Synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2]-tridecanes - A new class of peroxides

Article abstract of DOI:10.1016/j.tetlet.2005.11.107

The synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2]tridecanes, a new class of peroxide skeletons using Birch reduction of aromatic compounds followed by ozonolysis and acid catalysed cyclisation is described.

Full text of DOI:10.1016/j.tetlet.2005.11.107

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 771–774
Synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2]-
tridecanes—a new class of peroxides
q
a
a
a,
*
D. Naveen Kumar, N. Sudhakar, B. Venkateswara Rao,
b
b
K. Hara Kishore and U. Suryanarayana Murty
a
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b
Biology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 October 2005; revised 11 November 2005; accepted 18 November 2005
Abstract—The synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2]tridecanes, a new class of peroxide skeletons using Birch reduc-
tion of aromatic compounds followed by ozonolysis and acid catalysed cyclisation is described.
Ó 2005 Elsevier Ltd. All rights reserved.
Cyclic peroxides are important chemical frameworks in
O
O
O
many pharmacologically active compounds, for exam-
1
2
O
O
O
ple, artemisinin and yingzhaosu which are potent anti-
O
O
O
O
O O
3
malarial compounds and chondrillin which shows
1
2
3
significant antitumour activity. Many cyclic peroxides,
which exhibit antifungal, antibacterial and antitumour
activities have been reported previously from a number
of marine organisms, especially from sponges of the
Figure 1.
4
family Plakinidae, among which, plakinic acids con-
pounds exist in nature as sub-structures of many poly-
ether antibiotics, tricyclic bis-spiroperoxyketals are
5
10
tain a rare 1,2-dioxolane-ring systems. Owing to the
promising pharmacological activities of peroxide-con-
taining compounds, the design and synthesis of new per-
oxides and the development of new approaches has
novel skeletons. Herein, we report for the first time the
synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2]tri-
decane 1 and its 2,9-dimethyl derivatives 2 and 3 (Fig. 1)
and the evaluation of their antimicrobial activity.
6
become a burgeoning field in organic chemistry.
The preparation of 1,2-dioxolanes from 1,3-diketones
Initially, we carried out the synthesis of 1, as shown in
Scheme 1. Our synthesis commenced with the reduction
of commercially available m-phthalic acid 4 using LAH
in THF to give diol 5. Oxidation of 5 using TEMPO free
radicals afforded dialdehyde 6, which upon Wittig reac-
7
was known in the early 1960s and recently, Zvilichov-
8
sky and co-workers reported the formation of mixtures
of 1,2-dioxolane intermediates via ozonolysis of simple
alkyl derivatives of 1,4-cyclohexadienes. Based on this
information, we envisaged the synthesis of new tricyclic
bis-spiroperoxyketals by internal trapping of carbonyl
oxides during ozonolysis of products from Birch reduc-
tion of aromatic compounds. Earlier, this protocol was
utilised in our laboratory for the synthesis of biologi-
tion with PPh CHCOOEt in DCM resulted in com-
3
pound 7, the major product being the bis-trans-
diastereomer. Compound 7 upon hydrogenation using
H –Pd/C in MeOH followed by reduction with LAH
2
in THF gave compound 8. Birch reduction of com-
9
cally active compounds. Although the significance of
pound 8 using Li/liq. NH and EtOH in THF gave
3
tricyclic bis-spiroketals is well known, as these com-
1,4-dihydro compound 9 and this was without further
purification, subjected to ozonolysis in 10% MeOH in
DCM (compound 9 was partly soluble in neat DCM
at À78 °C) followed by treatment with catalytic TsOH
to give compound 1 as a solid (mp 50–52 °C). The over-
all yield of compound 1 was 27% from 8 and the average
q
IICT Communication No.: 050904.
*
Corresponding author. Tel.: +91 40 27160123x2614; fax: +91 40
7160512; e-mail: venky@iict.res.in
2
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.107

772
D. Naveen Kumar et al. / Tetrahedron Letters 47 (2006) 771–774
O
O
O
O
HO
OH
i
HO
O
OH
ii
H
H
4
5
6
O
iv
v
iii
EtO
OEt
HO
OH
7
8
OH
vi
X
HO
OH
O
O
O
+
H
9
X = OH or O-OH or OMe
6
HH
1
0
3
4
O
7
9
2
5
1O
O
O
8
O
O
O
O
1
cis-isomer
(not observed)
trans-isomer
Scheme 1. Reagents and conditions: (i) LAH, THF reflux, 75%; (ii) TEMPO, EtOAc/toluene, 0 °C, 83%; (iii) Ph
3
2
PCHCO Et, DCM 93%; (iv) (a) Pd/
C–H
2
, MeOH; (b) LAH, THF, 0 °C–rt, 79% overall yield for two steps; (v) Li–liq. NH
3
–EtOH, THF; (vi) (a) O , 10% MeOH in DCM; (b) catalytic
3
TsOH, the combined overall yield from 8 is 27%.
yield for each stage was calculated as 67%.11 Interest-
ingly, we isolated only the trans compound 1 and did
not observe formation of the corresponding cis-isomer.
The trans-stereochemistry of 1 was confirmed by its H
NMR spectrum in which the geminal protons of the C-
O
O
O
O
ii
i
H
H
1
6
10
OH
OH
OH
iii
OH
6
carbon appeared as a singlet at d 2.86. The C symme-
2
1 13
try of the molecule was evident from its H and
C
NMR spectra. In addition to this, we confirmed the
1
2
structure by mass and elemental analysis.
1
1
12
According to computational studies13 the trans-isomer
of 1 is more stable than the cis-isomer by 1.86 kcal/mol.
O
O
iv
+
O
O
O O
O O
With this result in hand, next we carried out the synthe-
sis of compounds 2 and 3 (Scheme 2). Dialdehyde 6
upon treatment with the phosphorane PPh CHCOCH
in DCM afforded compound 10 exclusively as the bis-
trans-diastereomer, which upon hydrogenation using
2
3
Scheme 2. Reagents and conditions: (i) Ph
ii) (a) Pd/C–H
two steps; (iii) Li–liq. NH
3
PCHCOCH
3
, DCM 96%;
3
3
(
2
, MeOH; (b) LAH, THF, 0 °C–rt, 82% overall yield for
–EtOH, THF; (iv) (a) O , 10% MeOH–
3
3
DCM; (b) catalytic TsOH, overall yield from 11 is 37%.
H –Pd/C in MeOH followed by reduction with LAH
2
in THF gave 11. Using the same procedure as described
earlier, compound 11 was subjected to Birch reduction
followed by ozonolysis and treatment with a catalytic
amount of TsOH gave a mixture of diastereomers 2
and 3 (1:1 ratio). These diastereomers were separated
using silica gel column chromatography to afford pure
compounds 2 (solid mp 53 °C) and 3 (colorless syrup).
The combined yield of compounds 2 and 3 was 37%
from compound 11 and the average yield for each stage
formed from racemic-12 and meso-12, respectively. Of
the two C -symmetric compounds possible from race-
2
mic-12, we observed only one isomer with trans–trans–
trans-stereochemistry (compound 2) and this was
confirmed by the observation of NOEÕs between the
C-6 protons and C-2 and C-9 methyls (Fig. 2).
Antimicrobial evaluation of the above three compounds
1
4
15
was 72%.
against six bacterial organisms
and two fungal
1
6
strains was investigated (Tables 1 and 2). The mini-
mum inhibitory concentrations (MIC) of the com-
pounds 1, 2 and 3 against six test organisms were
determined by the broth dilution method. Results
showed moderate antibacterial activity whilst none were
active against Pseudomonas aeruginosa. The agar cup
bioassay was employed for testing the antifungal activity
1
H NMR spectroscopy of both isomers 2 and 3 revealed
the existence of the intrinsic trans-stereochemistry at the
spiro centres. The geminal protons at the C-6 carbon
resonated at d 2.84 and 2.81 for 2 and 3, respectively,
as singlets. Other analytical data were in agreement with
1
7
1
2
the proposed structures. Compounds 2 and 3 are

D. Naveen Kumar et al. / Tetrahedron Letters 47 (2006) 771–774
773
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H C
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CH3
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O
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H
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O
O
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Figure 2. NOEÕs between the C-6 geminal protons and C-2 and C-9
methyls in compound 2.
Table 1. Antibacterial activity of compounds 1, 2 and 3 (MIC, lg/mL)
a
Microorganism
1
2
3
Ciprofloxacin
5
6
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(
Gram +ve)
Bacillus subtilis
Bacillus sphaericus
Staphylococcus aureus
50 25
25 12.5 25
50 50
25
0.78
0.78
0.39
25
(
Gram Àve)
. (a) Jin, H.-X.; Liu; Zhang, Q.; Wu, Y. Tetrahedron Lett.
Klebsiella aerogenes
50 50
25
0.78
2
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Pseudomonas aeruginosa
12.5 0.39
— 0.78
—
—
(
2
a
Ciprofloxacin is used as positive control (standard).
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1
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a
Microorganism
1
2
3
Clotrimazole
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2, 69–72; (h) Murakami, N.; Kawanishi, M.; Itagaki, S.;
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1
A
B
A
B
A
B
Aspergillus niger
Rhizopus oryzae
7
8
11
12
6
6
9
8
8
8
12 26
11 23
7
Chem. 2001, 5, 601–636; (j) Dussault, P. H.; Eary, C. T.;
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Soc. 1998, 120, 7133.
(
A = 30 lg/mL, B = 100 lg/mL); inhibitory zone diameters are in
millimetre.
a
Clotrimazole is used as positive control (standard).
7
8
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revealed moderate inhibition against Aspergillus niger
and Rhizopus oryzae.
9. (a) Shashidhar Kumar, A.; Bhaket, P.; Rao, B. V.
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In conclusion, we have demonstrated the synthesis
of new trans-1,8,12,13-tetraoxadispiro[4.1.4.2]tridecanes
and established the stereochemical outcome of the reac-
tion by NMR spectroscopy of each compound. Cur-
rently, studies are in progress to improve the yields, to
synthesise other analogues and to complete the evalua-
tion of their biological activity.
2
227.
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1. In most cases nearly 60% of 8 was recovered and the yields
quoted are calculated on the basis of starting material
recovery.
Acknowledgements
2. Analytical data for compounds 1, 2 and 3.
À1
Compound 1: White solid: mp 50–52 °C; IR (KBr, cm ):
D.N.K. and N.S. thank the UGC, New Delhi, for finan-
cial assistance (S.R.F.). The authors thank Dr. K. Bha-
nu Prakash, for helping with the energy calculations and
Dr. J. S. Yadav and Dr. A. C. Kunwar, for their support
and encouragement.
2
1
965, 2930, 2865, 1725, 1460, 1435, 1340, 1190, 1110, 1065,
1
010, 925, 900; H NMR (300 MHz, CDCl ): d 4.00–3.87
3
1
3
(
m, 4H), 2.86 (s, 2H), 2.32–1.82 (m, 8H); C NMR
(
75 MHz, CDCl ): d 114.89, 67.83, 51.43, 31.78, 24.42;
3
+
FAB-MS m/z: 187 [M+1] ; accurate mass calcd for
+
[
M+1] (C
Compound 2: White solid: mp 53 °C; IR (CHCl
2972, 2932, 1736, 1698, 1457, 1386, 1322, 1257, 1206, 1180,
9 17 4
H O ) = 187.0970, found: 187.0976.
À1
, cm ):
3
References and notes
1
1
142, 1120, 1062, 939, 892; H NMR (200 MHz, CDCl ):
3
1
. (a) Jefford, W.; Vicente, M. G. H.; Jacquier, Y.; Favarger,
F.; Marenda, J.; Millason-Schmidt, P.; Brunner, G.;
Burger, U. Helv. Chim. Acta 1996, 79, 1475–1487; (b)
d 4.23–4.10 (m, 2H), 2.84 (s, 2H), 2.30–1.97 (m, 6H), 1.54–
13
1.33 (m, 2H), 1.27 (d, 6H, J = 6 Hz); C NMR (75 MHz,
CDCl ): d 114.92, 75.29, 53.10, 32.21, 32.07, 20.46; ES-MS
3

774
D. Naveen Kumar et al. / Tetrahedron Letters 47 (2006) 771–774
+
+
m/z: 215 [M+1] ; accurate mass calcd for [M+1]
) = 215.1283, found: 215.1286.
Compound 3: Colourless syrup; IR (CHCl , cm ): 2971,
(MTCC 741) were obtained from the Institute of Micro-
bial Technology, Chandigarh. Cultures of the test organ-
isms were maintained on nutrient agar slants and were
sub-cultured in petri dishes prior to testing. The nutrient
agar and nutrient broth were procured from M/S Himeda,
Mumbai, India.
11 19 4
(C H O
À1
3
2
8
2
1
930, 1736, 1456, 1382, 1338, 1209, 1174, 1138, 1069, 936,
88; H NMR (200 MHz, CDCl ): d 4.33–4.09 (m, 2H),
3
.81 (s, 2H), 2.35–1.93 (m, 6H), 1.67 (m, 1H), 1.44 (m,
H), 1.33 (d, 3H, J = 5.9 Hz), 1.26 (d, 3H, J = 5.9 Hz);
C NMR (75 MHz, CDCl ): d 114.97, 114.76, 77.21,
3
5.27, 52.54, 33.81, 32.40, 32.08, 32.01, 22.72, 20.49; ES-
1
16. Two test organisms: Aspergillus niger (MTCC 281) and
Rhizopus oryzae (MTCC 262) were obtained from the
Institute of Microbial Technology, Chandigarh. Cultures
of test organisms were maintained on potato dextrose agar
slants and were sub-cultured in petri dishes prior to
testing. The nutrient agar and the potato dextrose agar
media were procured from M/S Himeda, Mumbai, India.
17. National Committee for Clinical Laboratory Standard
(NCCLS) method for dilution antimicrobial susceptibility
tests for bacteria, which grow aerobically. Nat. Comm.
Clin. Lab. Stands, Villanova; 1982; p 242.
1
3
7
+
+
MS m/z: 215[M+1] ; accurate mass calcd for [M+1]
) = 215.1283, found: 215.1281.
3. Computational studies were carried out on MOPAC
software using the Austin Model 1 (AM1) method.
4. In this case, we recovered 65% of the starting material 11
and the combined yields of 2 and 3 are based on this recovery.
5. Six test organisms: Bacillus subtilis (MTCC 441), B.
sphaericus (MTCC 511), Staphylococcus aureus (MTCC
11 19 4
(C H O
1
1
1
6
9
6), Klebsiella aerogenes (MTCC 39), Chromobacterium
18. Linday, M. E. Practical Introduction to Microbiology; E &
F.N. Spon Ltd, 1962; p 177.
violaceum (MTCC 2656) and Pseudomonas aeruginosa