), 146.1 (C-3), 167.3 (CO), 167.9 (CO),
170.1 (COCH3).
(C-30)p, 144.1 (C-8), 151.7 (C-2). Signal assignment may
be interchanged.
(2)-9-[(Benzyloxy)methyl-4,5-O-isopropylidene-2-cyclo-
penten-1-yl]-6-chloropurine (35); (2)-7-[(Benzyloxy)-
methyl-4,5-O-isopropylidene-2-cyclopenten-1-yl]-6-chloro-
purine (36). A suspension of 6-chloropurine (214 mg,
1.39 mmol) and triphenylphosphine (455 mg, 1.73 mmol)
in anhydrous tetrahydrofuran (3 mL) was treated with
diethylazodicarboxylate (303 mg, 1.73 mmol) under argon
atmosphere. The resulting mixture was vigorously stirred
for 10 min, then after a solution of alcohol 16 (319 mg,
1.16 mmol) in tetrahydrofuran (5 mL) was added in one
portion. The reaction mixture was stirred at room tempera-
ture for 1 h. The solvent was evaporated and the residue was
adsorbed on silica gel and puri®ed by column chromato-
graphy using hexane±EtOAc as eluant to afford 487 mg of
compound 35 and 90 mg of the N-7 derivative (compound
36). Compound 35: 1H NMR (CDCl3) d 1.37 (s, 3H, CH3),
1.49 (s, 3H, CH3), 4.25 (m, 2H, H-60a,b), 4.63 (s, 2H,
OCH2Ph), 4.75 (d, Jˆ5.5 Hz, 1H, H-50), 5.42 (d,
Jˆ5.5 Hz, 1H, H-40), 5.66 (s, 1H, H-10), 5.84 (s, 1H,
H-20), 7.34 (m, 5H, aromatic protons), 8.03 (s, 1H, H-8),
8.75 (s, 1H, H-2); 13C NMR (CDCl3) d 25.6 (CH3), 27.1
(CH3), 66.2 (C-10)p, 66.3 (C-60)p, 72.8 (OCH2Ph), 83.8
(C-40)p, 83.9 (C-50)p, 112.9 (C(CH3)2), 121.9 (C-20), 127.4
(Ph), 127.5 (Ph), 128.2 (Ph), 137.5 (Ph), 143.7 (C-8), 149.8
(C-30), 151.7 (C-2); MS (m/z, relative intensity) 414 (1), 412
(1), 357 (2), 355 (6), 327 (3), 325 (10), 250 (10), 248 (34),
(^)-6-Amino-9-[(2,3-dihydroxycyclopentan-1-yl]-purine
(32). A solution of 31 (50 mg; 0.23 mmol) in 60% acetic
acid (5 mL) was stirred for 1 h at 508C. The solvent was
evaporated to give 51 mg (92% yield) of 32 as a colorless
oil: 1H NMR (500 MHz, CD3OD) d 2.24 (m, 2H, H-50), 2.58
(m, 2H, H-40), 4.62 (m, 1H, H-10), 4.96 (m, 2H, H-20, H-30),
8.17 (s, 1H, H-8), 8.45 (s, 1H, H-2); 13C NMR (125 MHz,
CD3OD) d 32.5 (C-50), 33.8 (C-40), 62.5 (C-10), 65.3 (C-30),
75.8 (C-20), 118.5 (C-5), 139.0 (C-4), 140.4 (C-8), 145.0
(C-2), 158.8 (C-6).
1
201 (32), 157 (11), 155 (23), 91 (100). Compound 36: H
(^)-9-(2-Cyclohexen-1-yl)-6-chloropurine (33). A suspen-
sion of 6-chloropurine (1.90 g, 12.0 mmol) and triphenyl-
phosphine (4.00 mg, 15.0 mmol) in anhydrous tetra-
hydrofuran (30 mL) was treated with diethylazodicarboxyl-
ate (2.67 g, 15.0 mmol) under argon atmosphere. The
resulting mixture was vigorously stirred for 10 min. Then,
a solution of (^)-2-cyclohexen-1-ol (982 mg, 10.0 mmol)
in tetrahydrofuran (5 mL) was added in one portion. The
reaction mixture was stirred at room temperature for 2 h.
The solvent was evaporated and the residue was adsorbed on
silica gel and puri®ed by column chromatography using
hexane±EtOAc (4:1) as eluant to afford 641 mg (28%
yield) of pure compound 33 as a white solid: mp 1348C;
1H NMR (CDCl3) d 1.60±2.40 (m, 6H, H-40, H-50, H-60),
5.33 (m, 1H, H-10), 5.82 (m, 1H, H-20), 6.28 (s, 1H, H-30),
8.18 (s, 1H, H-8), 8.73 (s, 1H, H-2); 13C NMR (CDCl3) d
18.8 (C-50), 24.5 (C-60), 29.6 (C-40), 50.3 (C-10), 123.4
(C-30), 131.9 (C-5),134.9 (C-20), 144.1 (C-8), 150.7 (C-4),
151.31 (C-6), 151.5 (C-2).
NMR (500 MHz, CDCl3) d 1.35 (s, 3H, CH3), 1.47 (s, 3H,
CH3), 4.30 (m, 2H, H-60), 4.64 (d, Jˆ5.7 Hz, 1H, H-50), 4.66
(s, 2H, OCH2Ph), 5.24 (d, Jˆ5.5 Hz, 1H, H-40), 5.96 (s, 1H,
H-10), 6.04 (s, 1H, H-20), 7.34 (m, 5H, aromatic protons),
8.11 (s, 1H, H-8), 8.90 (s, 1H, H-2); 13C NMR (125 MHz,
CDCl3) d 27.0 (CH3), 27.1 (CH3), 66.2 (C-10), 66.6 (C-60),
72.1 (OCH2Ph), 83.0 (C-40)p, 83.5 (C-50)p, 112.6 (C(CH3)2),
121.2 (C-20), 127.4 (Ph), 127.6 (Ph), 128.1 (Ph), 137.3 (Ph),
146.1 (C-8), 151.2 (C-30), 152.2 (C-2). pSignals assignment
may be interchanged.
(2)-9-[(1R,4R,5S)-3-(Benzyloxy)methyl-4,5-dihydroxy-
cyclopent-2-en-1-yl]-6-chloropurine (37). A solution of 35
(400 mg) in 60% acetic acid (5 mL) was stirred for 24 h at
508C. The solvent was evaporated under vacuum and the
residue was puri®ed by column chromatography using
hexane±ethyl acetate (1:4) as eluant to yield 173 mg of 37
(40% yield, two steps from 16) as a colorless oil:
[a]2D4ˆ232.68 (c 0.68, CHCl3); UV (MeOH) lmaxˆ266 nm;
1H NMR (CDCl3) d 3.21 (br s, 1H, ±OH), 4.32 (m, 3H,
H-50, H-60a,b), 4.63 (s, 2H, OCH2Ph), 4.83 (d, Jˆ5.1 Hz,
1H, H-40), 5.56 (distorted t, Jˆ2.2, 1.5 Hz 1H, H-10), 6.06
(d, Jˆ1.5 Hz, 1H, H-20), 7.36 (m, 5H, Ph), 8.10 (s, 1H, H-8),
(^)-2-(6-Chloropurin-9-yl-7-oxabicyclo[4.1.0]heptane
(34). To a solution of compound 33 (200 mg, 0.85 mmol) in
methylene chloride (6 mL) was added dropwise a solution
of 80% m-chloroperbenzoic acid (588 mg, 1.70 mmol) in
methylene chloride (5 mL) at 08C. The reaction mixture
was stirred at room temperature for 24 h. The solvent was
evaporated and the residue was puri®ed by column chroma-
tography using hexane±EtOAc (1:1) as eluant to afford
137 mg (69% yield) of pure epoxide 34 as a colorless oil:
1H NMR (CDCl3) d 1.40±2.20 (m, 6H, H-40, H-50, H-60),
3.45 (m, 2H, H-20, H-30), 5.13 (m, 1H, H-10), 8.41 (s, 1H,
13
8.74 (s, 1H, H-2); C NMR (CDCl3) d 66.8 (C-10), 67.4
(C-60), 73.4 (OCH2Ph), 73.7 (C-40), 77.4 (C-50), 124.6 (C-
20), 127.9 (Ph), 128.1 (Ph), 128.6 (Ph), 143.4 (C-8), 147.8
(C-30), 151.8 (C-2); FAB MS (m/z, relative intensity) 373
([M1H]1, 100), 339 (17), 245 (16), 201 (14), 155 (94);
HRMS (FAB) Calcd for C18H18ClN4O3 373.1067, found
373.1073.
13
H-8), 8.73 (s, 1H, H-2); C NMR (CDCl3) d 20.2 (C-50),
(1R,2S,3S,4S,5R)-(2)-1-Benzyloxymethyl-4-(6-chloro-
purin-9-yl)-6-oxa-bicyclo[3.1.0]hexane-2,3-diol (38);
22.2 (C-60), 26.4 (C-40), 52.3 (C-10), 53.2 (C-20)p, 54.7

M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
4647
(1S,2S,3S,4S,5S)-(2)-1-benzyloxymethyl-4-(6-chloro-
purin-9-yl)-6-oxa-bicyclo[3.1.0]hexane-2,3-diol (39). To a
solution of compound 37 (167 mg, 0.45 mmol) in methylene
chloride (6 mL) was added dropwise a solution of 80% m-
chloroperbenzoic acid (116 mg, 0.54 mmol) in methylene
chloride (5 mL) at 08C. The reaction mixture was stirred
at room temperature for 10 days. The solvent was evapo-
rated and the residue was puri®ed by column chromato-
graphy (silica gel) eluting with hexane±EtOAc (2:3) to
produce 57 mg of pure epoxy alcohol 38 as a white solid
and 60 mg of pure epoxy alcohol 39 as a white solid (69%
overall yield). Compound 38: mp 53±548C, [a]2D4ˆ225.68
(c 0.89, CHCl3); UV (MeOH); lmaxˆ266 nm; IR (KBr,
cm21) 3270, 2952, 2867, 2367, 2339, 1719, 1605, 1569,
(1S,2S,3S,4S,5S)-(2)-4-(6-Amino-purin-9-yl)-1-benzyl-
oxymethyl-6-oxa-bicyclo[3.1.0]hexane-2,3-diol (41). Com-
pound 39 (50 mg, 0.13 mmol) was treated with methanolic
ammonia (2 mL, saturated at 2788C) and heated in sealed
tube at 708C for 2 h. The mixture was cooled to room
temperature and the solvent was evaporated. The residue
was puri®ed by column chromatography (silica gel) using
methylene chloride: methanol (95:5) as eluant to afford
30 mg (63% yield) of pure 41 as a white solid: mp 177±
1788C; [a]2D4ˆ254.38 (c 0.19, CH3OH); UV (MeOH)
Jˆ11.8 Hz, 1H, BnOCHaH), 3.83 (br s, 1H, H-50), 4.23
(dd, Jˆ7.7, 5.4, Hz 1H, H-30), 4.32 (d, Jˆ11.8 Hz, 1H,
BnOCHHb), 4.35 (d, Jˆ5.1 Hz, 1H, H-20), 4.78 (mAB,
2H, PhCH2O), 5.00 (d, Jˆ7.6 Hz, 1H, H-40), 7.33 (m, 5H,
aromatic protons), 8.21 (s, 1H, H-8), 8.27 (s, 1H, H-2); 13C
NMR (125 MHz, CD3OD) d 60.5 (C-50), 61.7 (C-40), 66.8
(C-10), 67.6 (BnOCH2), 70.0 (C-20), 74.5 (OCH2Ph), 75.8
(C-30), 120.0 (C-5), 128.8 (Ph), 128.9 (Ph), 129.2 (Ph),
139.4 (Ph), 140.6 (C-8), 151.5 (C-4), 153.9 (C-2), 157.4
(C-6); HRMS (FAB) Calcd for C18H20N5O4 370.1515,
found 370.1513.
1
lmaxˆ260 nm; H NMR (500 MHz, CD3OD) d 3.57 (d,
1
1412, 1341, 1113, 949, 849; H NMR (500 MHz, CDCl3)
d 3.76 (s, 1H, H-50), 4.02 (mAB, 2H, BnOCH2), 4.15 (d,
Jˆ6.8 Hz, 1H, H-30), 4.65 (mAB, 2H, PhCH2O), 4.95 (d,
Jˆ7.0 Hz, 1H, H-20), 5.06 (s, 1H, H-40), 7.33 (m, 5H, Ph),
8.20 (s, 1H, H-8), 8.65 (s, 1H, H-2); 13C NMR (125 MHz,
CDCl3) d 59.2 (C-50), 62.0 (C-40), 66.9 (BnOCH2), 69.9
(C-10), 71.4 (C-20), 73.9 (PhCH2O), 75.8 (C-30), 127.0
(Ph), 128.2 (Ph), 128.6 (Ph), 129.8 (C-5), 137.2 (Ph),
144.2 (C-8), 151.2 (C-6), 151.8 (C-4), 152.1 (C-2); FAB
MS (m/z, relative intensity) 389 ([M1H]1, 100), 355 (18),
155 (30). Compound 39: mp 63±648C, [a]2D4ˆ226.98 (c
(1R,2S,3S,4S,5R)-(2)-4-(6-Amino-purin-9-yl)-1-hydroxy-
methyl-6-oxa-bicyclo[3.1.0]hexane-2,3-diol (Neplanocin
C, 4). A solution of 40 (22 mg, 0.06 mmol) in methanol
(5 mL) in the presence of 5% palladium on charcoal
(5 mg) was treated with hydrogen at 3 atm. The reaction
was stirred at room temperature for 4 h. The mixture was
®ltered off and the solvent was evaporated. The residue was
puri®ed by column chromatography (silica gel) employing
CH2Cl2±MeOH (4:1) as eluant to produce 14 mg (88%
yield) of pure 4 as a white solid: mp.2708C (lit.7e mp
222±2268C, decomp.); [a]2D4ˆ241.58 (c 0.21, water), lit.7e
[a]2D4ˆ243.6 (c 0.6, water); UV (MeOH) lmaxˆ262 nm; 1H
NMR (500 MHz, DMSO-d6) d 3.60 (d, Jˆ12.5 Hz, 1H,
HOCHaH±), 3.62 (s, 1H, H-50), 3.96±4.00 (m, 2H,
HOCHHb, H-30), 4.64 (d, Jˆ7.3 Hz, 1H, H-20), 4.83 (s,
1H, H-40), 7.23 (s, 2H, NH2), 8.09 (s, 1H, H-8), 8.14 (s,
1.19, CHCl3); UV (MeOH) lmaxˆ266 nm; IR (KBr, cm21
)
3259, 2924, 2852, 2368, 2353, 1754, 1598, 1555, 1405,
1
1
1341, 1120, 963, 707; H NMR (500 MHz, CDCl3) d H
NMR (500 MHz, CDCl3) d 3.80 (d, Jˆ11.6 Hz, 1H,
BnOCHaH), 3.95 (br s, 1H, H-50), 4.18 (t, Jˆ5.9 Hz, 1H,
H-30), 4.21 (d, Jˆ11.6 Hz, 1H, BnOCHHb), 4.50 (d,
Jˆ5.0 Hz, 1H, H-20), 4.63 (d, Jˆ11.8 Hz, 1H, OCHaHPh),
4.67 (d, Jˆ11.8 Hz, 1H, OCHHbPh), 5.02 (dd, Jˆ6.6,
1.1 Hz, 1H, H-40), 7.36 (m, 5H, aromatic protons), 8.42 (s,
1H, H-8), 8.75 (s, 1H, H-2); 13C NMR (125 MHz, CDCl3) d
58.8 (C-50), 62.3 (C-40), 65.9 (C-10), 66.2 (BnOCH2), 69.3
(C-20), 73.8 (OCH2Ph), 75.1 (C-30), 127.9 (Ph), 128.1 (Ph),
128.6 (Ph), 130.0 (C-5), 137.3 (Ph), 143.4 (C-8), 151.0
(C-2); HRMS (FAB) Calcd for C18H18ClN4O4 389.1017,
found 389.1008.
13
1H, H-2); C NMR (125 MHz, DMSO-d6) d 57.5 (C-40),
58.6 (HOCH2±), 60.3 (C-50), 69.3 (C-20), 70.5 (C-10), 75.0
(C-30), 118.8 (C-5), 139.1 (C-8), 149.1 (C-4), 152.5 (C-2),
156.0 (C-6); HRMS (FAB) Calcd for C11H14N5O4 (MH1)
280.1046, found 280.1057.
(1R,2S,3S,4S,5R)-(2)-4-(6-Amino-purin-9-yl)-1-benzyl-
oxymethyl-6-oxa-bicyclo[3.1.0]hexane-2,3-diol (40). Com-
pound 38 (50 mg, 0.13 mmol) was treated with methanolic
ammonia (2 mL, saturated at 2788C) and heated in 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
CH2Cl2±methanol (9:1) as eluant to afford 22 mg (75%
yield) of pure 40 as a white solid: mp 77±788C; [a]2D4ˆ
(1S,2S,3S,4S,5S)-(2)-4-(6-Aminopurin-9-yl)-1-hydroxy-
methyl-6-oxa-bicyclo[3.1.0]hexane-2,3-diol (42). A solu-
tion of 41 (22 mg, 0.06 mmol) in methanol (5 mL) in the
presence of 5% palladium on charcoal (5 mg) was treated
with hydrogen at 3 atm. The reaction was stirred at room
temperature for 4 h. The mixture was ®ltered off and the
solvent was evaporated. The residue was puri®ed by column
chromatography (silica gel) employing CH2Cl2±MeOH
(4:1) as eluant to give 12 mg (72% yield) of pure 42 as a
white solid: mp.2708C, [a]2D4ˆ288.08 (c 0.13, water); UV
1
229.98 (c 0.69, CH3OH); UV (MeOH) lmaxˆ260 nm; H
NMR (500 MHz, CD3OD) d 3.74 (s, 1H, H-50), 3.82 (d,
Jˆ11.7 Hz, 1H, BnOCHaH), 4.11 (d, Jˆ11.7 Hz, 1H,
BnOCHHb), 4.14 (d, Jˆ6.9 Hz, 1H, H-30), 4.63 (mAB,
2H, PhCH2O), 4.85 (d, Jˆ7.3 Hz, 1H, H-20), 4.93 (s, 1H,
H-40), 7.27 (m, 5H, Ph), 8.09 (s, 1H, H-8), 8.13 (s, 1H, H-2);
13C NMR (125 MHz, CD3OD) d 60.6 (C-50), 62.9 (C-40),
67.7 (BnOCH2), 70.5 (C-10), 72.0 (C-20), 74.6 (OCH2Ph),
76.7 (C-30), 120.3 (C-5), 128.8 (Ph), 128.8 (Ph), 129.4
(Ph), 139.4 (Ph), 141.3 (C-8), 150.6 (C-4), 157.3 (C-6);
HRMS (FAB) Calcd for C18H20N5O4 370.1515, found
370.1513.
1
(MeOH) lmaxˆ262 nm; H NMR (500 MHz, DMSO-d6) d
3.16 (d, Jˆ5.2 Hz, 2H, HOCH2),3.48 (dd, 1H, Jˆ12.6,
5.5 Hz, ±OH), 3.77 (br s, 1H, H-50), 4.10±4.20 (m, 2H,
H-30, H-20), 4.83 (d, Jˆ7.5 Hz, 1H, H-40), 5.08 (d,
Jˆ7.6 Hz, 1H, ±OH), 5.34 (d, Jˆ5.2 Hz, 1H, ±OH), 7.21
(s, 2H, ±NH2), 8.15 (s, 1H, H-8), 8.16 (s, 1H, H-2); 13C
NMR (125 MHz, DMSO-d6)
d
57.3 (C-40), 59.2
(HOCH2), 59.5 (C-50), 66.7 (C-10), 67.9 (C-20), 73.1

4648
M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
(C-30), 119.0 (C-5), 138.5 (C-8), 150.1 (C-4), 152.5 (C-2),
156.0 (C-6); HRMS (FAB) Calcd for C11H14N5O4 (MH1)
280.1046, found 280.1065.
R. J.; Mitsuya, H.; George, C.; Barchi, J. J., Jr. J. Am. Chem. Soc.
1998, 120, 2780±2789. (d) Siddiqui, M. A.; Ford, H., Jr.; George,
C.; Marquez, V. E. Nucleosides Nucleotides 1996, 15, 235±250.
(e) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang,
J.; Wagner, R. W.; Mateucci, M. D. J. Med. Chem. 1996, 39, 3739±
3747. (f) Altmann, K. -H.; Kesselring, R.; Francotte, E.; Rihs, G.
Tetrahedron Lett. 1994, 35, 2331±2334. (g) Altmann, K.-H.;
Imwinkelried, R.; Kesselring, R.; Rihs, G. Tetrahedron Lett.
1994, 35, 7265±7268. (h) Marquez, V. E.; Russ, P.; Alonso, R.;
Siddiqui, M. A.; Shin, K.-J.; George, C.; Nicklaus, M. C.; Dai, F.,
Ford, H., Jr. Nucleosides Nucleotides 1999, 18, 521±530 (i) Jeong,
L. S.; Marquez, V. E.; Yuan, C.-S.; Borchardt, R. T. Heterocycles
1995, 41, 2651±2656. (j) Ezzitouni, A.; Marquez, V. E. J. Chem.
Soc. Perkin Trans 1 1997, 1073±1078. (k) Ezzitouni, A.; Russ, P.;
Marquez, V. E. J. Org. Chem. 1997, 62, 4870±4873. (l) Ezzitouni,
A.; Barchi, J. J., Jr.; Marquez, V. E. J. Chem. Soc. Chem. Commun.
1995, 1345±1346.
Acknowledgements
Â
Thanks are owed to the Fundacion Antorchas, the Agencia
Â
Â
Â
Nacional de Promocion Cientõ®ca y Tecnologica (PICT 06-
00000-00579), the National Research Council of Argentina
(CONICET) and the Universidad de Buenos Aires for ®nan-
cial support. We also thank Dr James A. Kelley, Laboratory
of Medicinal Chemistry, NCI, NIH for accurate mass deter-
mination, and Dr Carlos A. Pujol for antiviral assays.
References
11. 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.
1. (a) Herdewijn, P.; De Clercq, E. In A Textbook of Drug Design
and Development; 2nd ed.; Krogsgaard-Larsen, P., Liljefors, T.,
Madsen, U., Eds.; Harwood Academic Publishers: Amsterdam,
1996; pp 425±459. (b) Gringauz, A. Introduction to Medicinal
Chemistry; Wiley: New York, 1997; pp 115±125.
12. Rodriguez, J. B. Tetrahedron 1999, 55, 2157±2170.
13. Hough, L.; Jones, J. K. N.; Mitchell, D. L. Can. J. Chem. 1958,
36, 1720±1728.
14. Camps, P.; Cardellach, J.; Font, J.; OrtunÄo, R. M.; Ponsati, O.
Tetrahedron 1982, 38, 2395±2402.
2. (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229±9272.
(b) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571±
623. (c) Agrofolio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50,
10611±10670.
15. Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron
Lett. 1976, 17, 3251±3255.
16. Van Hijfte, L.; Little, R. D. J. Org. Chem. 1985, 50, 3940±
3942.
3. (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1±40.
(b) Marquez, V. E. In Advances in Antiviral Drug Design; De
Clercq, E., Ed.; JAI Press Inc.: Greenwich, CT, 1996; Vol. 2,
pp 89±146.
17. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480±2482.
18. Grif®th, W. P.; Ley, S. V.; Whitcomb, G. P.; White, A. D.
J. Chem. Soc. Chem. Commun. 1987, 1625.
4. (a) Van Roey, P.; Taylor, E. W.; Chu, C. K.; Schinazi, R. F.
Ann. N.Y. Acad. Sci. 1990, 616, 29±40. (b) Taylor, E. W.; Van
Roey, P.; Schinazi, R. F.; Chu, C. K.; Antiviral Chem. Chemother.
1990, 1, 163. (c) Van Roey, P.; Salerno, J. M.; Chu, C. K.;
Schinazi, R. F. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 3929.
(d) Van Roey, P.; Salerno, J. M.; Duax, W. L.; Chu, C. K.; Ahn,
M. K.; Schinazi, R. F. J. Am. Chem. Soc. 1988, 110, 2277±2282.
5. (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94,
8205±8212. (b) Saenger, W. Principles of Nucleic Acid Structure;
Springer: New York, 1984; pp 51±104.
19. Cai, S.; Stroud, M. D.; Hakomori, S.; Toyokuni, T. J. Org.
Chem. 1992, 57, 6693±6696.
20. (a) Bestmann, H. J.; Roth, D. Angew. Chem. Int. Ed. Engl.
1990, 29, 99±100. (b) Hill, J. M.; Hutchinson, E. J.; Le Grand,
D. M.; Roberts, S. M.; Thorpe, A. J.; Turner, N. J. J. Chem. Soc.
Perkin Trans 1 1994, 1483±1487. (c) Shiozaki, M.; Arai, M.;
Kobayashi, Y.; Kasuya, A.; Miyamoto, S.; Furukawa, Y.;
Takayama, T.; Haruyama, H. J. Org. Chem. 1994, 59, 4450±4460.
21. Whitesell, J. K.; Reynolds, D. J. Org. Chem. 1983, 48, 3548±
3551.
6. Koole, L. H.; Neidle, S.; Crawford, M. D.; Krayevski, A. A.;
22. Hembest, H. B.; Wilson, R. A. J. Chem. Soc. 1957, 1958±
1965.
È
Gurskaya, G. V.; Sandstrom, A.; Wu, J.-C.; Tong, W.;
Chattopadhyaya J. Org. Chem. 1991, 56, 6884±6892.
23. (a) Mitsunobu, O. Synthesis 1981, 1±28. (b) Jenny, T. F.;
Previsani, N.; Brenner, S. A. Tetrahedron Lett. 1991, 48, 7029±
7032. (c) Jenny, T. F.; Horlacher, J.; Previsani, N.; Brenner, S. A.
Helv. Chim. Acta 1992, 75, 1944±1954.
7. (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J. Antibiot. 1981, 34, 359±366. (b) Isono, K.
J. Antibiot. 1988, 41, 1711±1739. (c) De Clercq, E. Antimicrob.
Agents Chemother. 1985, 28, 84±89. (d) De Clercq, E.; Bernaerts,
R.; Bregstrom, D. E.; Robins, M. J.; Montgomery, J. A.; Holy, A.
Antimicrob. Agents Chemother. 1986, 29, 482±487. (e) Hayashi,
M.; Yaginuma, S.; Muto, N.; Tsujino, M. Nucleic Acids Res. Symp.
Ser. 1980, 8, s65±s67. (f) Otani, M; Yaginuma, S.; Tsujino, M.;
Muto, N.; Tagata, S. Ger. Pat., 1979, 29 17000; CA, 92, 109108.
8. Kinoshita, K.; Yaginuma, S.; Hayashi, M.; Nakatsu, K. Nucleo-
sides Nucleotides 1985, 4, 661±668.
24. Lewbart, M. L.; Schneider, J. J. J. Org. Chem. 1969, 34, 3505±
3512.
25. van Rijsbergen, R.; Anteunis, M. J. O.; De Bruyn, A.
J. Carbohydr. Chem. 1983, 2, 395±404.
26. Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623±1626.
27. Gallo-Rodriguez, C.; Ji, X.-D.; Melman, N.; Siegman, B.;
Sanders, L. H.; Orlina, J.; Fisher, B.; Pu, Q.; van Galen, P. J. M.;
Stiles, G.; Jacobson, K. A. J. Med. Chem. 1994, 37, 636±646.
28. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery,
J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam,
J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.;
Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson,
9. Comin, M. J.; Pujol, C. A.; Damonte, E. B.; Rodriguez, J. B.
Nucleosides Nucleotides 1999, 18, 2219±2231.
10. (a) Rodriguez, J. B.; Marquez, V. E.; Nicklaus, M. C.; Barchi,
J. J., Jr., Tetrahedron Lett. 1993, 34, 6233±6236. (b) Rodriguez, J.
B.; Marquez, V. E.; Nicklaus, M. C.; Mitsuya, H.; Barchi, J. J., Jr.,
J. Med. Chem. 1994, 37, 3389±3399. (c) Marquez, V. E.;
Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford, H., Jr.; Feldman,

M. J. Comin, J. B. Rodriguez / Tetrahedron 56 (2000) 4639±4649
4649
G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski,
J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong,
M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98, Revision A.6, Gaussian, Inc.:
Pittsburgh, PA, 1998.
29. Nokami, J.; Matsuura, H.; Takahashi, H.; Yamashita, M.
Synlett 1994, 491±493.