Regioselective and facile synthesis of 7,9-dialkyl-8-oxopurines from 7,9-dialkyl-7,8-dihydropurines: Total synthesis of heteromines i and J

Article abstract of DOI:10.1055/s-0033-1340499

A novel protocol for the synthesis of 6-halo-8-oxo-7,8-dihydro-9H-purines based on the oxidation of 7,9-dialkyl-7,8-dihydro-9H-purines has been developed. The presented methodology was used as a key step in the synthesis of heteromines I and J. Georg Thie

Full text of DOI:10.1055/s-0033-1340499

660▌
PAPER
paper
Regioselective and Facile Synthesis of 7,9-Dialkyl-8-oxopurines from
7,9-Dialkyl-7,8-dihydropurines: Total Synthesis of Heteromines I and J
Total Synthesis of Heteromines I and J
Tomáš Tobrman,* Dalimil Dvořák
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic
Fax +420(220)444288, tomas.tobrman@vscht.cz
Received: 21.10.2013; Accepted after revision: 09.12.2013
tives. Other methodologies rely on the rearrangement of
8-(allyloxy)purines,21 and N7- or N1-oxides.22 The oxida-
tion of adeninium salts with hydrogen peroxide also re-
sults in the formation of 8-oxopurines.23 As a part of our
ongoing research, we focused on the use of 7,8-dihydro-
9H-purines in the synthesis of novel purine derivatives.
We succeeded in developing a high-yielding and regiose-
lective preparation of 7-substituted halopurines,24 and 7-
substituted adenines, guanines, and 6-mercaptopurines.25
During the course of our studies, we observed that expo-
sure of a solution of 7,8-dihydro-9H-purine 2a to air af-
forded a small amount (≤10%) of 8-oxopurine 3a as the
product of spontaneous oxidation 26 (Scheme 1). Howev-
er, to the best of our knowledge procedure for the prepa-
ration of halo-substituted 8-oxopurines, valuable
intermediates in the synthesis of functionalized purines,
based on oxidation of 7,8-dihydro-9H-purines has not
been reported. Therefore, we decided to take advantage of
the spontaneous formation of 3a and explore the potential
of 7,9-dialkyl-7,8-dihydro-9H-purines in the synthesis of
7,9-dialkyl-6-halo-8-oxopurines from a synthetic point of
view.
Abstract: A novel protocol for the synthesis of 6-halo-8-oxo-7,8-
dihydro-9H-purines based on the oxidation of 7,9-dialkyl-7,8-di-
hydro-9H-purines has been developed. The presented methodology
was used as a key step in the synthesis of heteromines I and J.
Key words: oxidation, reduction, heterocycles, nucleobases, natu-
ral product
Caissarone1 and heteromines I and J are examples,2
among others,3 of naturally abundant 8-oxopurines (Fig-
ure 1). The 8-oxopurine scaffold is also found in modified
nucleobases that are formed as a result of a DNA lesion.4
These findings have led to an extensive study of the chem-
ical and biological properties of 8-oxopurines. The incor-
poration of 8-oxopurines into oligonucleotides has
enabled the study of the base-pairing properties of modi-
fied oligonucleotides.5 Apart from the fact that 8-oxopu-
rines represent one possible form of DNA damage, they
also exhibit a wide range of biological properties. For in-
stance, antitumor6 and antiviral7 activities have been re-
cently reported. 8-Oxopurines have also been used as
antagonists of corticotropin-releasing hormone receptor,8
corticotropin-releasing factor1 receptor,9 adenosine A2A
receptor,10 and an agonist of toll-like receptor 7.11 8-Oxo-
purines labeled with the 11C isotope have been used for
positron emission tomography imaging.12 In some cases,
immunostimulant13 and interferon-inducing14 activities,
as well as the selective inhibition of dipeptidyl peptidase
IV (DPPIV),15 have been observed.
I
Bn
N
N
CH=O
NH
N
Bn
I
I
Bn
Bn
4a
N
N
conditions
N
N
O
+
N
N
N
N
Me
OMe
N
N
Bn
Bn
OMe
Me
I
Me
Bn
H
N
2a
3a
N
N
N
N
N
N
N
O
O
O
OH
N
N
N
N
MeHN
Me2N
N
N
N
Me
Me
Me
Me
Bn
5a
caissarone (I)
heteromine I (II)
heteromine J (III)
Scheme 1 Oxidation of 7,9-dibenzyl-6-iodo-7,8-dihydro-9H-purine
(2a)
Figure 1 Structures of caissarone and heteromines I and J
Recent approaches to the synthesis of 8-oxopurines have
been based on the hydrolysis of 8-bromopurines16 or 8-
sulfanylpurines.17 The alternative route involves direct
construction of the 8-oxopurine heterocycle, beginning
with pyrimidine,18,13 uracil,19 or 2-oxoimidazole20 deriva-
For the initial study of the oxidation of 7,8-dihydro-9H-
purines 2 to 8-oxopurines 3, 7,9-dibenzyl-6-iodo-7,8-di-
hydro-9H-purine (2a) was used as the starting compound
(Scheme 1). The starting 2a was easily prepared from 9-
benzyl-6-iodo-9H-purine (1a) by a previously reported
procedure24 that involves the reduction of 9-benzyl-6-
iodo-9H-purine with diisobutylaluminum hydride, and al-
kylation by benzyl bromide using lithium hexamethyldi-
SYNTHESIS 2014, 46, 0660–0668
Advanced online publication: 09.01.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340499; Art ID: SS-2013-Z0689-OP
© Georg Thieme Verlag Stuttgart · New York

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Total Synthesis of Heteromines I and J
661
silazanide as the base. Dihydropurine 2a was thus isolated pounds 2b–l with yields ranging from 59–93% (Table 2,
in 85% yield. Initially we tested manganese dioxide in di- entries 1–11).
chloromethane for the oxidation of 2a to 3a. However, the
formation of a mixture of the desired oxopurine 3a and
Cl
Cl
R2
Cl
R2
formamidopyrimidine 4a was observed (Table 1, entry 1).
The 1H NMR spectrum of isolated 4a revealed that it is in
equilibrium with its cyclic form 5a in a ratio of 85:15. The
structure of 4a was determined by 2D NMR techniques.
Oxidation in acetonitrile instead of dichloromethane led
N
N
N
N
i)
ii)
N
N
N
O
N
R1
N
R1
X
N
X
N
X
N
R1
1
3
2
to the formation of formamidopyrimidine 4a in 79% iso- Scheme 2 Oxidation of 7,9-dialkyl-7,8-dihydro-9H-purines to 8-
oxopurines. Reagents and conditions: (i) 1. DIBAL-H, THF, r.t.; 2.
lated yield (entry 2). Application of pyridinium chloro-
chromate led to the decomposition of 2a (entry 3), but
LiHMDS, R2X, DMF–THF, –78°C to r.t.; (ii) MCPBA, CH2Cl2, 0 °C.
Jones reagent successfully oxidized 2a to 3a in 52% iso-
lated yield (entry 4). The oxidation with other chromium- The prepared 7,9-dialkyl-7,8-dihydro-9H-purines 2 were
based oxidants like pyridinium dichromate or chromium then used as starting compounds in the developed oxida-
trioxide–pyridine complex performed in dichloromethane tion protocol (Scheme 2). First we focused on the 6-chlo-
at room temperature or at 0 °C resulted in similar yields of ropurines 2b–e that have a benzyl group at position 9. As
oxopurine 3a (entries 5–7). When 3-chloroperoxybenzoic with 2a, 7,9-dibenzyl-6-chloro-7,8-dihydro-9H-purine
acid in dichloromethane at room temperature was used, (2b) was transformed to 8-oxopurine 3b in 77% isolated
the yield of 3a increased substantially (entry 8). Further yield (entry 1). Dihydropurine 2c, which has ester func-
improvement was achieved when oxidation with 3-chlo- tionality, was smoothly oxidized to 3c in 90% yield (entry
roperoxybenzoic acid was carried out in dichloromethane 2); the oxidation of 2c was also performed on a 10-mmol
at 0 °C (entry 9).
scale without a significant decrease in the yield. 7,9-
Dibenzyl-2,6-dichloro-9H-purine 2d was also converted
into 8-oxopurine 3d in a good yield (entry 3). However,
dihydropurine with an allyl group, 2e, was oxidized with
3-chloroperoxybenzoic acid to form a mixture of the de-
sired oxopurine 3e and oxopurine with an epoxidized dou-
ble bond. In this case, the chemoselective oxidation of 2e
to 3e was achieved using pyridinium dichromate (entry 4).
Attempts to oxidize dihydropurine 2f, the substrate that is
easily available by Michael addition to methyl vinyl ke-
tone, failed to give pure compound 3f (entry 5); in this
case, the isolated oxopurine 3f was 85% pure. Detailed
Table 1 Optimization of the Oxidation of 7,9-Dibenzyl-6-iodo-7,8-
dihydro-9H-purine (2a) to 7,9-Dibenzyl-6-iodo-8-oxo-7,8-dihydro-
9H-purine (3a)
Entry
Oxidant
Conditions
Yielda (%)
3a
4a + 5a
1
2
3
4
5
6
7
8
9
MnO2
MnO2
PCC
CH2Cl2, r.t.
MeCN, r.t.
49b
12
dec
52
64
50
64
71
91
44b
79
–
CH2Cl2, r.t.
acetone, 0 °C
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, 0 °C
CH2Cl2, r.t.
CH2Cl2, 0 °C
1
analysis of the H NMR spectrum of the crude reaction
mixture showed that 3f is contaminated by 9-benzyl-6-
chloro-9H-purine, which cannot be separated by simple
column chromatography. The oxidation of 2f with pyri-
dinium dichromate slightly improved the purity of 3f to
92%. We reasoned that the formation of 9-benzyl-6-chlo-
ro-9H-purine proceeds via acid-catalyzed retro-Michael
addition. When 2f was treated with benzoic acid in dichlo-
Jones
–
CrO3·py
PDC
–
–
PDC
–
MCPBA
MCPBA
–
1
romethane, 9-benzyl-6-chloropurine was detected by H
–
NMR after one hour, thus supporting our assumption.
Moderate yields of oxopurines 3g–i (entries 6–8) were ob-
tained if the starting dihydropurines 2g–i contained a
methyl group. On the other hand, the starting dihydropu-
rine containing an isopropyl group, 2j, gave a substantial-
ly higher yield (entry 9). The oxidation of dihydropurine
2k bearing a trityl group failed to give the expected prod-
uct, however 7-benzyl-6-chloro-7H-purine was isolated
in 52% yield as the product of deprotection and reoxida-
tion (entry 10). The 3-chloroperoxybenzoic acid oxidation
of dihydropurine 2l with a Boc-protected amino group
proceeded smoothly and the final product 3l was isolated
in 77% yield (entry 11).
a Isolated yield.
b 1H NMR yield with indene as internal standard.
To determine the scope of the presented protocol for the
oxidation of 7,8-dihydro-9H-purines 2 to 8-oxopurines 3,
a series of 7,9-disubstituted 7,8-dihydro-9H-purines 2b–l
were prepared (Scheme 2).24 With only one exception, the
reduction of all 9-alkyl-6-chloro-9H-purines using diiso-
butylaluminum hydride proceeded smoothly. In the case
of the Boc-protected 2-amino-9-benzyl-6-chloro-9H-pu-
rine, borane–tetrahydrofuran complex was used instead of
diisobutylaluminum hydride. Subsequent alkylation with
alkyl bromides and iodides produced the starting com-
In contrast to most of the reported procedures, our proto-
col enables easy and efficient synthesis of 8-oxopurines
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 660–668

662
T. Tobrman, D. Dvořák
PAPER
Table 2 Scope of the Developed Protocol for the Synthesis of 8-Oxopurines 3 from 9-Alkyl-9H-purines 1 via 7,9-Dialkyl-7,8-dihydro-9H-
purines 2 (Scheme 2)
Entry
1
X
R1
R2
2
Yielda (%) of 2
3
Yielda (%) of 3
1
1b
1b
1c
1b
1b
1d
1e
1e
1d
1f
H
Bn
Bn
Bn
Bn
Bn
i-Pr
Me
Me
i-Pr
Tr
Bn
2b24b
2c
2d
2e
2f
89
86
86
93
75
79
59
84
88
93
73
3b
3c
3d
3e
3f
3g
3h
3i
77
2
H
CHMeCO2Me
Bn
90 (86)b
69
3
Cl
H
4
CH2CH=CH2
(CH2)2Ac
Me
47c
5
H
54c,d
47 (9)c
56
6
H
2g
2h
2i
7
H
Me
8
H
Bn
58
9
H
CHMeCO2Me
Bn
2j
3j
–
77
10
11
H
2k
2l
52e
1g
NBoc2
Bn
CHMeCO2Me
3l
76
a Isolated yield.
b The oxidation was carried out on a 10-mmol scale.
c PDC was used instead of MCPBA.
d Inseparable mixture of 3f and 9-benzyl-6-chloro-9H-purine containing 92% 3f was isolated.
e Isolated yield of 7-benzyl-6-chloro-7H-purine.
that contain halogen atoms. The chlorine atom can be sub-
sequently substituted with various nucleophiles. The abil-
ity of the halogen atom to undergo a substitution reaction
Cl
N
Ph
N
CO2Me
CO2Me
ii)
CO2Me
O
N
N
N
N
i)
N
N
N
O
O
98%
was tested on compound 3c. It was demonstrated that 3c
readily coupled with phenylboronic acid under previously
described conditions,27 and the corresponding 6-phenyl
derivative 7 was isolated in 90% yield (Scheme 3, condi-
tions ii). Similarly, the palladium-catalyzed transfer hy-
drogenolysis of 3c carried out in dry dimethylformamide
at 100 °C produced dehalogenated compound 6 in quanti-
tative yield (Scheme 3, conditions i). Chlorine substitu-
tion with amines would enable access to 8-oxoadenine
derivatives. To test the feasibility of our protocol for the
synthesis of 8-oxoadenines, we chose piperazinyl deriva-
tive 8, a compound that was recently tested for DPPIV-in-
hibiting activity.28 The starting oxopurine 3i, which was
prepared from 2i in 49% yield (2 steps), was treated with
piperazine in dry acetonitrile at 80 °C for 20 hours. The
desired oxopurine 8 was produced in 95% yield after col-
umn chromatography (Scheme 3, conditions iii). The syn-
thesis of compound 8 from 6-chloro-9-methyl-9H-purine
was thus achieved in three steps with an overall yield of
46%.
90%
N
N
N
Bn
Bn
Bn
6
3c
7
H
N
Cl
N
N
N
Ph
O
Ph
O
N
N
N
N
N
iii)
95%
N
Me
Me
8
3i
Scheme 3 Reactivity of 6-chloro-8-oxopurines 3c and 3i. Reagents
and conditions: (i) HCO2Na, PdCl2(PPh3)2, DMF, 100 °C, 98%; (ii)
PhB(OH)2, K2CO3, Pd(PPh3)4, toluene, 100 °C, 20 h, 90%; (iii) piper-
azine, MeCN, 80 °C, 20 h, 95%.
methylated isomers in 87% isolated yield. Reduction of
this mixture with borane–tetrahydrofuran complex, meth-
ylation, and oxidation with 3-chloroperoxybenzoic acid in
dry dichloromethane resulted in the production of Boc-
protected 6-chloro-8-oxopurine 10 in 24% yield (3 steps).
Subsequent reaction of 10 with sodium methoxide result-
ed in the chemoselective deprotection of one Boc group as
well as chlorine displacement in one step. The corre-
sponding monoprotected purine 11 was isolated in 91%
yield. The preparation of heteromine I (12) was finalized
Recently, two new 8-oxopurine derivatives, heteromines I
(12) and J (13), have been isolated from Heterostemma al-
tum wight.2 We applied the developed protocol to the syn-
thesis of these compounds (Scheme 4). We began with
readily available Boc-protected 2-amino-6-chloropurine
9.29 Alkylation of 9 with methyl iodide in the presence of
potassium carbonate resulted in a mixture of N7- and N9-
Synthesis 2014, 46, 660–668
© Georg Thieme Verlag Stuttgart · New York

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Total Synthesis of Heteromines I and J
663
9H-purine (1e),32 6-chloro-9-trityl-9H-purine (1f),24b 2,6-dichloro-
9-benzyl-9H-purine (1c),30 and 2-amino-9-benzyl-6-chloro-9H-
purine33 were prepared by reported procedures, other compounds
were purchased.
by the alkylation of 11 with methyl iodide using lithium
hexamethyldisilazanide as the base, followed by the re-
moval of the Boc group with trifluoroacetic acid. The
overall isolated yield of heteromine I was 19% in six
steps. The alkylation of heteromine I (12) with methyl io- 9-Benzyl-2-[bis(tert-butoxycarbonyl)amino]-6-chloro-9H-pu-
rine (1g)
dide produced heteromine J (13) in quantitative yield.
Thus, the overall isolated yield of heteromine J was 18%
in seven steps.
THF (10 mL) was added to a mixture of 2-amino-9-benzyl-6-chlo-
ro-9H-purine (0.394 g, 1.52 mmol), DMAP (19 mg, 0.152 mmol),
and Boc2O (0.991 g, 4.55 mmol). The resultant mixture was stirred
for 24 h at r.t. The clear yellow solution was concentrated under re-
duce pressure and subjected to column chromatography (silica gel,
EtOAc–hexane, 1:1) afforded 1g (0.559 g, 80%) as a white solid;
mp 150–152 °C.
Cl
Cl
N
OMe
Me
Me
N
N
N
i), ii), iii)
Boc2N
iv)
N
N
N
O
O
1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 18 H, CH3), 5.42 (s, 2 H,
N
N
N
Boc2N
N
BocHN
N
H
CH2), 7.26–7.35 (m, 5 H, CHPh), 8.10 (s, 1 H, CH).
Me
Me
9
10
11
13C NMR (75.45 MHz, CDCl3): δ = 27.7, 47.7, 83.4, 127.7, 128.6,
OMe
OMe
129.0, 129.8, 134.5, 145.9, 150.3, 150.9, 151.8, 152.5.
Me
Me
N
N
HRMS (ESI): m/z [M + Na]+ calcd for C22H26ClN5O4Na: 482.1566;
found: 482.1570.
vi)
N
N
v)
O
O
11
N
N
MeHN
N
Me2N
N
7,9-Dialkyl-6-chloro-7,8-dihydro-9H-purines 2; General Proce-
dure
Me
Me
12
13
DIBAL-H (1.2 equiv) was added to a solution of 9-alkyl-6-chloro-
purine 1 in anhyd THF (5 mL/mmol). The resultant mixture was
stirred for 2 h at r.t., it was then diluted with CH2Cl2 and the reaction
was quenched with excess Na2SO4·10H2O. Then the mixture was
stirred for 10 min at r.t. and filtered through Celite. Evaporation to
dryness gave crude 9-alkyl-6-halo-7,8-dihydro-9H-purine, which
was dissolved in anhyd THF (1 mL/mmol) and anhyd DMF (4
mL/mmol). The prepared solution was cooled to –78 °C, and then
LiHMDS (1.2 equiv) was added and the mixture was stirred for 2
min at –78 °C. The alkyl halide (2 equiv) was added, and the mix-
ture was warmed to r.t. and stirred for 2 h at r.t. The mixture was
diluted with EtOAc and the organic layer was washed with brine (3
× 30 mL). The organic layer was dried (MgSO4), concentrated in
vacuo, and subjected to column chromatography (silica gel) to give
the final product.
heteromine I
heteromine J
(19% in 6 steps)
(18% in 7 steps)
Scheme 4 Straightforward synthesis of heteromines I and J. Re-
agents and conditions: (i) MeI, K2CO3, DMF, 87%; (ii) 1. BH3·THF,
THF, 2. LiHMDS, MeI, THF, DMF, 66%; (iii) MCPBA, CH2Cl2,
42%; (iv) NaOMe, MeOH, 91%; (v) 1. LiHMDS, MeI, THF, DMF,
2. TFA, CH2Cl2, 88%; (vi) LiHMDS, MeI, THF, DMF, 96%.
To summarize, 7,9-dialkyl-6-chloro-8-oxo-7,8-dihydro-
9H-purines can be easily synthesized by the oxidation of
the corresponding 7,8-dihydro-9H-purines using 3-chlo-
roperoxybenzoic acid in dichloromethane at 0 °C. The
presence of both primary and secondary alkyl groups at
positions N7 and N9 is well tolerated, producing the 8-oxo-
purines in 47–90% yields. The N9-trityl derivative(s) are
deprotected and oxidized to the corresponding N7-substi-
tuted purines under the reaction conditions. The chlorine
atom at position 6 of the resulting 8-oxopurines easily un-
dergoes Suzuki coupling and palladium-catalyzed transfer
hydrogenolysis. The nucleophilic displacement of chlo-
rine with piperazine is also smooth. Our protocol for the
synthesis of 8-oxopurines was applied to the synthesis of
heteromines I and J. Further applications of the use of 7,8-
dihydro-9H-purines in the synthesis of novel purine deriv-
atives are currently under investigation.
7,9-Dibenzyl-6-iodo-7,8-dihydro-9H-purine (2a)
General procedure starting from 1a (0.336 g, 1.0 mmol) using 1 M
DIBAL-H in hexane (1.2 mL, 1.2 mmol), 1 M LiHMDS in THF–
ethylbenzene (1.20 mL, 1.2 mmol), and BnBr (0.24 mL, 2.0 mmol),
with column chromatography (silica gel, EtOAc–hexane, 1:2) af-
forded 2a (0.365 g, 85%) as a yellow solid; mp 96–98 °C.
1H NMR (300 MHz, CDCl3): δ = 4.55 (s, 2 H, CH2), 4.68 (s, 2 H,
CH2), 4.70 (s, 2 H, CH2), 7.17–7.32 (m, 10 H, CHPh), 7.76 (s, 1 H,
CH).
13C NMR (75.45 MHz, CDCl3): δ = 46.3, 51.0, 70.9, 92.5, 127.7,
127.76, 127.79, 127.9, 128.7, 128.8, 134.2, 135.0, 136.2, 149.3,
157.7.
Methyl 2-[9-Benzyl-6-chloro-7,8-dihydro-9H-purin-7-yl]pro-
panoate (2c)
General procedure starting from 1b (0.735 g, 3.0 mmol) using 1 M
DIBAL-H in hexane (3.6 mL, 3.6 mmol), 1 M LiHMDS in THF–
ethylbenzene (3.6 mL, 3.6 mmol), and methyl 2-bromopropanoate
(0.67 mL, 6.0 mmol), with column chromatography (silica gel, EtO-
Ac–hexane, 1:2) afforded 2c (0.850 g, 86%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.39 (d, J = 7.2 Hz, 3 H, CH3), 3.63
(s, 3 H, CH3), 4.54, 4.63 (ABq, J = 15.3 Hz, 2 H, CH2), 4.84 (d, J =
3.3 Hz, 1 H, CH2), 4.96 (d, J = 3.3 Hz, 1 H, CH2), 5.03 (q, J = 7.2
Hz, 1 H, CH), 7.21–7.33 (m, 5 H, CHPh), 7.81 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 15.3, 46.5, 52.2, 53.5, 67.3,
127.4, 127.6, 127.8, 128.7, 129.4, 135.0, 149.3, 160.0, 172.0.
HRMS (APCI): m/z [M + H]+ calcd for C16H18ClN4O2: 333.1113;
found: 333.1120.
All reactions were performed under an argon atmosphere. NMR
spectra were measured on a Varian Gemini 300 (1H, 300.07 MHz;
13C, 75.46 MHz), a Bruker Avance III 500 MHz (1H, 500.13 MHz
and 13C, 125.77 MHz) or a Bruker 600 Avance III (1H, 600.13 MHz
and 13C, 150.90 MHz) spectrometer at 298 K. Unambiguous assign-
ment of the NMR signals is based on 13C{1H}, 13C APT, COSY,
HMQC, and 13C HMBC spectra. IR spectra were recorded on Nico-
let 740 FT-IR. Mass spectra were measured on ZAB-SEQ (VG An-
alytical). The solvents were dried and degassed by standard
procedures; silica gel (Merck, Geduran Si 60, 63–200 μm) was used
for column chromatography. 7,9-Dibenzyl-6-chloro-7,8-dihydro-
9H-purine (2b),24b 2-(Boc2-amino)-6-chloro-9H-purine (9),29 9-
benzyl-6-chloro-9H-purine (1b),30 9-benzyl-6-iodo-9H-purine
(1a),31 6-chloro-9-isopropyl-9H-purine (1d),32 6-chloro-9-methyl-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 660–668

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T. Tobrman, D. Dvořák
PAPER
7,9-Dibenzyl-2,6-dichloro-7,8-dihydro-9H-purine (2d)
General procedure starting from 1c (3.20 g, 11.5 mmol) using 1 M
DIBAL-H in hexane (13.8 mL, 13.8 mmol), 1 M LiHMDS in THF–
hexane (13.8 mL, 13.8 mmol), and BnBr (2.74 mL, 23.0 mmol),
with column chromatography (silica gel, EtOAc–hexane, 1:4) af-
forded 2d (3.67 g, 86%) as a yellow oil.
6-Chloro-7,9-dimethyl-7,8-dihydro-9H-purine (2h)
General procedure starting from 1e (1.63 g, 10.0 mmol) using 1 M
DIBAL-H in hexane (12.0 mL, 12.0 mmol), 1 M LiHMDS in THF–
ethylbenzene (12.0 mL, 12.0 mmol), and MeI (1.25 mL, 20.0
mmol), with column chromatography (silica gel, EtOAc) afforded
2h (1.10 g, 59%) as a white oil.
1H NMR (300 MHz, CDCl3): δ = 4.49 (s, 2 H, CH2), 4.55 (s, 2 H,
1H NMR (300 MHz, CDCl3): δ = 2.96 (s, 3 H, CH3), 3.05 (s, 3 H,
CH3), 4.83 (s, 2 H, CH2), 7.77 (s, 1 H, CH).
CH2), 4.71 (s, 2 H, CH2), 7.11–7.27 (m, 10 H, CHPh).
13C NMR (75.45 MHz, CDCl3): δ = 46.6, 51.1, 70.9, 127.2, 127.5,
127.7, 127.8, 128.0, 128.7, 128.75, 128.81, 134.3, 135.8, 148.1,
161.1.
13C NMR (75.45 MHz, DMSO-d6): δ = 28.9, 34.2, 74.5, 126.8,
128.8, 148.1, 160.1.
HRMS (APCI): m/z [M + H]+ calcd for C7H10ClN4: 185.0589;
found: 185.0589.
HRMS (APCI): m/z [M + H]+ calcd for C19H17Cl2N4: 371.0825;
found: 371.0832.
7-Benzyl-6-chloro-9-methyl-7,8-dihydro-9H-purine (2i)
General procedure starting from 1e (0.845 g, 5.0 mmol) using 1 M
DIBAL-H in hexane (6.0 mL, 6.0 mmol), 1 M LiHMDS in THF–
ethylbenzene (6.0 mL, 6.0 mmol), and BnBr (1.19 mL, 10.0 mmol),
with column chromatography (silica gel, EtOAc–hexane, 2:1) af-
forded 2i (1.1 g, 84%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 2.87 (s, 3 H, CH3), 4.62 (s, 2 H,
CH2), 4.74 (s, 2 H, CH2), 7.27–7.30 (m, 5 H, CHPh), 7.75 (s, 1 H,
CH).
7-Allyl-9-benzyl-6-chloro-7,8-dihydro-9H-purine (2e)
General procedure starting from 1b (0.735 g, 3.0 mmol) using 1 M
DIBAL-H in hexane (3.6 mL, 3.6 mmol), 1 M LiHMDS in THF–
ethylbenzene (3.6 mL, 3.6 mmol), and allyl bromide (0.52 mL, 6.0
mmol), with column chromatography (silica gel, EtOAc–hexane,
1:1) afforded 2e (0.800 g, 93%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 3.98 (d, J = 6.0 Hz, 2 H, CH2), 4.56
(s, 2 H, CH2), 4.75 (s, 2 H, CH2), 5.14–5.24 (m, 2 H, CH2), 5.71–
5.80 (m, 1 H, CH), 7.21–7.34 (m, 5 H, CHPh), 7.80 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 29.0, 51.1, 127.7, 127.77,
127.82, 127.9, 128.6, 136.2, 148.6, 159.8.
13C NMR (75.45 MHz, CDCl3): δ = 46.6, 49.9, 70.3, 118.4, 127.7,
127.77, 127.81, 128.7, 128.8, 132.3, 135.1, 148.8, 159.9.
HRMS (APCI): m/z [M + H]+ calcd for C15H16ClN4: 287.1058;
HRMS (APCI): m/z [M + H]+ calcd for C13H14ClN4: 261.0902;
found: 261.0903.
found: 287.1062.
Methyl 2-(6-Chloro-9-isopropyl-7,8-dihydro-9H-purin-7-
yl)propanoate (2j)
4-[9-Benzyl-6-chloro-7,8-dihydro-9H-purin-7-yl]butan-2-one
(2f)
General procedure starting from 1d (0.394 g, 2.0 mmol) using 1 M
DIBAL-H in hexane (2.4 mL, 2.4 mmol), 1 M LiHMDS in THF–
ethylbenzene (2.4 mL, 2.4 mmol), and methyl 2-bromopropanoate
(0.45 mL, 4.0 mmol), with column chromatography (silica gel,
EtOAc–hexane, 1:1) afforded 2j (0.504 g, 88%) as a yellow oil.
1 M DIBAL-H in hexane (12.0 mL, 12.0 mmol) was added to a so-
lution of 1b (2.45 g, 10 mmol) in anhyd THF (40 mL). The resultant
mixture was stirred for 2 h at r.t., diluted with CH2Cl2 and the reac-
tion was quenched with excess Na2SO4·10 H2O. Then the mixture
was stirred for 10 min at r.t., filtered through Celite, and evaporated
to dryness to give crude 6-chloro-9-benzyl-7,8-dihydro-9H-purine
which was dissolved in anhyd DMF (30 mL) then methyl vinyl ke-
tone (1.67 mL, 20 mmol) and DBU (1.8 mL, 12.0 mmol) were add-
ed via syringe. The mixture was stirred for 2 h at r.t., then the
mixture was diluted with EtOAc. The organic layer was washed
with brine (3 × 30 mL), dried (MgSO4), concentrated in vacuo, and
subjected to column chromatography (silica gel, EtOAc–hexane,
2:1) to give 2f (2.39 g, 75%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.13–1.17 (m, 6 H, CH3), 1.41 (d,
J = 7.0 Hz, 3 H, CH3), 3.62 (s, 3 H, CH3), 4.30 (s, J = 7.0 Hz 1 H,
CH), 4.93 (m, 1 H, CH2), 4.98 (q, J = 7.5 Hz, 1 H, CH), 5.05 (m, 1
H, CH2), 7.67 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 15.3, 18.8, 19.3, 44.1, 52.1,
53.5, 63.6, 127.8, 128.8, 149.3, 159.4, 172.1.
HRMS (APCI): m/z [M + H]+ calcd for C12H18ClN4O2: 285.1113;
found: 285.1117.
1H NMR (300 MHz, CDCl3): δ = 2.12 (s, 3 H, CH3), 2.73 (t, J = 6.6
Hz, 2 H, CH2), 3.58 (t, J = 6.6 Hz, 2 H, CH2), 4.53 (s, 2 H, CH2),
4.84 (s, 2 H, CH2), 7.20–7.30 (m, 5 H, CHPh), 7.76 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 30.1, 42.3, 42.9, 46.5, 71.8,
127.8, 127.85, 127.88, 128.0, 128.7, 135.1, 148.6, 159.7, 206.7.
HRMS (APCI): m/z [M + H]+ calcd for C16H18ClN4O: 317.1164;
found: 317.1173.
7-Benzyl-6-chloro-9-trityl-7,8-dihydro-9H-purine (2k)
General procedure starting from 1f (0.397 g, 1.0 mmol) using 1 M
DIBAL-H in hexane (1.2 mL, 1.2 mmol), 1 M LiHMDS in THF–
ethylbenzene (1.20 mL, 1.2 mmol), and BnBr (0.24 mL, 2.0 mmol),
with column chromatography (silica gel, EtOAc–hexane, 1:2) af-
forded 2k (0.455 g, 93%) as a white foam.
1H NMR (300 MHz, CDCl3): δ = 4.62 (s, 2 H, CH2), 4.95 (s, 2 H,
CH2), 7.22–7.35 (m, 16 H, CHPh); 7.36–7.38 (m, 4 H, CHPh), 7.63
(s, 1 H, CH).
6-Chloro-9-isopropyl-7-methyl-7,8-dihydro-9H-purine (2g)
General procedure starting from 1d (0.591 g, 3.0 mmol) using 1 M
DIBAL-H in hexane (3.6 mL, 3.6 mmol), 1 M LiHMDS in THF–
ethylbenzene (3.6 mL, 3.6 mmol), and MeI (0.37 mL, 6.0 mmol),
with column chromatography (silica gel, EtOAc–hexane, 1:1) af-
forded 2g (0.500 g, 79%) as a yellow oil.
13C NMR (75.45 MHz, CDCl3): δ = 51.4, 72.2, 74.6, 127.1, 127.6,
127.66, 127.71, 128.7, 129.4, 129.8, 130.3, 136.3, 141.7, 148.4,
160.1.
HRMS (APCI): m/z [M + H]+ calcd for C31H26ClN4: 489.1840;
1H NMR (300 MHz, CDCl3): δ = 1.23 (d, J = 6.6 Hz, 6 H, CH3), 3.05
(s, 3 H, CH3), 4.35 (sept, J = 6.6 Hz, 1 H, CH), 4.90 (s, 2 H, CH2),
7.75 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 19.4, 31.2, 39.0, 69.5, 126.9,
128.1, 148.5, 151.3.
HRMS (APCI): m/z [M + H]+ calcd for C9H14ClN4: 213.0901;
found: 213.0903.
found: 489.1843.
Methyl 2-{9-Benzyl-2-[bis(tert-butoxycarbonyl)amino]-7,8-di-
hydro-9H-purin-7-yl}propanoate (2l)
Reduction: 1 M BH3–THF complex in THF (1.1 mL, 1.1 mmol) was
added to a solution of 1g (0.460 g, 1.0 mmol) in anhyd THF (5 mL)
cooled to –78 °C. Then the mixture was stirred for 1 h at 0 °C,
quenched with sat. NH4Cl and vigorously stirred for 10 min at 0 °C.
The mixture was diluted with CH2Cl2 (30 mL), the organic layer
was separate and the aqueous layer was extracted with CH2Cl2 (3 ×
Synthesis 2014, 46, 660–668
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of Heteromines I and J
665
10 mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuo.
1H NMR (300 MHz, CDCl3): δ = 1.77 (d, J = 7.2 Hz, 3 H, CH3), 3.72
(s, 3 H, CH3), 5.10 (s, 2 H, CH2), 5.49 (q, J = 7.2 Hz, 1 H, CH), 7.24–
7.31 (m, 3 H, CHPh), 7.44–7.46 (m, 2 H, CHPh), 8.45 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 17.2, 44.2, 50.7, 52.9, 118.7,
128.1, 128.4, 128.6, 135.0, 135.8, 150.2, 150.6, 152.0, 169.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H16ClN4O3: 347.0905;
found: 347.0906.
Alkylation: The isolated crude 9-benzyl-6-chloro-2-[bis(tert-but-
oxycarbonyl)amino]-7,8-dihydro-9H-purine was dissolved in an-
hyd THF (1 mL) and anhyd DMF (4 mL). The solution was cooled
to –78 °C, subsequently 1 M LiHMDS in THF–ethylbenzene (1.2
mL, 1.2 mmol) was added and the mixture was stirred for 2 min at
–78 °C. Then methyl 2-bromopropanoate (0.22 mL, 2.0 mmol) was
added, the mixture was warmed to r.t. and stirred for 2 h at r.t. Then
the mixture was diluted with EtOAc and washed with brine (3 × 30
mL). The organic layer was dried (MgSO4), concentrated in vacuo
and subjected to column chromatography (silica gel, EtOAc–hex-
ane, 1:2) to give 2l (0.400 g, 73%) as a white foam.
7,9-Dibenzyl-2,6-dichloro-8-oxo-7,8-dihydro-9H-purine (3d)
General procedure starting from 2d (4.47 g, 12.05 mmol) using
MCPBA (7.44 g, 30.12 mmol) and CH2Cl2 (120 mL) followed by
column chromatography (silica gel, EtOAc–hexane, 1:4) afforded
3d (3.20 g, 69%) as a white solid; mp 115–116 °C.
1H NMR (300 MHz, CDCl3): δ = 1.34–1.47 (m, 21 H, CH3), 3.60 (s,
3 H, CH3), 3.60 (m, 2 H, CH2), 4.88–4.90 (m, 1 H, CH2), 4.99–5.05
(m, 1 H, CH2 and 1 H, CH), 7.25–7.34 (m, 5 H, CHPh).
13C NMR (75.45 MHz, CDCl3): δ = 15.2, 27.7, 46.4, 52.1, 53.5,
67.9, 82.4, 126.0, 127.7, 127.8, 128.5, 128.7, 135.0, 149.0, 150.5,
161.6, 171.8.
1H NMR (300 MHz, CDCl3): δ = 5.13 (s, 2 H, CH2), 5.29 (s, 2 H,
CH2), 7.25–7.35 (m, 8 H, CHPh), 7.51 (d, J = 6.9 Hz, 2 H, CHPh).
13C NMR (75.45 MHz, CDCl3): δ = 44.5, 45.3, 118.1, 127.1, 128.0,
128.3, 128.67, 128.73, 128.8, 134.7, 135.8, 136.0, 151.0, 151.5,
152.7.
HRMS (ESI): m/z [M + H]+ calcd for C19H15Cl2N4O: 385.0617;
found: 385.0621.
HRMS (ESI): m/z [M + H]+ calcd for C26H35ClN5O6: 548.2270;
found: 548.2274.
7-Allyl-9-benzyl-6-chloro-8-oxo-7,8-dihydro-9H-purine (3e)
PDC (0.786 g, 2.09 mmol) was added to a solution of 2e (0.300 g,
1.05 mmol) in anhyd CH2Cl2 (10 mL) cooled to 0 °C. The resultant
mixture was stirred for 180 min at 0 °C and quenched with i-PrOH
(2 mL). After 10 min the mixture was filtered through Celite, con-
centrated in vacuo and subjected to column chromatography (silica
gel, EtOAc–hexane 1:3) to afford 3e (0.150 g, 47%) as a white
foam.
1H NMR (300 MHz, CDCl3): δ = 4.74–4.76 (m, 2 H, CH2), 5.14 (s,
2 H, CH2), 5.25 (m, 2 H, CH2), 5.92–6.01 (m, 1 H, CH), 7.19–7.36
(m, 3 H, CHPh), 7.47–7.50 (m, 2 H, CHPh), 8.47 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 43.8, 44.1, 117.8, 119.1, 128.0,
128.5, 128.6, 132.0, 135.2, 135.7, 149.9, 150.5, 152.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H14ClN4O: 301.0851;
found: 301.0857.
8-Oxopurines 3; General Procedure
MCPBA (2.5 equiv) was added, in several portions, to a solution of
7,8-dihydropurine 2 (1 equiv) in CH2Cl2 (10 mL/mmol) cooled to
0 °C. The resultant mixture was stirred for 20 min at 0 °C. Then the
mixture was diluted with CH2Cl2 and washed with sat. Na2CO3. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The com-
bined layers were dried (MgSO4), evaporated in vacuo and subject-
ed to column chromatography (silica gel) to give the final product.
7,9-Dibenzyl-6-iodo-8-oxo-7,8-dihydro-9H-purine (3a)
General procedure starting from 2a (0.050 g, 0.12 mmol) using
MCPBA (0.074 g, 0.3 mmol) and CH2Cl2 (2 mL) followed by col-
umn chromatography (silica gel, EtOAc–hexane, 1:2) afforded 3a
(0.048 g, 91%) as a yellow solid; mp 94–95 °C.
1H NMR (300 MHz, CDCl3): δ = 5.16 (s, 2 H, CH2), 5.43 (s, 2 H
CH2), 7.25–7.31 (m, 8 H, CHPh), 7.49–7.51 (m, 2 H, CHPh), 8.35 (s,
1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 43.6, 44.0, 99.9, 125.4, 126.8,
127.7, 128.2, 128.6, 128.7, 135.2, 136.1, 148.1, 150.9, 153.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H16IN4O: 443.0363; found:
443.0369.
4-[9-Benzyl-6-chloro-8-oxo-7,8-dihydro-9H-purin-7-yl]butan-
2-one (3f)
PDC (0.752 g, 2.0 mmol) was added to a solution of 2f (0.317 g, 1.0
mmol) in anhyd CH2Cl2 (15 mL) cooled to 0 °C. The resultant mix-
ture was stirred for 180 min at 0 °C and quenched with i-PrOH (2
mL). After 10 min the mixture was filtered through Celite, concen-
trated in vacuo and subjected to column chromatography (silica gel,
EtOAc–hexane, 1:1) to afford 3f (0.180 g, 54%) as a white amor-
phous solid that was 92% pure (1H NMR spectroscopy).
7,9-Dibenzyl-6-chloro-8-oxo-7,8-dihydro-9H-purine (3b)
General procedure starting from 2b (0.200 g, 0.59 mmol) using
MCPBA (0.367 g, 1.48 mmol) and CH2Cl2 (6 mL) followed by col-
umn chromatography (silica gel, EtOAc–hexane, 1:3) afforded 3b
(0.160 g, 77%) as a white solid; mp 77–79 °C.
1H NMR (300 MHz, CDCl3): δ = 5.16 (s, 2 H, CH2), 5.33 (s, 2 H,
CH2), 7.26–7.33 (m, 8 H, CHPh), 7.51 (d, J = 7.8 Hz, 2 H, CHPh),
8.46 (s, 1 H, CH).
1H NMR (300 MHz, CDCl3): δ = 2.19 (s, 3 H, CH3), 2.95 (t, J = 7.5
Hz, 2 H, CH2), 4.41 (t, J = 7.5 Hz, 2 H, CH2), 5.05 (s, 2 H, CH2),
7.30–7.33 (m, 3 H, CHPh), 7.46–7.49 (m, 2 H, CHPh), 8.46 (s, 1 H,
CH).
13C NMR (75.45 MHz, CDCl3): δ = 29.9, 37.0, 42.7, 44.0, 118.9,
128.0, 128.4, 128.5, 135.0, 135.4, 149.9, 150.4, 152.2, 205.1.
13C NMR (75.45 MHz, CDCl3): δ = 44.2, 45.2, 119.1, 127.2, 127.8,
128.1, 128.5, 128.62, 128.63, 135.2, 135.8, 136.1, 150.0, 150.6,
152.8.
6-Chloro-9-isopropyl-7-methyl-8-oxo-7,8-dihydro-9H-purine
(3g)
General procedure starting from 2g (0.200 g, 0.94 mmol) using
MCPBA (0.580 g, 2.35 mmol) and CH2Cl2 (10 mL) followed by
column chromatography (silica gel, EtOAc–hexane, 1:3) afforded
3g (0.100 g, 47%) as a white solid; mp 105–109 °C.
1H NMR (300 MHz, CDCl3): δ = 1.51 (d, J = 6.6 Hz, 6 H, CH3), 3.61
(s, 3 H, CH3), 4.75 (sept, J = 6.6 Hz, 1 H, CH), 8.35 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 19.8, 28.8, 46.0, 119.5, 135.7,
149.8, 150.0, 152.3.
HRMS (ESI): m/z [M + H]+ calcd for C9H12ClN4O: 227.0694;
HRMS (ESI): m/z [M + H]+ calcd for C19H16ClN4O: 351.1007;
found: 351.1022.
Methyl 2-(9-Benzyl-6-chloro-8-oxo-7,8-dihydro-9H-purin-7-
yl)propanoate (3c)
General procedure starting from 2c (0.200 g, 0.60 mmol) using
MCPBA (0.371 g, 1.5 mmol) and CH2Cl2 (6 mL) followed by col-
umn chromatography (silica gel, EtOAc–hexane, 1:2) afforded 3c
(0.188 g, 90%) as a yellow oil.
found: 227.0697.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 660–668

666
T. Tobrman, D. Dvořák
PAPER
6-Chloro-7,9-dimethyl-8-oxo-7,8-dihydro-9H-purine (3h)
General procedure starting from 2h (0.200 g, 1.08 mmol) using
MCPBA (0.667 g, 2.70 mmol) and CH2Cl2 (10 mL) followed by
column chromatography (silica gel, EtOAc–hexane, 2:1) afforded
3h (0.120 g, 56%) as a white solid; mp 169–171 °C.
1H NMR (300 MHz, CDCl3): δ = 3.39 (s, 3 H, CH3), 3.59 (s, 3 H,
CH3), 8.32 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 26.5, 28.8, 119.6, 135.6, 150.1,
150.2, 153.0.
HRMS (ESI): m/z [M + H]+ calcd for C7H8ClN4O: 199.0381; found:
199.0383.
HRMS (ESI): m/z [M + H]+ calcd for C26H33ClN5O7: 562.2063;
found: 562.2065.
Equilibrium mixture of 4-(Benzylamino)-5-(N-benzylformami-
do)-6-iodopyrimidine (4a) and 7,9-Dibenzyl-8-hydroxy-6-iodo-
7,8-dihydro-9H-purine (5a)
Anhyd MeCN (10 mL) was added to a mixture of 2a (0.856 g, 2.0
mmol) and MnO2 (1.74 g, 20 mmol). The resultant mixture was
stirred for 3 h at r.t., concentrated under reduce pressure, and sub-
jected to column chromatography (silica gel, EtOAc–hexane, 1:2)
afforded oxopurine 3a (0.105 g, 12%) and a mixture of 4a and 5a
(85:15, 0.700 g, 79%) as a white solid; mp 125–127 °C.
1H NMR (300 MHz, CDCl3): δ = 4.02 (d, J = 14.1 Hz, 1 H, CH2),
4.09 (dd, J = 5.7, 14.7 Hz, 1 H, CH2), 4.32 (dd, J = 6.0, 14.7 Hz, 1
H, CH2), 4.525a (d, J = 14.4 Hz, 1 H, CH2), 4.82–4.85 (m, 1 H, NH),
4.875a (d, J = 14.4 Hz, 1 H, CH2), 5.39 (d, J = 14.1 Hz, 1 H, CH2),
6.91–6.95 (m, 2 H, CHPh), 7.16–7.28 (m, 8 H, CHPh), 8.03 (s, 1 H,
CH), 8.165a (s, 1 H, CH), 8.19 (s, 1 H, CH), 8.545a (s, 1 H, CH).
7-Benzyl-6-chloro-9-methyl-8-oxo-7,8-dihydro-9H-purine (3i)
General procedure starting from 2i (0.492 g, 1.89 mmol) using
MCPBA (1.16 g, 4.71 mmol) and CH2Cl2 (20 mL) followed by col-
umn chromatography (silica gel, EtOAc–hexane, 1:2) afforded 3i
(0.303 g, 58%) as a brown oil.
1H NMR (300 MHz, CDCl3): δ = 3.43 (s, 3 H, CH3), 5.25 (s, 2 H,
13C NMR (125.77 MHz, CDCl3): δ = 44.65a, 44.8, 48.7, 53.85a,
121.05a, 122.3, 127.25a, 127.45a, 127.5, 127.7, 128.375a, 128.43,
128.5, 128.8, 128.95a, 129.05a, 129.5, 131.65a, 134.0, 134.65a, 135.5,
137.0, 137.25a, 157.05a, 157.4, 158.15a, 159.1, 162.05a, 163.5.
CH2), 7.19–7.26 (m, 5 H, CHPh), 8.36 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 26.5, 44.9, 118.9, 127.1, 127.6,
128.4, 135.4, 136.0, 150.26, 150.31, 152.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H12ClN4O: 275.0694;
found: 275.0699.
Methyl 2-[9-Benzyl-8-oxo-7,8-dihydro-9H-purin-7-yl]propano-
ate (6)
Anhyd DMF (3 mL) was added to a mixture of 3c (0.050 g, 0.15
mmol), PdCl2(PPh3)2 (5.3 mg, 0.0075 mmol), and HCO2Na (0.020
g, 0.30 mmol). The resultant mixture was stirred for 30 min at
100 °C, diluted with EtOAc (40 mL) and the organic layer was
washed with brine (3 × 30 mL). The organic layer was dried
(MgSO4), concentrated in vacuo and subjected to column chroma-
tography (silica gel, EtOAc–hexane, 2:1) to give 6 (0.230 g, 98%)
as a white solid; mp 88–90 °C.
1H NMR (300 MHz, CDCl3): δ = 1.73 (d, J = 7.5 Hz, 3 H, CH3), 3.76
(s, 3 H, CH3), 5.13 (s, 2 H, CH2), 5.31 (q, J = 7.5 Hz, 1 H, CH), 7.26–
7.35 (m, 3 H, CHPh), 7.48–7.51 (m, 2 H, CHPh), 8.22 (s, 1 H, CH),
8.71 (s, 1 H, CH).
Methyl 2-[6-Chloro-9-isopropyl-8-oxo-7,8-dihydro-9H-purin-
7-yl]propanoate (3j)
General procedure starting from 2j (0.205 g, 0.72 mmol) using
MCPBA (0.444 g, 1.8 mmol) and CH2Cl2 (6 mL) followed by col-
umn chromatography (silica gel, EtOAc–hexane, 1:2) afforded 3j
(0.165 g, 77%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.50 (d, J = 6.9 Hz, 6 H, CH3), 1.71
(d, J = 7.2 Hz, 3 H, CH3), 3.68 (s, 3 H, CH3), 4.72 (sept, J = 6.9 Hz,
1 H, CH), 5.42 (q, J = 7.2 Hz, 1 H, CH), 8.35 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 17.2, 19.6, 46.1, 50.5, 52.8,
118.5, 135.6, 150.16, 150.23, 151.5, 170.0.
13C NMR (75.45 MHz, CDCl3): δ = 15.4, 43.4, 50.0, 52.5, 121.2,
127.7, 128.2, 128.3, 133.2, 135.2, 148.8, 151.1, 151.9, 169.8.
HRMS (ESI): m/z [M + H]+ calcd for C12H16ClN4O3: 299.0905;
found: 299.0908.
HRMS (ESI): m/z [M + H]+ calcd for C16H17N4O3: 313.1295; found:
313.1299.
Attempted Oxidation of 7-Benzyl-6-chloro-9-trityl-7,8-di-
hydro-9H-purine (2k)
MCPBA (0.309 g, 1.25 mmol) was added, in several portions, to a
solution of 2k (0.245 g, 0.5 mmol) in CH2Cl2 (5 mL) cooled to 0 °C.
The resultant mixture was stirred for 20 min at 0 °C. Then the mix-
ture was diluted with CH2Cl2 and washed with sat. Na2CO3. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The com-
bined layers were dried (MgSO4), evaporated in vacuo, and subject-
ed to column chromatography (silica gel, EtOAc–MeOH, 20:1) to
give 7-benzyl-6-chloro-7H-purine (0.064 g, 52%) as a white solid.
Methyl 2-[9-Benzyl-6-phenyl-8-oxo-7,8-dihydro-9H-purin-7-
yl]propanoate (7)
Anhyd toluene (5 mL) was added to a mixture of 3c (0.150 g, 0.43
mmol), phenylboronic acid (0.105 g, 0.86 mmol), K2CO3 (0.119 g,
0.86 mmol), and Pd(PPh3)4. The resultant mixture was stirred for 20
h at 100 °C, concentrated in vacuo, and subjected to column chro-
matography (silica gel, EtOAc–hexane, 1:2) to give 7 (0.150 g,
90%) as a white solid; mp 105–106 °C.
1H NMR (300 MHz, CDCl3): δ = 5.69 (s, 2 H, CH2), 7.15–7.18 (m,
2 H, CHPh), 7.34–7.37 (m, 3 H, CHPh), 8.25 (s, 1 H, CH), 8.87 (s, 1
H, CH), in accordance with an authentic sample prepared by report-
ed procedure.30
1H NMR (300 MHz, CDCl3): δ = 1.60 (d, J = 6.9 Hz, 3 H, CH3), 3.63
(s, 3 H, CH3), 4.48 (q, J = 7.2 Hz, 1 H, CH), 5.17 (s, 2 H, CH2), 7.27–
7.35 (m, 3 H, CHPh), 7.50–7.53 (m, 7 H, CHPh), 8.74 (s, 1 H, CH).
13C NMR (75.45 MHz, CDCl3): δ = 15.0, 43.6, 52.3, 52.6, 119.7,
127.9, 128.35, 128.41, 128.6, 128.7, 129.9, 135.4, 135.6, 143.9,
150.0, 150.9, 153.0, 169.7.
Methyl 2-{9-Benzyl-2-[bis(tert-butoxycarbonyl)amino]-8-oxo-
7,8-dihydro-9H-purin-7-yl}propanoate (3l)
General procedure starting from 2l (0.220 g, 0.40 mmol) using
MCPBA (0.248 g, 1.0 mmol) and CH2Cl2 (4 mL) followed by col-
umn chromatography (silica gel, EtOAc–hexane, 1:2) afforded 3l
(0.170 g, 76%) as a white foam.
1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 18 H, CH3), 1.78 (d, J =
7.2 Hz, 3 H, CH3), 3.72 (s, 3 H, CH3), 5.08 (s, 2 H, CH2), 5.47 (q,
J = 7.2 Hz, 1 H, CH), 7.26–7.31 (m, 3 H, CHPh), 7.40–7.43 (m, 2 H,
CHPh).
HRMS (ESI): m/z [M + H]+ calcd for C22H21N4O3: 389.1608; found:
389.1606.
7-Benzyl-9-methyl-8-oxo-6-(piperazin-1-yl)-7,8-dihydro-9H-
purine (8)
Anhyd MeCN (4 mL) was added to a mixture of piperazine (0.269
g, 3.13 mmol) and 3i (0.215 g, 0.78 mmol). The resultant mixture
was stirred for 20 h at 80 °C, concentrated in vacuo, and subjected
to column chromatography (silica gel, CH2Cl2–MeOH, 10:1 to 3:1)
to afford 8 (0.240 g, 95%) as a white foam.
13C NMR (75.45 MHz, CDCl3): δ =17.2, 27.7, 44.4, 50.9, 52.9,
83.5, 117.0, 128.1, 128.4, 128.7, 134.9, 135.7, 150.4, 151.5, 152.3,
169.8.
Synthesis 2014, 46, 660–668
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of Heteromines I and J
667
1H NMR (500.13 MHz, CDCl3): δ = 3.00 (m, 4 H, CH2), 3.25 (m, 4
H, CH2), 3.46 (s, 3 H, CH3), 5.17 (s, 2 H, CH2), 7.25–7.30 (m, 5 H,
CHPh), 8.40 (s, 1 H, CH).
13C NMR (125.77 MHz, CDCl3): δ = 26.4, 45.4, 46.2, 50.7, 111.3,
127.3, 127.7, 128.6, 136.4, 150.4, 150.8, 154.3, one signal is miss-
ing.
2-[(tert-Butoxycarbonyl)amino]-6-methoxy-7,9-dimethyl-8-
oxo-7,8-dihydro-9H-purine (11)
Na (0.012 g, 0.5 mmol) was added to MeOH (3 mL) and the mixture
was stirred until Na disappeared (approx, 2 min). 10 (0.041 g, 0.10
mmol) was added and the mixture was stirred for 30 h at r.t. The
MeOH was removed under reduced pressure and the residue was
subjected to column chromatography (silica gel, EtOAc–hexane,
1:1) to afford 11 (0.028 g, 91%) as a white solid; mp 184–186 °C.
HRMS (ESI): m/z [M + H]+ calcd for C17H21N6O: 325.1778; found:
325.1771.
1H NMR (300 MHz, CDCl3): δ = 1.52 (s, 9 H, CH3), 3.41 (s, 3 H,
CH3), 3.51 (s, 3 H, CH3), 4.02 (s, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): δ = 26.4, 28.0, 29.1, 53.7, 80.8,
2-[Bis(tert-Butoxycarbonyl)amino]-6-chloro-7,9-dimethyl-8-
oxo-7,8-dihydro-9H-purine (10)
Methylation: Anhyd DMF (4 mL) was added to a mixture of freshly
dried K2CO3 (0.247 g, 1.79 mmol) and chloropurine 9 (0.331 g, 0.89
mmol). Then MeI (0.11 mL, 1.79 mmol) was added and the resul-
tant mixture was stirred for 24 h at r.t. Then the mixture was diluted
with EtOAc (40 mL) and the organic layer was extracted with brine
(3 × 20 mL), dried (MgSO4), and subjected to column chromatog-
raphy (silica gel, EtOAc) to afford a mixture of N7- and N9-methyl-
2-[bis(tert-butoxycarbonyl)amino]-6-chloropurine (ratio N9/N7
75:25, 0.298 g, 87%).
103.2, 149.9, 150.49, 150.52, 152.6, 153.2.
HRMS (ESI): m/z [M + H]+ calcd for C13H20N5O4: 310.1510; found:
310.1506.
Heteromine I [6-Methoxy-7,9-dimethyl-2-(methylamino)-8-
oxo-7,8-dihydro-9H-purine, 12]
Methylation: 1 M LiHMDS in THF–ethylbenzene (0.12 mL, 0.12
mmol) was added to a solution of 11 (0.031 g, 0.10 mmol) in anhyd
DMF(1 mL) and THF (0.2 mL) cooled to –78 °C. Then the mixture
was stirred for 5 min at –78 °C followed by addition of MeI (0.019
mL, 0.30 mmol). The resultant mixture was stirred for 1 h at r.t., di-
luted with EtOAc (20 mL), and the organic layer was washed with
brine (3 × 10 mL), dried (MgSO4), concentrated in vacuo, and sub-
jected to column chromatography (silica gel, EtOAc–hexane, 1:1)
to afford methylated 11 (0.032 g, 99%) as a white solid; mp 107–
108 °C.
1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 18 H, CH3), 1.45 (s, 18 H,
CH3), 3.91 (s, 3 H, CH3), 4.16 (s, 3 H, CH3), 8.12 (s, 1 H, CHPu),
8.19 (s, 1 H, CHPu).
Reduction: The isolated mixture (0.290 g, 0.76 mmol) was dis-
solved in anhyd THF (4 mL), cooled to –78 °C and 1 M BH3–THF
in THF (0.91 mL, 0.91 mmol) was added. Then the mixture was
stirred for 1 h at 0 °C, quenched with sat. NH4Cl, and vigorously
stirred for 10 min at 0 °C. The mixture was diluted with CH2Cl2 (30
mL), the organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 10 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduce pressure.
1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 9 H, CH3), 3.35 (s, 3 H,
CH3), 3.40 (s, 3 H, CH3), 3.53 (s, 3 H, CH3), 4.02 (s, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): δ = 26.1, 28.0, 29.0, 34.8, 53.5, 80.5,
104.1, 149.5, 152.0, 153.28, 153.32, 153.9.
Alkylation: The isolated crude 7,8-dihydropurine was dissolved in
DMF (4.0 mL) and THF (1.5 mL), cooled to –78 °C and 1 M
LiHMDS in THF–hexane (0.91 mL, 0.91 mmol) was added. Then
the mixture was stirred for 2 min at –78 °C, followed by addition of
MeI (0.095 mL, 1.52 mmol) and the mixture was stirred for 2 h at
r.t., and diluted with EtOAc. The organic layer was washed with
brine (3 × 30 mL), dried (MgSO4), concentrated under reduce pres-
sure, and subjected to column chromatography (silica gel, EtOAc–
hexane, 1:1) to afford 2-[bis(tert-butoxycarbonyl)amino]-6-chloro-
7,9-dimethyl-7,8-dihydro-9H-purine (0.200 g, 66%) as a yellow
foam.
Deprotection: Methylated 11 (0.236 g, 0.73 mmol) was dissolved in
CH2Cl2 (1 mL) followed by addition of TFA (0.73 mL). The mix-
ture was stirred for 2 h at r.t., diluted with CH2Cl2 (20 mL), and
washed with sat. Na2CO3 (30 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 20 mL), and the combined organic layers were
dried (MgSO4) and concentrated under reduce pressure to afford
heteromine I (12; 0.144 g, 88%) as a white solid; mp 171–172 °C.
1H NMR (600.13 MHz, CDCl3): δ = 2.99 (s, 3 H, CH3-N2), 3.36 (s,
3 H, CH3-N9), 3.49 (s, 3 H, CH3-N7), 3.99 (s, 3 H, CH3O), 4.75 (br
s, 1 H, NH).
13C NMR (150.9 MHz, CDCl3): δ = 26.2 (CH3-N9), 28.7 (CH3-N2),
29.2 (CH3-N7), 53.2 (CH3O), 99.9 (C5), 151.1 (C4), 153.5 (C8),
153.7 (C6), 158.4 (C2).
1H NMR (300 MHz, CDCl3): δ = 1.36 (s, 18 H, CH3), 2.86 (s, 3 H,
CH3), 2.97 (s, 3 H, CH3), 4.81 (s, 3 H, CH2).
13C NMR (75.45 MHz, CDCl3): δ = 27.7, 29.1, 34.4, 75.5, 82.5,
126.9, 127.3, 148.0, 150.9, 161.5.
Heteromine J [2-(Dimethylamino)-6-methoxy-7,9-dimethyl-8-
oxo-7,8-dihydro-9H-purine, 13]
Oxidation:
2-[Bis(tert-butoxycarbonyl)amino]-6-chloro-7,9-di-
1 M LiHMDS in THF–ethylbenzene (0.51 mL, 0.51 mmol) was
added to a solution of 12 (0.094 g, 0.42 mmol) in anhyd DMF (5
mL) and THF (1.0 mL) cooled to –78 °C. Then the mixture was
stirred for 5 min at –78 °C followed by addition of MeI (0.062 mL,
1.0 mmol). The resultant mixture was stirred for 1 h at r.t., and di-
luted with EtOAc (50 mL). The organic layer was washed with
brine (3 × 20 mL), dried (MgSO4), concentrated in vacuo, and sub-
jected to column chromatography (silica gel, EtOAc–hexane, 2:1)
to afford 13 (0.096 mg, 96%) as a white solid; mp 124–126 °C.
methyl-7,8-dihydro-9H-purine (0.170 g, 0.43 mmol) was dissolved
in CH2Cl2 (5 mL) and cooled to 0 °C. Then MCPBA (0.263 g, 1.06
mmol) was added and the mixture was stirred for 20 min at 0 °C.
Then the mixture was diluted with CH2Cl2 (20 mL) and washed
with sat. Na2CO3 (20 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined layers were dried (MgSO4),
concentrated in vacuo and subjected to column chromatography
(silica gel, EtOAc–hexane, 1:2) to afford 10 (0.074 g, 42%) as a
white foam.
1H NMR (300 MHz, CDCl3): δ = 1.37 (s, 18 H, CH3), 3.38 (s, 3 H,
CH3), 3.60 (s, 3 H, CH3).
13C NMR (75.45 MHz, CDCl3): δ = 26.6, 27.7, 28.8, 83.3, 117.9,
135.4, 150.0, 150.4, 151.3, 153.2.
1H NMR (600.13 MHz, CDCl3): δ = 3.16 (s, 6 H, CH3-N2), 3.37 (s,
3 H, CH3-N9), 3.48 (s, 3 H, CH3-N7), 4.00 (s, 3 H, CH3O).
13C NMR (150.9 MHz, CDCl3): δ = 26.1 (CH3-N9), 29.2 (CH3-N7),
37.1 (CH3-N2), 52.9 (CH3O), 98.8 (C5), 151.1 (C4), 153.3 (C8),
153.6 (C6), 158.0 (C2).
HRMS (ESI): m/z [M + Na]+ calcd for C17H24ClN5O5Na: 436.1358;
found: 436.1363.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 660–668

668
T. Tobrman, D. Dvořák
PAPER
N.; Yoshida, Y.; Ogawa, M.; Fukumura, T.; Zhang, M.-R. J.
Med. Chem. 2011, 54, 6040. (b) Yamasaki, T.; Koike, S.;
Hatori, A.; Yanamoto, K.; Kawamura, K.; Yui, J.; Kumata,
K.; Ando, K.; Zhang, M.-R. J. Radiat. Res. 2010, 51, 57.
(13) Reitz, A. B.; Goodman, M. G.; Pope, B. L.; Argentieri, D.
C.; Bell, S. C.; Burr, L. E.; Chourmouzis, E.; Come, J.;
Goodman, J. H.; Klaubert, D. H.; Maryanoff, B. E.;
McDonnell, M. E.; Rampulla, M. S.; Schott, M. R.; Chen, R.
J. Med. Chem. 1994, 37, 3561.
(14) (a) Hirota, K.; Kazaoka, K.; Niimoto, I.; Kumihara, H.;
Sajiki, H.; Isobe, Y.; Takaku, H.; Tobe, M.; Ogita, H.;
Ogino, T.; Ichii, S.; Kurimoto, A.; Kawakami, H. J. Med.
Chem. 2002, 45, 5419. (b) Hirota, K.; Kazaoka, K.; Sajiki,
H. Bioorg. Med. Chem. 2003, 11, 2715.
(15) Yamazaki, K.; Yasuda, N.; Inoue, T.; Nagakura, T.; Kira, K.;
Shinoda, M.; Saeki, T.; Tanaka, I. J. Pharmacol. Exp. Ther.
2006, 319, 1253.
(16) (a) Ikehara, M.; Maruyama, T. Tetrahedron 1975, 31, 1369.
(b) Fujii, T.; Saito, T.; Mori, S. Heterocycles 1988, 27, 1145.
(17) Janeba, Z.; Holý, A.; Masojídková, M. Collect. Czech.
Chem. Commun. 2001, 66, 1393.
(18) (a) Dornow, A.; Hinz, E. Chem. Ber. 1958, 91, 1834.
(b) Goodman, M. G.; Goodman, J. H. J. Immunol. 1994,
130, 4081.
(19) Gaulon, C.; Dijkstra, H. P.; Springer, C. J. Synthesis 2005,
2227.
(20) (a) Kosaku, H.; Kazunori, K.; Itaru, N.; Hironao, S.
Heterocycles 2001, 55, 2279. (b) Zaki, M. E. E.; Proença, M.
F. Tetrahedron 2011, 67, 755.
(21) (a) Come, J.; Burr, L.; Chen, R. Tetrahedron Lett. 1991, 32,
4823. (b) Koukal, P.; Dvořáková, H.; Dvořák, D.; Tobrman,
T. Chem. Pap. 2013, 67, 3.
(22) (a) Fujii, T.; Ogawa, K.; Saito, T.; Kobayashi, K.; Itaya, T.;
Date, T.; Okamura, K. Chem. Pharm. Bull. 1995, 43, 53.
(b) Itaya, T.; Kanai, T.; Shimada, M.; Nishikawa, T.;
Takada, Y.; Hozumi, Y.; Mori, S.; Saito, T.; Fujii, T. Chem.
Pharm. Bull. 1997, 45, 1601.
(23) (a) Kameyama, K.; Sako, M.; Hirota, K.; Yoshifumi, M.
Synthesis 1983, 849. (b) Lee, J. M.; Niles, J. C.; Wishnok, J.
S.; Tannenbaum, S. R. Chem. Res. Toxicol. 2002, 15, 7.
(c) Madyastha, K. M.; Sridhar, G. R. J. Chem. Soc., Perkin
Trans. 1 1999, 677.
(24) (a) Kotek, V.; Tobrman, T.; Dvořák, D. Synthesis 2012, 44,
610. (b) Kotek, V.; Chudíková, N.; Tobrman, T.; Dvořák, D.
Org. Lett. 2010, 12, 5724.
(25) Maryška, M.; Chudíková, N.; Kotek, V.; Dvořák, D.;
Tobrman, T. Monatsh. Chem. 2013, 144, 501.
(26) Spontaneous air oxidation of 6-methoxy-2-dimethylamino-
7,9-dimethyl-7,8-dihydro-9H-purine to heteromine J along
with other byproducts was reported: Lin, Y.-L.; Huang,
R.-L. J. Nat. Prod. 1997, 60, 982.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
References
(1) Zelnik, R.; Haraguchi, M.; Matida, A. K.; Lavie, D.; Frolow,
F.; Weisb, A. L. J. Chem. Soc., Perkin Trans. 1 1986, 2051.
(2) Fu, W.-W.; Tan, C.-H.; Zhuang, P.-Y.; Yang, S.-M.; Luo,
H.-F.; Tan, J.-J.; Liu, P.; Zhu, D.-Y. Heterocycles 2011, 83,
1405.
(3) (a) Lindsay, B. S.; Almeida, A. M. P.; Smith, C. J.; Berlinck,
R. G. S.; da Rocha, R. M.; Ireland, C. M. J. Nat. Prod. 1999,
62, 1573. (b) Makarieva, T. N.; Guzii, A. G.; Dmitrenok, A.
S.; Dmitrenok, P. S.; Krasokhin, V. B.; Stonik, V. A. Nat.
Prod. Commun. 2006, 9, 711.
(4) Selected reviews on oxidative DNA cleavage: (a) Breen, A.
P.; Murphy, J. A. Free Radical Biol. Med. 1995, 18, 1033.
(b) Kasai, H.; Nishimura, S. In Oxidative Stress: Oxidants
and Antioxidants; Sies, H., Ed.; Academic Press: San Diego,
1991, 99–116. (c) Kryston, T. B.; Georgiev, A. B.; Pissis, P.;
Georgakilas, A. G. Mutat. Res. 2011, 711, 193. (d) Cooke,
M. S.; Evans, M. D.; Dizdaroglu, M.; Lunec, J. FASEB J.
2003, 17, 1195.
(5) Recent examples: (a) Kim, S. K.; Kim, J. Y.; Baek, A. K.;
Moon, B. J. Bioorg. Med. Chem. Lett. 2002, 12, 1977.
(b) Kim, S. K.; Yokoyama, S.; Takaku, H.; Moon, B. J.
Bioorg. Med. Chem. Lett. 1998, 8, 939. (c) Hamm, M. L.;
Billig, K. Org. Biomol. Chem. 2006, 4, 4068. (d) Cadena-
Amaro, C.; Delepierre, M.; Pochet, S. Bioorg. Med. Chem.
Lett. 2005, 15, 1069.
(6) (a) Sekine, M.; Okada, K.; Seio, K.; Kakeya, H.; Osada, H.;
Sasaki, T. Bioorg. Med. Chem. 2004, 12, 5193. (b) Sekine,
M.; Okada, K.; Seio, K.; Obata, T.; Sasaki, T.; Kakeya, H.;
Osada, H. Bioorg. Med. Chem. 2004, 12, 6343.
(c) Moriguchi, T.; Asai, N.; Okada, K.; Seio, K.; Sasaki, T.;
Sekine, M. J. Org. Chem. 2002, 67, 3290. (d) Sekine, M.;
Okada, K.; Seio, K.; Kakeya, H.; Osada, H.; Obata, T.;
Sasaki, T. J. Org. Chem. 2004, 69, 314. (e) Taguchi, H.;
Ohkubo, A.; Sekine, M.; Seio, K.; Kakeya, H.; Osada, H.;
Sasaki, T. Nucleosides, Nucleotides Nucleic Acids 2006, 25,
647. (f) Moriguchi, T.; Asai, N.; Wada, T.; Seio, K.; Sasaki,
T.; Sekine, M. Tetrahedron Lett. 2000, 41, 5881.
(7) (a) Ho, C. Y.; Kukla, M. J. Bioorg. Med. Chem. Lett. 1991,
1, 531. (b) Kelley, J. L.; Linn, J. A.; Selway, J. W. T. J. Med.
Chem. 1991, 34, 157. (c) Michael, M. A.; Cottam, H. B.;
Smee, D. F.; Robins, R. K.; Kini, G. D. J. Med. Chem. 1993,
36, 3431.
(8) Beck, J. P.; Arvanitis, A. G.; Curry, M. A.; Rescinito, J. T.;
Fitzgerald, L. W.; Gilligan, P. J.; Zaczek, R.; Trainor, G. L.
Bioorg. Med. Chem. Lett. 1999, 9, 967.
(9) Kumagai, T.; Okubo, T.; Kataoka-Okubo, H.; Chaki, S.;
Okuyama, S.; Nakazato, A. Bioorg. Med. Chem. 2001, 9,
1357.
(27) Havelková, M.; Hocek, M.; Česnek, M.; Dvořák, D. Synlett
1999, 1145.
(28) Kazunobu, K.; Richard, C.; Seiji, Y.; Taisuke, U. EP
1,568,699, 2005.
(29) Porcheddu, A.; Giacomelli, G.; Piredda, I.; Carta, M.;
Nieddu, G. Eur. J. Org. Chem. 2008, 5786.
(10) Shao, Y.; Cole, A. G.; Brescia, M.-R.; Qin, L.-Y.; Duo, J.;
Stauffer, M.; Rokosz, L. L.; McGuinness, B. F.; Henderson,
I. Bioorg. Med. Chem. Lett. 2009, 19, 1399.
(11) (a) Kurimoto, A.; Hashimoto, K.; Nakamura, T.; Norimura,
K.; Ogita, H.; Takaku, H.; Bonnert, R.; McInally, T.; Wada,
H.; Isobe, Y. J. Med. Chem. 2010, 53, 2964. (b) Nakamura,
T.; Wada, H.; Kurebayashi, H.; McInally, T.; Bonnert, R.;
Isobe, Y. Bioorg. Med. Chem. Lett. 2013, 23, 669.
(c) Weterings, J. J.; Khan, S.; van der Heden van Noort, G.
J.; Melief, C. J. M.; Overkleeft, H. S.; van der Burg, S. H.;
Ossendorp, F.; van der Marel, G. A.; Filippov, D. V. Bioorg.
Med. Chem. Lett. 2009, 19, 2249.
(30) Gundersen, L.-L.; Bakkestuen, A. K.; Aasen, A. J.; Øverås,
H.; Rise, R. Tetrahedron 1994, 50, 9743.
(31) McKenzie, T. C.; Epstein, J. W. J. Org. Chem. 1982, 47,
4881.
(32) Kim, B. Y.; Ahn, J. B.; Lee, H. W.; Kang, S. K.; Lee, J. H.;
Shin, J. S.; Ahn, S. K.; Hong, C. I.; Yoon, S. S. Eur. J. Med.
Chem. 2004, 39, 433.
(33) Zheng, Q.-H.; Liu, X.; Fei, X.; Wang, J.-Q.; Ohannesian, D.
W.; Erickson, L. C.; Stone, K. L.; Martinez, T. D.; Miller, K.
D.; Hutchins, G. D. J. Labelled Compd. Radiopharm. 2002,
45, 1239.
(12) (a) Kumata, K.; Yui, J.; Hatori, A.; Fujinaga, M.; Yanamoto,
K.; Yamasaki, T.; Kawamura, K.; Wakizaka, H.; Nengaki,
Synthesis 2014, 46, 660–668
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