Stereoselective synthesis of novel aristeromycin analogues as potential antiviral agents

Article abstract of DOI:10.1055/s-0028-1083146

A series of 3′-methyl-branched and purine-modified analogues of aristeromycin were synthesized via the SN₂ displacement of a key triflate, which was prepared from a readily available enantiopure building block in eight steps. The synthesized compounds were evaluated as potential antiviral agents against important viruses. Only the 2,6-diaminopurine derivative exhibited moderate activity against vesicular stomatitis virus.

Full text of DOI:10.1055/s-0028-1083146

PAPER
3253
Stereoselective Synthesis of Novel Aristeromycin Analogues as Potential
Antiviral Agents
Synthesis of
N
a
ovel
A
riste
u
romycin Ana
l
logues Brémond,a Gérard Audran,*a Honoré Monti,a Erik De Clercqb
a
Institut des Sciences Moléculaires de Marseille, ISM2 – UMR CNRS 6263, Equipe STéRéO, Université Paul Cézanne, Aix-Marseille
III, 13397 Marseille Cedex 20, France
Fax +33(4)91288862; E-mail: g.audran@univ-cezanne.fr
Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, 3000 Leuven, Belgium
b
Received 3 June 2008
spectrum of their biological activities.18–20 On the basis of
these relevant properties, and as a logical continuation of
our research into the preparation and pharmacological
evaluation of novel carbanucleosides, we report here as a
Abstract: A series of 3¢-methyl-branched and purine-modified an-
alogues of aristeromycin were synthesized via the SN2 displace-
ment of a key triflate, which was prepared from a readily available
enantiopure building block in eight steps. The synthesized com-
pounds were evaluated as potential antiviral agents against impor- full paper the synthesis of five 3¢-methyl-branched and
tant viruses. Only the 2,6-diaminopurine derivative exhibited
moderate activity against vesicular stomatitis virus.
purine modified aristeromycin analogues 2–6 (Figure 1),
based on the same synthetic pathway, and their antiviral
Key words: synthesis, carbanucleosides, nucleobases, SN2 dis-
placement, antiviral activity
evaluation. Except for the adenine carbocyclic derivative
1, previously described by our group, all the target com-
pounds are hitherto unknown.
Nucleoside analogues constitute an important class of
therapeutic agents in the treatment of cancers and viral in-
fections. Among them, aristeromycin (Figure 1), the nat-
ural carbocyclic analogue of adenosine isolated from
Streptomyces citricolor,1–3 has elicited numerous biologi-
cal studies due to its potent antiviral activities. The antivi-
ral activities have been correlated with its inhibitory
effects toward the cellular enzyme S-adenosylhomocys-
teine (AdoHcy) hydrolase,4–8 which is essential for viral
mRNA capping of most animal-infecting DNA and RNA
viruses.9,10 However, the high cytotoxicity of aristeromy-
cin has greatly hindered its therapeutic application.11,12 In
order to overcome this disadvantage for the development
of chemotherapeutic agents, chemical modifications have
been carried out on the carbasugar as well as on the base.
As part of these efforts, aristeromycin derivatives contain-
ing a methyl group at the C2¢-, C4¢- and C5¢- positions of
the carbasugar moiety have been synthesized.13–15 Recent-
ly, a series of adenosine analogues substituted at the ri-
bose ring with a methyl group have been synthesized and
evaluated for antitumor activity.16 From this study, 3¢-C-
methyladenosine (3¢-Me-Ado, Figure 1) has emerged as
an active derivative, and the structure–activity correlation
studies have pointed out that its structure is crucial for the
antitumor activity.16 In connection with these facts, we re-
ported in a preliminary communication an original syn-
thetic pathway to the carbasugar analogue, (–)-3¢-
methylaristeromycin, with the aim of studying in the near
future its biological potential (1, Figure 1).17 Modifica-
tions of the heterocyclic base moiety of carbocyclic nucle-
osides may also lead to significant changes in the
NH2
R1
N
N
N
N
N
N
HO
HO
R
3'
N
Me
N
R2
X
HO
OH
HO
2 R1
OH
NH
R = H (–)-aristeromycin
R = Me 3'-Me-Ado
R2 = H
X = CH2
X = O
X = CH2
=
3 R1 = OH
R2 = H
R1 = NH2
R = Me
1
4
R2 = NH2
R2 = NH2
5 R1
1 = OH
=
NH
2 = NH2
R
R
6
Figure 1 Aristeromycin and its modified analogues
The starting material was enantiopure ethyl (1S,4R)-4-hy-
droxy-2-methylcyclopent-2-ene-1-carboxylate [(–)-7],
obtained through enzymatic kinetic resolution21 of the
corresponding racemic 7 (Scheme 1). Osmium tetroxide
catalyzed cis-dihydroxylation of protected ester 8
(TBSCl, imidazole, DMF)22 yielded 86% of the expected
diol 9 as the major product, along with a small amount of
the b-face stereoisomer 9¢ (10:1 ratio). Column chroma-
tography on silica gel readily afforded pure 9. The alcohol
functionalities of 9 were protected as the corresponding
2¢,3¢-O-isopropylidene (acetonide) derivative 10 and ste-
reochemical confirmation was carried out at this stage by
NOESY technique (Figure 2). A NOE effect for one
methyl of acetonide (d = 1.49), CHCO2Et (d = 2.95) and
CHOTBS (d = 4.12–4.23 partially overlapped) estab-
lished the cis spatial orientation of these protons.
Treatment of 10 with tetrabutylammonium fluoride in tet-
rahydrofuran at room temperature afforded 11 in 88%
yield (Scheme 2). Attempts to invert the alcohol configu-
ration of 11 through a Mitsunobu reaction23 with acetic
acid failed. Probably depending on the high degree of ster-
ic hindrance, no reaction occurred even if the reaction
SYNTHESIS 2008, No. 20, pp 3253–3260
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083146; Art ID: P06008SS
© Georg Thieme Verlag Stuttgart · New York

3254
P. Brémond et al.
PAPER
EtO2C
EtO2C
EtO2C
EtO2C
OTBS
OH
OH
OTBS
OTBS
Me
O
Me
O
a
b
a
b
(–)-7
(–)-8
O
O
(+)-10
(+)-11
EtO2C
EtO2C
OTBS
c
Me
Me
EtO2C
HO
Me
O
Me
O
HO
OH
O
O
O
c
d
OH
O
O
(+)-9
(+)-10
Scheme 1 Reagents and conditions: (a) TBSCl, imidazole, DMF,
12 h, r.t., 90%; (b) OsO4 (cat.), NMO, acetone–H2O (3:1), 24 h, r.t.,
86%; (c) 2-methoxypropene, CSA (cat.), THF, 3 h, r.t., 93%.
(–)-12
(–)-13
AcO
AcO
Me
O
Me
O
e
EtO2C
OTBS
Me
O
OH
OTf
O
O
2.95
H
H
4.12–4.23
O
(+)-14
(–)-16
1.49
f
Figure 2 NOE of (+)-10
AcO
mixture was heated at reflux. Faced with this unfortunate
step, we decided to invert the hydroxyl function of 11 fol-
lowing a two-step procedure. First, oxidation of 11 with
tetrapropylammonium perruthenate24 in the presence of
N-methylmorpholine N-oxide gave 12 in 85% yield,
which was later reacted with lithium aluminum hydride to
give the diol 13 with 91% yield as the only product. After-
wards, protection of the primary alcohol in 13 was
achieved by enzymatic transesterification with vinyl ace-
tate using Candida antartica lipase (Novozym® 435) to
give the monoacetylated derivative 14 regioselectively
and in 95% yield. At this stage, the stereostructure of 14
was unequivocally determined by single crystal X-ray
crystallography of the corresponding 3,5-dinitrobenzoate
15 (Figure 3). Mitsunobu condensation of 6-chloropurine
with 14 in the presence of triphenylphosphine and diiso-
propyl azodicarboxylate, to give the corresponding purine
derivative failed. As previously, in the attempts to invert
the hydroxyl group of 11, no reaction occurred. With this
unexpected outcome, we therefore decided to first prepare
the corresponding triflate 16, and then look at the SN2 dis-
placement of this secondary triflate with the sodium salt
of nucleobases, adapting the protocol developed by Rob-
ins.25 For this purpose, 14 was treated with trifluo-
romethanesulfonyl chloride and 4-dimethylamino-
pyridine in dichloromethane at 0 °C to provide 16 in 92%
yield.
Me
O
NO2
NO2
O
C
O
O
(–)-15
Scheme 2 Reagents and conditions: (a) TBAF, THF, 1 h, r.t., 88%;
(b) TPAP, NMO, 4 Å MS, CH2Cl2, 12 h, r.t., 85%; (c) LiAlH4, THF,
6.5 h, –80 °C to r.t., 91%; (d) CAL-B, vinyl acetate, 5 h, r.t., 95%; (e)
TfCl, DMAP, CH2Cl2, 15 min, 0 °C, 92%; (f) 3,5-dinitrobenzoyl
chloride, Et3N, CH2Cl2, 12 h, r.t., 93%.
The SN2 displacement of triflate 16 with the sodium salt
of 6-chloropurine provided the protected 6-chloropurine
derivative 17 in 63% yield (Scheme 3). Construction of
the 6-cyclopropylaminopurine derivative 18 was accom-
plished using the following one-pot two-step sequence: (i)
conversion of the 6-chloro group into 6-cyclopropylami-
no group with cyclopropylamine in methanol at 50 °C and
(ii) evaporation in vacuo of the reaction mixture and
Figure 3 ORTEP projection of the molecular structure of 3,5-dini-
trobenzoate (–)-15
deacylation with methanolic ammonia at room tempera-
ture to provide the acetonide-protected derivative 18 in
78% yield for two steps. Subsequent treatment of the ma-
Synthesis 2008, No. 20, 3253–3260 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Aristeromycin Analogues
3255
terial with aqueous 1 M hydrochloric acid at 50 °C gave
the targeted nucleoside 2 in 87% yield. Hydrolytic remov-
al of the 6-chloro substituent required for the conversion
of 17 into the hypoxanthine derivative 19 was accom-
plished with 2-mercaptoethanol and NaOMe in refluxing
methanol.26 Under these conditions, the acyl group was si-
multaneously removed with an overall yield of 82%. Fi-
NH
N
NH
N
N
N
N
N
N
N
c
HO
Me
HO
Me
(–)-2
O
O
HO
OH
nally acetonide deprotection with aqueous
1 M
(–)-18
b
hydrochloric acid at 50 °C like earlier led efficiently to 3
in 86% yield.
Cl
N
N
N
N
AcO
The synthesis of 2-amino substituted targeted molecules
4–6 is outlined in Scheme 4. Reaction of triflate 16 with
the sodium salt of 2,6-diaminopurine in dimethylform-
amide at 60 °C gave the protected derivative 20 in 75%
yield. Deprotection of the acetonide group of 20 with tri-
fluoroacetic acid–water (2:1) at room temperature and
subsequent deprotection of the acetate group with metha-
nolic ammonia led to 4 in 70% yield for the two steps.
Preparation of 5 and 6 was subsequently accomplished in
a manner similar to that developed earlier. Reaction of 16
with the sodium salt of 2-amino-6-chloropurine afforded
21 in 70% yield. Treatment of 21 with cyclopropylamine
then methanolic ammonia gave 22 (76% yield), and the
desired deprotected product 5 was obtained by hydrolysis
with hydrochloric acid (90% yield). On the other hand, re-
Me
O
a
AcO
Me
O
OTf
O
O
d
(–)-16
(–)-17
OH
N
OH
N
N
N
N
N
N
HO
N
Me
O
HO
c
Me
(–)-3
O
HO
OH
(–)-19
Scheme 3 Reagents and conditions: (a) 6-chloropurine, NaH, action of 21 with 2-mercaptoethanol afforded guanine rel-
DMF, 2 h, 60 °C, 63%; (b) (i) cyclopropylamine, MeOH, 12 h, 50 °C;
(ii) NH3/MeOH, 12 h, r.t., 78%; (c) HCl, H2O, 12 h, 50 °C, 87% for
(–)-2, 86% for (–)-3; (d) 2-mercaptoethanol, MeONa, MeOH, 12 h,
acid (76% yield). 3¢-Methylaristeromycin (1) and the
reflux, 82%.
ative 23 (87% yield), from which 6 was obtained by
deprotection of the acetonide group with hydrochloric
newly synthesized carbocyclic nucleosides 2–6 have been
NH2
NH2
N
N
N
N
N
b
HO
N
AcO
Me
N
NH2
Me
O
N
NH2
(–)-4
HO
OH
O
(–)-20
a
AcO
Me
O
HN
HN
N
OTf
O
N
N
N
N
N
N
HO
(–)-16
HO
Me
N
NH2
Me
O
NH2
d
e
(–)-5
c
HO
OH
Cl
N
O
(–)-22
N
N
N
AcO
Me
O
NH2
OH
OH
N
N
N
N
N
N
O
HO
(–)-21
HO
Me
N
NH2
Me
O
N
NH2
f
e
(–)-6
HO
OH
O
(–)-23
Scheme 4 Reagents and conditions: (a) 2,6-diaminopurine, NaH, DMF, 2 h, 60 °C, 72%; (b) (i) trifluoroacetic acid–H2O (2:1), 12 h, r.t.; (ii)
NH3/MeOH, 24 h, r.t., 74%; (c) 2-amino-6-chloropurine, NaH, DMF, 2 h, 60 °C, 70%; (d) (i) cyclopropylamine, MeOH, 12 h, 50 °C; (ii) NH3/
MeOH, 12 h, r.t., 76%; (e) HCl, H2O, 12 h, 50 °C, 90% for (–)-5, 76% for (–)-6; (f) 2-mercaptoethanol, MeONa, MeOH, 12 h, reflux, 87%.
Synthesis 2008, No. 20, 3253–3260 © Thieme Stuttgart · New York

3256
P. Brémond et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 5.48 (m, 1 H), 4.78 (m, 1 H), 4.16
and 4.11 (ABX3, J = 13.4, 7.2, 7.2 Hz, 2 H), 3.18 (br t, J = 7.2 Hz, 1
H), 2.48 (ddd, J = 12.9, 8.9, 7.4 Hz, 1 H), 1.96 (ddd, J = 12.9, 7.3,
5.4 Hz, 1 H), 1.74 (q, J = 1.5 Hz, 3 H), 1.24 (ABX3, J = 7.2 Hz, 3
H), 0.87 (s, 9 H), 0.04 (br s, 6 H).
13C NMR (75 MHz, CDCl3): d = 173.3 (C), 139.9 (C), 131.8 (CH),
76.2 (CH), 60.4 (CH2), 51.9 (CH), 38.5 (CH2), 25.9 (3 × CH3), 18.1
(C), 15.4 (CH3), 14.2 (CH3), –4.7 (2 × CH3).
evaluated for their antiviral activity27 against herpes sim-
plex virus type 1 and type 2 (HSV-1, strain KOS and
HSV-2, strain G), vaccinia virus (VV), vesicular stomati-
tis virus (VSV) and thymine kinase-deficient herpes sim-
plex virus type 1 (TK- HSV-1, strain KOS, ACVr) in HEL
cells cultures, VSV, Coxsackie virus B4, and respiratory
syncytial virus (RSV) in HeLa cell cultures, Coxsakie vi-
rus B4, Sindbis virus and Punta Toro virus in Vero cell
cultures, and feline corona virus (FIPV) feline herpes vi-
rus in CRFK cell cultures, as well as for their cytotoxicity.
Anal. Calcd for C15H28O3Si: C, 63.33; H, 9.92. Found: C, 63.66; H,
9.87.
Ethyl (1S,2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-2,3-dihy-
droxy-2-methylcyclopentanecarboxylate [(–)-9] and Ethyl
(1S,2S,3R,4R)-4-(tert-Butyldimethylsilyloxy)-2,3-dihydroxy-2-
methylcyclopentanecarboxylate [(–)-9¢]
No significant cytotoxicities were reported for any of the
compounds. Compound 4 (EC50 20 mg/mL) showed a
moderate activity against vesicular stomatitis virus (HeLa
cells) without toxicity up to 100 mg/mL. None of other
compounds showed any antiviral activity against any of
the viruses tested.
To an ice-cold solution of alkene (–)-8 (5.0 g, 17.6 mmol) in ace-
tone–H2O (3:1, 240 mL) under argon was added a catalytic amount
of OsO4 (4% wt in H2O). The solution turned black, then NMO (4.2
g, 35.2 mmol, 2.0 equiv) was added. After stirring at r.t. for 24 h,
the solution was diluted with Et2O (200 mL) and poured into aq
Na2SO3 (8.8 g, 70 mmol, 4.0 equiv) cooled in an ice bath, and stirred
for 30 min. The aqueous layer was extracted with Et2O (3 × 200
mL), then the organic layers were combined, washed with H2O (200
mL), brine (200 mL), and dried (MgSO4). Concentration of the or-
ganic extracts in vacuo and purification of the residue by column
chromatography gave compounds (+)-9 (4.36 g, 78%) and (–)-9¢
(445 mg, 8%) as clear oils.
In summary, a series of 3¢-methyl-branched and purine-
modified analogues of aristeromycin 2–6 were synthe-
sized by the efficient SN2 displacement of the key triflate
16, prepared in eight steps using a procedure recently de-
veloped in our group. All derivatives were tested against
important viruses in order to determine their spectrum of
antiviral activity. However, only the 2,6-diaminopurine
carbocyclic nucleoside 4 displayed a moderate activity
against vesicular stomatitis virus.
(+)-9
[a]D25 +2.6 (c 1.0, CHCl3).
IR (neat): 3433, 1742, 1223, 1139 cm–1.
All air and/or water sensitive reactions were carried out under argon
with anhydrous, freshly distilled solvents using standard syringe-
cannula/septa techniques. All corresponding glassware was oven-
dried (80 °C) and/or carefully dried in line with a flameless heat
gun. All solvents were distilled under argon: THF from a blue solu-
tion of sodium-benzophenone ketyl radical prior to use; CH2Cl2 and
DMF from CaH2, and toluene from LiAlH4. Routine monitoring of
reactions was performed using Merck Silica gel 60 F254, aluminum
supported TLC plates; spots were visualized using a UV light and
ethanolic acidic p-anisaldehyde solution or ethanolic phosphomo-
lybdic solution, followed by heating. Purification by means of col-
umn chromatography was performed with silica gel 60 (230–400
mesh) and gradients of Et2O–petroleum ether (PE, bp 40–65 °C) or
CH2Cl2–MeOH as eluent, unless otherwise stated. 1H and 13C NMR
spectra were recorded in CDCl3, CD3OD or DMSO-d6 solutions on
a Bruker AM-500, Bruker AM-400, or Bruker AM-300 spectrome-
ter. Chemical shifts (d) in ppm are reported using residual nondeu-
terated solvents as internal reference. Optical rotations were
measured on a PerkinElmer 341 polarimeter. Microanalyses were
performed on a Thermo Finnigan EA 1112 apparatus. Melting
points are uncorrected. IR spectra were obtained as films or KBr
pellets using a PerkinElmer 1600 FTIR spectrophotometer.
1H NMR (300 MHz, CDCl3): d = 4.18 and 4.17 (ABX3, J = 13.4,
7.2, 7.2 Hz, 2 H), 4.02 (ddd, J = 8.5, 6.4, 3.5 Hz, 1 H), 3.51 (d,
J = 3.5 Hz, 1 H), 2.91 (dd, J = 10.5, 8.5 Hz, 1 H), 2.28 (dt, J = 13.8,
8.5 Hz, 1 H), 1.83 (ddd, J = 13.8, 10.5, 6.4 Hz, 1 H), 1.27 (ABX3
partially overlapped, J = 7.2 Hz, 3 H), 1.25 (s, 3 H), 0.87 (s, 9 H),
0.06 (s, 3 H), 0.05 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.3 (C), 83.6 (CH), 77.8 (C),
75.2 (CH), 60.7 (CH2), 50.9 (CH), 33.1 (CH2), 25.7 (3 × CH3), 22.2
(CH3), 17.9 (C), 14.3 (CH3), –4.8 (CH3), –4.9 (CH3).
Anal. Calcd for C15H30O5Si: C, 56.57; H, 9.49. Found: C, 56.85; H,
9.44.
(–)-9¢
[a]D25 –15.5 (c 1.0, CHCl3).
IR (neat): 3439, 1728, 1218, 1135 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.26–4.09 (m, 3 H), 3.44 (m, 1 H),
2.68 (dd, J = 10.3, 7.4 Hz, 1 H), 2.29 (ddd, J = 14.8, 7.4, 2.3 Hz, 1
H), 2.02 (ddd, J = 14.8, 10.3, 5.8 Hz, 1 H), 1.38 (s, 3 H), 1.26 (t,
J = 7.1 Hz, 3 H), 0.89 (s, 9 H), 0.13 (s, 3 H), 0.10 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.8 (C), 79.4 (C), 77.8 (CH),
73.5 (CH), 60.7 (CH2), 50.2 (CH), 32.3 (CH2), 25.7 (3 × CH3), 23.8
(CH3), 17.9 (C), 14.3 (CH3), –4.8 (CH3), –5.1 (CH3).
Ethyl (1S,4R)-4-(tert-Butyldimethylsilyloxy)-2-methylcyclo-
pent-2-enecarboxylate [(–)-8]
To an ice-cold solution of alcohol (–)-7 (5.0 g, 29.4 mmol) in DMF
(40 mL) under argon was added imidazole (8.0 g, 117.5 mmol, 4.0
equiv) followed by TBSCl (6.6 g, 44.1 mmol, 1.5 equiv). After stir-
ring at r.t. for 12 h, the solution was poured into H2O (200 mL). The
aqueous layer was extracted with Et2O (3 × 150 mL), then the or-
ganic layers were combined, washed with H2O (100 mL), brine (100
mL), and dried (MgSO4). Concentration of the organic extracts in
vacuo and purification of the residue by column chromatography
gave compound (–)-8 (7.5 g, 90%) as a clear oil; [a]D25 –18.2 (c 1.0,
CHCl3).
Anal. Calcd for C15H30O4Si: C, 56.57; H, 9.49. Found: C, 56.29; H,
9.56.
Ethyl (3aR,4S,6R,6aS)-6-(tert-Butyldimethylsilyloxy)-2,2,3a-
trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxy-
late [(+)-10]
To an ice-cold solution of diol (+)-9 (4.0 g, 12.6 mmol) in THF (200
mL) under argon were added 2-methoxypropene (2.4 mL, 25.1
mmol, 2.0 equiv) and a catalytic amount of CSA. The solution was
stirred for 3 h at r.t.; then the mixture was poured into aq NaHCO3
(100 mL). The aqueous layer was extracted with Et2O (3 × 100 mL),
IR (neat): 3055, 1729, 1215, 1150 cm–1.
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Synthesis of Novel Aristeromycin Analogues
3257
then the organic layers were combined, washed with aq NaHCO3
(100 mL), H2O (100 mL), brine (100 mL), and dried (MgSO4). Con-
centration of the organic extracts in vacuo and purification of the
residue by column chromatography gave compound (+)-10 (4.21 g,
93%) as a clear oil; [a]D25 +31.7 (c 1.0, CHCl3).
Anal. Calcd for C12H18O5: C, 59.49; H, 7.49. Found: C, 59.64; H,
7.53.
(3aS,4S,6R,6aR)-6-(Hydroxymethyl)-2,2,6a-trimethyltetrahy-
dro-3aH-cyclopenta[d][1,3]dioxol-4-ol [(–)-13]
To a stirred solution of the keto ester (–)-12 (1.5 g, 6.19 mmol) in
THF (70 mL) under argon was slowly added at –78 °C a 1.0 M so-
lution of LiAlH4 in THF (6.2 mL, 6.19 mmol, 1.0 equiv) dropwise.
After stirring for 30 min at –78 °C, another portion of LiAlH4 (1.0
M solution in THF, 6.2 mL, 6.19 mmol, 1.0 equiv) was added drop-
wise. The mixture was stirred for 6 h and the temperature was al-
lowed to rise slowly to 0 °C. Then, Celite (13 g) and Na2SO4·10H2O
(13 g) were carefully added, and the mixture was stirred for a further
1 h at r.t. Concentration of the organic extracts in vacuo and recrys-
tallization of the residue from Et2O–PE gave compound (–)-13
(1.14 g, 91%); white needles; mp 74–75 °C; [a]D25 –3.1 (c 1.0,
CHCl3).
IR (neat): 1728, 1237, 1205, 1094 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.23–4.12 (m, 3 H), 3.94 (d,
J = 1.8 Hz, 1 H), 2.95 (dd, J = 11.3, 7.1 Hz, 1 H), 2.32 (dt, J = 13.6,
7.1 Hz, 1 H), 2.06 (ddd, J = 13.6, 11.3, 7.1 Hz, 1 H), 1.49 (s, 3 H),
1.40 (s, 3 H), 1.35 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 0.88 (s, 9 H),
0.08 (s, 3 H), 0.07 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.2 (C), 112.0 (C), 93.5 (CH),
88.5 (C), 74.8 (CH), 60.5 (CH2), 53.3 (CH), 36.8 (CH2), 28.3 (CH3),
26.8 (CH3), 25.7 (3 × CH3), 21.7 (CH3), 17.9 (C), 14.3 (CH3), –4.9
(CH3), –5.0 (CH3).
Anal. Calcd for C18H35O5Si: C, 60.30; H, 9.56. Found: C, 60.19; H,
9.59.
IR (KBr): 3438, 1240, 1077 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.22–4.15 (m, 2 H), 3.64 and 3.57
(ABX, J = 10.7, 6.4, 6.4 Hz, 2 H), 2.26 (ABXCH2, quint, J = 6.4, 6.4
Hz, 1 H), 2.02–1.91 (m, 1 H) 1.82–1.72 (m, 1 H), 1.50 (s, 3 H), 1.44
(s, 6 H).
13C NMR (75 MHz, CDCl3): d = 112.4 (C), 89.9 (C), 86.5 (CH),
70.3 (CH), 62.2 (CH2), 48.1 (CH), 36.0 (CH2), 27.8 (CH3), 27.5
(CH3), 21.6 (CH3).
Ethyl (3aR,4S,6R,6aS)-6-Hydroxy-2,2,3a-trimethyltetrahydro-
3aH-cyclopenta[d][1,3]dioxole-4-carboxylate [(+)-11]
To an ice-cold solution of silyl ether (+)-10 (4.0 g, 11.2 mmol) in
THF (200 mL) under argon was added a 1.0 M solution of TBAF in
THF (33.5 mL, 33.5 mmol, 3.0 equiv) dropwise. After stirring for 1
h at r.t., the mixture was poured into H2O (100 mL). The aqueous
layer was extracted with Et2O (3 × 100 mL), then the organic layers
were combined, washed with H2O (100 mL), brine (100 mL), and
dried (MgSO4). Concentration of the organic extracts in vacuo and
purification of the residue by column chromatography gave the al-
cohol (+)-11 (2.4 g, 88%) as a clear oil; [a]D25 +64.7 (c 1.0, CHCl3).
Anal. Calcd for C10H18O4: C, 59.39; H, 8.97. Found: C, 58.99; H,
9.01.
[(3aR,4R,6S,6aS)-6-Hydroxy-2,2,3a-trimethyltetrahydro-3aH-
cyclopenta[d][1,3]dioxol-4-yl]methyl Ethanoate [(+)-14]
To a stirred solution of diol (–)-13 (1.0 g, 4.94 mmol) in vinyl ace-
tate (100 mL) was added CAL-B (Candida antarctica B, No-
vozym® 435, Novo Nordisk A/S, 100 mg). The solution was stirred
for 5 h at r.t., and then filtered through a short pad of Celite. Con-
centration of the filtrate in vacuo and purification of the residue by
column chromatography gave compound (+)-14 (1.15 g, 95%) as a
clear oil; [a]D25 –3.9 (c 1.0, CHCl3).
IR (neat): 3409, 1744, 1261, 1074 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.17–4.06 (m, 4 H), 3.02 (dd,
J = 8.8, 2.6 Hz, 1 H), 2.37 (ddd, J = 14.3, 8.8, 5.0 Hz, 1 H), 1.92 (br
d, J = 14.3 Hz, 1 H), 1.41 (s, 3 H), 1.33 (s, 3 H), 1.27 (s, 3 H), 1.22
(t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 176.7 (C), 110.3 (C), 92.6 (CH),
91.3 (C), 76.0 (CH), 61.5 (CH2), 55.9 (CH), 34.6 (CH2), 27.6 (CH3),
26.2 (CH3), 23.1 (CH3), 14.0 (CH3).
IR (neat): 3402, 1732, 1229, 1098 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.07–3.99 (m, 2 H), 3.94 and 3.84
(ABX, J = 11.3, 6.8, 5.9 Hz, 2 H), 2.25 (ABXCH2, br quint, J = 6.5
Hz, 1 H), 1.98–1.85 (m partially overlapped, 1 H), 1.94 (s, 3 H),
1.72–1.62 (m, 1 H), 1.38 (s, 3 H), 1.32 (s, 3 H), 1.29 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.6 (C), 111.9 (C), 89.2 (C), 86.1
(CH), 70.3 (CH), 63.8 (CH2), 44.7 (CH), 35.6 (CH2), 27.5 (CH3),
27.2 (CH3), 21.7 (CH3), 20.7 (CH3).
Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 58.73; H,
8.19.
Ethyl (3aR,4S,6aR)-2,2,3a-Trimethyl-6-oxotetrahydro-3aH-cy-
clopenta[d][1,3]dioxole-4-carboxylate [(–)-12]
To an ice-cold solution of alcohol (+)-11 (2.0 g, 8.19 mmol) in
CH2Cl2 (100 mL) under argon was added powdered 4 Å MS (10 g)
and a catalytic amount of TPAP. The solution turned deep green,
then NMO (2.88 g, 24.6 mmol, 3.0 equiv) was added. After stirring
at r.t. for 12 h, the solution was poured into aq Na2SO3 (6.2 g, 49.2
mmol, 6.0 equiv) cooled in an ice bath, and stirred for 30 min. The
aqueous layer was extracted with Et2O (3 × 100 mL), then the or-
ganic layers were combined, washed with H2O (100 mL), brine (100
mL), and dried (MgSO4). Concentration of the organic extracts in
vacuo and purification of the residue by column chromatography
gave the ketone (–)-12 (1.69 g, 85%) as a clear oil; [a]D25 –103.9 (c
1.0, CHCl3).
Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 59.11; H,
8.31.
(3aS,4S,6R,6aR)-6-(Acetoxymethyl)-2,2,6a-trimethyltetrahy-
dro-3aH-cyclopenta[d][1,3]dioxol-4-yl 3,5-Dinitrobenzoate
[(–)-15]
To an ice-cold stirred solution of (+)-14 (100 mg, 0.41 mmol) in an-
hyd CH2Cl2 (10 mL) was added Et3N (172 mL, 1.23 mmol, 3.0
equiv) followed by 3,5-dinitrobenzoyl chloride (142 mg, 0.61
mmol, 1.5 equiv). The red mixture was stirred at r.t. for 12 h, then
poured into H2O (30 mL). After extraction with Et2O (3 × 40 mL),
the combined organic layers were was washed with H2O (50 mL),
brine (50 mL), dried (MgSO4), and concentrated under reduced
pressure. Purification of the residue by column chromatography
gave crystalline (–)-15 (166 mg, 93%). A single crystal of (–)-15
that was suitable for X-ray diffractometry was obtained by dissolv-
ing the chromatographically purified product in the smallest possi-
ble quantity of Et2O in a vial, and then slowly evaporating the
IR (neat): 1736, 1714, 1251, 1076 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.13 (q, J = 7.1 Hz, 2 H), 4.08 (br
s, 1 H), 3.21 (dd, J = 8.4, 2.9 Hz, 1 H), 2.72 (dd, J = 18.6, 8.4 Hz, 1
H), 2.46 (br d, J = 18.6 Hz, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.28
(s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 212.7 (C), 172.8 (C), 112.4 (C),
86.3 (C), 83.2 (CH), 61.3 (CH2), 48.3 (CH), 39.3 (CH2), 28.3 (CH3),
28.2 (CH3), 21.1 (CH3), 13.9 (CH3).
Synthesis 2008, No. 20, 3253–3260 © Thieme Stuttgart · New York

3258
P. Brémond et al.
PAPER
25
solvent at r.t.; white needles; mp 96–97 °C; [a]D –12.3 (c 1.0,
IR (KBr): 1758, 1241, 1136 cm–1.
CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.62 (s, 1 H), 8.13 (s, 1 H), 4.82
(m, 1 H), 4.53 (d, J = 3.6 Hz, 1 H), 4.13 (d, J = 6.0 Hz, 2 H), 2.56–
2.36 (m, 3 H), 1.96 (s, 3 H), 1.56 (s, 3 H), 1.43 (s, 3 H), 1.22 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.6 (C), 151.4 (CH), 151.2 (C),
151.0 (C), 144.8 (CH), 132.2 (C), 113.7 (C), 90.1 (CH), 87.6 (C),
62.8 (CH2), 60.8 (CH), 46.9 (CH), 34.1 (CH2), 28.3 (CH3), 26.9
(CH3), 20.6 (2 × CH3).
IR (KBr): 1736, 1542, 1254 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.17 (t, J = 2.1 Hz, 1 H), 9.12 (d,
J = 2.1 Hz, 2 H), 5.30–5.23 (m, 1 H), 4.49 (d, J = 5.4 Hz, 1 H), 4.11
and 4.02 (ABX, J = 11.5, 5.5, 4.5 Hz, 2 H), 2.54–2.43 (m, 2 H),
2.10–2.03 (m partially overlapped, 1 H), 2.07 (s, 3 H), 1.44 (s, 3 H),
1.40 (s, 3 H), 1.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.7 (C), 162.1 (C), 148.7 (C),
133.8 (C), 129.5 (2 × CH), 122.5 (C), 112.2 (C), 89.8 (C), 84.4
(CH), 75.4 (CH), 64.1 (CH2), 44.4 (CH3), 32.4 (CH2), 27.9 (CH3),
27.8 (CH), 21.7 (CH3), 21.0 (CH3).
Anal. Calcd for C17H21ClN4O4: C, 53.62; H, 5.56; N, 14.71. Found:
C, 53.99; H, 5.61; N, 15.02.
6-Cyclopropylamino-9-[(1¢R,2¢S,3¢R,4¢R)-4¢-hydroxymethyl-
2¢,3¢-O-isopropylidene-3¢-methylcyclopent-1¢-yl]purine [(–)-18]
To a solution of (–)-17 (96 mg, 0.25 mmol) in MeOH (5 mL) under
argon was added cyclopropylamine (1 mL). The mixture was
brought to 50 °C, stirred for 12 h, allowed to cool to r.t. and concen-
trated in vacuo. The crude residue was dissolved in NH3/MeOH (ca.
7 M, 6 mL) and the resulting mixture stirred at r.t. for 12 h. Removal
of solvent and purification of the residue by chromatography on sil-
ica gel (gradient CH2Cl2–MeOH) gave (–)-18 (71 mg, 78%) as a
foam; [a]D25 –14.8 (c 1.0, MeOH).
Anal. Calcd for C19H22N2O10: C, 52.06; H, 5.06; N, 6.39. Found: C,
51.92; H, 5.10; N, 6.45.
X-ray Diffraction Analysis of (–)-15
C19H22N2O10, M = 438.39 g·mol–1. The colorless single crystal
(crystal size : 0.3 × 0.15 × 0.15) was analyzed at 293 K with a Bruk-
er Nonius Kappa-CCD automated four circle diffractometer using
graphite monochromated Mo-Ka radiation (l = 0.71073 Å). Crystal
data: monoclinic, space group C-2, a = 21.6317(7) Å, b = 5.9730(2)
Å, c = 18.2114(8) Å, b = 113.2400(10)°, V = 2162.10(14) Å3,
Z = 4, Dx = 1.347 g/cm3, F(000) = 920, and m(Mo-Ka) = 1.1 cm–1.
284 parameters were refined on F2 using 2789 reflections to final in-
IR (KBr): 3368, 1245, 1139 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.36 (s, 1 H), 7.73 (s, 1 H), 6.49
(br s, 1 H, D2O exch), 4.75 (m, 1 H), 4.53 (d, J = 3.4 Hz, 1 H), 3.86–
3.78 (m, 1 H), 3.70–3.62 (m, 1 H), 3.50 (br s, 1 H, D2O exch), 2.95
(m, 1 H), 2.43–2.31 (m, 3 H), 1.60 (s, 3 H), 1.48 (s, 3 H), 1.27 (s, 3
H), 0.85 (m, 2 H), 0.59 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 155.7 (C), 152.8 (CH), 148.9 (C),
139.2 (CH), 120.4 (C), 113.5 (C), 90.8 (CH), 88.2 (C), 61.3 (CH2),
60.4 (CH), 50.3 (CH), 34.2 (CH2), 28.5 (CH3), 27.0 (CH3), 23.5
(CH), 20.6 (CH3), 7.2 (2 × CH2).
dices R1 [F2 > 4s(F2)] = 0.0558, wR2 [(w = 1/[s2(Fo ) + (0.1109 P)2
2
+ 0.4306 P) where P = (Fo2 + 2 Fc2)/3] = 0.2127.28,29
[(3aR,4R,6S,6aS)-2,2,3a-Trimethyl-6-(trifluoromethylsulfonyl-
oxy)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl
Ethanoate [(–)-16]
To an ice-cold solution of alcohol (+)-14 (1.0 g, 4.09 mmol) in
CH2Cl2 (75 mL) under argon was added DMAP (3.0 g, 24.6 mmol,
6.0 equiv). After 5 min, TfCl (1.1 mL, 10.2 mmol, 2.5 equiv) was
added dropwise. After stirring for 15 min at 0 °C, the mixture was
poured into H2O (100 mL). The aqueous layer was extracted with
Et2O (3 × 100 mL), and then the organic layers were combined,
washed with H2O (100 mL), brine (100 mL), and dried (MgSO4).
Concentration of organic extracts in vacuo and purification of the
residue by column chromatography gave the triflate (–)-16 (1.42 g,
92% yield); white needles; mp 59–60 °C; [a]D25 –32.1 (c 1.0,
CHCl3).
Anal. Calcd for C18H25N5O3: C, 60.15; H, 7.01; N, 19.48. Found: C,
59.99; H, 7.08; N, 19.83.
6-Cyclopropylamino-9-[(1¢R,2¢S,3¢R,4¢R)-2¢,3¢-dihydroxy-4¢-hy-
droxymethyl-3¢-methylcyclopent-1¢-yl] purine [(–)-2]
A solution of (–)-18 (65 mg, 0.18 mmol) in HCl (1 M, 8 mL) was
stirred at 50 °C for 12 h. The mixture was then cooled, neutralized
with Amberlyst IRA-67, filtered, and concentrated. Purification of
the residue by chromatography on silica gel (gradient CH2Cl2–
25
IR (KBr): 1758, 1258, 1084 cm–1.
MeOH) gave (–)-2 (49 mg, 87%); white solid; mp 55 °C; [a]D
–26.0 (c 1.0, MeOH).
1H NMR (300 MHz, CDCl3): d = 5.13 (ddd, J = 8.8, 7.0, 5.6 Hz, 1
H), 4.32 (d, J = 5.6 Hz, 1 H), 4.06 and 4.00 (ABX, J = 11.6, 5.0, 4.8
Hz, 2 H), 2.50 (dt, J = 12.5, 8.8 Hz, 1 H), 2.44–2.38 (m, 1 H), 2.05
(s, 3 H), 2.05–1.98 (m partially overlapped, 1 H), 1.46 (s, 3 H), 1.42
(s, 3 H), 1.41 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.3 (C), 118.5 (q, J = 317 Hz,
CF3), 113.1 (C), 89.2 (C), 85.2 (CH), 84.4 (CH), 63.7 (CH2), 44.2
(CH), 32.9 (CH2), 27.6 (CH3), 27.5 (CH3), 21.6 (CH3), 20.7 (CH3).
IR (KBr): 3462, 1263, 1088 cm–1.
1H NMR (300 MHz, CD3OD): d = 8.24 (s, 1 H), 8.15 (s, 1 H), 4.86
(q, J = 9.6 Hz, 1 H, partially overlapped with HDO), 4.36 (d, J = 9.6
Hz, 1 H), 3.74 (d, J = 4.8 Hz, 2 H), 2.92 (m, 1 H), 2.61 (dt, J = 13.5,
9.6 Hz, 1 H), 2.15 (dq, J = 9.6, 4.8 Hz, 1 H), 2.04 (ddd, J = 13.5, 9.6,
4.8 Hz, 1 H), 1.36 (s, 3 H), 0.86 (m, 2 H), 0.63 (m, 2 H).
13C NMR (75 MHz, CD3OD): d = 157.0 (C), 153.1 (CH), 150.0 (C),
141.9 (CH), 121.1 (C), 81.0 (CH), 78.7 (C), 64.0 (CH2), 61.7 (CH),
48.6 (CH), 30.3 (CH2), 24.5 (CH), 21.6 (CH3), 7.6 (2 × CH2).
Anal. Calcd for C13H19F3O7S: C, 41.49; H, 5.09. Found: C, 41.73;
H, 5.13.
Anal. Calcd for C15H21N5O3: C, 56.41; H, 6.63; N, 21.93. Found: C,
56.17; H, 6.68; N, 22.11.
9-[(1¢R,2¢S,3¢R,4¢R)-4¢-Acetoxymethyl-2¢,3¢-O-isopropylidene-
3¢-methylcyclopent-1¢-yl]-6-chloropurine [(–)-17]
A mixture of NaH (113 mg, 2.82 mmol, 2.0 equiv) and 6-chloropu-
rine (544 mg, 3.52 mmol, 2.5 equiv) in DMF (30 mL) was brought
to 60 °C and stirred at this temperature for 2 h. The solution was
cooled to 0 °C, and triflate (–)-16 (530 mg, 1.41 mmol) in DMF (3
mL) was added dropwise. After stirring for 2 h at 60 °C, the mixture
was allowed to cool to r.t. and concentrated to leave a residue that
was purified by chromatography on silica gel (gradient CH2Cl2–
MeOH) to give (–)-17 (337 mg, 63% yield); white solid; mp 115 °C;
[a]D25 –13.7 (c 1.0, MeOH).
9-[(1¢R,2¢S,3¢R,4¢R)-4¢-Hydroxymethyl-2¢,3¢-O-isopropylidene-
3¢-methylcyclopent-1¢-yl]hypoxanthine [(–)-19]
To a solution of (–)-17 (96 mg, 0.25 mmol) in MeOH (5 mL) under
argon was added 2-mercaptoethanol (177 mL, 2.53 mmol, 10 equiv)
and NaOMe (5.0 M solution in MeOH, 505 mL, 2.53 mmol, 10
equiv). The mixture was heated to reflux for 12 h, allowed to cool
to r.t., and concentrated in vacuo. The residue was purified by chro-
matography on silica gel (gradient CH2Cl2–MeOH) to afford 66 mg
Synthesis 2008, No. 20, 3253–3260 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Aristeromycin Analogues
IR (KBr): 3402, 1237, 1079 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.99 (s, 1 H), 4.72 (q, J = 9.5 Hz,
1 H), 4.26 (d, J = 9.5 Hz, 1 H), 3.72 (d, J = 5.3 Hz, 2 H), 2.54 (dt,
J = 13.6, 9.5 Hz, 1 H), 2.12 (dq, J = 9.5, 5.3 Hz, 1 H), 1.97 (ddd,
J = 13.6, 9.5, 5.3 Hz, 1 H), 1.34 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 156.1 (C), 153.9 (C), 153.1 (C),
141.2 (CH), 113.7 (C), 80.8 (CH), 78.6 (C), 63.8 (CH2), 61.2 (CH),
48.6 (CH), 30.0 (CH2), 21.6 (CH3).
3259
(82%) of (–)-19; white solid; mp >235 °C (dec.); [a]D25 –8.9 (c 1.0,
MeOH).
IR (KBr): 3444, 1443, 1239, 1089 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.10 (br s, 1 H, D2O exch),
8.25 (s, 1 H), 8.05 (s, 1 H), 4.85 (m, 1 H), 4.42 (d, J = 4.2 Hz, 1 H),
3.60 and 3.39 (ABX, J = 10.5, 7.2, 4.8 Hz, 2 H), 3.50 (br s, 1 H, D2O
exch), 2.39–2.11 (m, 3 H), 1.44 (s, 6 H), 1.24 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 156.7 (C), 148.2 (C), 145.6
(CH), 139.4 (CH), 124.6 (C), 112.7 (C), 91.0 (CH), 87.8 (C), 60.1
(CH2), 59.0 (CH), 50.3 (CH), 34.8 (CH2), 28.7 (CH3), 27.4 (CH3),
20.8 (CH3).
Anal. Calcd for C12H18N6O3: C, 48.97; H, 6.16; N, 28.56. Found: C,
50.19; H, 6.12; N, 28.29.
9-[(1¢R,2¢S,3¢R,4¢R)-4¢-Acetoxymethyl-2¢,3¢-O-isopropylidene-
3¢-methylcyclopent-1¢-yl]-2-amino-6-chloropurine [(–)-21]
Starting from triflate (–)-16 (500 mg, 1.33 mmol) and 2-amino-6-
chloropurine (466 mg, 2.66 mmol), derivative (–)-21 (366 mg,
70%) was prepared according to the same procedure used in the
preparation of (–)-17; white solid; mp 128 °C; [a]D –9.8 (c 1.0,
MeOH).
IR (KBr): 3480, 1732, 1266, 1029 cm–1.
Anal. Calcd for C15H20N4O4: C, 56.24; H, 6.29; N, 17.49. Found: C,
55.89; H, 6.35; N, 17.76.
9-[(1¢R,2¢S,3¢R,4¢R)-2¢,3¢-Dihydroxy-4¢-hydroxymethyl-3¢-meth-
ylcyclopent-1¢-yl]hypoxanthine [(–)-3]
Starting from (–)-19 (55 mg, 0.17 mmol), compound (–)-3 (41 mg,
86%) was prepared in the same manner as that for (–)-2; white solid;
mp >250 °C (dec.); [a]D25 –18.8 (c 1.0, DMSO).
25
IR (KBr): 3387, 1461, 1233, 1090 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.26 (s, 1 H), 6.91 (br s, 2 H,
D2O exch), 4.82 (td, J = 10.8, 3.6 Hz, 1 H), 4.45 (d, J = 3.6 Hz, 1
H), 4.11 (dd, J = 7.2, 2.1 Hz, 2 H), 2.47–2.25 (m, 3 H), 2.01 (s, 3 H),
1.52 (s, 3 H), 1.44 (s, 3 H), 1.26 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C), 159.6 (C), 153.8 (C),
149.6 (C), 142.1 (CH), 123.7 (C), 112.7 (C), 90.3 (CH), 87.6 (C),
62.8 (CH2), 58.0 (CH), 46.6 (CH), 33.7 (CH2), 28.5 (CH3), 27.0
(CH3), 20.7 (CH3), 20.4 (CH3).
1H NMR (300 MHz, DMSO-d6): d = 12.28 (br s, 1 H, D2O exch),
8.16 (s, 1 H), 8.01 (s, 1 H), 5.06 (br s, 1 H, D2O exch), 4.71 (q,
J = 9.4 Hz, 1 H), 4.34 (br s, 1 H, D2O exch), 4.07 (d, J = 9.4 Hz, 1
H), 3.51 and 3.44 (ABX, J = 10.5, 6.4, 5.1 Hz, 2 H), 3.36 (br s, 1 H,
D2O exch), 2.34 (dt, J = 13.2, 9.4 Hz, 1 H), 1.97 (ABX, br dq,
J = 9.4, 5.8 Hz, 1 H), 1.70 (ddd, J = 13.2, 9.5, 5.8 Hz, 1 H), 1.18 (s,
3 H).
13C NMR (75 MHz, DMSO-d6): d = 156.8 (C), 148.8 (C), 145.2
(CH), 139.0 (CH), 124.2 (C), 79.4 (CH), 76.3 (C), 62.0 (CH2), 58.8
(CH), 47.0 (CH), 30.2 (CH2), 21.6 (CH3).
Anal. Calcd for C17H22ClN5O4: C, 51.58; H, 5.60; N, 17.69. Found:
C, 51.81; H, 5.65; N, 17.43.
2-Amino-6-cyclopropylamino-9-[(1¢R,2¢S,3¢R,4¢R)-4¢-hy-
droxymethyl-2¢,3¢-O-isopropylidene-3¢-methylcyclopent-1¢-
yl]purine [(–)-22]
Anal. Calcd for C12H16N4O4: C, 51.42; H, 5.75; N, 19.99. Found: C,
51.60; H, 5.79; N, 19.74.
Starting from (–)-21 (100 mg, 0.25 mmol), derivative (–)-22 (71
mg, 76%) was prepared according to the same procedure used in the
preparation of (–)-18; foam; [a]D25 –12.3 (c 1.0, MeOH).
IR (KBr): 3408, 1262, 1089 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44 (s, 1 H), 6.12 (br s, 1 H, D2O
exch), 4.96 (br s, 2 H, D2O exch), 4.62 (td, J = 10.6, 3.3 Hz, 1 H),
4.53 (d, J = 3.3 Hz, 1 H), 3.79 and 3.64 (ABX, J = 10.6, 6.4, 6.2 Hz,
2 H), 3.50 (br s, 1 H, D2O exch), 2.92 (m, 1 H), 2.45–2.24 (m, 3 H),
1.58 (s, 3 H), 1.50 (s, 3 H), 1.30 (s, 3 H), 0.80 (m, 2 H), 0.56 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 159.6 (C), 156.2 (C), 150.8 (C),
136.7 (CH), 115.1 (C), 113.2 (C), 90.7 (CH), 88.2 (C), 61.4 (CH2),
59.7 (CH), 50.3 (CH), 34.1 (CH2), 28.5 (CH3), 27.0 (CH3), 23.5
(CH), 20.6 (CH3), 7.3 (2 × CH2).
9-[(1¢R,2¢S,3¢R,4¢R)-4¢-Acetoxymethyl-2¢,3¢-O-isopropylidene-
3¢-methylcyclopent-1¢-yl]-2,6-diaminopurine [(–)-20]
Starting from triflate (–)-16 (200 mg, 0.53 mmol) and 2,6-diami-
nopurine (159 mg, 1.06 mmol), derivative (–)-20 (144 mg, 72%)
was prepared according to the same procedure used in the prepara-
tion of (–)-17; white solid; mp 151 °C; [a]D25 –15.4 (c 1.0, MeOH).
IR (KBr): 3309, 1748, 1238, 1092 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.83 (s, 1 H), 6.73 (br s, 2 H,
D2O exch), 5.78 (br s, 2 H, D2O exch), 4.73 (td, J = 9.8, 3.6 Hz, 1
H), 4.43 (d, J = 3.6 Hz, 1 H), 4.11 (d, J = 7.3 Hz, 2 H), 2.44–2.36
(m, 1 H), 2.29–2.22 (m, 2 H), 2.01 (s, 3 H), 1.52 (s, 3 H), 1.44 (s, 3
H), 1.26 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C), 160.1 (C), 156.2 (C),
151.5 (C), 136.3 (CH), 113.5 (C), 112.5 (C), 90.5 (CH), 87.5 (C),
62.9 (CH2), 57.4 (CH), 46.6 (CH), 34.1 (CH2), 28.5 (CH3), 27.0
(CH3), 20.7 (CH3), 20.5 (CH3).
Anal. Calcd for C18H26N6O3: C, 57.74; H, 7.00; N, 22.44. Found: C,
57.39; H, 6.97; N, 22.66.
Anal. Calcd for C17H24N6O4: C, 54.24; H, 6.43; N, 22.33. Found: C,
53.97; H, 6.48; N, 22.15.
2-Amino-6-cyclopropylamino-9-[(1¢R,2¢S,3¢R,4¢R)-2¢,3¢-dihy-
droxy-4¢-hydroxymethyl-3¢-methylcyclopent-1¢-yl]purine
[(–)-5]
2,6-Diamino-9-[(1¢R,2¢S,3¢R,4¢R)-2¢,3¢-dihydroxy-4¢-hydroxy-
methyl-3¢-methylcyclopent-1¢-yl]purine [(–)-4]
Starting from (–)-22 (60 mg, 0.16 mmol), compound (–)-5 (46 mg,
90%) was prepared according to the same procedure used in the
To an ice-cold solution of (–)-20 (100 mg, 0.27 mmol) in H2O (6
mL) under argon was carefully added CF3CO2H (12 mL) and the
mixture was stirred at r.t. for 12 h. The solvents were removed in
vacuo, the crude vic-diol dissolved in NH3/MeOH (ca. 7 M, 10 mL)
and the mixture stirred at r.t. for 24 h. After concentration, the resi-
due was purified by chromatography on silica gel (gradient
CH2Cl2–MeOH) to give 57 mg (74%) of (–)-4; white solid; mp
>220 °C (dec.); [a]D25 –16.4 (c 1.0, MeOH).
25
preparation of (–)-2; white solid; mp 96 °C; [a]D –38.4 (c 1.0,
MeOH).
IR (KBr): 3419, 1263, 1078 cm–1.
1H NMR (300 MHz, MeOH-d4): d = 7.76 (s, 1 H), 4.68 (q, J = 9.4
Hz, 1 H), 4.29 (d, J = 9.4 Hz, 1 H), 3.73 (d, J = 4.8 Hz, 2 H), 2.89
(tt, J = 7.0, 3.5 Hz, 1 H), 2.58 (dt, J = 13.5, 9.4, 1 H), 2.12 (dq,
Synthesis 2008, No. 20, 3253–3260 © Thieme Stuttgart · New York

3260
P. Brémond et al.
PAPER
(6) Cools, M.; De Clercq, E. Biochem. Pharmacol. 1989, 38,
J = 9.4, 4.8 Hz, 1 H), 2.02 (ddd, J = 13.5, 9.4, 4.8 Hz, 1 H), 1.35 (s,
3 H), 0.81 (m, 2 H), 0.59 (m, 2 H).
1061.
(7) De Clercq, E. Nucleosides Nucleotides 1998, 17, 625.
(8) De Clerq, E. Nucleosides, Nucleotides Nucleic Acids 2005,
24, 1395.
(9) Cantoni, G. L. In Biological Methylation and Drug Design;
Borchardt, R. T.; Creveling, C. R.; Ueland, P. M., Eds.;
Humana Press: Clifton NJ, 1986, 227–238.
13C NMR (75 MHz, MeOH-d4): d = 161.3 (C), 157.5 (C), 151.8 (C),
139.0 (CH), 115.3 (C), 80.9 (CH), 78.9 (C), 64.1 (CH2), 61.4 (CH),
48.6 (CH), 29.9 (CH2), 24.3 (CH), 21.5 (CH3), 7.6 (2 × CH2).
Anal. Calcd for C15H22N6O3: C, 53.88; H, 6.63; N, 25.13. Found:
C, 53.45; H, 6.69; N, 24.83.
(10) Turner, M. A.; Yang, X. D.; Kuczera, K.; Borchardt, R. T.;
Howell, P. L. Cell Biochem. Biophys. 2000, 33, 101.
(11) Bennet, L. L. Jr.; Brockman, R. W.; Rose, L. M.; Allan,
P. W.; Shaddix, S. C.; Shealy, Y. F.; Clayton, J. D. Mol.
Pharmacol. 1985, 27, 666.
9-[(1¢R,2¢S,3¢R,4¢R)-4¢-Hydroxymethyl-2¢,3¢-O-isopropylidene-
3¢-methylcyclopent-1¢-yl]guanine [(–)-23]
Starting from (–)-21 (100 mg, 0.25 mmol), derivative (–)-23 (73
mg, 87%) was prepared according to the same procedure used in the
preparation of (–)-19; foam; [a]D25 –7.2 (c 1.0, MeOH).
(12) Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1991, 34,
1521.
IR (KBr): 3429, 1264, 1072 cm–1.
(13) 2¢-Methylaristeromycin: Gosselin, G.; Griffe, L.; Meillon,
J.-C.; Storer, R. Tetrahedron 2006, 62, 906.
(14) 4¢-Methylaristeromycin: (a)Wachtmeister, J.; Mühlman, A.;
Classon, B.; Samuelsson, B. Tetrahedron 1999, 55, 10761.
(b) Gumina, G.; Chong, Y.; Choi, Y.; Chu, C. K. Org. Lett.
2000, 2, 1229. (c) Yin, X.-q.; Schneller, S. W. Tetrahedron
Lett. 2006, 47, 4057.
1H NMR (300 MHz, DMSO-d6): d = 11.11 (br s, 1 H, D2O exch),
7.82 (s, 1 H), 6.77 (br s, 2 H, D2O exch), 4.65 (ddd, J = 11.3, 7.4,
3.8 Hz, 1 H), 4.35 (d, J = 3.8 Hz, 1 H), 3.60 and 3.39 (ABX,
J = 10.4, 7.6, 5.1 Hz, 2 H), 3.50 (br s, 1 H, D2O exch), 2.35–2.00 (m,
3 H), 1.43 (s, 6 H), 1.24 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 157.0 (C), 153.8 (C), 151.0 (C),
136.2 (CH), 116.9 (C), 112.5 (C), 90.9 (CH), 87.8 (C), 60.2 (CH2),
57.9 (CH), 50.4 (CH), 35.0 (CH2), 28.7 (CH3), 27.2 (CH3), 20.7
(CH3).
(15) 5¢-Methylaristeromycin: Ye, W.; Schneller, S. W. J. Org.
Chem. 2006, 71, 8641.
(16) Franchetti, P.; Cappellacci, L.; Pasqualini, M.; Petrelli, R.;
Vita, P.; Jayaram, H. N.; Horvath, Z.; Szekerers, T.;
Grifantini, M. J. Med. Chem. 2005, 48, 4983.
(17) Brémond, P.; Audran, G.; Aubin, Y.; Monti, H. Synlett 2007,
1124.
(18) Marquez, V. E. In Advances in Antiviral Drug Design, Vol.
2; De Clercq, E., Ed.; JAI Press Inc.: Connecticut, 1996, 89–
146.
(19) Anti-HIV Nucleosides: Past, Present and Future; Mitsuya,
H., Ed.; R. G. Landes Co: Georgetown TX, 1997.
(20) Kitade, Y.; Kozaki, A.; Miwa, T.; Nakanishi, M.
Tetrahedron 2002, 58, 1271.
Anal. Calcd for C15H21N5O4: C, 53.72; H, 6.31; N, 20.88. Found: C,
54.01; H, 6.26; N, 21.19.
9-[(1¢R,2¢S,3¢R,4¢R)-2¢,3¢-Dihydroxy-4¢-hydroxymethyl-3¢-meth-
ylcyclopent-1¢-yl]guanine [(–)-6]
Starting from (–)-23 (60 mg, 0.18 mmol), compound (–)-6 (45 mg,
76%) was prepared according to the same procedure used in the
preparation of (–)-2, except that derivative (–)-6 was obtained as the
chlorhydrate salt after concentration and crystallization from
25
MeOH–H2O; white solid; mp >245 °C (dec.); [a]D –5.9 (c 1.0,
H2O).
(21) Audran, G.; Acherar, S.; Monti, H. Eur. J. Org. Chem. 2003,
IR (KBr): 3419, 1253, 1094 cm–1.
92.
1H NMR (400 MHz, D2O, 315 K): d = 8.99 (s, 1 H), 4.86 (q, J = 9.4
Hz, 1 H), 4.33 (d, J = 9.4 Hz, 1 H), 3.80 and 3.70 (ABX, J = 11.2,
7.1, 5.3 Hz, 2 H), 2.64 (dt, J = 13.9, 9.4 Hz, 1 H), 2.25 (ABX, m, 1
H), 1.96 (ddd, J = 13.9, 9.4, 6.5 Hz, 1 H), 1.35 (s, 3 H).
13C NMR (75 MHz, D2O, 315 K): d = 156.5 (2 × C), 151.8 (C),
137.9 (CH), 109.5 (C), 80.4 (CH), 78.7 (C), 63.6 (CH2), 62.4 (CH),
48.1 (CH), 29.7 (CH2), 21.8 (CH3).
(22) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190.
(23) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Jenny, T. F.;
Horlacher, J.; Previsani, N.; Benner, S. A. Helv. Chim. Acta
1992, 75, 1944. Review: (c) Hughes, D. L. Org. Prep.
Proced. Int. 1996, 28, 127. (d) But, T. Y. S.; Toy, P. H.
Chem. Asian J. 2007, 2, 1340.
(24) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.
(25) (a) Kazimierczuk, Z.; Revankar, G. R.; Robins, R. K.
Nucleic Acids Res. 1984, 12, 1179. (b) Kazimierczuk, Z.;
Cottam, H. B.; Revankar, G. R.; Robins, R. K. J. Am. Chem.
Soc. 1984, 106, 6379.
(26) (a) Pathak, T.; Bazin, H.; Chattopadhyaya, J. Tetrahedron
1986, 42, 5427. (b) Johnston, T. P.; Holum, L. B.;
Montgomery, J. A. J. Am. Chem. Soc. 1958, 80, 665.
(27) De Clercq, E. In Vivo and Ex Vivo Text Systems to
Rationalize Drug Design and Delivery; Cromelin, D.;
Couvreur, P.; Duchene, D., Eds.; Editions de Santé: Paris,
1994.
Anal. Calcd for C12H18ClN5O4: C, 43.44; H, 5.47; N, 21.11. Found:
C, 43.56; H, 5.42; N, 21.43.
Acknowledgment
P.B. thanks the Ministère de l’Education Nationale, de l’Enseigne-
ment Supérieur et de la Recherche for a Ph.D. grant. The authors are
thankful to Dr. R. Faure for 2D NMR experiments and to D. Pujol
for technical assistance. Sidaction (France) is gratefully acknowl-
edged for financial support (AI18-3-01375).
(28) Sheldrick, G. M. SHELXL-97, Program for Crystal
Structure Refinement; University of Göttingen: Germany,
1997.
(29) CCDC-689835 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336 033; E-mail:
deposit@ccdc.cam.ac.uk.
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T.; Mizuko, K. J. Antibiot. 1968, 21, 255.
(3) Kishi, T.; Muroi, M.; Kusaka, T.; Nishikawa, M.; Kamiya,
K.; Mizuno, K. Chem. Pharm. Bull. 1972, 20, 940.
(4) Ueland, P. M. Pharmacol. Rev. 1982, 34, 223.
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Synthesis 2008, No. 20, 3253–3260 © Thieme Stuttgart · New York