Synthesis of novel purinyl-1′-homocarbanucleosides based on a cyclopenta[b]pyrazine system

Article abstract of DOI:10.1248/cpb.56.654

cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dimethanol, prepared by Diels-Alder reaction from cyclopentadiene and appropriately protected 2-imidazolone-followed by dihydroxylation, glycol protection, diamine deprotection, condensation with benzyl, glycol deprotection, oxidative cleavage and reduction-, was used to synthesize (±)-cis-{[7-(6-chloro-9H-purin-9- yl)methyl]-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]-pyrazin-5-yl}methanol, a key intermediate for novel 1′-homocarbanucleosides based on a cyclopenta[b]pyrazine scaffold as shown by its conversion into several 6-substituted purinyl derivatives.

Full text of DOI:10.1248/cpb.56.654

654
Chem. Pharm. Bull. 56(5) 654—658 (2008)
Vol. 56, No. 5
Synthesis of Novel Purinyl-1ꢀ-homocarbanucleosides Based on a
Cyclopenta[b]pyrazine System
a
Carmen BALO, Carmen LÓPEZ, ,a Olga CAAMAÑO,a Franco FERNÁNDEZ,a Xerardo GARCÍA-MERA,a and
*
b
José Enrique RODRÍGUEZ-BORGES
a Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela; 15782-Santiago
b
de Compostela, Spain: and CIQ. Departamento de Química da Facultade de Ciencias do Porto; Ruado Campo Alegre,
687–4169007 Porto, Portugal.
Received November 29, 2007; accepted February 2, 2008; published online February 14, 2008
cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dimethanol, prepared by Diels–Alder reaction
from cyclopentadiene and appropriately protected 2-imidazolone—followed by dihydroxylation, glycol protec-
tion, diamine deprotection, condensation with benzyl, glycol deprotection, oxidative cleavage and reduction—,
was used to synthesize (ꢁ)-cis-{[7-(6-chloro-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]-
pyrazin-5-yl}methanol, a key intermediate for novel 1ꢀ-homocarbanucleosides based on a cyclopenta[b]pyrazine
scaffold as shown by its conversion into several 6-substituted purinyl derivatives.
Key words imidazolone; oxidative cleavage; hydroxylation; dihydropyrazine; epimerization; homocarbanucleoside
The success of abacavir (1) as reverse transcriptase in- Results and Discussion
hibitor in human immunodeficiency (HIV) clinical trials,1—4)
Our work was initially planned on a convergent synthesis
which led to its approval by FDA for treatment of HIV infec- (Chart 1) that brings together the preformed main blocs of
tion in 1998, has been attributed in large part to the rigidity the final structure through a Mitsunobu coupling, as in some
afforded by its double bond between C2ꢀ and C3ꢀ5,6) and to previous analogues.13) Now, while several purine derivatives
its cyclopropylamino group, which increases its lipophilicity are commercially available, this strategy compelled us to
and its ability to penetrate into the central nervous system, an achieve a properly functionalised cyclopenta[b]pyrazine de-
important reservoir of the HIV and other viruses.7)
rivative, and a dimethanol derivative of the type B was envis-
Inspired on that, our research group has been investigating aged as the key synthetic intermediate. B would be available
the biological properties of other carbanucleosides as well as through a sequence based on the retrosynthetic pathway
their 1ꢀ-homo-counterparts, in which the planar region of the B⇒E depicted in Chart 1.
carbocyclic double bond present in abacavir is replaced by a
Following 1,3-diacetylation of 2-imidazolone, compound 3
benzene ring8—10) or by an aromatic heterocycle,11—13) seek- (Chart 2) was obtained as per Whitney.14) Hydroxylation with
ing to modify the lipophilicity and polar interactions of this OsO4 and methylmorpholine N-oxide15) in acetone/water af-
region of the molecule while preserving its rigidity. Most of forded a 74% yield of glycol 4, which upon treatment with
the new compounds showed little if any antiviral activity dimethoxypropane gave acetonide 5. An attempt to convert 5
against HIV, but in a broader antiviral survey some of them into diamine 7 in one step by heating with KOH in methanol
in which there is a pyrazol ring fused to the cyclopentene at 155 °C afforded a complex mixture including only traces
ring such as in 2, proved to be highly active against varicella- of the desired product, while a two-steps process, heating of
zoster virus and cytomegalovirus at subcytotoxic concentra- compound 5 with KOH in methanol at 65 °C, isolation of the
tion,12) while an important number of both indan and cy- resulting imidazolone 6, and heating of 6 with KOH in
clopenta[c]pyrazole derivatives were found to have consider- methanol at 155 °C in a sealed tube,16) afforded a good yield
1
able cytostatic activity against human T lymphocytes (Molt4/ of a product that could be by identified as 7 by H-NMR
C8 and CEM/0 cells).8,9,13)
spectroscopy. Due to the lability and volatility of this kind of
These results pushed us to further explore the field of compounds,16) 7 was used in the next step without further pu-
compounds in which an heterocycle is fused to the cyclopen-
tene moiety of the carbanucleoside. Here we report a syn-
thetic way that leads to 1ꢀ-homonucleoside analogues of the
type A, based on a 6,7-dihydro-5H-cyclopenta[b]pyrazine
scaffold.
Chart 1
∗ To whom correspondence should be addressed. e-mail: qomcls@usc.es
© 2008 Pharmaceutical Society of Japan

May 2008
655
Reaction conditions: a) OsO4, NMO, 40 °C; b) 2,2-dimethoxypropane/Hꢂ, r.t.; c) KOH/MeOH, reflux. 5 h; d) KOH/MeOH, 155 °C, 48 h; e) benzil/THF/Hꢂ, reflux; f)
DDQ/toluene, reflux. 2.5 h; g) HCl/EtOH, 70 °C, 10 h; h) NaIO4/silica gel CH2Cl2, r.t.; i) NaBH4/MeOH, r.t.
Chart 2
rification. Thus, crude 7 was condensed with benzil in THF
with acetic acid as catalyst, and the resulting dihydropyrazine
(8) was aromatized in 86% yield by refluxing with 4,5-
dichloro-3,6-dioxo-1,4-cyclohexadiene-1-2-dicarbonitrile
(DDQ) in toluene for 2.5 h. Attempts to achieve mild cleav-
age of the acetonide moiety of compound 9 (treatment with
60% AcOH or HCO2H, at r.t. or under reflux, or with HClO4
or BF3·OEt2 at r.t.) were all unsuccessful, the starting mate-
rial being recovered or intractable mixtures of unidentified
products being obtained. Finally diol 10 was prepared in
good yield by moderate heating of 9 in EtOH in presence of
HCl.
Fig. 1. ORTEP Projection of the Molecular Structure of Compound 13
Oxidative cleavage of 10 with sodium periodate on silica
gel17) then gave dialdehyde 11 (as identified by IR spec- ride, triethylamine and 4-(dimethylamino)pyridine (DMAP)
troscopy), and reduction of crude 11 with NaBH4 in at 0 °C (Chart 2). Coupling 15 with 6-chloropurine by reac-
methanol finally afforded an approximately 2 : 1 mixture of tion in DMF in the presence of NaH and 18-crown-6 ether11)
the desired cis-diol 12 and its diastereomer 13; partial finally afforded nucleoside analogue 16 in 37% yield; an
epimerization is presumed to have occurred during these last alkene, thought to be 17 (two singlets at 5.36 and 6.17 ppm
1
two steps.
in the H-NMR spectra) and formed from 15, presumably
Diastereomers 12 and 13 were clearly distinguished and through a dehydromesyloxylation promoted by the basic
cis/trans relative configurations initially assigned to them on medium,11) was also detected as the main by-product (in an
1
the basis of their H-NMR spectra: each of the chemically estimated 25% yield).
unequivalent C6 protons of cis-diol 12 gives rise to a doublet
Suitability of chloropurine 16 to serve as an appropriate
of triplets, at d 1.61 (Jꢁ9.3, 13.1 Hz) and d 2.51 (Jꢁ8.3, key intermediate for the preparation of nucleoside analogues
13.1 Hz), while the two chemically equivalent C6 protons of this new class was shown through its smooth conversion
of trans-diol 13 give rise to a single triplet at d 2.18 into methoxypurine analogue 18 by treatment with methanol
(Jꢁ7.3 Hz). Compound 13 was then conclusively identified and aqueous HCl at room temperature (r.t.), and into amino
by X-ray crystallography (Fig. 1).18)
derivatives 19 and 20, by reaction with liquid ammonia and
Several attempts to perform Mitsunobu processes with 6- cyclopropylamine, respectively.
chloropurine on 12 or monoprotected derivatives of it were
In conclusion, this paper describes a convenient synthetic
fruitless and we then turned to more classical nuecleophilic procedure for the preparation of novel purinyl-1ꢀ-homocar-
displacements. Esterification of 12 with acetic anhydride and banucleoside derivatives 16, 18, 19 and 20, as examples of an
pyridine afforded a mixture including the starting compound, interesting new template in which the double bond of the cy-
its diacetate, and the monoacetate 14, which was converted clopentenyl nucleosides is embedded in a pyrazine ring, thus
into mesylate 15 in 69% yield by treatment with mesyl chlo- opening a route to a wide variety of other purinyl derivatives

656
Vol. 56, No. 5
amount of p-toluenesulphonic acid was stirred at r.t. until reaction was
judged to be complete on the basis of TLC monitoring (12 h). The reaction
mixture was then washed with saturated NaHCO3 solution and extracted
with CH2Cl2, and the organic phase was dried with Na2SO4 and concentrated
to dryness under reduced pressure, affording 5 as a white solid (3.23 g, yield
89%) from which a sample was taken and recrystallized from toluene for
analysis, mp 176—177 °C. IR (KBr) cmꢄ1: 2991, 2944, 1746, 1691, 1368,
1322, 1277, 1238, 1056. 1H-NMR (CDCl3) d: 1.24 (3H, s, CH3), 1.24—1.29
(1H, m, 9-HH), 1.42 (3H, s, CH3), 1.87 (1H, d, Jꢁ11.6 Hz, 9-HH), 2.52 (6H,
s, 2ꢅCH3), 2.92—2.94 (2H, m, 4-Hꢂ8-H), 3.98 (2H, d, Jꢁ1.4 Hz, 3a-
Hꢂ8a-H), 4.29 (2H, t, Jꢁ2.3 Hz, 4a-Hꢂ7a-H). 13C-NMR (CDCl3) d: 24.33
(CH3), 24.73 (CH3), 25.73 (CH3), 30.84 (CH2), 43.55 (CH), 53.60 (CH),
76.81 (CH), 109.45 (C), 152.41 (CO), 171.12 (CO). Anal. Calcd for
C15H20N2O5 (308.33): C, 58.43; H, 6.49; N, 9.09. Found: C, 58.67, H, 6.69,
N, 10.13.
(3aR,4R,4aR,7aS,8S,8aS)-2,2-Dimethylperhydro-4,8-methano[1,3]-
dioxolo[4,5-f]benzoimidazol-6-one (6)
A suspension of 5 (3.05 g,
9.9 mmol), methanol (12 ml) and 50% KOH (4.5 ml) was refluxed for 5 h
with TLC monitoring, and the solids were then filtered out, washed repeat-
edly with water, and dried to constant mass (1.67 g) in a vacuum desiccator.
The filtrate was neutralized and extracted with CHCl3, and the CHCl3 phase
was dried and concentrated to dryness under reduced pressure, yielding a
solid (0.32 g) with the same chromatographic Rf as the filtration residue.
Total yield, 91%. A sample was taken and recrystallized from toluene for
analysis, mp 310—312 °C. IR (KBr) cmꢄ1: 3358, 3236, 2977, 1693, 1379,
1
1249, 1213, 1039, 860. H-NMR (DMSO-d6) d: 1.05 (1H, d, Jꢁ10.7 Hz, 9-
HH), 1.20 (3H, s, CH3), 1.33 (3H, s, CH3), 1.53 (1H, d, Jꢁ10.7 Hz, 9-HH),
2.24 (2H, s, 4-Hꢂ8-H), 3.84 (2H, s, 3a-Hꢂ8a-H), 4.29 (2H, s, 4a-Hꢂ7a-H),
6.37 (2H, 2ꢅNH, exch. D2O). 13C-NMR (DMSO-d6) d: 24.13 (CH3), 25.78
(CH3), 30.13 (CH2), 44.06 (CH), 53.68 (CH), 77.13 (CH), 107.85 (C),
162.48 (CO). Anal. Calcd for C11H16N2O3 (224.25): C, 58.91; H, 7.19; N,
12.49. Found: C, 59.08; H, 7.32, N, 12.61.
(3aR,4R,5R,6S,7S,7aS)-2,2-Dimethylperhydro-4,7-methano-1,3-benzo-
dioxole-5,6-diamine (7) A suspension of 6 (1.9 g, 8.5 mmol) in methanol
(8.6 ml) and 50% KOH (21 ml) was heated at 155 °C in a sealed tube for
48 h, allowed to cool to r.t., concentrated, and extracted with CHCl3. The
CHCl3 phase was dried over Na2SO4, and removal of the solvent under re-
Reaction conditions: i) Ac2O/Pyr, r.t.; ii) MeSO2Cl, NEt3/DMAP; iii) 6-chloropurine,
NaH, 18-crow-6 ether; HCl, MeOH, r.t.; iv) MeOH/HCl, r.t.; v) MeOH/NH3, 75 °C; vi)
cyclopropylamine/EtOH, reflux.
Chart 3
with similar cyclopenta[b]pyrazine scaffolds.
Experimental
All chemical used were of reagent grade and were obtained from Aldrich duced pressure left a yellow solid (1.63 g) that was used in the next step
Chemical Co. and used without further purification. Melting points were
measured in a Reichert Kofler Thermopan and are uncorrected. Infrared
without further purification. 1H-NMR (DMSO-d6) d: 1.03—1.08 (1H, m, 8-
HH), 1.20—1.58 (11H, m, 2ꢅCH3ꢂ8-HHꢂ2ꢅNH2, exch. four with D2O),
spectra were recorded on a Perkin-Elmer 1640 FT-IR spectrophotometer. 1H- 2.64 (2H, s, 4-Hꢂ7-H), 3.34 (2H, s, 3a-Hꢂ7a-H), 4.32 (2H, s, 5-Hꢂ6-H).
and 13C-NMR spectra were recorded in a Bruker AMX-300 spectrometer at
(3aR,4R,4aR,8aS,9S,9aS)-2,2-Dimethyl-6,7-diphenyl-3a,4,4a,8a,9,9a-
300 and 75 MHz, respectively, using TMS as internal standard (chemical hexahydro-4,9-methano[1,3]dioxolo[4,5-g]quinoxaline (8) A solution of
shifts in d values, J in Hz). Microanalyses were performed in a LECO benzil (1.72 g, 8.2 mmol) in THF (6 ml) was added to a solution of crude 7
CHNS-932 Elemental Analyser at the University of Santiago Microanalysis (1.63 g, 8.2 mmol) in the same solvent (20 ml), a catalytic amount of acetic
Service. Analyses indicated by the symbols of elements were within ꢃ0.4%
acid was added, and the mixture was refluxed until reaction was deemed
of the theoretical values. Flash chromatography was performed on silica gel complete on the basis of TLC monitoring (4 h). Concentration to dryness left
(Merck 60, 230—240 mesh) and analytical TCL on pre-coated silica gel a yellow solid that was purified by chromatography on silica gel with (2 : 1)
plates (Merck 60, F254, 0.25 mm). MPLC separations were carried out using
hexane/EtOAc as eluent followed by recrystallization from ethanol (1.92 g,
a Biotage Flash 4Di system with a Biotage column (Si-40B, silica gel). X- yield 63%), mp 166—167 °C. IR (KBr) cmꢄ1: 2984, 2912, 1570, 1461,
1
Ray diffraction data were collected in an Enraf-Nonius CAD4 automatic dif- 1206, 1057. H-NMR (CDCl3) d: 1.16—1.20 (4H, m, CH3ꢂ10-HH), 1.39
fractometer using the programme CAD4-EXPRESS.
(3H, s, CH3), 1.73 (1H, d, Jꢁ10.7 Hz, 10-HH), 2.98 (2H, m, 4-Hꢂ9-H),
(3aR,4R,5R,6S,7S,7aS)-1,3-Diacetyl-5,6-dihydroxyperhydro-4,7- 4.19—4.21 (2H, m, 3a-Hꢂ9a-H), 4.22 (2H, d, Jꢁ1.2 Hz, 4a-Hꢂ8a-H),
methanobenzo-imidazol-2-one (4) A solution of 3 (4.0 g, 17 mmol) in
7.03—7.21 (10H, m, arom). 13C-NMR (CDCl3) d: 24.29 (CH3), 25.80
(4 : 1 acetone/water) (35 ml) was heated to 40 °C and methylmorpholine N- (CH3), 27.18 (CH2), 47.05 (CH), 54.69 (CH), 78.04 (CH), 108.90 (C),
oxide (2.2 g, 18.9 mmol) was added, followed after 5 min at the same tem- 128.24 (CH), 128.44 (CH), 129.39 (CH), 139.37 (C), 156.76 (C). Anal.
perature by a 4% (w/w) solution of OsO4 in water (0.5 ml), which immedi- Calcd for C24H24N2O2 (372.46): C, 77.39; H, 6.49; N, 7.52. Found: C, 77.18;
ately caused the mixture to turn brown. After 90 min stirring at 40 °C the re-
action mixture was filtered through celite, concentrated, and treated with sat-
H, 6.75, N, 7.33.
(3aR,4R,9S,9aS)-2,2-Dimethyl-6,7-diphenyl-3a,4,9,9a-tetrahydro-4,9-
urated NH4Cl solution. This mixture was extracted with EtOAc, the organic methano[1,3]-dioxolo[4,5-g]quinoxaline (9) A solution of DDQ (1.09 g,
phase was washed with brine and dried over Na2SO4, the solvent was re- 4.8 mmol) in toluene (20 ml) was added to a solution of 8 (1.79 g, 4.8 mmol)
moved under reduced pressure, and purification of the residue by chromatog- in the same solvent (28 ml), and the mixture was refluxed under argon for
raphy on silica gel with 1 : 1 hexane/EtOAc as eluent afforded 4 as a white 2.5 h, vacuum filtered, and concentrated to dryness, leaving a reddish solid
solid (3.55 g, yield 74%). A sample was recrystallized from toluene for
that was recrystallized from EtOH/EtOAc (1.53 g, yield 86%), mp 237—
analysis, mp 178—179 °C. IR (KBr) cmꢄ1: 3479, 2957, 1755, 1683, 1274, 239 °C. IR (KBr) cmꢄ1: 2984, 2907, 1454, 1360, 960. H-NMR (CDCl3) d:
1239. 1H-NMR (CDCl3) d: 1.39 (1H, d, Jꢁ11.7 Hz, 8-HH), 2.04 (1H, d, 1.30 (3H, s, CH3), 1.51 (3H, s, CH3), 2.19 (1H, dd, Jꢁ1.4, 10.1 Hz, 10-HH),
Jꢁ11.7 Hz, 8-HH), 2.53 (6H, s, 2ꢅCH3), 2.69 (2H, s, 2ꢅOH, D2O exch.), 2.48 (1H, d, Jꢁ10.1 Hz, 10-HH), 3.50 (2H, s, 4-Hꢂ9-H), 4.47 (2H, d,
2.83 (2H, s, 4Hꢂ7H), 3.76 (2H, s, 5Hꢂ6H), 4.27 (2H, s, 3aHꢂ7aH). 13C- Jꢁ1.2 Hz, 3a-Hꢂ9a-H), 7.16—7.32 (10H, m, arom.). 13C-NMR (CDCl3) d:
NMR (CDCl3) d: 24.80 (CH3), 31.16 (CH2), 46.76 (CH), 54.16 (CH), 68.99 24.75 (CH3), 26.15 (CH3), 41.61 (CH2), 48.77 (CH), 80.86 (CH), 114.20
1
(CH), 152.55 (CO), 172.00 (CO). Anal. Calcd for C12H16N2O5 (268.27): C,
(C), 128.55 (CH), 128.68 (CH), 130.15 (CH), 139.39 (C), 150.50 (C),
53.73; H, 6.01; N, 10.44. Found: C, 53.70, H, 5.99, N, 10.43.
158.89 (C). Anal. Calcd for C24H22N2O2 (370.45): C, 77.81; H, 5.99; N,
(3aR,4R,4aR,7aS,8S,8aS)-5,7-Diacetyl-2,2-dimethylperhydro-4,8- 7.56. Found: C, 77.53, H, 6.11, N, 7.38.
methano[1,3]dioxolo[4,5-f]benzoimidazol-6-one (5) A solution of diol 4
(3.18 g, 11.9 mmol) in 2,2-dimethoxypropane (8 ml) containing a small
(5R,6R,7S,8S)-2,3-Diphenyl-5,6,7,8-tetrahydro-5,8-methanoquinoxa-
line-6,7-diol (10) 12 N HCl (1.5 ml) was added to a suspension of 9

May 2008
657
(1.31 g, 3.54 mmol) in ethanol (60 ml) at 0 °C, and the mixture was heated at
70 °C until TLC showed no starting compound (10 h). Following removal of
the solvent under reduced pressure, the residue was taken into methanol and
passed through an ion-exchange column (Amberlite IRA 400 OHꢄ), and the
methanolic eluate was concentrated to dryness. Column chromatography
of the residue on silica gel with 3 : 1 hexane/EtOAc as eluent afforded a
solid (0.84 g, yield 72%), a sample of which was recrystallized from
hexane/EtOAc for analysis, mp 185—187 °C. IR (KBr) cmꢄ1: 3384, 1449,
1364, 1222, 1144, 949. 1H-NMR (CDCl3) d: 2.15 (1H, d, Jꢁ10.1 Hz, 9-
HH), 2.44 (1H, d, Jꢁ10.1 Hz, 9-HH), 3.42 (2H, s, 5-Hꢂ8-H), 3.97 (2H, s, 6-
Hꢂ7-H), 4.37 (2H, br s, 2ꢅOH, exch. D2O), 7.26—7.19 (10H, m, arom.).
13C-NMR (CDCl3) d: 42.22 (CH2), 51.59 (CH), 70.41 (CH), 128.44 (CH),
128.68 (CH), 130.13 (CH), 138.42 (C), 146.78 (C), 157.77 (C). Anal. Calcd
for C21H18N2O2 (330.38): C, 76.34; H, 5.49; N, 8.48. Found: C, 76.00, H,
5.68, N, 8.81.
2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dicarbalde-
hyde (mixture of cis and (ꢁ)-trans) (11) A 0.65 M aqueous solution of
NaIO4 (6.06 ml) was added to a suspension of silica gel (5.9 g) in CH2Cl2
(50 ml), and the mixture was shaken vigorously by hand and, following the
formation of a flaky precipitate, added to a solution of 10 (1.0 g, 3.03 mmol)
in CH2Cl2 (6.0 ml). This mixture was stirred at room temperature until TLC
showed no starting compound (15 min), and was then filtered through
Na2SO4 and concentrated under reduced pressure, affording a vivid orange
solid that was identified as compound 11 (on the basis of the strong carbonyl
band at 1723 cmꢄ1 in its IR spectrum) and was used without further purifica-
tion in the next step.
(1H, dd, Jꢁ7.1, 11.1 Hz, CHHOAc), 4.72 (1H, dd, Jꢁ4.6, 11.1 Hz,
CHHOAc), 7.25—7.40 (10H, m, arom.). 13C-NMR (CDCl3) d: 21.35 (CH3),
29.39 (CH2), 42.14 (CH), 43.63 (CH), 66.19 (CH2), 66.32 (CH2), 128.60
(CH), 128.87 (CH), 128.92 (CH), 130.22 (CH), 139.08 (C), 139.26 (C),
155.85 (C), 158.41 (C), 171.53 (CO). Anal. Calcd for C23H22N2O3 (374.44):
C, 73.78; H, 5.94; N, 7.48. Found: C, 73.69; H, 6.05; N, 7.22.
(ꢁ)-cis-{[7-(Methanesulfonyloxymethyl)-2,3-diphenyl-6,7-dihydro-5H-
cyclopenta[b]pyrazin-5-yl]}methyl Acetate (15) To a solution of 14
(400 mg, 1.07 mmol) in dry chloroform (5 ml) in an ice bath were added
Et3N (0.5 ml) and a catalytic amount of DMAP. Following dropwise addition
of mesyl chloride (0.25 ml, 3.2 mmol), the mixture was stirred at r.t. for 2 h,
refluxed for 12 h with TLC monitoring, poured over ice-water, and left stir-
ring for 1 h, after which the organic phase was drawn off, washed with 1 N
NaOH and brine, dried with Na2SO4 and concentrated under reduced pres-
sure, affording compound 15 as an oil that was purified by column chro-
matography with (2 : 1) hexane/AcOEt as eluent (330 mg, yield 69%). IR
(film) cmꢄ1: 3450, 3025, 2989, 1735, 1456, 1285, 1250, 1045, 977, 879,
755. 1H-NMR (CDCl3) d: 1.94—2.04 (1H, m, 6-HH), 2.08 (3H, s, CH3CO),
2.77 (1H, dt, Jꢁ8.8, 13.5 Hz, 6-HH), 2.99 (3H, s, CH3SO3), 3.65—3.73 (2H,
m, 5-Hꢂ7-H), 4.40 (1H, dd, Jꢁ6.8, 9.8 Hz, CHH), 4.62 (1H, dd, Jꢁ6.8,
10.0 Hz, CHH), 4.71—4.81 (2H, m, 2ꢅCHH), 7.26—7.54 (10H, m, arom.).
13C-NMR (CDCl3) d: 21.35 (CH3), 28.35 (CH2), 38.01 (CH3SO3), 40.21
(CH), 42.57 (CH), 67.90 (CH2), 68.85 (CH2), 128.01 (CH), 128.77 (CH),
129.33 (CH), 138.26 (C), 138.97 (C), 155.60 (C), 158.32 (C), 171.50 (CO).
Anal. Calcd for C24H24N2O5S (452.52): C, 63.70; H, 5.35; N, 6.18; S, 7.08.
Found: C, 63.98; H, 5.55; N, 6.34; S, 6.89.
cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-di-
methanol (12) and (ꢁ)-trans-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta-
[b]pyrazine-5,7-dimethanol (13) NaBH4 (56.74 mg, 1.5 mmol) was added
to a solution of 10 (90 mg, 0.27 mmol) in MeOH (15 ml) and the mixture
was left stirring (colour change). When TLC showed no remaining starting
compound (30 min), water (10 ml) was added and stirring was continued for
15 min, after which the methanol was removed under reduced pressure and
the remaining aqueous solution was extracted with EtOAc. The organic
phase was dried with Na2SO4 and concentrated to dryness, leaving a solid
(ꢁ)-cis-{[7-(6-Chloro-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihy-
dro-5H-cyclopenta[b]pyrazin-5-yl]}methyl Acetate (16) A solution of 6-
chloropurine (148 mg, 0.96 mmol), NaH (24 mg, 0.96 mmol) and 18-crown-
6 ether (170 mg, 0.66 mmol) in DMF (8 ml) was heated to 55 °C, a solution
of mesylate 15 (300 mg, 0.66 mmol) in the same solvent (4 ml) was added,
and heating was continued for 20 h. The solvent was removed under reduced
pressure, and chromatography of the residue on silica gel with (1 : 1)
hexane/EtOAc as eluent finally afforded compound 16 as a white solid
(180 mg, yield 37%), mp 196—198 °C. IR (KBr) cmꢄ1: 3323, 2990, 1739,
1
that following chromatography on
a silica gel column with (1 : 2)
1594, 1336, 1044, 768. H-NMR (CDCl3) d: 1.86 (1H, dt, Jꢁ8.8, 13.2 Hz,
hexane/EtOAc as eluent afforded a solid foam (81 mg, yield 80%) with two
components. Further chromatography on an MPLC column with (98 : 2)
CH2Cl2/MeOH as eluent afforded the 12 (52 mg) followed by the 13
(29 mg).
6-HH), 1.99 (3H, s, CH3), 2.72 (1H, dt, Jꢁ8.4, 13.2 Hz, 6-HH), 3.60—3.67
(1H, m, 5-H), 3.85—3.93 (1H, m, 7-H), 4.36 (1H, dd, Jꢁ6.6, 11.0 Hz, 5-
CHH), 4.64 (1H, dd, Jꢁ4.2, 11.1 Hz, 5-CHH), 4.87 and 4.78 (2H, AB part
of an ABX system, JAXꢁ6.0, JBXꢁ6.2, JABꢁ14.1 Hz, 7-CH2), 7.26—7.50
(10H, m, arom.), 8.29 and 8.72 (2H, 2s, 2ꢀ-Hꢂ8ꢀ-H). 13C-NMR (CDCl3) d:
20.89 (CH3), 30.86 (CH2), 41.17 (CH), 42.25 (CH), 46.31 (CH2), 65.15
(CH2), 128.12 (CH), 128.18 (CH), 128.55 (CH), 128.89 (C), 129.50 (CH),
129.66 (CH), 129.77 (C), 138.30 (C), 138.39 (C), 146.01 (CH), 151.32 (C),
151.81 (CH), 152.02 (C), 152.22 (C), 154.36 (C), 154.93 (C), 170.73 (CO).
Anal. Calcd for C26H21ClN6O (464.94): C, 66.82; H, 4.54; N, 17.45. Found:
C, 66.59, H, 4.51, N, 17.92.
Compound 12: mp 126—128 °C (from EtOAc/Et2O). IR (KBr) cmꢄ1
:
1
3411, 2899, 1594, 1449, 1386, 1238, 1059, 950. H-NMR (CDCl3) d: 1.61
(1H, dt, Jꢁ9.3, 13.1 Hz, 6-HH), 2.51 (1H, dt, Jꢁ8.3, 13.1 Hz, 6-HH),
3.51—3.71 (4H, m, 5-Hꢂ7-Hꢂ2ꢅOH (two of them D2O exch.), 3.92 (2H,
dd, Jꢁ7.9, 10.8 Hz, 2ꢅCHHOH), 4.05 (2H, dd, Jꢁ4.9, 10.8 Hz,
2ꢅCHHOH), 7.24—7.41 (10H, m, arom.). 13C-NMR (CDCl3) d: 28.09
(CH2), 44.10 (CH), 66.07 (CH2), 128.63 (CH), 128.94 (CH), 130.19 (CH),
139.04 (C), 151.56 (C), 158.63 (C). Anal. Calcd for C21H20N2O2 (332.40):
C, 75.88; H, 6.06; N, 8.43. Found: C, 76.08, H, 6.18, N, 8.69.
(ꢁ)-cis-{[7-(6-Methoxy-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihy-
dro-5H-cyclopenta[b]pyrazin-5-yl]}methanol (18)
A solution of 16
Compound 13: mp 207—209 °C (from EtOAc/Et2O). IR (KBr) cmꢄ1
:
(305 mg, 0.59 mmol), MeOH (4 ml) and HCl 1 N (4 ml) was stirred at r.t. for
14 h, and after removal of the solvent the resulting residue was dissolved in
EtOAc (20 ml). This solution was washed with brine (20 ml) and the solvent
removed under reduced pressure, leaving a oil (260 mg) that after chro-
matography on silica gel with CH2Cl2–MeOH (92 : 8) as eluent afforded 18
as a oil (120 mg; 43% yield). IR (film) cmꢄ1: 3400, 2989, 2869, 1602,1486,
1414, 1285, 1045, 977, 879, 755. 1H-NMR (CDCl3) d: 1.71 (1H, dt,
Jꢁ13.3 Hz, 6-HH), 2.48 (1H, dt, Jꢁ13.3 Hz, 6-HH), 3.42 (3H, s, OCH3),
3.55—3.62 (1H, m, 5-H), 3.78—3.84 (2H, m, 5-CH2), 3.98—4.04 (1H, m,
7-H), 4.13 (1H, br s, OH, D2O exch), 4.55—4.61 (part A of an ABX system
1
3380, 3225, 2921, 2864, 1459, 1387, 1141, 772. H-NMR (CDCl3) d: 1.65
(1H, br s, OH, D2O exch.), 2.18 (2H, t, Jꢁ7.3 Hz, 6-HH), 3.08 (1H, br s,
OH, D2O exch.) 3.51—3.61 (2H, m, 5-Hꢂ7-H), 3.91 (2H, dd, Jꢁ7.8,
10.5 Hz, 2ꢅCHHOH), 4.02 (2H, dd, Jꢁ5.9, 10.5 Hz, 2ꢅCHHOH), 7.13—
7.52 (10H, m, arom.). 13C-NMR (CDCl3) d: 27.38 (CH2), 43.89 (CH), 65.84
(CH2), 128.12 (CH), 128.40 (CH), 128.68 (CH), 138.53 (C), 151.15 (C),
157.62 (C). Single crystals suitable for X-ray diffractometry were obtained
by dissolving a sample of 13 in the least possible quantity of cold EtOAc in
an open vial that was then placed in a larger container with a little hexane at
the bottom; the container was closed, and after a few days in a cool, dark
place free from vibrations some single crystals were formed, one of which
was analysed by X-ray diffractometry.
J
J
AXꢁ5.7, JABꢁ14.3 Hz, CHHN) 4.75—4.86 (part B of an ABX system
BXꢁ7.7, JBAꢁ14.3 Hz, CHHN), 7.19—7.34 (10H, m, arom.), 7.88 and 8.01
(2H, 2s, 2ꢀ-Hꢂ8ꢀ-H). 13C-NMR (CDCl3) d: 32.8 (CH2), 35.2 (CH), 44.2
(CH), 45.8 (CH3), 46.3 (CH2), 62.1 (CH2), 121.1 (C), 127.8 (CH), 128.7
(CH), 128.9 (CH), 129.8 (C), 136.3 (CH), 136.8 (C), 142.0 (CH), 146.5 (C),
151.4 (C), 152.3 (CH), 158.4 (C), 160.2 (C), 162.3 (C). Anal. Calcd for
C27H24N6O2 (464.52): C, 69.81; H, 5.21; N, 18.09. Found: C, 69.98, H, 5.52,
N, 17.86.
(ꢁ)-cis-[7-(Hydroxymethyl)-2,3-diphenyl-6,7-dihydro-5H-
cyclopenta[b]pyrazin-5-yl]methyl Acetate (14) Acetic anhydride
(180 mg, 1.8 mmol) was added to a solution of 12 (60 mg, 0.18 mmol) in
pyridine (2 ml), the mixture was stirred under argon at r.t. for 12 h, water
was added, and following extraction with AcOEt the organic phase yielded a
residue from which chromatography on silica gel with hexane/EOtAc (3 : 1)
as eluent separated the diester (12 mg), the desired monoester 14 (as oil)
(53 mg, yield 52%), and starting diol 12 (10 mg). IR (film) cmꢄ1: 3360,
1738, 1443, 1247, 1038, 782. 1H-NMR (CDCl3) d: 1.76 (1H, dt, Jꢁ8.8,
13.2 Hz, 6-HH), 2.07 (3H, s, CH3), 2.62 (1H, dt, Jꢁ8.6, 13.3 Hz, 6-HH),
3.53 (1H, dq, Jꢁ5.3, 8.6 Hz, 7-H), 3.63—3.72 (2H, m, CHHOHꢂ5-H), 3.93
(1H, dd, Jꢁ8.1, 10.6 Hz, CHHOH), 4.03 (1H, br s, OH, exch. D2O), 4.39
(ꢁ)-cis-{[7-(6-Amino-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihy-
dro-5H-cyclopenta[b]pyrazin-5-yl]}methanol (19)
A solution of 16
(150 mg, 0.32 mmol) in MeOH (4 ml) and liquid NH3 (3 ml) was heated in a
bomb at 75 °C for 60 h. Once the reaction mixture had cooled to r.t., the sol-
vent was evapored under reduced pressure and 19 was isolated as a white
solid (0.07 g, 51% yield), mp 224—226 (Et2O). IR (film) cmꢄ1: 3353, 1653,
1556, 1418, 1319, 1238, 1074, 798, 776. 1H-RMN (CDCl3) d: 1.73 (1H, dt,

658
Vol. 56, No. 5
M., Good S. S., Antimicrob. Agents Chemother., 41, 1099—1107
(1997).
4) Foster R. H., Faulds D., Drugs, 55, 729—736 (1998).
5) Krayevsky A. A., Watanabe K. A., “Modified Nucleosides as Anti-
AIDS Drugs: Current Status and Perspectives,” Bioinform, Moscow,
1993.
6) Lea A. P., Faulds D., Drugs, 51, 846—852 (1996).
7) Thomas S., McDonall J. E., Cheah V., Bye A., Segal M. B., The Entry
of Abacavir into the Guinea Pig Brain: Comparison with Other Re-
verse Transcriptase Inhibitors; Presented at the 12th World AIDS Con-
ference, Geneva, 1998.
Jꢁ8.5, 13.1 Hz, 6-HH), 2.34 (1H, dt, Jꢁ8.3, 13.3 Hz, 6-HH), 3.54—3.60
(1H, m, 5-H), 3.70—3.79 (2H, m, 5-CH2), 3.88 (1H, br s, OH, D2O exch.),
4.03—4.12 (1H, m, 7-H), 4.34—4.50 (part A of an ABX system JAXꢁ5.2,
J
J
ABꢁ13.3 Hz, CHHN) 4.55—4.68 (part B of an ABX system JBXꢁ7.5,
BAꢁ13.3 Hz, CHHN), 6.76 (2H, NH2, D2O exch). 7.11—7.44 (10H, m,
arom.), 7.80 and 7.89 (2H, 2s, 2ꢀ-Hꢂ8ꢀ-H). 13C-NMR (CDCl3) d: 31.6
(CH2), 34.2 (CH), 44.5 (CH), 47.3 (CH2), 61.2 (CH2), 120.1 (C), 128.0
(CH), 128.9 (CH), 129.6 (C), 135.4 (CH), 135.7 (C), 141.2 (CH), 145.5 (C),
150.4 (C), 151.8 (CH), 158.4 (C), 158.2 (C), 160.3 (C). Anal. Calcd for
C26H23N7O (449.51). C, 69.47; H, 5.16; N, 21.81.Found: C, 69.32; H, 5.23;
N, 22.00.
8) Fernández F., García-Mera X., Morales M., Rodríguez-Borges J. E.,
De Clercq E., Synthesis, 2002, 1084—1091 (2002).
9) Yao S. W., López V. H., Fernández F., García-Mera X., Morales M.,
Rodríguez-Borges J. E., Cordeiro M. N., Bioorg. Med. Chem., 11,
4999—5006 (2003).
10) Fernández F., García-Mera X., Morales M., Vilariño L., Caamaño O.,
De Clercq E., Tetrahedron, 60, 9245—9253 (2004).
11) Caamaño O., Gómez G., Fernández F., García M. D., García-Mera X.,
De Clercq E., Synthesis, 2004, 2855—2861 (2004).
12) García M. D., Caamaño O., Fernández F., López C., De Clercq E., Syn-
thesis, 2005, 925—932 (2005).
13) García M. D., Caamaño O., Fernández F., García-Mera X., Pérez-Cas-
tro I., Synthesis, 2006, 3967—3972 (2006).
(ꢁ)-cis-{[7-(6-Cyclopropylamino-9H-purin-9-yl)methyl]-2,3-diphenyl-
6,7-dihydro-5H-cyclopenta[b]pyrazin-5-yl]}methanol (20) A solution of
16 (150 mg, 0.31 mmol) and cyclopropylamine (127 mg, 2.22 mmol) in
EtOH (10 ml) was refuxed for 22 h. Removal of the solvent under reduced
pressure left a brown oil from which, following chromatography on silica gel
with CH2Cl2–MeOH (95 : 5) as eluent, 20 (78 mg, 52%) was isolated as a
ligh oil. IR (film) cmꢄ1: 3410, 2360, 1740, 1635, 1476, 1377, 1298, 1074,
768, 676. 1H-NMR (CDCl3) d: 0.54—0.58 (m, 2H, cyclopropyl), 0.80—0.93
(m, 2H, cyclopropyl), 1.73 (1H, dt, Jꢁ8.5, 13.1 Hz, 6-HH), 2.34 (1H, dt,
Jꢁ7.3, 13.1 Hz, 6-HH), 2.93—2.98 (m, 1H, 1cyclopropylH), 3.54—3.60 (1H, m,
5-H), 3.79—3.97 (2H, m, 5-CH2), 4.11 (1H, br s, OH, D2O exch.), 4.18—
4.22 (1H, m, 7-H), 4.35—4.51 (part A of an ABX system JAXꢁ5.7,
JABꢁ13.3 Hz, CHHN), 4.55—4.68 (part
B of an ABX, JBXꢁ7.5,
14) Whitney R. A., Tetrahedron Lett., 22, 2063—2066 (1981).
15) Kobayashi J. E., Kobayashi S., Molecules, 5, 1062—1067 (2000).
16) Eissenstat M. A., Weaver III J. D., J. Org. Chem., 58, 3387—3390
(1993).
J
BAꢁ13.3 Hz, CHHN), 7.11—7.44 (10H, m, arom.), 7.80 and 7.89 (2H, 2s,
2ꢀ-Hꢁ8ꢀ-H). 13C-NMR (CDCl3) d: 7.2 (2ꢅCH3), 29.6 (CH), 31.6 (CH2),
34.2 (CH), 44.5 (CH), 47.3 (CH2), 61.2 (CH2), 120.1 (C), 128.0 (CH), 128.9
(CH), 129.6 (CH), 135.4 (CH), 135.7 (C), 141.2 (CH), 145.5 (C), 150.4
(CH), 151.8 (C), 158.4 (C), 158.2 (C), 160.3 (C). Anal. Calcd for C29H27N7O
(489.58). C, 71.15; H, 5.56; N, 20.03. Found: C, 71.3; H, 5.76; N, 19.88.
17) Zhong Y. L., Shing T. K. M., J. Org. Chem., 62, 2622—2624 (1997).
18) Crystallographic data (excluding structure factors) for the structures
13 in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication, no. CCDC 242738.
Empirical formula: C21H20N2O2 formula weight: 332.39; crystal size:
0.88ꢅ0.08ꢅ0.04; crystal system: monoclinic; unit cell dimensions:
aꢁ14.6253(13) Å, bꢁ6.2834(5) Å, cꢁ18.6333(7) Å; aꢁ90°, aꢁ
92.811(8)°, gꢁ90°; Vꢁ1710.3(2) Å3; space group: P2(1)/n; Dcalcꢁ
1.291 Mg/m3; F(000)ꢁ704; R1ꢁ0.0569, wR2ꢁ0.1624. Diffractome-
ter: Smart-1000 BRUKER.
Acknowledgements Authors thank Xunta de Galicia for financial sup-
port under project PGIDIT02BTF20305PR.
References and Notes
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2) Dando T. M., Scott L. J., Drugs, 65, 285—302 (2005).
3) Faletto M. B., Miller W. H., Garvey E. P., St. Clair M. H., Daluge S.