New cycloheptane nucleoside analogues

Article abstract of DOI:10.1016/j.mencom.2015.03.014

Epoxidation of 1-phenylcyclohept-4-ene-1-carbonitrile gives mostly E-isomer of the desired epoxy derivative, whose ring opening with adenine or thymine proceeds stereoselectively providing access to novel cycloheptane nucleoside analogues.

Full text of DOI:10.1016/j.mencom.2015.03.014

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 121–123
New cycloheptane nucleoside analogues
Aleksandr I. Tsybin* and Valeriy P. Perevalov
D. I. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russian Federation.
Fax: +7 499 978 9991; e-mail: aleks.tsybin@gmail.com, pvp@muctr.ru
DOI: 10.1016/j.mencom.2015.03.014
Epoxidation of 1-phenylcyclohept-4-ene-1-carbonitrile gives mostly E-isomer of the desired epoxy derivative, whose ring opening
with adenine or thymine proceeds stereoselectively providing access to novel cycloheptane nucleoside analogues.
Carbocyclic nucleosides are compounds in which endocyclic
oxygen atom of nucleoside sugar is replaced by a methylene
group. A large number of five- and six-membered ring nucleoside
Table 1 Epoxidation of 1-phenylcyclohept-4-ene-1-carbonitrile 1.
Overall
yield (%) E-2:Z-2
Ratio
Epoxidation system
T/°C t/h
1
–4
analogues have recently been synthesized as potential chemo-
therapeutic agents. At the same time, seven-membered analogues
H2O2 (10 equiv.), DMF, 0.2 m NaHCO3 20
buffer, 1 mol% MnSO4
5
5
25
57
3:1
3:1
5,6
possessing promising biological activities, are not sufficiently
7
H O (5 equiv.), DMF, NaHCO
3
20
5
studied.
2
2
(
0.2 m buffer), 1 mol% MnSO4,
mol% salicylic acid
Oxone (3 equiv.), CH Cl /H O,
Ring-closing metathesis is an advanced access to a variety
ofthesubstitutedcycloheptenes.8 Inaddition, 1,2-disubstituted
cycloheptane nucleoside analogues have been readily obtained
through an epoxidation of the cycloheptene double bond fol-
lowed by epoxide ring opening.13 However, this approach and
other transformations of the double bond have not been applied
to the synthesis of highly functionalized cycloheptane nucleoside
analogues from substituted cycloheptenes.
4
–12
5
5
35
50
5:2
3:1
2
2
2
acetone, 0.2 m Na HPO buffer,
2
4
18-crown-6 (cat.)
Oxone (3 equiv.), CH Cl /H O,
5
2
2
2
acetone, 0.2 m Na HPO buffer,
2
4
+
–
[
Bu N] HSO (cat.)
4 4
mCPBA (1.1 equiv.), CH2Cl2,
.2 m Na HPO4
20
20
5
5
85
90
7:1
0
2
Herein, we report a brief study of epoxidation of 1-phenyl-
cyclohept-4-ene-1-carbonitrile 1 leading to diastereomeric
mCPBA (1.1 equiv.), benzene,
.2 m Na HPO4
21:1
0
2
4
-phenyl-8-oxabicyclo[5.1.0]octane-4-carbonitriles 2.
Ph
Ph
using Oxone14 or hydrogen peroxide15 (Table 1) provided lower
i
yields of products 2.
Diastereomeric ratio E-2: Z-2 was found to be increased to
21:1 by conducting epoxidation with mCPBA in benzene, and the
major isomer E-2 was simply isolated by flash chromatography.
Apparently, axially oriented nitrile group is close to the double
bond in the preferred molecular conformation of compound 1,
thus it considerably inhibits the attack of the epoxidizing species
at this molecule surface in epoxidation processes. Structures of
epoxides E-2 (Figure 1) and Z-2 (Figure 2) were confirmed by an
N
N
3
1
Ph
Ph
ii or iii
O
+
O
N
N
E-2
Z-2
Scheme 1 Reagents and conditions: i, DCM, 0.25 mol% 1st generation
Grubbs catalyst, reflux, 3 h, 99%; ii, DCM, mCPBA, Na HPO , 0°C, 1 h, then
‡
X-ray crystallographic analysis.
2
4
2
2
0°C, 85% overall, de 75%; iii, benzene, mCPBA, Na HPO , 0°C, 1 h, then
0°C, 87% overall, de 91%.
2 4
pressure. The crude residue was purified by flash chromatography on silica
gel (hexane–EtOAc, 4:1) to give 9.0 g (86%) of E-2 and 0.4 g (4%) of Z-2.
1
Isomer E-2: white crystalline solid. H NMR (400 MHz, CDCl ) d:
3
Cycloheptene 1 was obtained in a quantitative yield by
1.63 (m, 2H), 2.25 (m, 2H), 2.50 (m, 4H), 3.25 (m, 2H), 7.25 (t, 1H,
9
refluxing available diene 3 in dichloromethane in the presence
of 1 generation Grubbs catalyst (Scheme 1; for details, see
Online Supplementary Materials). Epoxidation of 1 with mCPBA
in dichloromethane afforded diastereomeric epoxides 2 as E: Z =
J 8.5 Hz), 7.35 (t, 2H, J 8.5 Hz), 7.5 (d, 2H, J 8.5 Hz). MS, m/z: 214.2
st
+
[
M + H] . Found (%): C, 78.88; H, 7.02; N, 6.51. Calc. for C H NO (%):
14 15
C, 78.84; H, 7.09; N, 6.57.
Isomer Z-2: white crystalline solid. H NMR (400 MHz, DMSO-d ) d:
1
6
†
=
7:1 mixture in the 85% overall yield. Similar epoxidation
1.63 (m, 2H), 1.80 (m, 2H), 2.12 (m, 2H), 2.35 (m, 2H), 3.05 (m, 2H),
7
.25 (t, 1H, J 8.5 Hz), 7.38 (t, 2H, J 8.5 Hz), 7.50 (d, 2H, J 8.5 Hz). MS,
†
+
4
-Phenyl-8-oxabicyclo[5.1.0]octane-4-carbonitriles 2. Finely pulverized
m/z: 214.2 [M+H] . Found (%): C, 78.87; H, 7.02; N, 6.51. Calc. for
Na HPO (35.8 g, 250 mmol) was added to a vigorously stirred solution
C H NO (%): C, 78.84; H, 7.09; N, 6.57.
Crystal data for 2. Single crystals of compounds E-2 and Z-2 (C H NO,
2
4
14 15
‡
of compound 1 (9.9 g, 50 mmol) in benzene (400 ml). The suspension
was cooled to 0°C and mCPBA (14.6 g, 85 mmol) was then added portion-
wise over 0.5 h. The resulting mixture was warmed to room temperature
14
15
M = 213.28) were grown from ethyl acetate. X-ray analysis was performed
on a Bruker SMART APEX II diffractometer equipped with a CCD area
detector. Using Olex2,20 the structure was solved with the ShelXS-1997
structure solution program using direct methods and refined with the
olex2.refine refinement package using Gauss-Newton minimisation.
Both structures were refined in anisotropic approximation for non-
hydrogen atoms. Hydrogen atoms were refined using ‘riding’ model.
21
and allowed to stand overnight. Then the saturated aqueous K CO3
2
solution (300 ml) was added and the mixture was vigorously stirred for
1
h at room temperature. The organic layer was separated and the aqueous
layer was extracted with DCM (2×200 ml). The combined organic layers
were dried over Na SO and the solvent was evaporated under reduced
2
4
©
2015 Mendeleev Communications. Published by ELSEVIER B.V.
–
121 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2015, 25, 121–123
Table 2 Epoxide opening in compound E-2.
N(1)
C(8)
C(1)
Reactants
1 equiv.)
Yield
(%)
Conditions
T/°C
t/h Product
(
C(10)
C(3)
C(4)
C(11)
C(12)
C(2)
C(6)
Adenine
Thymine
4a
4b
–
–
K CO (3.0 equiv.)/DMF 130
4
2
3
C(9)
C(5)
C(7)
Adenine
Thymine
4a
4b
10
16
C(14)
NaH (1.5 equiv.)/DMF
50–100
4
O(1)
C(13)
Adenine
Thymine
DBU (1.5 equiv.)/DMF/
microwave irradiation
4a
4b
45
40
1
40
40
1
Figure 1 X-ray crystal structure (ORTEP) of E-2.
Adenine
Thymine
DBU (1.5 equiv.)/EtOH/
microwave irradiation
4a
4b
87
80
1
1
N(1)
C(8)
adenine, i
thymine, i
E-2
C(11)
C(10)
C(3)
C(4)
C(1)
N
C(2)
C(12)
C(13)
NH2
H
O
O(1)
N
N
O
C(9)
C(6)
C(7)
C(5)
Ph
N
N
N
Ph
N
C(14)
Me
OH
OH
Figure 2 X-ray crystal structure (ORTEP) of Z-2.
N
4
a
4b
Aiming to obtain new cycloheptane nucleoside analogues, we
examined ring opening of epoxide cycle in major diastereomer
E-2 with adenine and thymine (Scheme 2).§
Treatment of epoxide E-2 with nucleobases in the presence
of sodium hydride in DMF16 yielded complex mixtures of un-
detectable compounds with the low amounts of desired products
ii
ii
N
NH2
H
N
O
N
O
N
Ph
N
Ph
N
Me
4
a,b (Table 2). A brief screening of procedures showed that
OH
OH
2
using DBU as a base in absolute ethanol under microwave
NH2
NH2
5
a
5b
Crystals of E-2 are monoclinic, space group P2 /n (no. 14), a = 6.8214(3),
1
Scheme 2 Reagents and conditions: i, adenine or thymine (1.0 equiv.),
DBU (1.5 equiv.), EtOH, 140°C, 1 h, microwave irradiation, 80–87%;
ii, Raney-Ni, MeOH/NH , H , 20°C, 12 h, ~100%.
3
b = 8.9966(4) and c = 18.6522(9) Å, b = 89.6379(7)°, V = 1144.65(9) Å ,
–1
–3
Z = 4, T = 296.15 K, m(MoKa) = 0.078 mm , d = 1.2375 g cm ,
calc
3
2
1
3373 reflections measured (5.02° £ 2q £ 55.98°), 2745 unique (Rint
=
=
0.0192, R = 0.0156) which were used in all calculations. The final R
irradiation17 at 140°C to be the optimal pathway for obtaining
s
1
was 0.0449 [I ³ 2s(I)] and wR was 0.1307 (all data).
2
compounds 4a,b in good yields and with good stereoselectivity.
Crystals of Z-2aremonoclinic, space group P2 /c(no. 14), a=10.3400(11),
1
1
3
The configuration of products 4a,b was confirmed by 2D H NMR
b = 9.5196(10) and c = 12.6101(13) Å, b = 111.314(2)°, V = 1156.3(2) Å ,
Z = 4, T = 296.15 K, m(MoKa) = 0.077 mm , d = 1.2250 g cm ,
1
13
–1
–3
NOESY and H- C HMBC experiments (see Online Supple-
calc
mentary Materials).
1
3656 reflections measured (5.5° £ 2q £ 56°), 2789 unique (Rint
=
=
0.0208, R = 0.0180) which were used in all calculations. The final R1
The further transformations of nitrile groups in compounds
s
18
was 0.0423 [I ³ 2s(I)] and wR was 0.1296 (all data).
4a,b are closely connected to the general concept for obtaining
2
CCDC 978617 and 978618 contain the supplementary crystallographic data
forthispaper.ThesedatacanbeobtainedfreeofchargefromTheCambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
Compounds 4a,b. A solution of epoxide E-2 (3.2 g, 15 mmol), adenine
or thymine (15 mmol) and DBU (3.4 g, 22.5 mmol) in anhydrous ethanol
versatile building blocks. Unfortunately, attempted basic or acidic
Compounds 5a,b. The corresponding nitrile (4a or 4b, ~6 mmol) was
§
dissolved in 100 ml of MeOH saturated with NH (15–20 wt%). Raney
3
nickel (0.6 g) was pre-washed twice with methanol and resulting suspen-
sion was added to the solution. The formed suspension was flushed with
argon and placed into Parr shaker-type apparatus. Hydrogenation was
completed in ~18 h at a hydrogen pressure of 2–3 atm and 20°C. Then
the resulting mixture was filtered through the pad of celite. The solvent
was evaporated under reduced pressure to give corresponding amine 5a
or 5b in a quantitative yield.
(
15 ml) was heated under microwave irradiation at 140°C over 1 h. The
mixture was diluted with DCM (250 ml) and washed with brine (150 ml).
The organic layer was passed through the pad of celite and dried over
Na SO . The solvents were removed under reduced pressure, the residue
2
4
was purified by flash chromatography on silica gel (eluent, ethylacetate)
to give compounds 4a or 4b, respectively.
(
1RS,4SR,5SR)-4-(6-Amino-9H-purin-9-yl)-5-hydroxy-1-phenylcyclo-
(
1S,2S,5R)-5-Aminomethyl-2-(6-aminopurin-9-yl)-5-phenylcyclo-
heptane-1-carbonitrile 4a: yield 4.5 g (87%), white crystalline solid.
heptanol 5a: yield 2.1 g (~100%), reaction time 20 h, white crystalline
1
H NMR (400 MHz, DMSO-d ) d: 1.85 (m, 2H), 2.15 (m, 2H), 2.25 (m,
1
6
solid. H NMR (400 MHz, DMSO-d ) d: 0.90 (br., 2H), 1.40 (m, 1H),
6
3
H), 2.65 (m, 1H), 4.30 (br., 1H), 4.45 (br., 1H), 5.00 (br., 1H), 6.95 (br.,
1.75 (m, 4H), 2.25 (m, 3H), 2.65 (m, 2H), 4.10 (m, 2H), 4.65 (br., 1H),
2
8
H), 7.30 (t, 1H, J 8.5 Hz), 7.45 (t, 2H, J 8.5 Hz), 7.55 (d, 2H, J 8.5 Hz),
.15 (s, 2H). MS, m/z: 349.2 [M+H] . Found (%): C, 65.53; H, 5.84;
6
.90 (br., 2H), 7.20 (m, 1H), 7.35 (m, 5H), 8.15 (s, 2H). MS, m/z: 353.3
+
+
[M+H] . Found (%): C, 64.78; H, 6.93; N, 23.62. Calc. for. C H N O
1
9
24
6
N, 24.32. Calc. for C H N O (%): C, 65.50; H, 5.79; N, 24.12.
19
20
6
(%): C, 64.74; H, 6.86; N, 23.85.
(
1RS,4SR,5SR)-4-Hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-
1-[(1S,2S,5R)-5-Aminomethyl-2-hydroxy-5-phenylcycloheptyl)-5-methyl-
1H-pyrimidine-2,4-dione 5b: yield 2.0 g (~100%); reaction time 18 h,
pyrimidin-1-yl)-1-phenylcycloheptane-1-carbonitrile 4b: yield 4.1 g (80%),
1
1
white crystalline solid. H NMR (400 MHz, DMSO-d ) d: 1.70 (m, 1H),
thick colorless oil. H NMR (400 MHz, DMSO-d ) d: 0.85 (br., 2H),
6
6
1
2
.78 (s, 3H), 1.85 (m, 1H), 2.05 (m, 2H), 2.15 (m, 1H), 2.25 (m, 2H),
.38 (m, 2H), 4.00 (br., 1H), 4.25 (br., 1H), 5.00 (br., 1H), 7.25 (t, 1H,
1.25 (m, 1H), 1.50 (m, 3H), 1.65 (m, 1H), 1.75 (s, 3H), 2.00 (m, 1H),
2.20 (m, 2H), 2.60 (m, 2H), 3.70 (m, 1H), 3.95 (m, 1H), 4.65 (br., 1H),
7.25 (m, 1H), 7.30 (m, 4H), 7.55 (s, 1H). MS, m/z: 344.2 [M+H] . Found
+
J 8.5 Hz), 7.50 (t, 2H, J 8.5 Hz), 7.53 (d, 2H, J 8.5 Hz), 7.60 (s, 1H),
1
+
0.70 (br., 1H). MS, m/z: 340.1 [M+H] . Found (%): C, 67.27; H, 6.30;
(%): C, 66.48; H, 7.27; N, 12.12. Calc. for C H N O (%): C, 66.45;
19
25
3
3
N, 12.26. Calc. for C H N O (%): C, 67.24; H, 6.24; N, 12.38.
H, 7.34; N, 12.24.
19
21
3
3
–
122 –

Mendeleev Commun., 2015, 25, 121–123
6
7
8
Y. Nishizuka, Nature (London), 1984, 308, 693.
hydrolysis brought about complex mixtures of unidentified com-
pounds. The chemical reduction of nitrile groups in 4a,b
occurred simultaneously with the reduction of nucleobase
K. Singha, B. Achari and S. B. Mandal, Arkivoc, 2003, ix, 75.
I. W. Ashworth, D. Carboni, D. J. Nelson, J. M. Percy, G. Rinaudo,
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9 Y.-J. Wu and H. He, US Patent 2006/19992 A1, 2006.
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of Raney nickel and ammonia19 in methanol cleanly afforded
5
-aminomethyl-2-hydroxy-5-phenylcycloheptane nucleoside
1
1 M. J. Rishel, C. J. Thomas, Z. Tao, C. Vialas, C. J. Leitheiser and
S. M. Hecht, J. Am. Chem. Soc., 2003, 125, 10194.
§
analogues 5a,b in quantitative yields.
In summary, novel 5-aminomethyl-2-hydroxy-5-phenylcyclo-
heptane nucleoside analogues were synthesized in good yields
using simple procedures, the key steps occurring stereoselectively.
1
1
2 J. Marco-Contelles and E. de Opazo, J. Org. Chem., 2000, 65, 5416.
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We are grateful to Dr. A. Kh. Bulay for NMR analysis and
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.03.014.
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Received: 1st July 2014; Com. 14/4412
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