Preparative synthesis of pentacyclo[6.3.0.02,6.03,10.05,9]undecan-4-one (D 3-trishomocubanone)

Full text of DOI:10.1134/S1070428014100224

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 10, pp. 1542–1544. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.M. Mishura, A.S. Sklyarova, T.V. Shamota, V.N. Rodionov, A.A. Fokin, 2014, published in Zhurnal Organicheskoi Khimii, 2014,
Vol. 50, No. 10, pp. 1552–1554.
SHORT
COMMUNICATIONS
2
,6 3,10 5,9
Preparative Synthesis of Pentacyclo[6.3.0.0 .0 .0 ]undecan-
-one (D -Trishomocubanone)
4
3
A. M. Mishura, A. S. Sklyarova, T. V. Shamota, V. N. Rodionov, and A. A. Fokin
“
Kyiv Polytechnic Institute” National Technical University of Ukraine, pr. Pobedy 37, Kiev, 03056 Ukraine
e-mail: vnr@xtf.kpi.ua
Received February 21, 2014
DOI: 10.1134/S1070428014100224
Highly symmetrical chiral structure of the pentacy-
in [13] improved the yield of II to 70%, and the pro-
posed workup procedure made chloro hydroxy ketone
II readily accessible.
2
,6 3,10 5,9
clo[6.3.0.0 .0 .0 ]undecane (D -trishomocubane)
3
molecule combines high lipophilicity and conforma-
tional rigidity, which makes its derivatives promising
as medicinal agents [1]. Some amino derivatives of
D -trishomocubane exhibit biological activity, and they
can be used as building blocks for a new generation of
NMDA antagonists [2] and neuroprotectors [3, 4].
We now describe a new method of synthesis of
D -trishomocubanone (V), which includes Wolff–
3
3
Kishner reduction of II to syn-1-chloropentacyclo-
2,6 3,10 5,9
[
6.3.0.0 .0 .0 ]undecan-11-ol (III) (yield 80%).
The subsequent dehalogenation of III with Li/t-BuOH
The key intermediate product in the synthesis of
in THF gives D -trishomocuban-4-ol (IV) in 90%
3
various D -trishomocubane derivatives is D -trishomo-
3
3
yield. The conversion of III was monitored by capil-
lary column GLC, and an additional amount of tert-
butyl alcohol was added (if necessary). Alcohol IV
without additional purification was oxidized with
cubanone whose preparation was described in [5, 6].
D -Trishomocubane is the C H stabilomer [7], and
3
11 14
its carbon skeleton is constructed under harsh condi-
tions via acid-catalyzed rearrangement of secondary
Dess–Martin periodinane (DMP) to target pentacyclo-
2,6 3,10 5,9
mono- and dihydroxypentacyclo[5.4.0.0 .0 .0 ]un-
decanes. This approach implies preliminary reduction
of accessible Cookson’s diketone, pentacyclo-
2,6 3,10 5,9
[
6.3.0.0 .0 .0 ]undecan-4-one (V, 90%) [14].
Compound V can be subjected to enantiomeric resolu-
tion [15] or further transformations to obtain various
functional derivatives.
2
,6 3,10 5,9
[
5.4.0.0 .0 .0 ]undecane-8,11-dione (I), to the
corresponding diol, which elongates the synthetic
scheme and reduces the preparative yield to 25–30%
Thus we have proposed a convenient procedure for
the synthesis of D -trishomocubanone from commer-
3
[
8–11]. Alternatively, it was proposed to build up
cially available diketone I in an overall yield of 55%.
s y n - 6 - C h l o r o - 7 - h y d r o x y p e n t a c y c l o -
D -structure by rearrangement of diketone I in chloro-
3
sulfonic acid [12], which allows one to avoid the
reduction step. The rearrangement procedure described
2
,6 3,10 5,9
[6.3.0.0 .0 .0 ]undecan-4-one (II). A 7.5-g por-
O
O
O
Cl
Cl
N H , KOH
2
4
3
Steps
H
diethylene glycol
H
HO
HO
I
II
III
Li, t-BuOH, THF
DMP, CH Cl
2 2
HO
O
IV
V
1
542

2,6 3,10 5,9
PREPARATIVE SYNTHESIS OF PENTACYCLO[6.3.0.0 .0 .0 ]UNDECAN-4-ONE
1543
tion of the mixture obtained by reaction of Cookson’s
diketone (I) with chlorosulfonic acid according to the
procedure described in [13] was treated with 150 mL
of 10% aqueous sulfuric acid. The mixture was heated
for 8 h under reflux with stirring, cooled, and extracted
with methylene chloride. The organic phase was
washed with water and dried over sodium sulfate, the
solvent was distilled off under reduced pressure, and
the residue was recrystallized twice from hexane–
lithium was quenched by adding water on cooling. The
aqueous phase was extracted with methylene chloride,
the extract was dried over Na SO , and the solvent was
2
4
distilled off under reduced pressure. Yield 3.31 g
1
(91%), mp 85–86°C (from hexane). H NMR spec-
trum, δ, ppm: 1.22–2.91 m (8H, CH), 1.59–1.43 d.d
(2H, CH ), 2.11–1.92 d.d (2H, CH ), 4.17 s (1H,
2
2
CHOH). Mass spectrum, m/z (I , %): 162 (15), 144
rel
(75), 129 (22), 116 (15), 95 (100), 91 (35), 79 (85), 66
(55). Found, %: C 81.47; H 9.25. C H O. Calculated,
propan-2-ol (7:3). Yield 3.8 g (83%), mp 183–184°C
11
14
1
(
from hexane). H NMR spectrum, δ, ppm: 1.68 s (2H,
%: C 81.39; H 9.33.
CH), 2.08 d (2H, CH ), 2.33 s (1H, CH), 2.53 m (4H,
2,6 3,10 5,9
2
Pentacyclo[6.3.0.0 .0 .0 ]undecan-4-one (V).
A solution of 11.66 g (2.75 mmol) of DMP in 120 mL
of methylene chloride was added to a solution of 4 g
1
3
CH), 3.25 s (1H, OH), 4.12 s (1H, CHOH). C NMR
spectrum, δ , ppm: 36.5 (CH ), 37.7 (CH), 39.9 (CH),
C
2
4
(
6.6 (CH), 48.2 (CH), 49.7 (CH), 50.5 (CH), 51.6
(
2.5 mmol) of compound IV in 80 mL of methylene
CH), 72.8 (CCl), 78.7 (CHOH), 212.2 (C=O). Mass
chloride. The mixture was stirred for 30 min at room
temperature and diluted with 300 mL of diethyl ether,
+
spectrum, m/z (I , %): 212/210 (5/10) [M] , 175 (7)
rel
+
[
(
M – Cl] , 164 (25), 146 (28), 129 (46), 116 (40), 82
1
50 mL of 5% aqueous sodium hydroxide was added,
80), 66 (100). Found, %: C 62.87; H 5.21. C H ClO.
11
13
and the mixture was stirred for 10 min. The organic
phase was separated, washed with three portions of
water until neutral reaction, and dried over Na SO ,
Calculated, %: C 62.91; H 5.54.
2
,6 3,10 5,9
syn-1-Chloropentacyclo[6.3.0.0 .0 .0 ]un-
decan-11-ol (III). Ketone II, 1 g (4.76 mmol), was
added to a solution of 1.43 g of 85% potassium
hydroxide in 5.6 mL of diethylene glycol, 2 mL of 98–
2
4
and the solvent was distilled under reduced pressure.
Yield 3.71 g (91%), mp 163–164°C (from hexane).
1
H NMR spectrum, δ, ppm: 1.53–1.57 d.d (4H, CH ),
2
1
3
1
00% hydrazine hydrate was added, and the mixture
1.60–2.90 m (8H, CH). C NMR spectrum, δ , ppm:
C
was left overnight. The mixture was then heated on
an oil bath (180–190°C) under stirring until the reac-
tion was complete (6–8 h), cooled, diluted with water,
and extracted with methylene chloride. The extract was
3
4
5
3.00 (CH ), 33.68 (CH ), 40.67 (CH), 41.23 (CH),
2
2
3.14 (CH), 44.21 (CH), 47.14 (CH), 47.45 (CH),
2.22 (CH), 53.49 (CH), 77.45 (C=O). Mass spectrum,
m/z (I , %): 162 (25), 132 (20), 91 (15), 66 (100).
rel
washed with water and dried over Na SO , and the
2
4
Found, %: C 82.52; H 7.45. C H O. Calculated, %:
C 82.49; H 7.51.
11
12
solvent was distilled off under reduced pressure. Yield
1
0
.73 g (78%), mp 195–196°C (from hexane). H NMR
The H and 13C NMR spectra were recorded on
1
spectrum, δ, ppm: 1.33–1.53 m (2H, CH ), 1.57–
2
a Bruker DPX-400 spectrometer at 400.13 and
1
1
.83 m (2H, CH ), 2.05 s (1H, CH), 2.09–2.19 m (3H,
2
00.61 MHz, respectively, using CDCl as solvent and
3
CH), 2.15 s (1H, CH), 2.28 s (1H, CH), 2.55 s (1H,
CH), 2.87 br.s (1H, OH), 4.07 s (1H, CH). 13C NMR
tetramethylsilane as internal reference. The mass
spectra (electron impact, 70 eV) were obtained on
a Hewlett Packard 5971A mass-selective detector
coupled with an HP 5890 gas chromatograph (HP-5
capillary column, injector temperature 250°C, oven
temperature programming from 60 to 250°C at a rate
of 20 deg/min). GLC analysis was performed on
a Shimadzu GC-14B chromatograph equipped with
a flame ionization detector (Optima-1 column, injector
temperature 275°C, oven temperature programming
from 80 to 250°C at a rate of 20 deg/min).
spectrum, δ, ppm: 31.9 (CH ), 34.1 (CH ), 40.3 (CH),
2
2
4
(
5.8 (CH), 46.2 (CH), 47.3 (CH), 47.9 (CH), 49.2
CH), 50.7 (CH), 77.3 (CCl), 78.3 (CHOH). Mass
+
spectrum, m/z (I , %): 198/196 (9/18) [M] , 180 (10),
rel
+
1
61 (100) [M – Cl] , 143 (23), 130 (22), 128 (23), 115
(
20), 95 (60), 91 (46), 79 (69), 66 (71), 51 (34). Found,
%
: C 67.17; H 6.61. C H ClO. Calculated, %:
1
1
13
C 67.19; H 6.63.
2
,6 3,10 5,9
Pentacyclo[6.3.0.0 .0 .0 ]undecan-4-ol (IV).
Thin lithium wire, 7.2 g (1.02 mol), was added to
a solution of 4.4 g (2.24 mmol) of compound III and
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