First enantioselective synthesis of (-)-neplanocin F

Article abstract of DOI:10.1016/j.tet.2007.04.094

(-)-Neplanocin F, the natural isomer of a component of the neplanocin family was enantioselectively synthesized starting from d-γ-ribonolactone. The synthetic approach was based on the preparation of a suitable carbocyclic precursor bearing three hydroxyl

Full text of DOI:10.1016/j.tet.2007.04.094

Tetrahedron 63 (2007) 7165–7171
First enantioselective synthesis of (L)-neplanocin F
y
y
*
ꢀ
Sergio Rodriguez, Dolores Edmont, Christophe Mathe and Christian Perigaud
ꢁ
ꢁ
´
Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Universite Montpellier 2, Case Courrier 1705,
´
Place E. Bataillon, 34095 Montpellier cedex 05, France
Received 22 March 2007; revised 25 April 2007; accepted 26 April 2007
Available online 3 May 2007
Abstract—(ꢀ)-Neplanocin F, the natural isomer of a component of the neplanocin family was enantioselectively synthesized starting from
D-g-ribonolactone. The synthetic approach was based on the preparation of a suitable carbocyclic precursor bearing three hydroxyl groups
orthogonally protected. The key steps of the synthesis were the regioselective protection of a secondary allylic alcohol over a homoallylic
one and the coupling of the nucleobase with a triflate intermediate.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(ꢀ)-neplanocin A, were reported including the total syn-
thesis as a racemate5 of (+/ꢀ)-neplanocin F as well as the
enantioselective synthesis of its unnatural (+) enantiomer.6
In order to evaluate the biological properties of such carba-
nucleoside against emerging pathogens, its enantioselective
synthesis was reconsidered. In addition, (ꢀ)-neplanocin F
could be considered as an attractive template giving an
access, through appropriate chemical modifications, to new
series of nucleoside derivatives displaying potential biolog-
ical properties. In this paper, results concerning the optimi-
zation of the enantioselective synthesis of (ꢀ)-neplanocin
F are presented.
The neplanocin derivatives are an important class of natu-
rally occurring carbocyclic nucleosides isolated from
Ampullariella regularis.1 To date, five distinct components
were identified: (ꢀ)-neplanocin A (1), (ꢀ)-neplanocin B
(2), (ꢀ)-neplanocin C (3), (ꢀ)-neplanocin D (4) and
(ꢀ)-neplanocin F (5) (Fig. 1). Among these, (ꢀ)-neplanocin
A received greater attention due to its interesting biological
properties2 and numerous syntheses of neplanocin A3 as well
as its analogues were published.4 Conversely, only two
syntheses of neplanocin F, the allylic rearranged isomer of
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
2. Results and discussion
HO
HO
N
N
N
O
HO
HO
2.1. Retrosynthetic pathway
O
The synthesis of the natural isomer of (ꢀ)-neplanocin F (5)
was envisioned via SN2 coupling of the heterocyclic nucleo-
base with a suitable carbocyclic intermediate bearing appro-
priate protective groups (Fig. 2). Such an intermediate can be
obtained from (4R,5R)-4,5-isopropylidene-2-cyclopente-
none (6). Compound 6 is readily prepared from commer-
cially available D-g-ribonolactone following previously
established procedures.7 The cyclopentenone 6 was exten-
sively used as chiral starting material in organic synthesis.8
Indeed, numerous natural and unnatural products, such as
carbocyclic nucleosides,9 were prepared from this cyclopen-
tenone derivative. For our part, compound 6 seemed to us as
the ideal precursor for the synthesis of the carbocyclic inter-
mediate in which the hydroxyl group at C-5 was free, while
the other hydroxyl groups (at C-1, C-4 and C-6) remained
protected. Introduction of the base and removal of the pro-
tective groups should finally afford (ꢀ)-neplanocin F (5).
HO OH
1
OH
HO OH
3
2
O
NH2
N
N
N
N
N
NH
HO
HO
HO
N
N
HO OH
4
OH
5
Figure 1. Naturally occuring carbocyclic nucleosides from the neplanocin
family.
Keywords: Neplanocin; Carbocyclic nucleosides; Enantioselective synthesis.
* Corresponding author. Tel.: +33 04 67 14 47 76; fax: +33 04 67 04 20 29;
e-mail: cmathe@univ-montp2.fr
y
S.R. and D.E. contributed equally to this work.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.094

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S. Rodriguez et al. / Tetrahedron 63 (2007) 7165–7171
NH2
N
of the benzyl and benzoyl protective groups, the orthogonal
tert-butyldimethylsilyl group was chosen. Thus, treatment
of compound 10 with tert-butyldimethylsilyl triflate and
2,6-lutidine in dry CH2Cl2 at ꢀ78 ꢁC gave 11.13 The struc-
ture of compound 11 was confirmed by 1H NMR and
1H–1H COSY experiments as well as with selective irradia-
tion of protons H-1, H-2, H-4 and H-5.
N
N
6
HO
HO
OPg
1
PgO
N
4
2
5
3
OH
OH
OPg
5
Once the synthesis of the suitable carbocyclic intermediate
bearing appropriate protective groups 11 was achieved,
introduction of the base (6-chloropurine) was attempted
via a Mitsunobu-type reaction (Scheme 2), which was suc-
cessfully employed to provide carbocyclic nucleosides.14
Different reaction conditions (Table 1) were attempted. As
the coupling product was inseparable from the attendant
hydrazine generated from DIAD,15 a silyl group deprotec-
tion of the latter using polymer supported TBAF in THF
was undertaken providing compound 12.
HO
O
O
O
O O
O O
6
Figure 2. Retrosynthetic pathway. Pg¼various protective groups.
2.2. Synthesis
Addition of the carbanion (Scheme 1), generated in situ from
BnOCH2SnBu3 and n-butyllithium in dry THF at ꢀ78 ꢁC, to
compound 6 gave cyclopentenyl alcohol 7 stereoselectively
by an 1,2-addition mechanism. The stereochemistry of 7
may be explained by a nucleophilic attack from the less hin-
dered b-face due to the presence of the isopropylidene
group.10 1H and 13C NMR spectra were in accordance with
the presence of an unique epimer (the stereoisomer result-
ing from a a-nucleophilic attack was not detected). The
alcohol 7 was then protected using benzoyl chloride in pyr-
idine at room temperature. From benzoate 8, the carbocyclic
frame of the natural isomer of (ꢀ)-neplanocn F can be read-
ily obtained following a [3,3]-sigmatropic rearrangement.11
Thus, treatment of the allylic ester 8 with a catalytic amount
of PdCl2[CH3CN]2 and p-benzoquinone in dry THF under
reflux provided the regioisomer 9.12 Cleavage of the aceto-
nide group via treatment with acetic acid at 60 ꢁC gave the
desired diol 10 in good yield. Nevertheless, the benzoate
group of compound 10 has a tendency to migrate on standing
for long time at room temperature and therefore it must be
kept at ꢀ20 ꢁC. At this stage of the synthesis, the selective
protection of the allylic alcohol of 10 was the key step for
the synthesis of the target molecule. Owing to the presence
Cl
N
N
HO
BnO
1) Mitsunobu
conditions
N
N
11
2) supported TBAF
OBz
12
Scheme 2. Reagents and conditions: see Table 1.
However, the Mitsunobu conditions did not give the desired
product with satisfactory yields. The best result (entry 7) was
obtained when DIAD (3 equiv) was added over a mixture of
PPh3 (3 equiv) and 6-chloropurine (3 equiv) in dry THF at
0 ꢁC and under an argon atmosphere. After 30 min, a solution
of 11 in THF was added and the reaction was heated at 55 ꢁC
for 24 h. After work-up and purification by column chroma-
tography, the crude material was dissolved in THF and
treated with polymer supported TBAF in THF for 90 min
to afford after purification compound 12 with 20% yield.
As an alternative attempt, we have tried to activate the homo-
allylic hydroxyl group by means of its triflate in order to
introduce the base via a nucleophilic substitution, however
without success (data not shown). Therefore, at this stage
OBn
OBn
OR
a
c
6
Table 1. Mitsunobu coupling conditions between 11 and 6-chloropurine
BzO
Entry Mitsunobu conditionsa Time and temperature Yield (%)
O O
O O
1
2
3
4
5
6
7
8
A
A
A
24 h at rt
96 h at rt
No coupling
14
14
14
12
19
7 (R= H)
48 h at 50 ꢁC
24 h at 75 ꢁC
24 h at 75 ꢁC
72 h at rt
9
d
b
A
8 (R= Bz)
Ab
B
B
24 h at 55 ꢁC
10 min at 80 ꢁC
20
No coupling
OR
OH
Ac
BnO
BnO
e
OH
OH
Yields of compound 12 after TBDMS group deprotection.
a
Method A: DIAD (3 equiv) was added over the mixture formed by PPh3
(3 equiv), 6-chloropurine (3 equiv) and alcohol 11 (1 equiv) in dry THF,
at 0 ꢁC under argon; Method B: DIAD (3 equiv) added over the mixture
formed by PPh3 (3 equiv) and 6-chloropurine (3 equiv) in THF, at 0 ꢁC
under argon. After 30 min at 0 ꢁC, 11 (1 equiv) in THF was added.
Reaction was carried out in 1,4-dioxane.
OBz
11 (R= TBDMS)
OBz
10
Scheme 1. Reagents and conditions: (a) BnOCH2SnBu3, n-BuLi, THF,
ꢀ78 ꢁC, 74%; (b) BzCl, pyridine, rt, 72%; (c) PdCl2[CH3CN]2, p-benzoqui-
none, THF, 85 ꢁC, 82%; (d) AcOH (50%)/H2O, 60 ꢁC, 80% and (e)
TBDMSOTf, 2,6-lutidine, CH2Cl2, ꢀ78 ꢁC to rt, 78%.
b
c
Microwave was used (1 bar, 40 W). The reaction was performed in
a sealed tube (Pyrex).

S. Rodriguez et al. / Tetrahedron 63 (2007) 7165–7171
7167
of the synthesis, compound 12 seemed not to be the ideal
carbocyclic precursor for the synthesis of (ꢀ)-neplanocin
F. Thus, the synthesis of such a precursor was reconsidered
from compound 9. The modifications envisioned were the
introduction of a benzyl group at C-1 position as well as
the selective protection of the allylic alcohol after acetonide
removal. In this regard, compound 9 (Scheme 3) was treated
with NaOH in methanol giving 13 after purification by
column chromatography.
providing 19 in 75% yield. Finally, compound 19 was fully
deprotected by treatment with boron trichloride in methyl-
ene chloride affording the target molecule (ꢀ)-neplanocin
F (5). The 1H NMR was superimposable with that previously
reported for the racemic product5 as well as for the unnatural
enantiomer.6 The optical rotation value was in agreement
with the one previously reported.18
NH2
NH2
N
N
N
N
N
MOMO
HO
N
BnO
N
O
O
N
BnO
BnO
a
BnO
b
a
b
17
O
O
9
OBn
18
OBn
19
OH
OBn
13
14
c
c
NH2
N
N
N
OMOM
OH
BnO
BnO
HO
HO
d
N
OR
OH
OBn
OBn
15
OH
16 (R= H)
5
e
17 (R= Tf)
Scheme 4. Reagents and conditions: (a) K2CO3, 18-crown-6 ether, DMF,
60 ꢁC, 60%; (b) TFA (18%)/CH2Cl2, 75% and (c) (i) BCl3, CH2Cl2,
ꢀ78 ꢁC; (ii) MeOH, ꢀ78 ꢁC, 84% overall yield.
Scheme 3. Reagents and conditions: (a) NaOH (1%) in MeOH, rt, 90%;
(b) BnBr, NaH, DMF, rt, 88%; (c) AcOH (60%)/H2O, 50 ꢁC, 93%; (d) (i)
HC(OCH3)3, Ce(NH4)2(NO3)6, CH2Cl2, rt; (ii) DIBAL-H, toluene,
ꢀ78 ꢁC, 60% overall yield and (e) Tf2O, DMAP, CH2Cl2, 0 ꢁC, 97%.
In conclusion, the efficient synthesis of natural isomer (ꢀ)-
neplanocin F (5) was realized from 2,3-O-isopropylidene-D-
1,4-ribonolactone in 15 steps. The synthetic methodology
can give an access, through appropriate functionalizations
to new series of carbanucleosides. Further investigations
are in progress in our laboratory.
Compound 13 was converted into 14 using standard condi-
tions. The cleavage of the acetonide group was accom-
plished by treatment of 14 with acetic acid at 50 ꢁC for
16 h to afford in quantitative yield the diol 15. The selective
protection of the allylic hydroxyl position of the resulting
diol 15 was achieved following a procedure recently re-
ported.6 Such an approach is based upon the preparation of
an orthoester intermediate from the corresponding diol
with trimethyl orthoformate followed by reductive cleavage
with DIBAL-H in methylene chloride at low temperature.
Under these conditions, compound 16 was obtained in
60% yield. The position of the MOM protective group at
the allylic position was confirmed by selective irradiation
of the protons of the cyclopentene ring. Mitsunobu-type
reaction was envisioned between the precursor 16 and
6-chloropurine but gave the coupling product with low
yields (z30%). Our data are not in agreement with those
previously reported in the lit. 6. To overcome these low
yields in the coupling reaction, we attempted a nucleophilic
displacement on an activated sugar precursor with the
heterocyclic base. Thus, compound 16 was treated with
Tf2O16 and DMAP in dry CH2Cl2 to afford 17 in good yield
after purification by silica gel column chromatography.
Thereafter, treatment of 17 (Scheme 4) with K2CO3, adenine
and a catalytic amount of 18-crown-6 ether in dry DMF17
under an argon atmosphere at 60 ꢁC for 3 h afforded the
N-9 alkylated compound 18 without a trace of the undesired
3. Experimental
3.1. General
All moisture-sensitive reactions were carried out in oven-
dried glassware under an argon atmosphere. Unless other-
wise noted, chemicals were commercially available and
used without further purification. Solvents were distilled
before use. Tetrahydrofuran was distilled from sodium/
benzophenone, methylene chloride was distilled from phos-
phorous pentoxide. Anhydrous N,N-dimethylformamide and
pyridine were used as supplied from Fluka.
Nuclear magnetic resonance spectra were recorded using
a Bruker AC-300 MHz or Bruker AC-400 MHz spectrome-
ter. Chemicals shifts are reported in parts per million relative
to TMS as an internal standard. The 1H NMR spectra are ref-
erenced with respect to CDCl3 at 7.26 ppm or to DMSO-d6
at 2.50 ppm. 13C NMR spectra were fully decoupled and ref-
erenced to CDCl3 at 77.0 ppm or to DMSO-d6 at 39.5 ppm.
Splitting patterns are designated as follows: s, singlet; d,
doublet; q, quadruplet; dd, doublet of doublets and m, mul-
tiplet. Melting points were taken on a B€uchi-545 capillary
melting point apparatus and are uncorrected. Column chro-
matography was carried out on Silica Gel 60 (Merck, Art.
9385). Reverse phase (C18) purification was performed by
1
N-7 isomer as by-product, as established by H NMR and
UV spectra. From compound 18, the deprotection of MOM
ether group can give access to subsequent functionalizations
of this allylic position. The selective MOM group removal6
was carried out with diluted TFA in methylene chloride

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S. Rodriguez et al. / Tetrahedron 63 (2007) 7165–7171
Silica Merck LiChroprep RP-18. UV spectra were recorded
on an Uvikon 931 (Kontron) spectrophotometer. Mass spec-
tra were recorded on a JEOL SX 102 in FAB positive-ion or
negative-ion mode. The matrix was a mixture (50:50, v/v) of
glycerol and thioglycerol (GT). Specific rotations were mea-
sured on a Perkin Elmer model 341 spectropolarimeter (path
length 1 cm). Elemental analyses were performed by The
Service de Microanalyses du CNRS, Division de Vernaison
(France).
Calcd for C23H24O5: C, 72.61; H, 6.36. Found: C, 72.74;
H, 6.63.
3.1.3. (L)-(1R,4S,5S)-1-Benzoyloxy-3-[(benzyloxy)-
methyl]-4,5-(isopropylidenedioxy)-2-cyclopentene (9).
A
mixture of 8 (6.88 g, 18.1 mmol) under argon,
PdCl2[CH3CN]2 (470 mg, 1.81 mmol) and p-benzoquinone
(1.55 g, 14.5 mmol) in freshly distilled THF (335 mL) was
heated under reflux for 24 h. The reaction mixture was
cooled to room temperature and filtered through a Celite
pad. The solvent was concentrated to dryness under reduced
pressure. The residue was purified by column chromato-
graphy using petroleum ether/diethyl ether (6:4, v/v) to
give 9 as a colourless syrup (5.65 g, 82% yield); [a]D20
ꢀ9.9 (c 1.0, EtOHabs); 1H NMR (CDCl3, 300 MHz)
d 7.98–8.04 (m, 2H, ArH), 7.19–7.53 (m, 8H, ArH), 5.86
(d, 1H, J¼1.64 Hz, H2), 5.54 (dd, 1H, J¼2.0, 3.5 Hz, H1),
4.94–5.01 (m, 2H, H4, H5), 4.54 (s, 2H, CH2), 4.10–4.24
(m, 2H, CH2), 1.29 (s, 3H, CH3), 1.28 (s, 3H, CH3); 13C
NMR (CDCl3, 75 MHz) d 166.06 (C]O), 146.0 (Cq),
137.9 (Cq), 132.9 (ArH), 130.0 (Cq), 129.8 (ArHꢂ2),
128.4 (ArHꢂ2), 128.3 (ArHꢂ2), 127.7 (ArHꢂ2), 127.7
(ArH), 126.4 (C2), 113.0 (Cq), 83.0 (C4), 77.4 (C5), 75.8
(C1), 73.0 (CH2), 66.6 (CH2), 27.4 (CH3), 26.8 (CH3);
FABMS (>0) m/z 381 [M+H]+. Anal. Calcd for C23H24O5:
C, 72.61; H, 6.36. Found: C, 72.47; H, 6.51.
3.1.1. (L)-(1S,4R,5R)-1-[(Benzyloxy)methyl]-4,5-(iso-
propylidenedioxy)-3-cyclopenten-1-ol (7). To a stirred so-
lution of Bu3SnCH2OBn19 (64 g, 2 equiv) in freshly distilled
THF (470 mL) was added n-butyllithium (73 mL, 1.5 equiv)
at ꢀ78 ꢁC and the resulting solution was stirred for 20 min.
To this mixture was added 6 (11.91 g, 77.337 mmol) in
freshly distilled THF (234 mL) at ꢀ78 ꢁC and the mixture
was stirred for 1 h and 20 min. The reaction was quenched
with a saturated ammonium chloride solution (100 mL),
then diluted with diethyl ether (700 mL), washed succes-
sively with water (300 mL), brine (300 mL), dried
(Na2SO4) and concentrated to dryness under reduced pres-
sure. The residue was purified by column chromatography
using petroleum ether/ethyl acetate (8:2–6:4, v/v) to give 7
as a colourless syrup (15.84 g, 74% yield): Rf (petroleum
ether/ethyl acetate; 8:2 v/v) 0.26; [a]2D0 ꢀ95 (c 1.0, EtOHabs);
1H NMR (CDCl3, 300 MHz) d 7.29–7.37 (m, 5H, ArH), 5.95
(dd, 1H, J¼1.7, 7.5 Hz, H3), 5.79 (d, 1H, J¼7.25 Hz, H2),
5.07 (dd, 1H, J¼1.65, 5.45 Hz, H4), 4.59 (s, 2H, CH2),
4.54 (d, 1H, J¼5.45 Hz, H5), 3.59 (d, 1H, J¼9.46 Hz,
CH2O), 3.47 (d, 1H, J¼9.47 Hz, CH2O), 3.21 (br s, 1H,
OH), 1.47 (s, 3H, CH3), 1.42 (s, 3H, CH3); 13C NMR
(CDCl3, 75 MHz) d 137.97 (Cq), 136.96 (C3), 132.96
(C2), 128.39 (ArHꢂ2), 127.69 (ArHꢂ2), 127.60 (ArH),
112.60 (Cq), 83.87 (C4), 81.71 (Cq), 80.42 (C5), 73.97
(CH2), 73.60 (CH2), 27.72 (CH3), 26.60 (CH3); FABMS
(<0) m/z 275 [MꢀH]ꢀ. Anal. Calcd for C16H20O4: C,
69.54; H, 7.30. Found: C, 69.24; H, 7.26.
3.1.4. (L)-(1R,4S,5S)-1-Benzoyloxy-3-[(benzyloxy)-
methyl]-2-cyclopentene-4,5-diol (10). A solution of 9
(8.25 g, 21.71 mmol) in acetic acid (163 mL) and water
(43 mL) was heated at 50 ꢁC during 3 h. The solvent was
evaporated and the residue was partitioned between
CH2Cl2 (150 mL) and aqueous NaHCO3 (50 mL). The
organic layer was washed with brine, dried (Na2SO4) and
concentrated to dryness. The residue was purified by column
chromatography using diethyl ether to give 10 as a colourless
syrup (5.89 g, 80% yield): Rf (diethyl ether) 0.32; [a]2D0 ꢀ52
1
(c 1.0, EtOHabs); H NMR (CDCl3, 300 MHz) d 8.00–8.24
(m, 2H, ArH), 7.20–7.50 (m, 8H, ArH), 6.00–6.10 (m, 1H,
H2), 5.70–5.79 (m, 1H, H1), 4.52 (s, 2H, CH2), 4.41–4.49
(m, 1H, H4), 4.35–4.41 (m, 1H, H5), 4.20 (s, 2H, CH2),
2.66 (br s, 1H, OH), 2.55 (br s, 1H, OH); 13C NMR
(CDCl3, 75 MHz) d 166.06 (C]O), 148.03 (Cq), 137.65
(Cq), 133.26 (ArH), 129.82 (Cq), 128.53 (ArHꢂ2), 128.45
(ArHꢂ2), 127.93 (ArHꢂ2), 127.82 (ArHꢂ2), 126.73 (C2),
76.23 (C1), 73.82 (C4), 73.23 (CH2), 71.09 (C5), 67.21
(CH2); FABMS (>0) m/z 341 [M+H]+, 93 (100%). Anal.
Calcd for C20H20O5: C, 70.58; H, 5.92. Found: C, 70.25;
H, 5.99.
3.1.2. (L)-(1S,4R,5R)-1-Benzoyloxy-1-[(benzyloxy)-
methyl]-4,5-(isopropylidenedioxy)-3-cyclopentene (8).
To a stirred solution of 7 (7.4 g, 27 mmol) in dry pyridine
(90 mL) was added dropwise benzoyl chloride (4.7 mL,
40.5 mmol) and the resulting solution was stirred overnight
at room temperature. The solvent was removed and the
residue was partitioned between CH2Cl2 (100 mL) and
water (100 mL). The organic layer was washed with brine
(100 mL), dried (Na2SO4), filtered and concentrated. The
residue was purified by column chromatography using di-
chloromethane/ethyl acetate (99:1, v/v) to give 8 as a colour-
less syrup (7.38 g, 72% yield): Rf (dichloromethane) 0.63;
3.1.5. (L)-(1R,4S,5S)-1-Benzoyloxy-3-[(benzyloxy)-
methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclo-
penten-5-ol (11). A magnetically stirred solution of 10
(2.29 g, 6.74 mmol) in dry CH2Cl2 (49 mL) was cooled to
ꢀ78 ꢁC and a solution containing freshly distilled 2,6-
lutidine (1.7 mL, 14.57 mmol) and tert-butyldimethylsilyl-
trifluoromethane sulfonate (1.6 mL, 6.95 mmol) in dry
CH2Cl2 (11 mL) was added slowly dropwise over a
15-min period. After 1 h at ꢀ78 ꢁC, the reaction mixture
was allowed to reach room temperature and stirred continu-
ally overnight. The reaction was quenched with absolute
EtOH (11 mL). The solvent was evaporated and the residue
was partitioned between CH2Cl2 (100 mL) and water
1
[a]2D0 ꢀ58 (c 1.0, CHCl3); H NMR (CDCl3, 300 MHz)
d 7.95–7.98 (m, 2H, ArH), 7.45–7.50 (m, 1H, ArH), 7.33–
7.38 (m, 2H, ArH), 7.16–7.26 (m, 5H, ArH), 6.12 (d, 1H,
J¼6.0 Hz, H2), 6.02 (dd, 1H, J¼1.5, 6.0 Hz, H3), 5.04 (d,
1H, J¼0.86, 5.5 Hz, H4), 4.85 (d, 1H, J¼5.5 Hz, H5), 4.45
(s, 2H, CH2), 3.90 (q, 2H, J¼9.5 Hz, CH2), 1.27 (s, 3H,
CH3), 1.24 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz)
d 164.5 (C]O), 136.7 (Cq), 133.6 (C3), 132.6 (C2), 131.7
(ArH), 129.7 (Cq), 128.7 (ArHꢂ2), 127.3 (ArHꢂ2), 127.1
(ArHꢂ2), 126.6 (ArHꢂ2), 126.4 (ArH), 111.2 (Cq), 88.2
(Cq), 82.9 (C4), 80.0 (C5), 72.5 (CH2), 70.5 (CH2), 26.6
(CH3), 26.1 (CH3); FABMS (>0) m/z 381 [M+H]+. Anal.

S. Rodriguez et al. / Tetrahedron 63 (2007) 7165–7171
7169
(50 mL). The organic layer was washed with brine, dried
(Na2SO4) and concentrated to dryness. The residue was
purified by column chromatography using petroleum ether/
diethyl ether (1:1, v/v) to give 11 as a colourless syrup
(2.392 g, 78% yield): Rf (petroleum ether/diethyl ether;
(300 mL). The organic layer was washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. The
residue was purified by column chromatography using petro-
leum ether/ethyl acetate (1:1, v/v) to give 13 as an oil
(4.35 g, 90% yield): Rf (petroleum ether/ethyl acetate; 1:1,
1
1
1:1, v/v) 0.52; [a]2D0 ꢀ51.4 (c 1.05, EtOHabs); H NMR
v/v) 0.31; [a]D20 ꢀ41.4 (c 1.0, EtOHabs); H NMR (CDCl3,
(CDCl3, 300 MHz) d 8.09 (d, 2H, J¼8.35 Hz, ArH), 7.10–
7.88 (m, 8H, ArH), 5.88 (d, 1H, J¼1.43 Hz, H2), 5.48 (dd,
1H, J¼2.06, 4.29 Hz, H1), 4.44 (d, 1H, J¼5.22 Hz, H4),
4.39 (s, 2H, CH2), 4.20–4.31 (m, 1H, H5), 4.00 (s, 2H,
CH2), 2.58 (br s, 1H, OH), 0.76 (s, 9H, 3ꢂCH3), 0.00 (s,
3H, SiCH3), ꢀ0.012 (s, 3H, SiCH3); 13C NMR (CDCl3,
75 MHz) d 166.05 (C]O), 147.17 (Cq), 137.75 (Cq),
132.99 (ArHꢂ2), 130.07 (Cq), 129.77 (ArHꢂ2), 128.46
(ArHꢂ2), 128.30 (ArHꢂ2), 127.84 (ArHꢂ2), 127.01 (C2),
76.17 (C1), 73.67 (C4), 72.95 (CH2), 71.07 (C5), 66.54
(CH2), 25.72 (3ꢂCH3), 18.12 (Cq), ꢀ4.76 (SiCH3), ꢀ4.90
(SiCH3); FABMS (>0) m/z 455 [M+H]+, 93 (100%). Anal.
Calcd for C26H34O5Si: C, 68.69; H, 7.54. Found: C, 68.48;
H, 7.79.
300 MHz) d 7.28–7.43 (m, 5H, ArH), 5.83 (s, 1H, H2),
4.99 (d, 1H, J¼5.5 Hz, H4), 4.79 (t, 1H, J¼5.5 Hz, H5),
4.58 (s, 3H, H1, CH2), 4.18 (s, 2H, CH2), 2.72 (br s, 1H,
OH), 1.44 (s, 3H, CH3), 1.42 (s, 3H, CH3); 13C NMR
(CDCl3, 75 MHz) d 141.5 (Cq), 136.9 (Cq), 131.4 (C2),
128.4 (ArHꢂ2), 127.7 (ArHꢂ2), 127.6 (ArH), 111.5 (Cq),
82.9 (C4), 77.7 (C5), 73.3 (C1), 72.9 (CH2), 66.2 (CH2),
27.6 (CH3), 26.6 (CH3); FABMS (>0) m/z 277 [M+H]+;
Anal. Calcd for C16H20O4: C, 69.55; H, 7.30. Found: C,
69.19; H, 7.45.
3.1.8. (L)-(1R,4S,5S)-1-Benzyloxy-3-[(benzyloxy)-
methyl]-4,5-(isopropylidenedioxy)-2-cyclopentene (14).
To a stirred suspension of NaH (66 mg, 1.51 mmol, mineral
oil dispersion, 55–65%) in dry DMF (1.1 mL) was added,
at 0 ꢁC and under argon, 13 (300 mg, 1.08 mmol) in dry
DMF (1 mL). The resulting yellow solution was stirred at
0 ꢁC for 5 min and benzyl bromide (180 mL, 1.51 mmol)
was added dropwise. After 1 h at room temperature, the
reaction was cooled down at 0 ꢁC and quenched by addition
of an aqueous saturated NH4Cl solution (2 mL). The mixture
was extracted with CH2Cl2 (3ꢂ20 mL). The combined
organic layers were washed with brine (5ꢂ20 mL), dried
(Na2SO4) and concentrated to dryness under reduced pres-
sure. The residue was purified by column chromatography
using petroleum ether/ethyl acetate (4:1, v/v) to give 14 as
a colourless oil (350 mg, 88% yield): Rf (petroleum ether/
ethyl acetate; 4:1, v/v) 0.26; [a]2D0 +2.0 (c 1, CHCl3), lit.6
3.1.6. (L)-9-[(1R,2S,5R)-2-Benzoyloxy-4-(benzyloxy)-
methyl-5-hydroxy-cyclopent-3-en-1-yl]-6-chloropurine
(12). To a stirred solution, at 0 ꢁC, of triphenylphosphine
(1.13 g, 4.32 mmol) and 6-chloro-9H-purine (667 mg,
4.32 mmol) under argon in dry THF (25 mL) was added
DIAD (850 mL, 4.32 mmol). The solution was stirred at
room temperature for 30 min and a solution of 11
(656 mg, 1.44 mmol) in dry THF (5 mL) was added drop-
wise. The reaction mixture was stirred at 55 ꢁC overnight.
The solvent was removed under vacuum and the residue
was purified by column chromatography using petroleum
ether/ethyl acetate (2.5:1, v/v) to give the protected 6-chloro-
nucleoside contaminated with hydrazine by-product. The
compound was added to TBAF supported on silica (2.6 g,
2.88 mmol) [1.1 mmol Fꢀ/g of resin] in dry THF (15 mL).
The reaction was stirred at room temperature for 2 h and fil-
tered through a Celite pad. The solvent was removed under
vacuum and the residue was purified by column chromato-
graphy using diethyl ether to give 12 as a white solid
(120 mg, 20% yield from 11): Rf (diethyl ether) 0.43; UV
(EtOH, 96%) lmax¼264.4 nm (3¼8287); [a]2D0 ꢀ187 (c
1
[a]2D4 ꢀ3.8 (c 1.2, CHCl3); H NMR (CDCl3, 300 MHz)
d 7.15–7.31 (m, 10H, 2ꢂArH), 5.72 (d, 1H, J¼1.0 Hz,
H2), 4.83 (d, 1H, J¼5.0 Hz, H4), 4.74 (d, 1H, J¼5.0 Hz,
H5), 4.73 (d, 1H, J¼12.0 Hz, OCH2), 4.53 (d, 1H, J¼
12.0 Hz, OCH2), 4.46 (s, 2H, CH2), 4.30 (m, 1H, H1), 4.08
(s, 2H, CH2), 1.37 (s, 3H, CH3), 1.32 (s, 3H, CH3); 13C
NMR (CDCl3, 75 MHz) d 143.1 (Cq), 138.4 (Cq), 138.1
(Cq), 128.84 (C2), 128.39 (ArHꢂ2), 128.05 (ArHꢂ2),
127.70 (ArHꢂ2), 127.66 (ArHꢂ2), 112.4 (Cq), 82.9 (C4),
79.7 (C1), 78.0 (C5), 72.8 (CH2), 71.8 (OCH2), 66.4
(CH2), 27.6 (CH3), 26.8 (CH3).
1
1.9, CHCl3); H NMR (CDCl3, 300 MHz) d 8.60 (s, 1H,
H2), 7.98–8.04 (m, 3H, H8 and ArH), 6.9–7.6 (m, 8H,
ArH), 6.21 (s, 1H, H30), 5.93 (d, 1H, J¼3.5 Hz, H50), 5.60
(d, 1H, J¼5.5 Hz, H20), 4.99 (t, 1H, J¼6.0 Hz, H10), 4.29
(d, 1H, J¼12.0 Hz, CH2), 4.14 (d, 1H, J¼12.0 Hz, CH2),
3.92 (d, 1H, J¼13.0 Hz, CH2), 3.71 (d, 1H, J¼13.0 Hz,
CH2); 13C NMR (CDCl3, 75 MHz) d 166.6 (C]O), 151.9
(C2), 151.5 (Cq), 151.1 (Cq), 145.2 (C8), 144.1 (C30),
141.6 (Cq), 136.6 (Cq), 133.5 (ArH), 129.8 (ArHꢂ2),
129.3 (Cq), 128.5 (Cq), 128.4 (ArHꢂ2), 128.2 (ArHꢂ2),
128.0 (ArHꢂ2), 127.7 (ArH), 75.8 (C10), 75.4 (C50), 73.1
(CH2), 66.8 (C20), 65.9 (CH2); FABMS (>0) m/z 477
[M+H]+.
3.1.9. (L)-(1R,4S,5S)-1-Benzyloxy-3-[(benzyloxy)-
methyl]-2-cyclopentene-4,5-diol (15). A solution of 14
(2.43 g, 6.6 mmol) in acetic acid (18 mL) and water
(12 mL) was heated at 50 ꢁC for 16 h. The solvent was evap-
orated and the residue was partitioned between CH2Cl2
(100 mL) and aqueous NaHCO3 (50 mL). The organic layer
was washed with brine, dried (Na2SO4) and concentrated to
dryness under reduced pressure. The residue was purified by
column chromatography using ethyl acetate/petroleum ether
(2:1, v/v) to give 15 as a white solid (2.01 g, 93% yield): Rf
(ethyl acetate/petroleum ether; 2:1, v/v) 0.46; mp 59–61 ꢁC
(lit. mp 57–58 ꢁC); [a]D20 ꢀ32 (c 1, CHCl3), lit.6 [a]D24 +15.3
(c 1.7, CHCl3); 1H NMR (CDCl3, 300 MHz) d 7.17–7.34 (m,
10H, 2ꢂArH), 5.81 (s, 1H, H2), 4.60 (q, 2H, J¼11.5 Hz,
OCH2), 4.48 (s, 2H, CH2), 4.28 (m, 2H, H1, H4), 4.17 (d,
1H, J¼5.0 Hz, H5), 4.12 (s, 2H, CH2), 2.76 (s, 2H,
2ꢂOH); 13C NMR (CDCl3, 75 MHz) d 147.0 (Cq), 138.0
3.1.7. (L)-(1R,4S,5S)-3-[(Benzyloxy)methyl]-4,5-(isopro-
pylidenedioxy)-2-cyclopenten-1-ol (13). To a solution of 9
(6.66 g, 17.5 mmol) at room temperature in methanol
(85 mL) was added a 1% NaOH solution (350 mL) in meth-
anol and the resulting mixture was stirred for 90 min. The
solvent was removed under vacuum and the residue was
partitioned between ethyl acetate (200 mL) and water

7170
S. Rodriguez et al. / Tetrahedron 63 (2007) 7165–7171
(Cq), 137.6 (Cq), 128.5 (ArHꢂ2), 128.4 (ArHꢂ2), 128.0
(ArHꢂ2), 127.9 (ArHꢂ2), 127.7 (ArHꢂ2), 126.6 (C2),
79.9 (C1), 74.3 (C4), 73.0 (OCH2), 72.1 (CH2), 70.6 (C5),
66.8 (CH2); FABMS (>0) m/z 327 [M+H]+. Anal. Calcd
for C20H22O4: C, 73.60; H, 6.79. Found: C, 73.54; H, 6.82.
4.09 (s, 2H, CH2), 3.31 (s, 3H, CH3); 19F NMR (CDCl3,
282 MHz) d ꢀ75.0 (s, SO2CF3); 13C NMR (CDCl3,
75 MHz) d 142.3 (Cq), 136.6 (Cq), 136.4 (Cq), 127.45
(C2), 126.93 (ArHꢂ2), 126.87 (ArHꢂ2), 126.84 (ArHꢂ2),
126.77 (ArHꢂ2), 117.5 (q, J¼315 Hz, CF3), 95.1
(OCH2O), 84.5 (C5), 76.8 (C4), 75.6 (C1), 72.0 (CH2),
71.7 (OCH2), 65.0 (CH2), 55.0 (CH3); FABMS (>0) m/z
503 [M+H]+.
3.1.10. (L)-(1R,4S,5S)-1-Benzyloxy-3-[(benzyloxy)-
methyl]-4-[(methoxy)methoxy]-cyclopent-2-en-5-ol (16).
A solution of diol 15 (2.01 g, 6.16 mmol) in anhydrous
CH2Cl2 (100 mL) was treated with trimethyl orthoformate
(2.0 mL, 18.5 mmol) in the presence of ceric ammonium
nitrate (236 mg, 0.43 mmol) under argon. The reaction
mixture was stirred at room temperature for 3 h. The solution
was cooled at ꢀ78 ꢁC and a 1.5 M solution of DIBAL-H in
toluene (61.5 mL, 92.3 mmol) was added. The mixture was
stirred for 1 h and then cooled down in an ice bath. After
10 min, the mixture was carefully added to an aqueous
1.0 M HCl solution (100 mL). An aqueous saturated solu-
tion of sodium and potassium tartrate (150 mL) was added
and the phases were separated. The aqueous phase was ex-
tracted with CH2Cl2 (2ꢂ100 mL) and the combined organic
layers were washed with brine (2ꢂ100 mL). The aqueous
phase was extracted again with EtOAc (2ꢂ100 mL) and
the combined organic layers were washed with brine
(2ꢂ100 mL). The combined organic phases were dried
(Na2SO4) and the solvent was removed under reduced pres-
sure. The residue was purified by column chromatography
using diethyl ether/petroleum ether (4:1, v/v) to afford 16
as a solid (1.34 g, 60% yield): Rf (diethyl ether/petroleum
ether; 4:1, v/v) 0.28; [a]2D0 ꢀ66.7 (c 0.93, CHCl3), lit.6
3.1.12. (L)-9-[(1R,2S,5R)-2-Benzyloxy-4-(benzyloxy)-
methyl-5-(methoxy)methoxy-cyclopent-3-en-1-yl]-6-
aminopurine (18). To a solution of 17 (100 mg, 0.20 mmol)
in dry DMF (2 mL) was added successively K2CO3 (88 mg,
0.63 mmol), adenine (62 mg, 0.45 mmol) and 18-crown-6
ether (20 mg, 0.07 mmol). The mixture was heated at
60 ꢁC for 3 h and poured into brine (50 mL) and ethyl ace-
tate (50 mL). The aqueous phase was extracted with ethyl
acetate (3ꢂ50 mL) and the combined organic phases were
washed with brine (5ꢂ50 mL), dried (Na2SO4) and evapo-
rated under reduced pressure. Purification by column chro-
matography using ethyl acetate/methanol (96:4, v/v) gave
18 as a colourless syrup (58 mg, 60% yield): Rf (ethyl ace-
tate/methanol; 9:1 v/v) 0.32; mp 114–116 ꢁC; UV (EtOH,
96%) lmax¼260.0 nm (3¼10,844); [a]2D0 ꢀ21 (c 1.0,
1
CHCl3); H NMR (CDCl3, 300 MHz) d 8.19 (s, 1H, H2),
7.62 (s, 1H, H8), 7.00–7.29 (m, 10H, 2ꢂArH), 6.01 (br s,
3H, H40, NH2), 5.10 (d, 1H, J¼5.5 Hz, H50), 4.96 (d, 1H,
J¼5.5 Hz, H20), 4.64 (t, 1H, J¼6.0 Hz, H10), 4.30–4.6 (m,
6H, 3ꢂCH2), 4.05–4.19 (m, 2H, CH2), 3.01 (s, 3H, CH3);
13C NMR (CDCl3, 75 MHz) d 155.8 (Cq), 152.6 (C2),
149.8 (Cq), 143.1 (C30), 140.8 (C8), 137.9 (Cq), 137.6
(Cq), 128.4 (ArHꢂ2), 128.3 (ArHꢂ2), 128.1 (ArHꢂ2),
127.8 (ArHꢂ2), 127.7 (Cq), 127.6 (ArHꢂ2), 120.3 (Cq),
96.8 (CH2), 82.6 (C50), 82.5 (C20), 72.7 (CH2), 71.8 (CH2),
70.5 (C10), 66.1 (CH2), 55.4 (CH3); FABMS (>0) m/z 488
[M+H]+ (100%). Anal. Calcd for C27H29N5O4: C, 66.51;
H, 6.00; N, 14.36. Found: C, 66.17; H, 6.20; N, 14.38.
1
[a]2D4 +31.4 (c 1.8, CHCl3); H NMR (CDCl3, 300 MHz)
d 7.24–7.29 (m, 10H, 2ꢂArH), 5.89 (s, 1H, H2), 4.76 (d,
1H, J¼6.5 Hz, OCH2O), 4.68 (d, 1H, J¼12.0 Hz, OCH2),
4.62 (d, 1H, J¼6.5 Hz, OCH2O), 4.58 (d, 1H, J¼12.0 Hz,
OCH2), 4.41–4.50 (m, 2H, CH2), 4.30 (d, 1H, J¼5.0 Hz,
H4), 4.14–4.19 (m, 2H, H1, H5), 4.09 (s, 2H, CH2), 3.31
(s, 3H, CH3), 2.90 (br s, 1H, OH); 13C NMR (CDCl3,
75 MHz) d 144.9 (Cq), 138.2 (Cq), 137.9 (Cq), 128.8
(ArH), 128.4 (ArHꢂ3), 127.8 (ArHꢂ3), 127.79 (C2),
127.74 (ArHꢂ3), 96.6 (OCH2O), 79.5 (C1), 78.5 (C4),
72.8 (OCH2), 72.1 (CH2), 71.3 (C5), 66.9 (CH2), 55.8
(CH3); FABMS (<0) m/z 369 [MꢀH]ꢀ. Anal. Calcd for
C22H26O5: C, 71.33; H, 7.07. Found: C, 71.47; H, 7.32.
3.1.13. (L)-9-[(1R,2S,5R)-2-Benzyloxy-4-(benzyloxy)-
methyl-5-hydroxy-cyclopent-3-en-1-yl]-6-aminopurine
(19). To a solution of 18 (84 mg, 0.17 mmol) in CH2Cl2
(3.6 mL) was added dropwise TFA (0.81 mL). The solution
was stirred at room temperature for 48 h, then poured into an
aqueous saturated NaHCO3 solution and extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic layers were
dried (Na2SO4) and evaporated to dryness. Purification by
column chromatography using ethyl acetate/methanol
(96:4, v/v) gave 19 as a white solid (57.6 mg, 75% yield):
Rf (ethyl acetate/methanol, 9:1) 0.36; mp 160–161 ꢁC (lit.
mp 157–158 ꢁC); UV (EtOH, 96%) lmax¼262.0 nm
(3¼17,283); [a]D20 ꢀ30 (c 2.0, DMSO), lit.6 [a]2D4 +42.2 (c
3.1.11. (L)-(1R,4S,5S)-1-Benzyloxy-3-[(benzyloxy)-
methyl]-4-[(methoxy)methoxy]-5-(trifluoro-methanesul-
fonate)-2-cyclopentene (17). To a solution of 16 (500 mg,
1.34 mmol) and DMAP (1.65 g, 13.5 mmol) at 0 ꢁC and
under argon in dry CH2Cl2 (150 mL) was added trifluoro-
methanesulfonic anhydride (680 mL, 4.04 mmol). The
cloudy mixture was stirred at 0 ꢁC for 30 min and poured
into saturated NaHCO3 solution (150 mL). The aqueous
phase was extracted with CH2Cl2 (2ꢂ150 mL) and the com-
bined organic phases were washed with an aqueous saturated
NaHCO3 solution (2ꢂ100 mL), brine (2ꢂ100 mL), dried
(Na2SO4) and evaporated under reduced pressure. Purifica-
tion by column chromatography using diethyl ether/petro-
leum ether (4:1, v/v) gave 17 as a colourless syrup (661 mg,
97% yield): Rf (diethyl ether/petroleum ether; 4:1, v/v)
0.44; [a]2D0 ꢀ47 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) d 7.20–7.30 (m, 10H, 2ꢂArH), 5.86 (m, 1H,
H2), 5.22 (t, 1H, J¼5.0 Hz, H5), 4.51–4.71 (m, 5H, H4,
OCH2, OCH2O), 4.45 (s, 2H, CH2), 4.35 (m, 1H, H1),
1
0.8, CHCl3); H NMR (DMSO-d6, 300 MHz) d 8.30 (s,
1H, H2), 8.09 (s, 1H, H8), 7.08–7.38 (m, 12H, 2ꢂArH,
NH2), 5.98 (s, 1H, H40), 5.74 (d, 1H, J¼7.0 Hz, OH),
4.99–5.03 (m, 1H, H20), 4.95 (d, 1H, J¼6.0 Hz, H50),
4.62–4.66 (m, 1H, H10), 4.56 (s, 1H, OCH2), 4.55 (s, 1H,
OCH2), 4.44 (s, 2H, CH2), 4.14 (s, 2H, CH2); 13C NMR
(DMSO-d6, 75 MHz) d 65.3 (CH2), 69.4 (CH2), 70.5 (C10),
71.2 (OCH2), 75.0 (C20), 81.2 (C50), 118.9 (Cq), 124.7
(Cq), 126.7 (ArHꢂ2), 126.9 (ArHꢂ2), 127.0 (ArHꢂ2),
127.4 (ArHꢂ2), 127.7 (ArHꢂ2), 137.5 (Cq), 137.7 (Cq),
140.5 (C8), 144.4 (C30), 148.9 (Cq), 151.5 (C2), 155.5
(Cq); FABMS (>0) m/z 444 [M+H]+. Anal. Calcd for

S. Rodriguez et al. / Tetrahedron 63 (2007) 7165–7171
7171
Chemother. 1986, 29, 482–487; (c) Isono, K. J. Antibiot.
1988, 41, 1711–1739.
C25H25N5O3$0.3H2O: C, 66.89; H, 5.75; N, 15.60. Found:
C, 66.88; H, 5.74; N, 15.50.
3. (a) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.;
Tomioka, K. J. Org. Chem. 2001, 66, 8199–8203; (b) Gallos,
J. K.; Stathakis, C. I.; Kotoulos, S. S.; Koumbis, A. E. J. Org.
Chem. 2005, 70, 6884–6890.
4. (a) Seley, K. L.; Mosley, S.; Zeng, F. Org. Lett. 2003, 5, 4401–
4403; (b) Kim, H. O.; Yoo, S. J.; Ahn, H. S.; Choi, W. J.; Moon,
H. R.; Lee, K. M.; Chun, M. W.; Jeong, L. S. Bioorg. Med.
Chem. Lett. 2004, 14, 2091–2093; (c) Moon, H. R.; Lee,
H. J.; Kim, K. R.; Lee, K. M.; Lee, S. K.; Kim, H. O.; Chun,
M. W.; Jeong, L. S. Bioorg. Med. Chem. Lett. 2004, 14, 5641–
5644; (d) Wu, Y.; Hong, J. H. Arch. Pharm. 2005, 338, 517–521.
5. Bodenteich, M.; Marquez, V. E.; Hallows, W. H.; Goldstein,
B. M. J. Org. Chem. 1992, 57, 2071–2076.
3.1.14. (L)-9-[(1R,2S,5R)-2,5-Dihydroxy-4-(hydroxyl)-
methyl-cyclopent-3-en-1-yl]-6-aminopurine (5). Under
argon, to a solution of 19 (146 mg, 0.33 mmol) in anhydrous
methylene chloride (25 mL), at ꢀ78 ꢁC was added 2.6 mL
(2.63 mmol) of a 1.0 M solution of BCl3 in heptane. The
reaction mixture was stirred at ꢀ78 ꢁC for 5 h and then for
1 h at ꢀ45 ꢁC. The mixture was cooled again to ꢀ78 ꢁC,
then MeOH (6.5 mL) was added and the mixture was stirred
at ꢀ78 ꢁC for an additional hour. The reaction was allowed
to reach room temperature and the solvent was evaporated.
Methanol (4ꢂ20 mL) was added and evaporated after each
addition. The residue was purified by reverse phase column
chromatography (C18 octadecyl), eluting with water, to give
5 as a white solid after lyophilization (72 mg, 84% yield): Rf
(i-PrOH/H2O/NH4OH, 7:2:1) 0.60; mp 221–223 ꢁC (lit.18
mp 223 ꢁC); UV (H2O) lmax¼259.3 nm (3¼12,454); [a]D20
6. Comin, M. J.; Leitofuter, J.; Rodriguez, J. B. Tetrahedron 2002,
58, 3129–3136.
7. (a) Beer, D.; Meuwly, R.; Vasella, A. Helv. Chim. Acta 1982,
65, 2570–2582; (b) Sano, H.; Sugai, S. Tetrahedron:
Asymmetry 1995, 6, 1143–1150; (c) Borcherding, D. R.;
Scholtz, S. A.; Borchardt, R. T. J. Org. Chem. 1987, 52,
5457–5461.
8. Johnson, C. R. Acc. Chem. Res. 1998, 31, 333–341.
9. (a) Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69,
3993–3996; (b) Jin, Y. H.; Liu, P.; Wang, J.; Das, U.; Baker, R.;
Huggins, J.; Chu, C. K. J. Org. Chem. 2003, 68, 9012–9018.
10. Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3985–3993.
11. Oehschlager, A. C.; Mishra, P.; Dhami, S. Can. J. Chem. 1984,
62, 791–797.
1
ꢀ7.2 (c 0.8, H2O), lit.18 [a]D20 ꢀ6.6 (c 0.8, H2O); H NMR
(DMSO-d6, 400 MHz) d 8.70 (s, 1H, H2), 8.49 (s, 1H,
H8), 5.70 (d, 1H, J¼1.5 Hz, H30), 4.88–4.98 (m, 2H, H20,
H50), 4.49 (t, 1H, J¼6.65 Hz, H10), 4.14 (d, 1H, J¼
16.0 Hz, CH2), 4.03 (d, 1H, J¼15.5 Hz, CH2); 13C NMR
(DMSO-d6, 125 MHz) d 151.0 (Cq), 149.3 (Cq), 147.3
(C30), 145.4 (C2), 144.5 (C8), 126.8 (Cq), 119.1 (Cq), 76.3
(C50), 75.2 (C20), 74.4 (C10), 58.1 (CH2); HRMS: calcd for
C11H14N5O3 264.1097. Found 264.1089.
12. Nokami, J.; Matsuura, H.; Takahashi, H.; Yamashita, M.
Synlett 1994, 491–492.
Acknowledgements
13. Askin, D.; Angst, C.; Danishefsky, S. J. Org. Chem. 1987, 52,
622–635.
14. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127–164.
S.R. and D.E. are particularly grateful to The Ministerio de
Educion y Ciencia, (Spain) and Sidaction (France), respec-
tively, for post-doctoral fellowships. Sidaction (France) is
gratefully acknowledged for financial support.
15. Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org. Lett.
2006, 8, 5069–5072.
References and notes
16. Kim, H. S.; Jacobson, K. A. Org. Lett. 2003, 5, 1665–1668.
17. Bolon, P. J.; Sells, T. B.; Nuesca, Z. M.; Purdy, D. F.; Nair, V.
Tetrahedron 1994, 50, 7747–7764.
18. Yaginuma, S.; Tsujino, M.; Muto, N.; Otani, M.; Hayashi, M.;
Ishimura, F.; Fujii, T.; Watanabe, S.; Matsuda, T.; Watanabe,
T.; Abe, J. Current Chemotherapy and Infectious Disease;
American Society for Microbiology: Washington, DC, 1979;
Vol. 2; pp 1558–1559.
1. (a) Hayashi, M.; Yaginuma, S.; Muto, N.; Tsujino, M. Nucl.
Acids Res. Symp. Ser. 1980, 8, s65–s67; (b) Yaginuma, S.;
Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M.
J. Antibiot. 1981, 34, 359–366.
2. (a) De Clercq, E. Antimicrob. Agents Chemother. 1985, 28, 84–
89; (b) De Clercq, E.; Bernaerts, R.; Bregstrom, D. E.; Robins,
M. J.; Montgomery, J. A.; Holy, A. Antimicrob. Agents
19. Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481–1487.