Efficient synthesis of 4-halo-D3-trishomocubane derivatives

Article abstract of DOI:10.24820/ark.5550190.p010.772

Reaction of C_s-trishomocubane-8,11-diol with hydrohalic acids results in haloalcohols – 4,7-disubstituted derivatives of D₃-trishomocubane. The reaction involves the rearrangement of the trishomocubane skeleton and the stereoselective formation of 4,7-D₃-trishomocubanediol and 5‐oxahexacyclo[5.4.1.0^2,6.0^3,10.0^4,8.0^9,12]-dodecane as side products. The mechanism of the rearrangement was proposed. 7-Halo-D₃-trishomocuban-4-ols were oxidized to the corresponding haloketones. The structure of the major isomers of the haloketones was confirmed through X-ray analysis.

Full text of DOI:10.24820/ark.5550190.p010.772

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Efficient synthesis of 4-halo-D -trishomocubane derivatives
3
a
a
a
b
c
Igor A. Levandovskiy, Alexandr V. Gaidai, Yevheniia Y. Zhyhadlo, Dmitry I. Sharapa, Oleg V. Shishkin,
c
a,d
Svitlana V. Shishkina, and Yuliya V. Rassukana*
a
Department of Organic Chemistry, Igor Sikorsky Kiev Polytechnic Institute, Pr. Pobedy 37, 03056 Kiev, Ukraine
b
Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, University Erlangen-
Nuremberg, Nagelsbachstr. 25, 91052, Germany
Division of Functional Materials Chemistry, SSI ‘Institute for Single Crystals’, National Academy of Science of
C
Ukraine, Lenina Ave. 60, Kharkov 61001, Ukraine
Institute of Organic Chemistry, National Academy of Sciences, 5 Murmanska st, Kiev, Ukraine, 02660
d
Email: juvivi@ukr.net
Received 10-03-2018
Accepted 11-15-2018
Published online 11-28-2018
Abstract
Reaction of C
derivatives of D
and the stereoselective formation of 4,7-D
dodecane as side products. The mechanism of the rearrangement was proposed. 7-Halo-D
s
-trishomocubane-8,11-diol with hydrohalic acids results in haloalcohols – 4,7-disubstituted
3
-trishomocubane. The reaction involves the rearrangement of the trishomocubane skeleton
2
,6 3,10 4,8 9,12
3
-trishomocubanediol and 5‐oxahexacyclo[5.4.1.0 .0 .0 .0 ]-
-trishomocuban-4-
3
ols were oxidized to the corresponding haloketones. The structure of the major isomers of the haloketones
was confirmed through X-ray analysis.
Keywords: C
s
-Trishomocubane, D -trishomocubane, skeletal rearrangement, haloketone
3
DOI: https://doi.org/10.24820/ark.5550190.p010.772
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Introduction
The chemistry of polycyclic cage compounds remains fascinating and continues to draw the attention of
organic chemists since the middle of the last century. Interest in the pharmacology of polycyclic cage
compounds was stimulated when the wide range of pharmacological properties of adamantane derivatives
1
have been discovered. Since then, plenty of polycyclic hydrocarbon three-dimensional scaffolds were
developed. Some of them, like bicyclo[1.1.1]pentane or cubane are considered to be key bioisosteres of
2
,3
traditional flat aromatic systems.
-Symmetrical trishomocubane (pentacyclo[6.3.0.0 .0 .0 ]undecane) has attracted particular
attention, because it has specific properties valuable for novel drug design, viz., a relatively large cage size,
high lipophilicity, and a conformational rigidity. Actually, around fifty derivatives of D -trishomocubane have
been tested against 5-HT, adenosine A1, DAT1, dopamine and as NMDA receptors and some of them indeed
2
,6 3,10 5,9
D
3
3
4
-6
display pronounced activity. Furthermore, unlike the above cages, D -trishomocubane is internally chiral,
3
which may also considerably increase the drug efficiency.7
However, despite the fact that D
their syntheses often remain tricky and the mechanisms of the transformations are still unclear. In particular,
rearrangement of C -trishomocubane-8,11-diol 1 in acidic media, which is the main method of synthesis of 4,7-
disubstituted D -trishomocubanes, leads to a mixture of products, and the ratio of them strongly depends on
3
-trishomocubane derivatives have great potential for drug discovery,
s
3
the conditions8 . Thus, the result of the interaction of diol 1 with hydrobromic or hydroiodic acid at 100 C is
-10
o
the formation of a mixture of hexacyclic ether 2 and 7-halo-D
a,b. At the same time, reaction of C
3
-trishomocubane-4-ol diastereomers 3a,b or
-diol 1 with HI under harsh conditions (160°C, 20 h) or of the tosylate of
8
4
s
1
0
this diol with NaI in HMPA results in a mixture of diastereomers of diiodide 5, an important compound for
the synthesis of homohypostrophene, D -trishomocubane, and their derivatives. Another problem is the
instability of the yields of 7-iodo-D -trishomocubane-4-ols (4a,b, Scheme 1), which are varying in a very wide
range (from 44% up to 86%) for unclear reasons (stated by Kent and Helmchen , confirmed by us ).
3
3
8
9
11
Scheme 1. Reaction of C -trishomocubane-8,11-diol (1) with HI and HBr.
s
Note, 7-halo-D
chiral D -trishomocubane-carboxylic acid , valuable intermediates for a wide range of D
derivatives. Because much in the C -trishomocubane-8,11-diol rearrangement under the acidic conditions is
3
-trishomocubane-4-ols are starting materials for the synthesis of D
3
-trishomocubanone and
1
1
3
3
-trishomocubane
s
still unclear, we decided to reinvestigate this reaction more thoroughly and gain a deeper insight into its
mechanism. Optimization of the rearrangement step would increase the overall yield for these compounds,
too.
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Results and Discussion
s
First, we carefully investigated the rearrangement of C -trishomocubane-8,11-diol 1 in hydroiodic and
hydrobromic acids. In our hands, the reaction of 1 with hydroiodic acid gave nearly the same results (with
insignificant differences in yields and product ratios) as reported previously.8
,9,11
In the case of aqueous
hydrobromic acid, the rearrangement of 1 (Scheme 1) with usual work-up of the reaction mixture (poured into
water, extracted by an organic solvent that was then dried and evaporated) results in the mixture of two
diastereomeric 7-bromo-D
11% yield). Evaporation of the water layer under normal pressure results in the formation of a chloroform
soluble mixture of diastereomeric bromoalcohols 3a,b and dibromides 7 (approx. 7% yield) (Scheme 2). We
suggested that D -trishomocubane-4,7-diol 6 can be formed as a by-product of the rearrangement, be well-
soluble in aqueous acidic media (unlike C -diol 1, 7-bromo-D -trishomocubane-4-oles, and hexacyclic ether 2)
3
-trishomocubane-4-oles 3a,b in 3:1 ratio (63% yield) with admixture of ether 2
(
3
s
3
and under heating undergo nucleophilic substitution of the hydroxyl group(s) with bromine. This suggestion
can explain the solubility of initially insoluble residue in organic solvent after further boiling in HBr.
Scheme 2. Reaction of D -trishomocubane-4,7-diol (6) with HBr.
3
To prove our assumption about the structure of the water-soluble admixture, we attempted the
rearrangement of the C -diol 1 while boiling in hydrochloric acid (Scheme 3), followed by the treatment as
discussed above (extraction with CHCl , evaporation, etc.). Analysis of the products from the organic phase
s
3
revealed the presence of the hexacyclic ether 2 and two chloroalcohols 8 in a 5:1 ratio (these diastereomers
were separated by crystallization). At the same time, evaporation of the aqueous phase under high vacuum
resulted in the formation of a white hygroscopic precipitate. After drying, the precipitate was subjected to
NMR and GS/MS analysis and was identified as compound 6. The yield of 4,7-D
3
-trishomocubanediol 6 is ca.
2
0-25%. Difference in ratios of stereoisomers of halo-alcohols (3:1 for 3a,b and 5:1 for 8a,b), formed after the
reaction of Cs-trishomocubane-8,11-diol with hydrohalic acids, might be explained with different
nucleophilicity of the halide anions.
s
Scheme 3. Reaction of C -diol 1 with hydrochloric acid.
Despite the fact that the synthesis of 4,7-D
articles, there is not much physico-chemical data on compound 6 – only IR spectra was reported by Barborak
3
-trishomocubanediol 6 was described earlier in a few
1
2
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13
13
and later by Naemura. Based on C NMR, it was concluded that while compound 6 can exist as three
different isomers (one С
one, 6a, takes place.
1
- and two С -symmetrical, Figure 1), in the course of the reaction formation of only
2
1
3
While structures 6b and 6c would have only 6 signals (or 12 in the case of their mixture), in the C spectra
there are 11 signals, that correspond to structure 6a.
Figure 1. Isomerism and symmetry of 4,7-disubstituted-D -trishomocubane with the same substituents.
3
Also structure of 6a was proven by X-ray analysis (Figure 2). The hydroxyl groups were shown to have a
different orientation in relation to the trishomocubane fragment: the hydroxyl at the C1 atom has an endo-
position while the hydroxyl group at the C4 atom has an exo-position (the O1-C1-C2-C3 and C2-C3-C4-O2
torsion angles are -60.8(1)° and 177.0(1)°).
Figure 2. Molecular structure of compound 6a according to X-ray diffraction data. Thermal ellipsoids are
shown at 50% probability level.
It turned out that upon continuous reflux in hydrochloric acid of hexacyclic ether, 2 also undergoes
rearrangement to give a mixture of chloroalcohols 8a,b in approx. 4:1 ratio. However, the reaction proceeds
slower than in the case of diol 1. Treatment of ether 2 with AlCl
3
in dichloromethane leads to the same results.
-diol 1 in hydrohalic acids suggested earlier by Kent (via
Obviously, the mechanism of rearrangement of the C
s
8
a concerted halide-displacement/protonation), does not explain the formation of all the observed products. It
predicts the formation of only one stereoisomer of 7-halo-D -trishomocubane-4-oles while 2 isomers are
3
observed in the mixtures and does envisage the formation of 4,7-D
3
-trishomocubanediol 6. We suggested,
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that the mechanism can have additional alternative pathways (Scheme 4), which can be realized via formation
+
4
14
of a nonclassical C D -trishomocubane (type A). In our previous work we have suggested that a similar
3
rearrangement occurs via the formation of an analogous nonclassical cation. We assume that the formation of
cation A from diol 1 involves protonation of 1, dehydration, and further rearrangement of the protonated
hexacyclic ether 2. Nucleophilic attack of A by a halogen leads to the formation of the major isomer of
haloalcohol (3, 4, or 8). The competing reaction of A with water affords protonated diol 6, where the hydroxyl
groups can be further substituted with halogen(s) to furnish the minor isomer of haloalcohol and dihalide.
Scheme 4. Proposed rearrangement pathway.
Hydrochloric acid is seen to be the most convenient among the hydrohalic acids for the C -
s
trishomocubane-8,11-diol rearrangement because of its high thermal stability and relatively low boiling point.
This makes chloroalcohol 8 the most easily accessible haloalcohol and, in advance, the most preferable
starting material for further syntheses.
Therefore, we decided to develop the procedure for the chiral resolution of its enantiomers. So, the
major isomer of chloroalcohol 8a, obtained after the fractional crystallization of 8a,b from acetone, was
treated sequentially with phthalic anhydride and (R)-(+)-α-phenylethylamine to obtaine a mixture of
diastereomeric esters 10 (Scheme 5). The mixture was separated by fractional crystallization from acetone and
the isolated major diastereomer was subjected to basic hydrolysis to furnish the pure enantiomer of 7-chloro-
D
3
-trishomocubane-4-ol (
=+69.3(c 1.17, CHCl
3
) in 35% yield.
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Scheme 5. Chiral resolution of 7-chloro-D -trishomocubane-4-ol.
3
7
-Halo-D
3
-trishomocubane-4-oles 3, 4, 8 as well as 4,7-D
3
-trishomocubanediol 6 were oxidized with
Jones reagent to the corresponding haloketones 11–13 and 4,7-D
3
-trishomocubanedione 14 (Scheme 7).
Scheme 7. Oxidation of haloalcohols 3, 4 and 8 and diol 6 with Jones reagent.
The ratio of the haloketone diastereomers was 2:1 for the chloroketone and 4:1 for the bromo- and
iodoketone, the major isomers were isolated from the mixture by crystallization. 2D-NMR of the main
diastereomers of the haloketones show an anti-orientation of the halogen. Such a structure was confirmed
through X-ray analysis of the bromoketone. The bromide substituent has an exo-position in relation to the
cubane fragment (the C2-C3-C4-Br1 torsion angle is -179.5(1)°).
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Figure 3. Molecular structure of compound 11 according to X-ray diffraction data. Thermal ellipsoids are
shown at 50% probability level.
Conclusions
We have reported a new synthetic pathway leading to the stereoselective formation of 7-halo-D
trishomocuban-4-ones and 4,7-D -trishomocubanediol. On the basis of the experimental results, a possible
reaction mechanism has been proposed. The obtained 7-halo-D -trishomocuban-4-ols were oxidized to the
3
-
3
3
corresponding haloketones. The structure of the major isomers of the haloketones was confirmed through X-
ray analysis.
Experimental Section
1
13
General. H and C NMR spectra were recorded using BrukerAvance NMR spectrometers operating at 400 and
1
13
5
(
00 H frequency (101 and 126 MHz for C experiments). Chemical shifts are reported relative to internal TMS
H) standard. Melting points are uncorrected. Solvents were dried before use according to standard methods.
1
Elemental analysis was carried out in the analytical laboratory of Institute of Organic Chemistry, NAS of
Ukraine.
Reaction of C
s
-trishomocubane-8,11-diol (1) with hydrobromic acid. A mixture of C -trishomocubane-8,11-
s
diol 1 (6.80 g, 38.2 mmol) and 48% aqueous hydrobromic acid (45 mL) was heated to 100°C for 4 h, then
cooled to r.t., and poured into water (100 mL). The obtained mixture was extracted with dichloromethane (4 ×
5
0 mL). The combined organic extracts were washed with 3% aqueous NaOH until neutral pH and water (100
mL), dried over Na SO , and evaporated under reduced pressure to give 7.16 g of crude product, which was
subjected to column chromatography (Al , hexane, then methanol) to give 5.80 g (yield 63%) of pure 7-
bromo-D -trishomocubane-4-ol 3a,b (two diastereomeric pairs of products in approx. 3:1 ratio) and 0.65 g
yield 11%) of 5‐oxahexacyclo[5.4.1.0 .0 .0 .0 ]dodecane 2. The aqueous layer was evaporated under
2
4
2 3
O
3
2
,6 3,10 4,8 9,12
(
reduced pressure to afford 0.70 g (yield 7%) of a mixture of compounds 3 and 7 in approx. 5:1 ratio. Physico-
chemical constants of compounds 2, 3, and 7 were in agreement with literature data. 8
, 15
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Reaction of C
s
s
-trishomocubane-8,11-diol with hydrochloric acid. A mixture of C -trishomocubane-8,11-diol 1
(
5.00 g, 28.1 mmol) and 36% aqueous hydrochloric acid (30 mL) was heated to 100°C for 4 h, then cooled to
r.t., and poured into water (50 mL). The obtained mixture was extracted with dichloromethane (4 × 20 mL).
The combined organic layers were washed with water (100 mL), dried over Na SO , and evaporated under
reduced pressure to give 3.60 g of crude product, which was subjected to column chromatography (Al O ,
2
4
2
3
2
,6 3,10 4,8 9,12
hexane, then methanol) to give 0.85 g (yield 19%) of 5‐oxahexacyclo[5.4.1.0 .0 .0 .0 ]dodecane 2 and
2
5
7
2
.00 g (yield 33%) of 7-chloro-D -trishomocubane-4-ol 8a,b (two diastereomeric pairs of products in approx.
3
:1 ratio) as a white solid. It was recrystallized from acetone (3 mL) to obtain 0.82 g of diastereomerically pure
1
-chloro-D
3
-rishomocubane-4-ol (8a). mp 80°C. H NMR (CDCl
3
, 400 MHz): δ 4.20 (1H, br. s.), 4.11 (1H, br. s.),
.80 - 2.94 (1H, m), 2.66 - 2.79 (1H, m), 2.31 - 2.47 (1H, m), 2.15 - 2.30 (2H, m), 1.93 - 2.13 (4H, m), 1.37, 1.45
1
3
(
Abq, J 10.4 Hz, 2H). C NMR (CDCl
Anal. Calcd for C11 13ClO: C 67.18, H 6.66. Found: C 67.20, H 6.67.
The acidic aqueous solution was evaporated to dryness under reduced pressure and the obtained viscous oil
was triturated with acetone and collected by filtration to obtain 1.40 g (yield 28%) of D -trishomocubane-4,7-
, 500 MHz): δ 4.53 (2H, br. s), 3.90 (2H, s), 2.60 (1H,
3
, 126 MHz): δ 77.1, 64.0, 53.2, 53.0, 52.4, 49.0, 45.3, 43.6, 41.1, 40.4, 32.9.
H
3
3
1
diol 6 as white crystals. mp 203-205°C. H NMR (DMSO-d
s), 2.28 (1H, br. s), 2.01 - 2.17 (2H, m), 1.77 - 1.91 (4H, m), 1.32, 1.20 (Abq, J 9.8 Hz, 2H). C NMR (DMSO-d
6
1
3
6
,
1
7
26 MHz): δ 75.8, 75.7, 53.2, 51.9, 50.7, 47.7, 44.2, 42.7, 40.6, 39.9, 33.5. Anal. Calcd for C11
.92. Found: C 74.16, H 7.90.
H
14
2
O : C 74.13, H
Chiral resolution of 7-chloro-D
pure diastereomer) (2.85 g, 13.4 mmol), phthalic anhydride (1.08 g, 7.29 mmol), benzene (60 mL), and
pyridine (3 mL) was refluxed for 12 h, cooled to r.t., washed with 3% aqueous citric acid (50 mL), and extracted
with 10% aqueous Na CO (3 × 30 mL). The basic aqueous extract was acidified with 5% hydrochloric acid and
extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over Na SO , and
evaporated under reduced pressure to obtain 2.50 g (yield 54%) of 7-chloro-D -trishomocubane-4-ol hydrogen
3
-trishomocubane-4-ol. A mixture of 7-chloro-D -trishomocubane-4-ol 8a
3
(
2
3
2
4
3
phthalate 9. The phthalate 9 (2.30 g, 6.67 mmol) was dissolved in diethyl ether (30 mL) and treated with a
solution of (R)-α-phenylethylamine (0.900 g, 7.43 mmol) in diethyl ether (10 mL) at r.t. The precipitated solid
was collected by filtration, washed with diethyl ether, and dried to obtain 2.70 g (yield 87%) of 7-chloro-D -
3
trishomocubane-4-ol phenylethylammonium hydrogen phthalate 10 (mixture of two diastereomers) as a
white solid. Its fractional crystallization from acetone afforded 0.60 g (yield 44%) of diastereomerically pure
salt 10. The latter was dissolved in 80% aqueous ethanol (5 mL) and treated with NaOH (0.052 g, 1.29 mmol).
The mixture was refluxed for 4 h and then concentrated in vacuo. The residue was mixed with water (15 mL)
and extracted with diethyl ether (4 × 20 mL). The combined organic layers were washed with 5% hydrochloric
acid (3 × 10 mL), dried over Na
2
SO
4
, and evaporated to give 0.20 g (yield 80%) enantiomerically pure
chloroalcohol (+)-8a, mp 118°C.
=+69.3(c 1.17, CHCl )
3
D
3
-Trishomocubane-4,7-dione (14). To a stirred solution of D
in acetone (30 mL) Jones reagent (a mixture of CrO (1.00 g, 10.0 mmol), H
2.1 mL)) was added dropwise and the reaction mixture was stirred for 1 h at r.t. Then it was poured into
water and extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with water
20 mL), dried over Na SO , and evaporated under reduced pressure to obtain 0.75 g (yield 77%) of D
trishomocubane-4,7-dione 14. Physico-chemical constants of compound 14 were in agreement with literature
3
-trishomocubane-4,7-diol 6 (1.00 g, 5.61 mmol)
3
2
SO (1.7 mL, 31.9 mmol), and water
4
(
(
2
4
3
-
12
1
data mp 212°C-213°С (lit. 213°C-214°С). H NMR (CDCl
3
, 500 MHz): δ 2.73 - 2.90 (4H, m), 2.17 - 2.27 (2H, m),
, 126 MHz): δ 213.3, 54.6, 53.1, 50.1, 48.4, 47.6, 47.1, 42.2,
1
3
2
4
.05 - 2.16 (2H, m), 1.77 (2H, s). C NMR (DMSO-d
0.2, 40.1, 34.6. Anal. Calcd for C11
6
H
10
O
2
: C 75.84, H 5.79. Found: C 75.80, H 5.81.
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General procedure for the preparation of 7-halo-D
3
-trishomocubane-4-ones. To a cooled to 0°C solution of 7-
halo-D
mmol), H
0°C and the reaction mixture was stirred for 30 min at 10°C and for 12 h at r.t. Then it was poured into water
50 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over Na SO
and evaporated under reduced pressure to obtain the crude product, which was purified by column
chromatography (Al , hexane/ethyl acetate 9:1) to obtain the appropriate 7-halo-D -trishomocubane-4-one
3
-trishomocubane-4-ol (15.0 mmol) in acetone (40 mL) Jones reagent (a mixture of CrO
3
(2.70 g, 27.0
2
SO (2.9 mL, 54.4 mmol), and water (5.1 mL)) was added dropwise maintaining temperature below
4
1
(
2
4
2
O
3
3
as a mixture of two diastereomers. Further recrystallization from hexane ethyl acetate mixture afforded a
single diastereomer of the halo-ketone.
2
,6 3,10 5,9
7
-Bromopentacyclo[6.3.0.0 .0 .0 ]undecane-4-one (11). Obtained in 78% yield as 4:1 mixture of isomers.
1
Recrystallization (hexane/ethyl acetate 3:2) gave 33% yield of diastereomerically pure 11; mp 90-91°C. H
NMR (CDCl , 500 MHz): δ 4.06 (1H, br. s.), 3.17 (1H, br. s.), 2.57 - 2.72 (3H, m), 2.50 - 2.57 (1H, m), 2.38 - 2.49
3
1
3
(
1H, m), 1.83 - 2.00 (2H, m),1.68, 1.52 (Abq, J 10.8 Hz, 2H). C NMR (CDCl
3
, 126 MHz): δ213.3, 54.6, 53.1, 50.1,
4
7
8.4, 47.6, 47.1, 42.2, 40.2, 40.1, 34.6. Anal. Calcd for C11H11BrO: C 55.25, H 4.64. Found: C 55.29, H 4.62.
2
,6 3,10 5,9
-Iodopentacyclo[6.3.0.0 .0 .0 ]undecane-4-one (12). Obtained in 81% yield as 4:1 mixture of isomers.
1
Recrystallization (hexane/ethyl acetate 4:1) gave 31% yield of diastereomerically pure 12. H NMR (CDCl
3
, 500
MHz): δ 3.90 (1H, s), 3.26 (1H, br. s), 2.84 (1H, br. s), 2.67 - 2.73 (1H, m), 2.54 - 2.62 (2H, m), 2.43 (1H, q, J 5.6
1
3
Hz), 1.86 - 1.98 (2H, m), 1.72, 1.50 (Abq, J 10.5 Hz, 2H). C NMR (CDCl
3
, 126 MHz): δ 213.1, 54.2, 50.4, 50.0,
9.1, 48.9, 42.9, 40.4, 39.5, 34.4, 30.5. Anal. Calcd for C11H11IO: C 46.18, H 3.88. Found: C 46.21, H 3.85.
4
2
,6 3,10 5,9
7
-Chloropentacyclo[6.3.0.0 .0 .0 ]undecane-4-one (13). Obtained in 75% yield as 2:1 mixture of isomers.
Recrystallization (hexane/ethyl acetate 3:7) gave 25% yield of diastereomerically pure 13; mp 85°C. H NMR
1
(
CDCl , 500 MHz): δ 4.08 (1H, s), 3.11 (1H, br. s.), 2.63 (1H, q, J 5.4 Hz), 2.52 - 2.60 (2H, br. d, J 12.5 Hz), 2.40 -
3
1
3
2
5
6
.52 (2H, m), 1.87 - 1.99 (2H, m), 1.69, 1.56 (Abq, J 10.6 Hz, 2H). C NMR (CDCl
3
, 126 MHz): δ 213.6, 63.8,
2.9, 49.8, 47.8, 46.9, 46.0, 41.8, 40.0 (overlapped), 34.8. Anal. Calcd for C11
7.90, H 5.68.
H11ClO: C 67.87, H 5.70. Found: C
X-ray crystallography. The crystals of 6a (C11
H
14
O
2
) are monoclinic. At 293 K a = 24.316(4), b = 7.5252(9), c =
3
3
1
0.432(2) Å,  = 114.51(2), V = 1736.9(5) Å , Mr = 178.22, Z = 8, space group C2/c, dcalc = 1.363 g/cm , (MoK
-
1
) = 0.092 mm , F(000) = 768. Intensities of 6794 reflections (2533 independent, Rint = 0.030) were measured
on the “Xcalibur-3” diffractometer (graphite monochromated MoK
60).
α
radiation, CCD detector, ω-scaning, 2Θmax
=
The crystals of 11 (C11
V = 905.5(3) Å , Mr = 239.11, Z = 4, space group P2
H
11OBr) are monoclinic. At 293 K a = 6.364(1), b = 20.331(5), c = 7.030(1) Å, β = 95.42(2)°,
3
3
-1
1
/c, dcalc= 1.754 g/cm , (MoK) = 4.491 mm , F(000) = 480.
Intensities of 6805 reflections (2624 independent, Rint = 0.050) were measured on the«Xcalibur-3»
diffractometer (graphite monochromated MoK radiation, CCD detector, ω-scaning, 2Θmax = 60).
α
The structures were solved by direct method using SHELXTL package [16]. The absorption correction for 11 was
performed using the multi-scan method (Tmin = 0.346, Tmax = 0.467). Position of the hydrogen atoms were
located from electron density difference maps and refined by “riding” model with Uiso = nUeq of the carrier
atom (n = 1.5 for methyl groups and n = 1.2 for other hydrogen atoms) in structure 6a and using isotropic
2
approximation in structure 11. Full-matrix least-squares refinement of the structures against F in anisotropic
approximation for non-hydrogen atoms using 2479 (6a), 2595 (11) reflections was converged to: wR
2
= 0.144
(R
1
= 0.053 for 1763 reflections with F>4σ(F), S = 1.014) for structure 6a and wR = 0.072 (R = 0.037 for 1839
2
1
reflections with F>4σ(F), S = 0.902) for structure 11. The final atomic coordinates, and crystallographic data for
molecules 6a and 11 have been deposited to with the Cambridge Crystallographic Data Centre, 12 Union Road,
Page 9
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Levandovskiy, I. A. et al.
CB2 1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and are available on request quoting the
deposition numbers CCDC 1870778 for 6a and CCDC 1870777 for 11).
Acknowledgements
We thank Enamine Ltd for financial support.
References
1
2
3
. Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem. Rev. 2013, 113, 3516.
https://doi.org/10.1021/cr100264t
. Stockdale, T. P.; Williams, C. M. Chem. Soc. Rev., 2015, 44, 7737.
https://doi.org/10.1039/C4CS00477A
. Stepan, A. F.; Subramanyam, C.; Efremov, I. V.; Dutra, J. K.; O’Sullivan, T. J.; DiRico, K. J.;. McDonald, W.S.;
Won, A.; Dorff, P.H.; Nolan, C. E. J. Med. Chem., 2012, 55, 3414.
https://doi.org/10.1021/jm300094u
4
5
. Oliver, D. W.; Dekker, T. G.; Snyckers, F. O.; Fourie, T. G. J. Med. Chem., 1991, 34, 851.
https://doi.org/10.1021/jm00106a053
. Banister, S. D.; Moussa, I. A.; Beinat, C.; Reynolds, A. J.; Schiavini, P.; Jorgensen W. T.; Kassiou, M. Bioorg.
Med. Chem. Lett., 2011, 21, 38.
https://doi.org/10.1016/j.bmcl.2010.11.075
6
7
8
9
1
1
. Hasegawa, T.; Nigo, T.; Kakita, T.; Toyoda, H.; Toya, H.; Ueda, I. Chem. Pharm. Bull., 1993, 41, 1760.
https://doi.org/10.1248/cpb.41.1760
. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem., 2009, 52, 6752.
https://doi.org/10.1021/jm901241e
. Kent, G. J.; Godleski, S. A.; Osawa, E.; Schleyer, P. v. R. J. Org. Chem. 1977, 42, 3852.
https://doi.org/10.1021/jo00444a012
. Helmchen, G.; Staiger, G. Angew. Chem. Int .Ed. 1977, 16, 116.
https://doi.org/10.1002/anie.197701161
0. Marchand, A. P.; Chou, T. C.; Ekstrand, J. D.; Van der Helm, D. J. Org. Chem. 1976, 41, 1438.
https://doi.org/10.1021/jo00870a033
1. Gaidai, A. V.; Volochnyuk, D. M.; Shishkin, O. V.; Fokin, A. A.; Levandovskiy, I. A.; Shubina, T. E. Synthesis
2
012, 44, 810.
https://doi.org/10.1055/s-0031-1289708
1
1
1
2. Smith, E. C.; Barborak, J. C.; J. Org. Chem., 1976, 41, 1433.
https://doi.org/10.1021/jo00870a032
3. Nakazaki, M.; Naemura, K.; Arashiba, N.; J. Org. Chem., 1978, 43, 689.
https://doi.org/10.1021/jo00398a038
4. Sharapa, D. I.; Gayday, A. V.; Mitlenko, A. V.; Levandovskiy, I. A.; Shubina, T. Eur. J. Org. Chem. 2011, 13,
2
554.
https://doi.org/10.1002/ejoc.201001731
1
5. Marchand, A. P.; LaRoe, W. D.; Sharma, G. M.; Suri, S. C.; Reddy, D. S. J. Org. Chem. 1986, 51, 1622.
Page 10
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Levandovskiy, I. A. et al.
https://doi.org/10.1021/jo00359a054
1
6. Sheldrick, G. Acta Crystallogr. A. 2008, 64, 112.
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