Synthesis of N6-[endo-2′-(endo-5′-hydroxy)norbornyl] -8-(N-methylisopropylamino)-9-methyladenine (WRC-0571): A potent and selective adenosine A1 receptor antagonist

Article abstract of DOI:10.1055/s-2006-958939

A new versatile synthesis of N⁶-[endo-2′-(endo-5′- hydroxy)norbornyl]-8-(N-methylisopropylamino)-9-methyladenine (WRC-0571), a highly potent and selective antagonist for adenosine A₁ receptor, is presented. The overall yield is 14%.

Full text of DOI:10.1055/s-2006-958939

PAPER
219
Synthesis of N6-[endo-2¢-(endo-5¢-Hydroxy)norbornyl]-8-(N-methylisopropyl-
amino)-9-methyladenine (WRC-0571): A Potent and Selective Adenosine A1
Receptor Antagonist
Synthesis of
WRh
Organic and Medicinal Chemistry, Science and Engineering Group, Research Triangle Institute, PO Box 12194, Research Triangle Park,
NC 27709, USA
Fax +1(919)5416499; E-mail: cjin@rti.org
Received 7 September 2006
genation of N6-[endo-2¢-(endo-5¢-hydroxy)norbornyl]-9-
Abstract: A new versatile synthesis of N6-[endo-2¢-(endo-5¢-hy-
methyladenine and subsequent coupling with N-methyl-
isopropylamine, were not reported. As a part of an ongo-
ing research program, gram quantities of WRC-0571 were
droxy)norbornyl]-8-(N-methylisopropylamino)-9-methyladenine
(WRC-0571), a highly potent and selective antagonist for adenosine
A1 receptor, is presented. The overall yield is 14%. The key step in-
volved the stereoselective reduction of endo-2-(diphenylmethyl- needed. In this paper, we report a new versatile synthetic
amino)norbornan-5-one to generate the endo-5-hydroxy substituent
using the Luche reagent (NaBH4–CeCl3) at –40 °C.
approach to WRC-0571 in 14% overall yield.
Retrosynthetic analysis of WRC-0571 (1) (Scheme 1)
Key words: WRC-0571, Luche reduction, palladium-catalyzed
suggests two potential fragments: endo-2-amino-endo-5-
amination
hydroxynorbornane (2) and 6-chloro-8-(N-methylisopro-
pylamino)-9-methylpurine (3). This new synthetic ap-
proach was designed to take advantage of the key
intermediate 2 that has endo configurations on both C-2
and C-5 for the coupling reaction with purine. Further
cleavage of the purine C-8–N bond in 3 provides 6-chlo-
ro-8-iodo-9-methylpurine (4) and N-methylisopropyl-
amine (5) as potential precursors.
Adenosine is a purine nucleoside that is widely distributed
throughout the body and exerts a variety of physiological
functions through interactions with extracellular recep-
tors.1 Adenosine mediates a large variety of effects, e.g.
on the cardiovascular, immune, and central nervous sys-
tems. To date, four distinct subclasses of adenosine recep-
tors (A1, A2a, A2b and A3) have been cloned and
H
characterized pharmacologically. Numerous adenosine
receptor ligands have been synthesized and studied as
adenosine receptor agonists and antagonists, which have
HO
many potential uses including cardiac imaging and in the
NH
treatment of cardiac arrhythmia, edema and depression.2,3
N
N
N
In 1996, Martin and co-workers reported N6-[endo-2¢-(en-
N
1
N
do-5¢-hydroxy)norbornyl]-8-(N-methylisopropylamino)-
9-methyladenine (WRC-0571) to be one of the most po-
tent and selective antagonists for adenosine A1 receptor
both in vitro and in vivo.4 WRC-0571 inhibited [3H]-N6-
cyclohexyladenosine (CHA) binding to guinea pig A1 re-
ceptor with a Ki value of 1.1 nM and was 200-fold less po-
tent at inhibiting [3H]-5¢-N-ethylcarboxamidoadenosine
binding to bovine A2a receptor. In human adenosine re-
ceptors, WRC-0571 is 62-fold selective for the A1 vs. A2a
and 4670-fold selective for the A1 vs. A3 receptors. The
synthesis of WRC-0571, a nine-step linear synthetic se-
quence, was first reported in a patent by Peck et al.5 How-
ever, their synthesis had several steps with low yields,
especially the key NaBH4 reduction of N6-[endo-2¢-(5¢-
oxo)norbornyl]-9-methyladenine to generate the corre-
sponding endo-5¢-hydroxy substituent (51% yield). In
addition, experimental details of the last two steps, halo-
H
Cl
N
HO
N
N
N
+
N
NH2
2
3
Cl
N
N
H
N
N
I
+
N
5
4
Scheme 1
The synthesis of endo-2-amino-endo-5-hydroxynorbor-
nane (2) was first investigated (Scheme 2). endo-2-
(Diphenylmethylamino)norbornan-5-one ethylene ketal
(9) was prepared in 41% yield from commercial cyclo-
pent-2-en-1-one ethylene ketal (6) following the reported
SYNTHESIS 2007, No. 2, pp 0219–0224
Advanced online publication: 14.12.2006
DOI: 10.1055/s-2006-958939; Art ID: M05906SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7

220
C. Jin et al.
PAPER
procedure.5,6 Thus, treatment of 6 with 2-chloroacryloni- iodomethane afforded 6-chloro-9-methylpurine (13)10 in
trile in refluxing acetonitrile gave the cycloaddition prod- 68% yield. Treatment of 13 with N-iodosuccinimide11
uct 7, which was readily hydrolyzed using potassium (NIS) in refluxing THF provided 6-chloro-8-iodo-9-meth-
hydroxide to the ketone 8 in 44% yield. Reductive amina- ylpurine (4) in 63% yield. Palladium-catalyzed coupling
tion of 8 with aminodiphenylmethane provided endo- reactions between 6,8-dihalopurines and organometallic
amine 9 in 93% yield.7 Deketalization of 9 with HCl then reagents have been reported to give 8-substituted purines
led to endo-2-(diphenylmethylamino)norbornan-5-one with good yields and high selectivity.11,12 However, this
(10) quantitatively. Reduction of ketone 10 to generate the facile palladium-catalyzed reaction has not been investi-
endo-5-hydroxy substituent was first carried out using gated on the selective amination of 6,8-dihalopurines. Pal-
NaBH4 in MeOH at 0 °C, yielding alcohol 11 as an 84:16 ladium-catalyzed amination of aryl and heteroaryl halides
1
diastereoisomeric mixture as determined by H NMR has been shown to be a general method for the formation
spectroscopy. Use of LiAlH4 or the bulkier reducing agent of aromatic carbon–nitrogen bonds.13 Unfortunately,
9-BBN did not give better results.8 After extensive opti- treatment of 4 with N-methylisopropylamine (5) using
mization, Luche reduction9 using NaBH4 and CeCl3·7H2O Buchwald’s conditions for aryl iodides14 [Pd2(dba)3,
in MeOH at –40 °C for three hours gave an approximately P(o-tolyl)3, t-BuONa, 18-C-6, THF, r.t.] led to decompo-
95:5 diastereoisomeric mixture of 11 quantitatively. The sition. The desired product 3 was not detected by 1H NMR
major isomer was isolated by recrystallization from ace- or MS analysis of the crude product mixture. Recently,
tone–hexanes (major/minor >97:3) and the stereochemis- Meyers et al.15 reported regioselective palladium-cata-
try was determined by NMR studies.
lyzed aminations of 2-chloro-3-iodopyridine with anilines
on the 3-position using the mild base Cs2CO3. However,
reaction of 4 with 5 using Meyers’ conditions [Pd(OAc)2,
BINAP, Cs2CO3, toluene, reflux] also did not produce 3.
Instead 14, a substitution product on the 6-position, was
isolated in 36% yield16 (Scheme 3). We believe that the
formation of 14 was through a nucleophilic aromatic sub-
stitution reaction and the Pd catalyst was simply a specta-
tor.
A two dimensional ROESY NMR spectrum was obtained
on the major isomer of 11. Strong correlations were ob-
served between H-2 and H-7b and between H-5 and H-7a,
indicating that these respective pairs of protons were
proximal (Scheme 2). This observation is best explained
by the endo configurations of both the 2-diphenylmethyl-
amino and 5-hydroxy groups in the major isomer of 11.
Subsequent hydrogenolysis of 11 (diastereoisomeric mix-
ture) with palladium hydroxide gave 2 in 98% yield.
Cl
Cl
Cl
N
N
N
N
N
O
a
N
b
N
N
O
I
O
b
O
a
O
N
H
N
N
N
Cl
O
13
4
O
8
12
6
7 CN
c
c
O
Cl
O
N
N
O
HO
N
d
e
N
N
N
N
N
HN
Ph
N
I
HN
Ph
N
HN
11
Ph
Ph
10
9
Ph
Ph
3
14
f
Scheme 3 Reagents and conditions: (a) NaH, MeI, DMF, r.t., 68%;
(b) NIS, THF, reflux, 63%; (c) Pd(0), N-methylisopropylamine (5).
H7a
H5
HO
H7b
HO
H2
Nucleophilic substitutions of 6,8-dichloropurines are
well-documented in the literature.17,18 However, the fac-
tors determining the regiochemistry of substitution reac-
tions of 6,8-dihalopurines appear to be complex. The
nucleophilic substitution of 6-chloro-8-iodo-9-methylpu-
rine (4) with amine was also investigated. Treatment of 4
with amine 2 (97:3 diastereoisomeric mixture) and trieth-
ylamine in refluxing MeOH containing a catalytic amount
of tetrabutylammonium iodide gave N6-[endo-2¢-(endo-
5¢-hydroxy)norbornyl]-8-iodo-9-methyladenine (15) in
73% yield as well as 16 in 7% yield (Scheme 4). Both 15
and 16 were isolated as single diastereoisomers. Unfortu-
HN
11 (major isomer)
Ph
NH2
2
Ph
Scheme 2 Reagents and conditions: (a) 2-chloroacrylonitrile, 2,6-
dimethylpyridine, MeCN, reflux, 66%; (b) KOH, DMSO, 55 °C,
67%; (c) aminodiphenylmethane, PtO2, H2, 45 psi, 93%; (d) 3 N HCl,
MeOH, reflux, ~100%; (e) NaBH4, CeCl3·7H2O, MeOH, –40 °C,
99%; (f) H2, Pd(OH)2, 45 psi, 98%.
The synthesis of 3 was attempted following the route out-
lined in Scheme 3. N-Methylation of commercially avail-
able 6-chloropurine (12) using sodium hydride and
Synthesis 2007, No. 2, 219–224 © Thieme Stuttgart · New York

PAPER
Synthesis of WRC-0571
221
H
nately, subsequent reaction of 15 with N-methylisopropyl-
amine (5) gave a 64% yield of the reductive product 17.
Only a small amount of the desired product 1 was detected
by 1H NMR and MS analyses.
Cl
N
HO
HO
a
N
N
N
+
NH
N
N
NH2
H
H
N
2
13
HO
HO
17
N
HO
a
b
+
NH
HN
N
N
N
N
N
H
H
NH2
I
2
15
16
N
TBDMSO
TBDMSO
Cl
N
c
N
b
NH
N
NH
N
N
N
N
N
I
H
N
19
18
N
d
HO
NH
N
N
N
H
H
N
HO
TBDMSO
17
e
Scheme 4 Reagents and conditions: (a) 4, Bu4NI, MeOH, Et3N, re-
flux, 15: 73%; 16: 7%; (b) N-methylisopropylamine (5), DMSO,
130 °C, 64%.
NH
NH
N
N
N
N
N
N
N
1
20
N
N
N
In order to investigate the amination reaction of the 8-bro-
mo or 8-chloro analogue of 15, direct bromination or chlo-
Scheme 5 Reagents and conditions: (a) Bu4NI, propan-1-ol, Et3N,
rination of 17 using Br2 in CHCl3,19 Br2 in Na2HPO4 and reflux, 89%; (b) TBDMSCl, imidazole, DMF, r.t., 99%; (c) LDA,
H2O (pH 7),20 or N-chlorosuccinimide (NCS)19 was also
tried but met with little success. In most cases, the oxida-
THF, –78 °C, then I2, 65%; (d) N-methylisopropylamine (5), toluene,
155 °C, 66%; (e) TBAF, THF, r.t., 95%.
tion product of the 5¢-hydroxy group to the corresponding
5-hydroxy substituent 11 (90% de) quantitatively using
ketone was observed, suggesting that the 5¢-hydroxy
the Luche reagent (NaBH4-CeCl3).
group needed to be masked for the halogenation and ami-
nation sequence (Scheme 5). Thus, the substitution reac-
tion of 13 with amine 2 (93:7 diastereoisomeric mixture)
was carried out in refluxing propan-1-ol to give 17 in 89%
yield as a single diastereoisomer. The 5¢-hydroxy group
was then protected by treatment with tert-butyldimethyl-
Melting points were determined on a MEL-TEMP II capillary melt-
ing point apparatus and are uncorrected. NMR (1H, 13C, COSY and
ROESY) spectra were obtained using a Bruker Avance DPX-300
MHz or a Varian Unity Inova 500 MHz NMR spectrometer. Chem-
ical shifts are reported in parts per million (ppm) with reference to
silyl chloride (TBDMSCl) and imidazole in DMF to pro-
vide 18 in almost quantitative yield. Iodination21 of 18 by
lithiation of the C-8 position using three equivalents of
LDA in THF followed by addition of iodine yielded 19.
Compound 19 was then treated with 5 in toluene at 155 °C
in a steel bomb for three days to produce 20 in 40% yield.
Recovered starting material 19 was then recycled to gen-
erate additional 20 (66% overall yield after two cycles).
Subsequent deprotection of the 5¢-O-tert-butyldimethyl-
silyl group using tetrabutylammonium fluoride (TBAF) in
THF provided WRC-0571 (1) in 95% yield.
internal solvent. HRMS were recorded on a Waters Autospec
Ultima mass spectrometer and were performed at the University of
Michigan, Ann Arbor, MI. Elemental analysis was done by Atlantic
Microlab Inc., Norcross, GA. Analytical TLC was carried out using
EMD silica gel 60 F254 TLC plates. Flash column chromatography
was done on a CombiFlash Companion system using Isco pre-
packed silica gel columns. Reagents were obtained from Aldrich
Chemical Company and used as received unless otherwise noted.
THF was freshly distilled from sodium-benzophenone.
(endo,exo)-2-Carbonitrile-2-chloronorbornan-5-one Ethylene
Ketal (7)
A mixture of cyclopent-2-en-1-one ethylene ketal (6; 14.5 g, 115
mmol) and 2-chloroacrylonitrile (30.2 g, 345 mmol) in anhydrous
MeCN (290 mL) containing 2,6-dimethylpyridine (2.00 g, 18.4
mmol) was heated at 75 °C under argon for 22 h. After cooling to
r.t., the pale yellow solution was concentrated in vacuo. Chromatog-
raphy (120 g Isco silica gel column) using 4% EtOAc–20%
CH2Cl2–76% hexanes afforded 7 (16.3 g, 66%) as a mixture of
diastereoisomers.
In conclusion, we have developed a new versatile synthet-
ic approach to N6-[endo-2¢-(endo-5¢-hydroxy)norbornyl]-
8-(N-methylisopropylamino)-9-methyladenine (WRC-
0571) in 14% overall yield from commercially available
cyclopent-2-en-1-one ethylene ketal (6). The key step in-
volved stereoselective reduction of endo-2-(diphenyl-
methylamino)norbornan-5-one (10) to generate the endo-
Synthesis 2007, No. 2, 219–224 © Thieme Stuttgart · New York

222
C. Jin et al.
PAPER
1H NMR (300 MHz, CDCl3): d (major isomer) = 1.85–2.12 (m, 3
H), 2.20–2.39 (m, 3 H), 2.40–2.60 (m, 1 H), 2.70–2.88 (m, 1 H),
3.77–4.06 (m, 4 H).
isomer (major/minor >97:3) was isolated by recrystallization from
acetone–hexanes; mp 113–116 °C.
1H NMR (500 MHz, CDCl3): d = 1.29–1.40 (m, 2 H), 1.47–1.54 (m,
2 H), 1.62–1.70 (m, 1 H), 1.72–1.80 (m, 1 H), 2.09 (br s, 2 H), 2.14–
2.20 (m, 2 H), 3.00–3.60 (m, 1 H), 4.14–4.21 (m, 1 H), 4.74 (s, 1 H),
7.16–7.40 (m, 10 H).
13C NMR (125 MHz, CDCl3): d = 29.1, 32.0, 38.0, 40.3, 43.0, 56.3,
65.5, 72.7, 127.2, 127.4, 127.6, 127.7, 127.8, 128.7, 143.9, 144.6.
HRMS-ESI: m/z [M + Na]+ calcd for C20H23NO + Na: 316.1677;
found: 316.1666.
2-Oxonorbornan-5-one Ethylene Ketal (8)
To a stirred solution of 7 (15.0 g, 70.2 mmol) in DMSO (62.5 mL)
was added a solution of KOH (13.9 g, 210 mmol) in H2O (7.5 mL).
The mixture was heated at 55 °C for 4 h. The resultant orange solu-
tion was poured into H2O (300 mL) and extracted with CH2Cl2
(3 × 100 mL). The combined organic extracts were washed with
brine (3 × 50 mL), dried (Na2SO4) and concentrated in vacuo. Chro-
matography (40 g Isco silica gel column) using 10% EtOAc–20%
CH2Cl2–70% hexanes afforded 8 (7.90 g, 67%) as an oil.
1H NMR (300 MHz, CDCl3): d = 1.72–1.88 (m, 2 H), 1.82–2.08 (m,
2 H), 2.13 (dd, J = 14.1, 5.1 Hz, 1 H), 2.34 (dd, J = 18.2, 4.1 Hz, 1
H), 2.46–2.63 (m, 2 H), 3.80–4.08 (m, 4 H).
endo-2-Amino-(endo,exo)-5-hydroxynorbornane Hydro-
chloride (2)
A degassed mixture of 11 (93:7 diastereoisomeric mixture, 2.90 g,
10.0 mmol,) and Pd(OH)2 (145 mg) in MeOH (60 mL) was hydro-
genated at 45 psi for 28 h. The suspension was filtered through a
short pad of Celite, washed with MeOH (3 × 10 mL) and the filtrate
was concentrated in vacuo. The resultant residue was treated with 1
M HCl solution in Et2O to give 2 (1.60 g, 98%) as a white solid,
which was used in the next step without further purification; mp
164–167 °C.
1H NMR (300 MHz, CD3OD): d (major isomer) = 1.26 (d, J = 14.4
Hz, 1 H), 1.59 (s, 2 H), 1.78–2.02 (m, 3 H), 2.31 (br t, 1 H), 2.41 (br
t, 1 H), 3.52–3.63 (m, 1 H), 4.22–4.32 (m, 1 H).
13C NMR (75 MHz, CD3OD): d = 26.4, 31.2, 38.1, 41.6, 44.2, 53.3,
72.1.
HRMS-EI: m/z [M]+ calcd for C7H13NO: 127.0997; found:
127.0997.
13C NMR (75 MHz, CDCl3): d = 36.2, 38.2, 38.8, 43.0, 49.4, 64.3,
64.7, 114.3, 215.7.
endo-2-(Diphenylmethylamino)norbornan-5-one Ethylene
Ketal (9)
A degassed mixture of 8 (7.80 g, 46.0 mmol), aminodiphenyl-
methane (7.92 mL, 46.0 mmol) and AcOH (3.97 mL, 69.0 mmol) in
MeOH (59 mL) containing PtO2 (281 mg) was hydrogenated at 45
psi for 6 h. The suspension was filtered through a short pad of
Celite, washed with MeOH (3 × 10 mL) and the filtrate was concen-
trated in vacuo. Chromatography (120 g Isco silica gel column) us-
ing 0 → 50% EtOAc–hexanes afforded 9 (14.3 g, 93%) as an oil.
1H NMR (300 MHz, CDCl3): d = 1.21–1.38 (m, 2 H), 1.58–1.76 (m,
3 H), 1.77–1.91 (m, 1 H), 1.94–2.10 (m, 2 H), 2.27 (br s, 1 H), 2.91–
3.06 (m, 1 H), 3.71–3.96 (m, 4 H), 4.78 (s, 1 H), 7.11–7.46 (m, 10
H).
N6-[endo-2¢-(endo-5¢-Hydroxy)norbornyl]-9-methyladenine
(17)
13C NMR (75 MHz, CDCl3): d = 31.0, 35.4, 37.2, 38.5, 44.2, 55.8,
63.9, 64.5, 65.6, 116.1, 127.0, 127.4, 127.5, 128.5, 144.0, 144.8.
A mixture of 2 (93:7 diastereoisomeric mixture, 1.20 g, 7.36 mmol),
6-chloro-9-methylpurine (13;10 1.21 g, 7.22 mmol), Bu4NI (26.6
mg, 0.072 mmol) and Et3N (4.03 mL, 28.9 mmol) in propan-1-ol
(25 mL) was refluxed under argon for 20 h. After cooling to r.t., pro-
pan-1-ol was removed in vacuo. The resultant residue was dissolved
in CH2Cl2 (200 mL), washed with brine (3 × 50 mL), dried
(Na2SO4) and concentrated in vacuo. Chromatography (40 g Isco
silica gel column) using 0 → 10% MeOH–CH2Cl2 afforded 17 (sin-
gle isomer, 1.66 g, 89%) as a white solid; mp 222–224 °C.
1H NMR (300 MHz, CD3OD): d = 1.35–1.45 (m, 1 H), 1.52–1.70
(m, 2 H), 1.76–1.90 (m, 2 H), 1.92–2.07 (m, 1 H), 2.28 (br t, 1 H),
2.55 (br t, 1 H), 3.81 (s, 3 H), 4.20–4.30 (m, 1 H), 4.48 (br s, 1 H),
8.02 (s, 1 H), 8.24 (s, 1 H).
endo-2-(Diphenylmethylamino)norbornan-5-one (10)
To a stirred solution of 9 (3.35 g, 10.0 mmol) in MeOH (20 mL),
was added 3 N HCl (20 mL). After refluxing for 1 h, the mixture
was poured into aq sat. NaHCO3 solution (50 mL) and extracted
with EtOAc (3 × 50 mL). The combined organic extracts were
washed with brine (3 × 30 mL) and dried (Na2SO4). Removal of sol-
vent in vacuo afforded 10 (2.95 g, ~100%) as a white solid, which
was used in the next step without further purification; mp 130–132
°C.
1H NMR (500 MHz, CDCl3): d = 1.10 (ddd, J = 13.5, 4.5, 3.0 Hz, 1
H), 1.54–1.60 (m, 1 H), 1.62 (br s, 1 H), 1.67–1.72 (m, 1 H), 1.94
(dd, J = 18.0, 4.5 Hz, 1 H), 2.13–2.02 (m, 1 H), 2.46–2.56 (m, 3 H),
3.22–3.26 (m, 1 H), 4.78 (s, 1 H), 7.18–7.38 (m, 10 H).
13C NMR (75 MHz, CD3OD): d = 28.3, 30.3, 31.7, 37.9, 42.5, 44.2,
53.9, 73.3, 120.4, 142.9, 150.5, 153.8, 156.3.
HRMS-ESI: m/z [M + H]+ calcd for C13H17N5O + H: 260.1511;
found: 260.1508.
13C NMR (125 MHz; CDCl3): d = 33.8, 37.0, 38.3, 38.6, 50.6, 55.8,
65.7, 127.4, 127.6, 127.7, 128.7, 128.8, 143.8, 144.3, 217.8.
N6-{endo-2¢-[endo-5¢-O-(tert-Butyldimethylsilyl)]norbornyl}-9-
methyladenine (18)
HRMS-ESI: m/z [M + Na]+ calcd for C20H21NO + Na: 314.1521;
found: 314.1525.
To a stirred solution of 17 (1.30 g, 5.02 mmol) in DMF (20 mL) at
r.t. under N2, was added imidazole (0.85 g, 12.6 mmol) followed by
TBDMSCl (0.94 g, 6.02 mmol). After stirring at r.t. for 5 h, the mix-
ture was poured into ice-water and extracted with CH2Cl2 (3 × 50
mL). The combined CH2Cl2 extracts were washed with brine
(3 × 30 mL), dried (Na2SO4) and concentrated in vacuo. Chroma-
tography (40 g Isco silica gel column) using 0 → 3% MeOH–
CH2Cl2 afforded 18 (1.85 g, 99%) as an oil.
1H NMR (300 MHz, CDCl3): d = 0.03 (s, 3 H), 0.06 (s, 3 H), 0.90
(s, 9 H), 1.33–1.43 (m, 1 H), 1.44–1.51 (m, 1 H), 1.54–1.64 (m, 1
H), 1.65–1.86 (m, 2 H), 1.87–2.00 (m, 1 H), 2.21 (br t, 1 H), 2.55
(br t, 1 H), 3.77 (s, 3 H), 4.18–4.28 (m, 1 H), 4.56 (br s, 1 H), 5.93
(br s, 1 H), 7.68 (s, 1 H), 8.36 (s, 1 H).
endo-2-(Diphenylmethylamino)-(endo,exo)-5-hydroxy-
norbornane (11)
To a stirred solution of 10 (2.95 g, 10.0 mmol) in MeOH (500 mL)
at –40 °C was added CeCl3·7H2O (1.85 g, 5.00 mmol) followed by
NaBH4 (0.19 g, 5.00 mmol). After stirring at –40 °C for 3 h, the re-
action was quenched by the addition of aq sat. NH4Cl solution (20
mL). The MeOH was removed in vacuo and the resultant aqueous
solution was extracted with CH2Cl2 (3 × 100 mL). The combined
CH2Cl2 extracts were washed with brine (3 × 50 mL), dried
(Na2SO4) and concentrated in vacuo. Chromatography (40 g Isco
silica gel column) using 0 → 10% MeOH–CH2Cl2 afforded 11 (93:7
diastereoisomeric mixture, 2.90 g, 99%) as a white solid. The major
Synthesis 2007, No. 2, 219–224 © Thieme Stuttgart · New York

PAPER
Synthesis of WRC-0571
223
13C NMR (75 MHz, CDCl3) d = –4.9, –4.8, 18.1, 26.0, 28.5, 29.5,
32.6, 37.1, 40.9, 43.2, 51.4, 72.5, 120.0, 139.9, 148.5, 153.0, 154.9.
H), 3.62–3.78 (m, 1 H), 4.35–4.46 (m, 1 H), 4.51–4.65 (m, 1 H),
5.03 (br s, 1 H), 6.56 (d, J = 6.0 Hz, 1 H), 8.35 (s, 1 H).
HRMS-ESI: m/z [M + Na]+ calcd for C19H31N5OSi + Na: 396.2196;
found: 396.2194.
13C NMR (75 MHz, CDCl3): d = 19.2, 19.3, 26.9, 29.8, 30.4, 31.2,
36.9, 41.4, 43.4, 52.5, 52.9, 72.8, 116.9, 150.3, 151.4, 153.0, 155.3.
HRMS-ESI: m/z [M + H]+ calcd for C17H26N6O + H: 331.2246;
found: 331.2239.
N6-{endo-2¢-[endo-5¢-O-(tert-Butyldimethylsilyl)]norbornyl}-8-
iodo-9-methyladenine (19)
Anal. Calcd for C17H26N6O·0.25H2O: C, 60.96; H, 7.97; N, 25.09.
Found: C, 61.14; H, 7.82; N, 25.34.
To a stirred solution of diisopropylamine (1.25 mL, 8.84 mmol) in
THF (10 mL) at –78 °C under N2 was added BuLi (1.6 M in hex-
anes, 5.03 mL, 8.04 mmol). The yellow solution was stirred at
–78 °C for 15 min and then at 0 °C for another 15 min. After cooling
to –78 °C, a solution of 18 (1.00 g, 2.68 mmol) in THF (15 mL) was
slowly added over 10 min. The resultant dark solution was stirred at
–78 °C for 2 h and then a solution of I2 (2.38 g, 9.38 mmol) in THF
(19 mL) was added at once. After stirring at –78 °C for 30 min, the
mixture was poured into a stirred 5% AcOH solution (70 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined CH2Cl2 extracts
were washed with NaHCO3 (30 mL), Na2S2O3 (30 mL), brine (30
mL), dried (Na2SO4) and concentrated in vacuo. Chromatography
(40 g Isco silica gel column) using 0 → 1% MeOH–CH2Cl2 afford-
ed 19 (0.87 g, 65%) as a white solid; mp 135–137 °C.
6-Chloro-8-iodo-9-methylpurine (4)
To a stirred solution of 13 (1.68 g, 10.0 mmol) in THF (160 mL) at
r.t. under N2 was added N-iodosuccinimide (11.3 g, 50 mmol). After
refluxing for 3 d, the mixture was concentrated in vacuo. The brown
residue was dissolved in CH2Cl2 (300 mL) and aq sat. NaHSO3 was
added until the solution became colorless. The CH2Cl2 layer was
separated, washed with brine (3 × 50 mL), dried (Na2SO4) and con-
centrated in vacuo. The resultant yellow solid was washed with
CH2Cl2 (3 × 10 mL) to give 4 (1.85 g, 63%) as a white solid; mp
250–252 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 3.76 (s, 3 H), 8.64 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 0.07 (s, 3 H), 0.09 (s, 3 H), 0.94
(s, 9 H), 1.30–1.40 (m, 1 H), 1.45–1.55 (m, 1 H), 1.56–1.62 (m, 1
H), 1.65–1.80 (m, 2 H), 1.82–2.00 (m, 1 H), 2.23 (br t, 1 H), 2.56
(br t, 1 H), 3.72 (s, 3 H), 4.22–4.30 (m, 1 H), 4.54 (br s, 1 H), 5.99
(br s, 1 H), 8.39 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 33.1, 115.1, 133.0, 147.5,
151.7, 153.4.
HRMS-ESI: m/z [M + H]+ calcd for C6H4ClIN4 + H: 294.9247;
found: 294.9245.
13C NMR (75 MHz, CDCl3): d = –4.6, 18.4, 26.2, 28.8, 32.3, 32.9,
6-(N-Methylisopropylamino)-8-iodo-9-methyladenine (14)
A mixture of Pd(OAc)2 (0.011 g, 0.05 mmol) and BINAP (0.031g,
0.05 mmol) in toluene (5 mL) was stirred at r.t. under argon for 10
min. The resultant catalyst solution was transferred into a stirred so-
lution of 4 (0.29 g, 1.00 mmol), N-methylisopropylamine (0.11 mL,
1.10 mmol) and Cs2CO3 (1.63 g, 5.00 mmol) in toluene (5 mL). Af-
ter refluxing for 16 h, the mixture was diluted with EtOAc (100
mL), the EtOAc layer was washed with brine (3 × 30 mL), dried
(Na2SO4) and concentrated in vacuo. Chromatography (40 g Isco
silica gel column) using 0 → 100% EtOAc–hexanes afforded 14
(0.12 g, 36%) as a pale yellow solid; mp 126–128 °C.
1H NMR (300 MHz, CDCl3): d = 1.26 (d, J = 6.6 Hz, 6 H), 3.31 (br
s, 3 H), 3.71 (s, 3 H), 5.68 (br s, 1 H), 8.26 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.7, 28.8, 32.3, 47.0, 97.4, 122.9,
151.9, 152.4, 153.2.
37.4, 41.1, 43.4, 51.7, 72.7, 99.3, 122.5, 151.0, 153.3, 153.8.
HRMS-ESI: m/z [M + Na]+ calcd for C19H30IN5OSi + Na: 522.1162;
found: 522.1159.
N6-{endo-2¢-[endo-5¢-O-(tert-Butyldimethylsilyl)]norbornyl}-8-
(N-methylisopropylamino)-9-methyladenine (20)
A mixture of 19 (0.87 g, 1.74 mmol) and N-methylisopropylamine
(4.6 mL) in toluene (4.6 mL) was heated at 155 °C in a steel bomb
for 3 days. After cooling to r.t., the mixture was concentrated in vac-
uo. Chromatography (40 g Isco silica gel column) using 0 → 2%
MeOH–CH2Cl2 afforded 20 (0.31 g, 40%) as an oil. The recovered
starting material 19 (0.38 g) was then recycled to provide additional
0.20 g of 20 (total 0.51 g, 66% after two cycles).
1H NMR (300 MHz, CDCl3): d = 0.06 (s, 3 H), 0.09 (s, 3 H), 0.95
(s, 9 H), 1.23 (d, J = 6.0 Hz, 3 H), 1.25 (d, J = 6.0 Hz, 3 H), 1.35–
1.51 (m, 2 H), 1.53–1.75 (m, 2 H), 1.78–2.00 (m, 2 H), 2.23 (br t, 1
H), 2.57 (br t, 1 H), 2.81 (s, 3 H), 3.59 (s, 3 H), 3.70–3.82 (m, 1 H),
4.20–4.30 (m, 1 H), 4.60 (br s, 1 H), 5.60 (d, J = 6.0 Hz, 1 H), 8.59
(s, 1 H).
13C NMR (75 MHz, CDCl3): d = –4.7, –4.6, 18.2, 19.2, 19.3, 26.2,
29.4, 29.8, 31.5, 33.3, 37.6, 41.3, 43.4, 51.1, 52.1, 72.4, 117.6,
150.0, 151.0, 152.9, 155.7.
HRMS-ESI: m/z [M + Na]+ calcd C23H40N6OSi + Na: 467.2931;
found: 467.2923.
HRMS-ESI: m/z [M + H]+ calcd for C10H14IN5 + H: 332.0372;
found: 332.0364.
N6-[endo-2¢-(endo-5¢-Hydroxy)norbornyl]-8-iodo-9-methyl-
adenine (15) and 6-Chloro-N8-[endo-2¢-(endo-5¢-hydroxy)nor-
bornyl]-9-methylpurine (16)
A mixture of hydrochloride 2 (97:3 diastereoisomeric mixture, 0.17
g, 1.02 mmol), 4 (0.29 g, 1.00 mmol), Bu4NI (3.70 mg, 0.01 mmol)
and Et3N (0.56 mL, 4.00 mmol) in MeOH (10 mL) was refluxed un-
der N2 for 2 d. After cooling to r.t., MeOH was removed in vacuo.
The resultant residue was dissolved in CH2Cl2 (100 mL), the
CH2Cl2 solution was washed with brine (3 × 30 mL), dried
(Na2SO4) and concentrated in vacuo. Chromatography (40 g Isco
silica gel column) using 0 → 10% MeOH–CH2Cl2 afforded 15 (sin-
gle isomer, 0.28 g, 73%) as a white solid and 16 (single isomer, 0.02
g, 7%) as a white solid.
N6-[endo-2¢-(endo-5¢-Hydroxy)norbornyl]-8-(N-methylisopro-
pylamino)-9-methyladenine (1)
To a stirred solution of 20 (0.28 g, 0.63 mmol) in THF (5 mL) at r.t.
under N2 was added Bu4NF (1 M solution in THF, 1.26 mL, 1.26
mmol). After stirring at r.t. for 1 h, the mixture was diluted with
CH2Cl2 (100 mL), the CH2Cl2 layer was washed with brine (3 × 30
mL), dried (Na2SO4) and concentrated in vacuo. Chromatography
(40 g Isco silica gel column) using 0 → 2% MeOH–CH2Cl2 afford-
ed 1 (0.20 g, 95%) as a white solid; mp 191–193 °C.
1H NMR (300 MHz, CDCl3): d = 1.24 (d, J = 6.0 Hz, 6 H), 1.48–
1.55 (m, 1 H), 1.57–1.70 (m, 2 H), 1.75–1.90 (m, 1 H), 1.91–2.01
(m, 2 H), 2.25 (br s, 1 H), 2.55 (br t, 1 H), 2.83 (s, 3 H), 3.59 (s, 3
15
Mp 242–244 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 1.18–1.30 (m, 1 H), 1.40–1.55
(m, 2 H), 1.60–1.88 (m, 3 H), 2.09 (br s, 1 H), 2.38 (br t, 1 H), 2.63
(s, 3 H), 3.95–4.06 (m, 1 H), 4.40–4.51 (m, 1 H), 4.65 (d, J = 8.4 Hz,
1 H), 7.60 (d, J = 6.3 Hz, 1 H), 8.15 (s, 1 H).
Synthesis 2007, No. 2, 219–224 © Thieme Stuttgart · New York

224
C. Jin et al.
PAPER
(7) The endo stereochemistry at C-2 of 9 was confirmed by
13C NMR (125 MHz, DMSO-d6): d = 25.6, 30.3, 31.8, 36.0, 40.3,
42.6, 51.7, 71.8, 103.0, 121.5, 150.2, 152.3, 152.9.
NMR studies of compound 11.
(8) Reduction of 10 to 11 using LiAlH4 or 9-BBN did not
improve the stereoselectivity significantly. In the case of
LiAlH4, some side reactions occurred to give a mixture of
crude products as detected by 1H NMR spectroscopy.
(9) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454.
(10) de Ligt, R. A. F.; van der Klein, P. A. M.; von Frijtag Drabbe
Künzel, J. K.; Lorenzen, A.; Maate, F. A. E.; Fujikawa, S.;
van Westhoven, R.; van de Hoven, T.; Brussee, J.; Ijzerman,
A. P. Bioorg. Med. Chem. 2004, 12, 139.
HRMS-ESI: m/z [M + H]+ calcd for C13H16IN5O + H: 386.0478;
found: 386.0475.
16
Mp 283–285 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 1.20–1.31 (m, 1 H), 1.38–1.54
(m, 2 H), 1.56–1.70 (m, 1 H), 1.71–1.82 (m, 2 H), 2.11 (br s, 1 H),
3.60 (s, 3 H), 4.01–4.11 (m, 1 H), 4.12–4.23 (m, 1 H), 4.59 (d,
J = 6.0 Hz, 1 H), 7.30 (d, J = 5.4 Hz, 1 H), 8.33 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 25.3, 28.0, 30.1, 35.6, 40.0,
42.4, 54.6, 71.5, 131.1, 139.6, 147.2, 153.6, 155.9.
(11) Nolsøe, J. M. J.; Gundersen, L.-L.; Rise, F. Acta Chem.
Scand. 1999, 53, 366.
(12) Laufer, S. A.; Domeyer, D. M. T.; Scior, R. F.; Albrecht, W.;
Hauser, D. R. J. J. Med. Chem. 2005, 48, 710.
(13) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125.
HRMS-ESI: m/z [M + H]+ calcd for C13H16ClN5O + H: 294.1122;
found: 294.1117.
(14) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066.
(15) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.;
Lemière, G. L. F.; Dommisse, R. A. J. Org. Chem. 2004, 69,
6010.
Acknowledgment
This work was supported by the National Institute of Mental Health
under contract N01-MH-32005. We thank Dr. James Windak, Che-
mistry Department, University of Michigan, Ann Arbor, MI for the
high-resolution mass spectral analyses.
(16) The coupling reaction was also tried with a similar outcome
using (N-methylisopropylamino)tributyltin, generated from
N-methylisopropylamine(5) and (N,N-dimethylamino)tri-
butyltin, and Pd[(2-furyl)3P]4 in toluene at 80 °C.
(17) Sutcliffe, E. Y.; Robins, R. K. J. Org. Chem. 1963, 28, 1662.
(18) Kelley, J. L.; McLean, E. W.; Linn, J. A.; Krochmal, M. P.;
Ferris, R. M.; Howard, J. L. J. Med. Chem. 1990, 33, 196.
(19) Moravec, J.; Kryštof, V.; Hanuš, J.; Havlíček, L.;
Moravcová, D.; Fuksová, K.; Kuzma, M.; Lenobel, R.;
Otyepka, M.; Strnad, M. Bioorg. Med. Chem. Lett. 2003, 13,
2993.
(20) Roelen, H.; Veldman, N.; Spek, A. L.; Künzel, J. F. D.;
Mathôt, R. A. A.; Ijzerman, A. P. J. Med. Chem. 1996, 39,
1463.
(21) Hayakawa, H.; Tanaka, H.; Sasaki, K.; Haraguchi, K.;
Saitoh, T.; Takai, F.; Miyasaka, T. J. Heterocycl. Chem.
1989, 26, 189.
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Synthesis 2007, No. 2, 219–224 © Thieme Stuttgart · New York