Stereoselective preparation of mono- and bis-derivatives of pentacyclo[6.3.0.02,6.03,10.05,9] undecane (D 3-trishomocubane)

Article abstract of DOI:10.2478/s11532-013-0339-8

The rearrangement of easily accessible Cookson's diketone with chlorosulfonic acid in chloroform followed by the acidic hydrolysis gave 6-chloro-7-hydroxy-dichloropentacyclo[6.3.0.0^2,6.0 ^3,10.0^5,9]undecane-4-one, whose syn-stereochemistry was assigned through the X-ray crystal structure analysis. This key structure was used for the stereoselective synthesis of the D ₃-trishomocubane derivatives as well as for the preparation of potential drugs bearing hydroxy- and amino-functional groups. A new multigram preparative synthesis of D ₃-trishomocubane was developed.

Full text of DOI:10.2478/s11532-013-0339-8

Cent. Eur. J. Chem. • 11(12) • 2013 • 2144-2150
DOI: 10.2478/s11532-013-0339-8
Central European Journal of Chemistry
Stereoselective preparation of mono- and bis-
derivatives of pentacyclo[6.3.0.02,6.03,10.05,9]
undecane (D3-trishomocubane)
Research Article
Anastasiia M. Mishura1, Anna S. Sklyarova1,
Dmitriy I. Sharapa1, Igor’ A. Levandovsky1,
Michael Serafin2, Andrey A. Fokin1, Vladimir N. Rodionov1*
1Department of Organic Chemistry,
Kiev Polytechnic Institute, 03056 Kiev, Ukraine
2Institute of Organic Chemistry, Justus-Liebig University,
D-35392 Giessen, Germany
Received 27 March 2013; Accepted 27 June 2013
Abstract:
The rearrangement of easily accessible Cookson’s diketone with chlorosulfonic acid in chloroform followed by the acidic hydrolysis gave
6-chloro-7-hydroxy-dichloropentacyclo[6.3.0.02,6.03,10.05,9]undecane-4-one, whose syn-stereochemistry was assigned through the
X-ray crystal structure analysis. This key structure was used for the stereoselective synthesis of the D3-trishomocubane derivatives as
well as for the preparation of potential drugs bearing hydroxy- and amino- functional groups. A new multigram preparative synthesis of
D3-trishomocubane was developed.
Keywords: D3-trishomocubane • Aminoalcohol • Propeller chirality • Hydroxyketone
© Versita Sp. z o.o.
through the acid-promoted cationic rearrangements
of mono- and dihydroxy substituted pentacyc-
Pentacyclo[6.3.0.02,6.03,10.05,9]undecane (D3-trishomocu- lo[5.4.0.02,6.03,10.05,9]undecane
(Cs-trishomocubane)
bane), one of the few known molecules that possess derivatives [5-7]. Ketones and alcohols of
1. Introduction
propeller chirality, combines high lipophilicity with D3-trishomocubane series were obtained in optically-
conformational rigidity, and attracts growing attention active forms. The enantioseparation of D3-trishomocu-
of theoreticians and experimentalists specialized in banol is possible through the reaction with phthalic
drug design and catalysis [1]. Recent report describes anhydride and crystallization of salts with (+)-2-(1-amino-
the 3D-QSAR studies of a new generation of potential ethyl)naphthalene[8]or,alternatively,throughthereaction
M2 inhibitors based on a combination of the lipophilic of amino-acetal of D3-trishomocubanone with l-ephedrine
D3-trishomocubane moiety and polar groups (hydroxy, [9] that are difficult to perform even at the gram scale.
carboxy, urea/thiourea) separated from cage with the Biochemical methods of the synthesis of enantiopure
one-carbon-atom bridge [2]. A number of homological D3-trishomocubane derivatives display only moderate
cubylaminesthattopologicallyrelatetotheneuroprotector enatioselectivities [10]. Current lack of multigram
3,5-dimethyl-1-aminoadamantane (Memantine) were preparative methods for the selective synthesis of
also reported to serve as fast, voltage-dependent NMDA D3-trishomocubanes hampers further applications of
receptor antagonists [3].
this promising class of molecules in medicine and
D3-Trishomocubane is
a
С11Н14 stabilomer [4], makes the development of new stereoselective methods
and was obtained under harsh reaction conditions particularly important.
* E-mail: vnr@xtf.kpi.ua
2144

A. M. Mishura et al.
was removed in vacuo to give 12.4 g of the mixture of
ethyleneketals7and8asaviscousoil, whichcrystallized
on storing. This mixture was stirred under reflux with
triphenylphosphine (13.3 g, 0.05 mol) in 120 mL of
carbon tetrachloride for 5 h, 1 mL of MeOH was added
and the mixture refluxed for additional 1 h. After cooling
of the reaction the precipitate of triphenylphosphine
oxide was separated by filtration, carbon tetrachloride
was removed in vacuo from the filtrate, the residue was
treated with 100 mL of diethyl ether.The undissolved
precipitate of triphenylphosphine oxide was filtered off,
4-5 g of finely dispersed lithium iodide monohydrate
was added to the filtrate and the mixture was stirred for
1.5–2 h at room temperature. The formed precipitate
was filtered through silica gel, the solvent was removed
in vacuo yielding ethylene ketal of dichloroketone
2. Experimental procedure
The 1Н NMR (400.13 MHz) and 13С NMR
(100.61 MHz) spectra were recorded on a Bruker DPX-
400 spectrometer; solvent – СDCl3, internal standard
– ТMS. GC/MS measurements were performed on
Hewlett-Packard 5971A (EI 70 eV, mass-selective
detector), chromatograph НР 5890, column HP-5 (5%
phenylmethyl silicone), evaporator temperature 250°С,
column oven temperature 60–250°С, temperature
gradient 20°С min-1. GLC-analyses were performed on
ShimadzuGC-14Bchromatographwithaflameionization
detector, column Optima-1, evaporator temperature
275°С, oven temperature 80–250°С, temperature
gradient 20°С min-1. The X-Ray study was carried out
on an automatic diffractometer STOE IPDS, equipped
with graphitic monochromator, utilizing standard
procedure [20]. The structure was solved by the direct
method and refined according to full-frame anisotropic
approximation for all carbon atoms. All H-atoms could
be found in the difference fourier syntheses and were
refined isotropically. Calculations were performed
using SHELX97 software [20,21]. The results of the
crystal structure analysis of 6-chloro-7-hydroxypentacy
clo-[6.3.0.02,6.03.10.05,9]undecane-4-one ethyleneketal (8)
were deposited at the Cambridge Crystallographic Data
Centre and allocated the deposition number CCDC
930939. Tetrahydrofurane was refluxed before use with
sodium metal in presence of benzophenone and was
distilled under argon flow.
7
(11.8 g, 75 %), m.p. 103–105 °С (ethanol).
1Н NMR (CDCl3), δ, ppm: 1.38–1.57 m (2Н, СН2), 1.91–
2.02 m (1Н, СН), 2.02–2.15 m (1Н, СН), 2.26–2.39 m
(1H, CH), 2.39–2.56 m (2H, CH), 2.56–2.64 m (1H, CH),
3.04–3.11 br s (1Н, СНCl), 3.8–4.09 m (4Н, СН2), 4.09–
4.17 m (1H, CH). 13С NMR (CDCl3), δ, ppm: 33.8 (1C,
СH2), 41.9 (1C, СH), 43.1 (1C, СH), 48.0 (1C, СH), 49.4
(1C, СH), 50.8 (1C, СH), 51.3 (1C, СH), 51.9 (1C, СH),
64.1 (1C, CH2), 65.4 (1C, CH2), 68.8 (1C, CCl), 78.4
(1C, СHCl), 118.9 (1C, COO). MS m/z, (Ir, %): 276 (0.6)
[M(37Cl)]+, 274 (3.6) [M(37Cl35Cl)]+, 272 (6.2) [M(35Cl)]+,
239 (37.2) [M – Cl(37Cl)], 237 (100) [M – Cl(35Cl)], 137
(48.7), 129 (48.0), 115 (47.6), 99 (48.7), 91 (19.5) [C7H7],
89 (23.8), 77 (78.9) [C6H5], 73 (66.8) [C3H5O2], 66 (99.2)
[C5H6], 65 (71.5) [C5H5], 51 (50.0). Found, %: C, 57.14;
H, 5.21. С13H14Cl2O2.Calc. %: C, 57.16; H, 5.17.
4-Ethyleneketal
6,7-dichloropentacyc
lo[6.3.0.02,6.03,10.05,9]undecane-4-one (7). To a cold
stirred solution of Cookson’s diketone (1) (10 g, 0.0574
mol)in20mLofchloroform,freshlydistilledchlorosulfonic
acid (20 mL, 0.3 mol) was added dropwise. After 24 h
of stirring, the reaction mixture was poured onto ice,
and extracted with chloroform. The combined organic
layers were washed with water to pH=6, dried over
anhydrous Na2SO4, and the solvent was evaporated in
vacuo. To the resulting yellow solid (15.2 g) a solution
of sodium bicarbonate (10% 150 mL) was added. The
reaction mixture was heated under reflux for 4 h and
extracted with chloroform after cooling. The combined
extracts were dried over anhydrous Na2SO4, and the
solvent was removed in vacuo to give 10.85 g of the
mixture of chloro ketol 3 and dichloroketone 4 in 4.5:1
ratio (GLC). The mixture was dissolved in 200 mL of
dry benzene; ethylene glycol (10 g, 0.16 mol) and
p-toluenesulfonic acid monohydrate (0.2 g) were added.
The reaction mixture was refluxed with the Dean-Stark
receiver for 6 h, and the benzene solution was washed
with a 10%-solution of sodium bicarbonate, water and
brine,. Organic layer was dried over Na2SO4, the solvent
4-Ethyleneketal
pentacyclo[6.3.0.02,6.03,10.05,9]
undecane-4-one (9). To a solution of dichloride 7
(9.4 g, 0.0344 mol) in 200 mL of dry ТHF and 20 mL
t-BuOH, thin lithium wire (7.2 g, 1.02 mol) was added.
The mixture was refluxed with condenser for 2 h,
additional 6 mL of t-BuOH were added and mixture
was refluxed for 2–3 h. Any excess of lithium was
decomposed by addition of water. The water solution
was extracted with methylene chloride, the extract
was dried over anhydrous Na2SO4 and the solvent
was removed in vacuo. Yield 6.67 g (95%), b.p.
1
138–144 °С (13 mm. Hg). Н NMR (CDCl3), δ, ppm.:
1.33 d and 1.39 d (АВ system, 4Н, СН2, JАВ = 12 Hz),
1.69–1.72 m (2Н, СН), 2.10–2.16 m (4Н, СН), 2.40–
2.45 m (2Н, СН), 3.90–3.94 m (4Н, СН2).13С NMR
(CDCl3), δ, ppm.: 33.8 (2С, CH2), 41.5 (2С, CH), 44.1
(2С, CH), 47.2 (2С, CH), 51.0 (2С, CH), 64.7 (2С,
CH2O), 120.1 (1С, COO). MS, m/z, (Ir, %): 204 (33.3)
[M]+, 149 (11.8), 139 (8.8) [M – C5H5], 138 (43.7) [M –
C5H6], 137 (45.7), 117 (23.4), 99 (32.3), 91 (35.8) [C7H7],
79 (28.1), 78 (33.5), 77 (33.3) [C6H5], 73 (47.3) [C3H5O2],
2145

Stereoselective preparation of mono- and bis-derivatives
of pentacyclo[6.3.0.02,6.03,10.05,9]undecane (D3-trishomocubane)
66 (100) [C5H6], 65 (42.2)[C5H5], 51 (23.3). Found,%: C, СНОН). 13С NMR (CDCl3), δ, ppm.: 33.6 (1С, CH2), 40.5
76.43; H, 7.93. С13H16O2. Calc.,%: C, 76.44; H, 7.90.
(1C, СH), 40.6 (1C, СH), 43.8 (1C, СH), 44.0 (1C, СH),
Pentacyclo[6.3.0.02,6.03,10.05,9]undecane-4-one 46.4 (1C, СH), 49.7 (1C, СH), 50.7 (1C, СH), 51.6 (1C,
(10). To a solution of ketal 9 (1.2 g, 0.0055 mol) in 10 mL CH2), 64.7 (2C, CH2O), 77.1 (1C, CH), 119.9 (1C, COO).
of ТHF 40 mL of the water solution of 10%-sulfuric acid MS, m/z, (Ir, %): 220 (97.3) [M]+, 192 (14.6), 154 (43.7)
was added, the mixture was heated to 80°С and stirred [M – C5H6], 137 (91.0), 125 (39.5), 112 (43.7), 99 (43.2),
for 5 h. The sulfuric acid was neutralized by adding of 91 (64.1) [C7H7], 78 (41.0) [C6H6], 77 (56.5) [C6H5], 73
solid sodium hydroxide until рН=7–8, the product was (100) [C3H5O2], 66 (58.7) [C5H6], 65 (47.9) [C5H5], 51
extracted with methylene chloride, extract was dried (29.6). Found,%: C, 70.88; H, 7.32. С13H16O3. Calc.,%:
over anhydrous Na2SO4, the solvent was removed C, 70.89; H, 7.32.
in vacuo. Yield 0.96 g (98%), m.p. 163–164°С (after
sublimation). The spectroscopic properties are identical 4-one (12) was obtained from hydroxy ketal 11
syn-7-Hydroxypentacyclo[6.3.0.02,6.03,10.05,9]undecane-
to those described previously [22].
(3.19 g, 0.015 mol) according to procedure, as described
6-Chloro-7-hydroxypentacyclo[6.3.0.02,6.03,10.05,9]- above for the preparation of (10). Yield 2.46 g (98%), as
1
undecane-4-one (4). To 7.5 g of the mixture obtained after a viscous colourless liquid. Н NMR (CDCl3), δ, ppm.:
reaction of Cookson’s diketone (5 g, 0.0287 mol) with 1.45 d and 1.56 d ( АВ system, 2Н, СН2, JАВ = 10 Hz),
chlorosulfonic acid, according to method as described 1.7–1.85 m (2Н, СН), 2.1–2.55 m (5Н, СН), 2.88 s (1Н,
above for substance (10), a water solution of sulfuric СН), 3.64 m (1Н, ОН), 4.07 s (1Н, СНОН). 13С NMR
acid 10%, 150 mL was added, the mixture was stirred (CDCl3), δ, ppm.: 35.3 (1С, CH2), 39.0 (1C, СH), 39.7
under reflux for 7-8 h. The reaction mixture was cooled, (1C, СH), 41.2 (1C, СH), 44.8 (1C, СH), 45.6 (1C, СH),
dried over anhydrous Na2SO4, the solvent removed in 45.8 (1C, СH), 49.6 (1C, СH), 51.3 (1C, CH), 77.8 (1C,
vacuo. Yield 5.1 g (85%), m.p. 183–184°С (ethanol) (lit. CH), 216.4 (1C, C=O). MS is identical to spectrum
183–185°C). The spectroscopic properties are identical described previously [17].
to those described previously [13].
syn-7-(Hydroxyimino)pentacyclo[6.3.0.02,6.03,10.05,9]
4-Ethyleneketal syn-6-chloro-7-hydroxypentacyc- undecane-4-ol (15). To a solution of 1.2 g (0,018 mol)
lo[6.3.0.02,6.03,10.05,9]undecane-4-one (8) was synthesized of hydroxylamine hydrochloride in 4.2 mL of water and
from chloroketol 4 (5 g, 0.0238 mol) according to 4.2 mL of solution of sodium hydroxide 10% a solution of
procedure as described above for 7, crystallized from 0.5 g (2.84 mmol) hydroxy ketone 12 in 6.2 mL of ethanol
mixture of hexane : 2–propanol = 7:3. Yield 4.92 g was added. The resulting mixture was refluxed for 30 h,
1
(81%), m.p. 111–112°С. Н NMR (CDCl3), δ, ppm.: 1.32 ethanol was evaporated on an oil bath, the residue was
d and 1.42 d (АВ system, 2Н, СН2, JАВ = 12 Hz), 1.82– diluted with 10 mL of water and left for crystallization
1.92 m (1H, CH), 1.92–2.02 м (1Н, СН), 2.02–2.13 m overnight. The precipitate was filtered off and washed
(1Н, СН), 2.25–2.56 m (4Н, СН), 2.91–3.02 br s (1Н, twice with water. Yield 0.45 g (83%), as a white
СН), 3.75–4.05 m (4Н, СН2; 1H, OH). 13С NMR (CDCl3), crystalline substance with mp. 149–150°С (aqueous
1
δ, ppm.: 34.4 (1C, СH2), 40.7 (1C, СH), 42.1 (1C, СH), ethanol). Н NMR (DMSO)–d6) δ, ppm.: 1.31–1.47 m
46.7 (1C, СH), 47.1 (1C, СH), 50.1 (1C, СH), 50.7 (1C, (2Н, СН2), 1.84–2.01 m (2Н, СН), 2.02–2.34 m (4Н,
СH), 51.7 (1C, СH), 64.1 (1C, CH2), 65.4 (1C, CH2), СН), 2.62–2.79 m (2Н, СН), 3.95 br.s. (1Н, ОН), 4.82 d
77.8 (1C, CCl), 78.9 (1C, СHOH), 118.9 (1C, OCO). MS (1H, CHOH), ~8.00 s (1H, N-OH). 13С NMR (CDCl3), δ,
m/z, (Ir, %): 256 (5.9) [M(37Cl)]+ 254 (10.4) [M(35Cl)]+, 219 ppm.: 33.6 (СH2), 37.8 (СH), 40.0 (СH), 41.1 (СH), 43.8
(13.3) [M – Cl], 183 (29.4), 137 (72.8), 128 (37.2), 115 (СH), 44.3 (СH), 46.4 (СH), 49.1 (СH), 50.6 (СH), 75.7
(100), 112 (64.7), 91 (75.0) [C7H7], 77 (63.6) [C6H5], 73 (СHOH), 165.4 (С=NOH). MS, m/z,(Ir, %): 191 (26.8)
(31.7) [C3H5O2], 66 (47.1) [C5H6], 65 (55.6) [C5H5], 51 [M]+, 174 (42.8) [M – NH3] 156 (11.9) [M – (NH3+H2O)],
(27.1). Found%: C, 61.33; H, 5.92. С13H15ClO3. Calc.,%: 144 (25.6), 125 (78.0) [M – C5H6], 115 (29.8), 104
C, 61.30; H, 5.94.
(16.8), 97 (91.9), 91 (53.8) [C7H7], 80 (55.1) [C6H8], 79
4-Ethyleneketal
syn-7-hydroxypentacyc- (68), 78 (52.7), 77 (78.3) [C6H5], 67 (51.8), 66 (100), 65
lo[6.3.0.02,6.03,10.05,9]undecane-4-one (11) was obtained (71.4) [C5H5], 53 (61.8), 52 (50.9), 51 (69.7). Found,%:
from compound 8 (6.5 g, 0,0255 mol) according to C, 69.12; H, 6.82. С11H13NO2. Calc.,%: C, 69.09; H,
procedure, as described above for the preparation of 6.85.
9. Yield 4.79 g (85.4%), m.p. 91–92 °С (hexane 2–
7-Aminopentacyclo[6.3.0.02,6.03,10.05,9]undecane-4-ol
1
propanol = 7:3). Н NMR (CDCl3), δ, ppm.: 1.35–1.45 (16). To a solution of oxime 15 (0.1 g, 0.52 mmol) in
м (2Н, СН2), 1.7–1.85 m (2Н, СН), 2.02 s (1Н, СН), 30 mL of anhydrous methanol in a high pressure reactor
2.1–2.4 m (3Н, СН), 2.48 s (1Н, СН), 2.71 s (1Н, СH), was added 0.1 g of 5% palladium on carbon. High
3.71 m (1Н, ОН), 3.77–4.05 m (4H, CH2O), 4.06 s (1Н, pressure reactor was filled several times with hydrogen
2146

A. M. Mishura et al.
and left under excessive pressure 1.0–1.2 MPa over anhydrous Na2SO4, and the solvent was removed
overnight at room temperature for 24 h. The reaction in vacuo. Yield 0.71 g (78%), m.p. 85–86°С (hexane).
mixture was separated from catalyst by filtration through The spectroscopic properties are identical to those
fine silica gel, the methanol was removed in vacuo, the described previously [4].
residue was dissolved in a minimum amount of diethyl
ether and the amine was precipitated by stepwise
addition of diethyl ether saturated with gaseous 3. Results and discussion
hydrogen chloride yielding 0.08 g (82%) of hygroscopic
white crystals. Obtained amine hydrochloride was TheprecursorofD3-trishomocubane,Cookson’sdiketone
treated with 10% water solution of КОН, extracted with (pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione, 1) [11]
diethyl ether, extract was dried over anhydrous КОН, the is easily available from inexpensive 1,4-benzoquinone
solvent removed in vacuo. 1Н NMR (DMSO-d6) δ, ppm.: and cyclopentadiene in two steps with quantitative yield.
1.3–1.5 m (2Н, СН2), 1.7–2.35 m (8Н, СН), 3.26, 3.35 Previously, the rearrangement of 1 was performed in
d (1Н, СНNH2, JW=2 Hz), 3.95, 4.0 s (1Н, CHOH), chlorosulfonic acid and resulted in 6-chloro-7-chlorosu-
4.77 s, 4.78 s (1Н, ОН), ~8.25 br s (2H, NH2). 13С lfonylhydroxypentacyclo[6.3.0.02,6.03,10.05,9]undecane-4-
NMR (DMSO-d6) δ, ppm.: 32.2, 32.3, 32.5, 32.6 (1С, one (2) in 64% preparative yield [12]. Chloroketone (3)
СH2), 51.3, 51.4, 55.0, 55.1 (1С, CHNH2), also carbon was further hydrolyzed to 6-chloro-7-hydroxypentacyclo-
atoms connected to hydroxyl group, δ, ppm.: 74.4, [6.3.0.02,6.03,10.05,9]undecane-4-one (4). Alternatively, the
74.5, 74.8, 74.9 (1С, CHOH), carbon atoms of the cage preparation of 1-chloropentacyclo[6.3.0.02,6.03,10.05,9]-
have chemical shift in intervals 39.0–40.7, 42.5–45.5, undecane (6) through the rearrangement of 1 in the
46.3–49.9 (8С, СH). MS, m/z, (Ir, %): 177 (16.8) [M]+, mixture of chlorosulfonic acid with chloroform was
160 (22.6) [M – NH3], 144 (11.2), 104 (62.8), 91 (8.8) described (Scheme 1) [13]. Under milder reaction
[C7H7], 79 (12), 78 (22.4), 77 (78.3) [C6H5], 70 (100), 65 conditions the yield of 4 increases substantially, however
(35.4) [C5H5], 53 (40.8), 52 (26.9), 51 (91.7). Found,%: this causes an increase of the by-product formation (up
C, 74.52; H, 8.51. С11H15NO. Calc.,%: C, 74.54; H, to 20%). This approach allows direct rearrangement
8.53.
of 1 with increase of the preparative yields however
Pentacyclo[6.3.0.02,6.03,10.05,9]undecane-4,7-dione the preparative potential of this reaction still remains
(14). To a stirred and cooled 20 mL of pyridine chromium undisclosed.
trioxide (1.5 g, 15 mmol) was added in small portions.
We have found that the rearrangement of 1 in
To the resulting solution the hydroxy ketone 12 (1 g, chlorosulfonic acid gave ketones 3 and 4 without the
5.7 mmol) in 7.5 mL of dry pyridin was added dropwise. admixtures of chlorosulfonic derivative after the workup
The reaction mixture was stirred for 14–15 h at of the reaction mixture with 10% sodium bicarbonate
temperature 25°С, then 25 mL of diethyl ether was solution (Scheme 2).
added and the mixture filtered through a glass filter.
Ketones 3 and 4 are separable by column
Precipitate was washed thoroughly 4 times with 15 mL chromatography, but such separation was omitted and
of diethyl ether. The ethereal filtrate was washed twice the keto-groups were protected by reflux with ethylene
with 20 mL of 5% hydrochloric acid, 2 times with 15 mL glycol in benzene in the presence of p-toluensulfonic
of saturated solution of sodium bicarbonate, twice with acid to give a mixture of the respective ethylene ketals
15 mL of brine, and was dried over anhydrous Na2SO4, 7 and 8. Chlorohydroxylation of thus obtained mixture in
the solvent was removed in vacuo to give 0.8 g (81%) the PPh3–CCl4 system gave 7 in 80% preparative yield.
of white solid, m.p. 213–214°С (after sublimation). The Dichloride 7 was reduced to pentacyclo[6.3.0.02,6.03,10.05,9]
spectroscopic properties are identical to those described undecane-4-one 4-ethyleneketal (9) in the lithium–tert-
previously [23].
butanol system under the GC control, which allows
Pentacyclo[6.3.0.02,6.03,10.05,9]undecane-4-ol monitoring the completion of the reaction by adding
(13). To a solution of 1.43 g 85% of KOH in 5.6 mL new portions of tert-butanol, if necessary. Hydrolysis
of the diethylene glycol hydroxy ketone 12 (1 g, of the D3-trishomocubanone ethylene ketal (9) gave the
5.7 mmol)
and 2 mL of 98–100% hydrazine respective ketone 10 in 80 % yield. We thus developed
monohydrate was added. The reaction mixture was left a simple procedure for the preparation of ketone 10
overnight and then stirred under heating on an oil bath to directly from Cookson diketone with total yield ca
180–190°С. An alcohol condensed in the reflux 50% avoiding column chromatography separations.
condenser was washed with diethyl ether in the This is in contrast to the methods of synthesis of
separate bulb. After the end of the reaction (6–8 h), D3-trishomocubanone described in literature that
combined ether layers were washed with water, dried involve reduction of Cookson’s diketone to pentacy-
2147

Stereoselective preparation of mono- and bis-derivatives
of pentacyclo[6.3.0.02,6.03,10.05,9]undecane (D3-trishomocubane)
Scheme 1. Chlorosulfonation of Cookson’s diketone (1).
Scheme 2. Multigram synthesis of D3-trishomocubanone (10).
clo[5.4.0.02,6.03,10.05,9]undecane-8,11-diol,
undergoes skeleton rearrangement with formation of hydrolysis of the reaction mixture after the isomerization
which
further method for preparation of 4 we replaced the basic
D3-trishomocubane structure [4,8,14].
of 1 in chlorosulfonic acid for acidic one (Scheme 3).
Our results are in full agreement with the fact
The stereochemistry of thus obtained 4–ethylen-
that the rearrangement of 1 with formation of the eketal- 6-chloro-7-hydroxypentacyclo[6.3.0.02,6.03,10.05,9]
D3-trishomocubane skeleton [15] occurs with the undecane-4-one (8) was defined through the X-ray
participation of only one keto-group that gives anti-7- crystal structure analysis (Fig. 1, see Supplementary
chlorosulfonate-6-chloropentacyclo[6.3.0.02,6.03,10.05,9]- Information for further details). It confirms an almost
undecane-4-one (2) stereoselectively. This is also in ideal D3-propeller structure of the cage and syn-
accord with the stereoselectivity of the rearrangement substitution stereochemistry. This is in contrast to anti-
of the substituted tertiary СS–trishomocubane alcohols substitution pattern of the 7-chlorosulfonate-6-chloro-
[16]. As only one diastereomer dominates in the mixture pentacyclo[6.3.0.02,6.03,10.05,9]undecane-4-one (2) [15]
of chlorohydroxy ketones 4, we attempted to isolate it and reveals the inversion of stereochemistry at the
and characterized it individually taking into account that 7C-position under hydrolysis.
this molecule is seen to be a good precursor for further
enantioseparations.
The epimer 8 was converted into the individual syn-
stereoisomer of 7-hydroxypentacyclo[6.3.0.02,6.03,10.05,9]
We found that the treatment of dichloro ketone undecane-4-one (12) through the effective reduction-
with 10%-sulfuric acid quantitatively gives deprotection procedure. The epimeric ketone 12 was
3
chlorohydroxyketone 4. In order to develop simple available previously only through
a cumbersome
2148

A. M. Mishura et al.
Scheme 3. Preparation of individual epimers of 4,7- disubstituted D3-trishomocubane derivatives.
We thus developed
a convenient preparative
pathway to 12, which is a key synthon of various
D3-trishomocubane 4,7-derivatives, including optically
active ones. As hydroxyamines are among most
promising bifunctional homocubane derivatives, we
incorporated the amino function into the structure.
The reaction of hydroxylamine with hydroxyketone 12
gave the respective oxime 15, whose reduction on Pd
gave 7-aminopentacyclo-[6.3.0.02,6.03,10.05,9]undecane-
1
4-ol (16). From the analysis of the NMR Н and 13С
spectra amine 16 forms as two diastereomers in the
2:3 ratio (from integral intensities of α-hydroxy proton
signals at 4.00 and 4.05 ppm). In the NMR 13С spectrum
the pairs of the resonances at 74.4, 74.5, 74.8, 74.9 ppm
belong to the carbons attached to the CHOH fragment.
Analysis of the NMR 13С DEPT-spectrum of 16 allows
assignment of the carbon resonances of the CH2-
fragments at 32.2, 32.3, 32.5, 32.6 ppm. The biological
activity of aminoalcohol 16 is of high interest in view of
high activities of many parent D3-trishomocubyilamines
[18-19].
Figure 1. The X-ray crystal structure of 6-chloro-7-hydroxypentacyc
lo[6.3.0.02,6.03,10.05,9]undecane-4- one ethylene ketal (8).
pyrolysis of the Rh-complex of anti-octahydro-1,2,4-
metheno-lH-cyclobuta[cd]pentalen-1-ol [17] and may be
useful for enantioseparations. Its oxidation gave penta-
cyclo[6.3.0.02,6.03,10.05,9]undecane-4,7-dione (14), which
is a useful building block for H-bonded ladderanes [18] 4. Conclusions
the reduction of 12 gave pentacyclo[6.3.0.02,6.03,10.05,9]-
undecane-4-ol (13) – a useful precursor for optical We suggest an effective and simple method for the
resolution as well as for further functionalizations.
construction of the D3-trishomocubanone skeleton
2149

Stereoselective preparation of mono- and bis-derivatives
of pentacyclo[6.3.0.02,6.03,10.05,9]undecane (D3-trishomocubane)
directly from Cookson’s diketone avoiding of usage
of harsh reaction conditions and chromatographic
Acknowledgment
separation steps. The isolation and characterization of This work was supported through German Academic
individual epimer of the disubstituted D3-trishomocubane Exchange Service and the Ministry of Science and
cage opens new routes to stereoisomers of 4,7- Education of Ukraine. We are grateful to the Institute
disubstituted D3-trishomocubane that are potentially of Organic Chemistry Justus-Liebig-University Giessen
useful for optical resolutions and preparation of new for spectroscopic analyses and to Prof. Dr. Peter R.
pharmacologically active compounds.
Schreiner for productive discussions.
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