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Jamonline / 2(2); 2012 / 176–181 Research Article

Alok Majumder et al

Journal of Atoms and Molecules
An International Online Journal
ISSN – 2277 – 1247

TOTAL SYNTHESIS OF 9 – OXO – BICYCLO [3.3.1] NONANE Alok Majumder*,Amitava Mandal, Pranab Ghosh Department of Chemistry, University of North Bengal, Raja Rammohunpur, Darjeeling, West Bengal, India 734 013 Received on: 10-04-2012 Abstract: A simple, cost effective method for the total synthesis of 9-oxo-bicyclo [3.3.1] nonane (1) is described. The structure of the compound was elucidated on the basis of spectral data as well as by comparison with that reported in literature. Key Words: Total synthesis, cost effective, deprotection approach. Revised on: 17-04-2012 Accepted on: 27–04–2012

Introduction: Bicyclic systems are very much ubiquitous in nature.1 * Corresponding author Alok Majumder, Email: Tel: +91 353 2776 381 The wide range of chemistry

associated to this class of entities ranging from the study of anchimeric assistance to the modern drug design.2 Of its many forms, 9oxo-bicyclo [3.3.1] nonane (1) is quite common in biologically active polyprenylated polycyclic natural acylphloroglucines where four family of



substituents are relatively arranged around the central core of 1.3 The rigid bicyclic frame work with its lipophilic skeleton and its hydrophilic ketone moieties represents a nature derived lead structure. Therefore, arranging the different substituents into a defined topographical orientation around the All rights reserved© 2011 176

Jamonline / 2(2); 2012 / 176–181 central three dimensional core of 9-oxobicyclo [3.3.1] nonane is a demanding approach in the contemporary medicinal research. Notable synthetic and biosynthetic pathways involve formation
4 a-d

Alok Majumder et al skeleton. Moreover, since the core of 9-oxobicyclo [3.3.1] nonane is conserved among Garsubellin A (2), Guttiferae classification, including nemorosone II (3),3,4 a versatile construction of this framework might find application in future synthetic investigations of this biologically diverse family of


transformation of this frame work.

The potential significance of 1 in biology and medicine prompted us to pursue an efficient and economic total synthesis of this frame work, the success of which was contingent upon developing a trustworthy methodology for constructing its remarkable bicyclic

compounds. Herein we describe an improved method for the construction of the 9-oxobicyclo [3.3.1] nonane (1) frame work from easily available, cheap starting materials and reagents.

OH O O O O (1) (2) HO O O


O (3)

Figure 1 Core strucyure of 9-oxo-bicyclo [3.3.1] nonane (1), garsubellin A (2) and nemorosone II (3)

Results and Discussion There are a number of reported syntheses; the most direct method used 9-BBN5 (9

dichloromethyl methyl ether). The latter method is unattractive because of the toxicity of Ni(CO)4. The synthesis of Foote and Woodward [7], starting from the




and the reaction6 of 1,5-cyclooctadiene with Ni(CO)4 employed moderately (60%). syringe costly The 9-BBN method and is

cyclohexanone enamine and acrolein, has been the most used route in the older literature, but the overall yield is only ca. 20%.

techniques (9-BBN,


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Jamonline / 2(2); 2012 / 176–181

Alok Majumder et al

7 8 6 9 5 4 1 2






(1a) H CN

O (1b) CO2Et

CN (5)




Scheme 1 General retrosynthetic analysis of 1

In light of this, we considered a strategy as outlined in the simplified retrosynthetic analysis (Scheme 1). Examination of the general skeleton 1 led to the realization that the disconnection of 4,5-bond would generate intermediate 1a that could be readily

1d. Both the synthetic equivalents 1c and 1d could be generated exclusively from the readily available pair of synthons 4 and 5 that can be easily attached through base catalyzed 1,4-addition path way (Michael type addition) to generate 1b effectively. The whole reaction sequence to 1 is shown in scheme 2.

synthesized from the precursor 1b. A further possible disconnection of the appropriate bond would generate the intermediates 1c and

O CO2Et CN 5 NaOEt




4 EtOH/H2SO4 reflux


6 COOEt 1,2-ethane diol p-TsCl O O COOEt CH3MgI Dry ether 9 O O CH2OTs Dry pyridine


8 O p-TsCl Pyridine, 0oC 11


Reflux 1

Scheme 2 Synthesis of 9-oxobicyclo-[3.3.1] nonane (1)

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Jamonline / 2(2); 2012 / 176–181 Ethyl-2-oxocyclohexane carboxylate (4) and acrylonitrile (5) were condensed with sodium ethoxide in Micheal type 1,4-addition path way forming 6, which on subsequent acid hydrolysis followed by decarboxylation gave 7. Compound 7 was esterified to 8. At this juncture, our aim is to transform the ester functionality to a primary alcoholic group, till direct reduction of 8 with lithium aluminium hydride was not performed due to the attached keto function at C-1. Therefore, we applied a protection-deprotection approach. Protection of the keto function was done by introduction to a hemiketal function at C-1 (9). Grignard addition on 9 afforded the desired 10 in which the ester function had been changed a primary alcoholic moiety. Corresponding tosylate and possible deprotection of the hemi ketal form was accomplished by a reaction of compound 10 with para toluenesulfonic acid in dry pyridine at 0 C. Compound 11 on reflux with dry pyridine afforded compound 1 in 62% overall yield. The structure of compound 1, a pale yellow liquid of boiling point 150-160oC (reported 155-158 C) was established on the basis of spectral data as well as that reported in literature. In its IR spectrum it showed a characteristic peak for the presence of a carbonyl group at 1730 cm-1. In 1H NMR spectrum it showed peaks at δH 2.1 (4H, t, J = 6.5 Hz), at δH 2.4 (8H, m) and at δH 4.3 (2H, t, J = 6.6 Hz). These data was also comparable to that reported in literature for compound 1. All rights reserved© 2011
8 o o

Alok Majumder et al Conclusion In conclusion it can be said that we have developed a simple, cost effective protocol for the synthesis of 9-oxo-bicyclo [3.3.1] nonane that forms the core structure of many biologically active natural products in 62% overall yield. The method will be very much useful for the large scale production as well. Experimental General All the chemicals were purchased from Aldrich, Merck, Fluka, Loba etc. companies and purified prior to their use. IR was recorded in Perkin-Elmer NMR spectra FT-IR were


recorded in a Bruker-Avance 300 MHz spectrometer in CDCl3 taking TMS

(Tetramethyl Silane) as the internal standard. The NMR chemical shift was reported in ppm relative to 7.20 and 77.40 ppm of CDCl3 solvent as the standards.1H spectra were recorded in 300 MHz frequencies. Coupling constant ‘J’ was calculated in Hz. Preparation of 6 Ethyl-2-oxocyclohexane carboxylate (4) and sodium ethoxide was stirred at 80 oC under nitrogen atmosphere. Acrylonitrile was added dropwise to this solution over a period of 1 hour. Stirring was continued for another two hour maintaining the temperature at 80 oC. Chloroform was added to the solution after cooling to room temperature. The solution was washed sequentially with water, 10% 179

Jamonline / 2(2); 2012 / 176–181 aqueous HCl , 5% sodium hydrogen Preparation of 1

Alok Majumder et al

carbonate and satured brine; the organic layer was extracted, dried over anhydrous sodium sulfate and concentrated. Preparation of 9 1,2-ethane diol was added to a stirring solution of 8 in dry dichloromethane. Para toluenesulfonic acid was then added in small lots to the reaction mixture at cold. Stirring was continued for anther 6 hours. The prepared product was used further without any purification. Preparation of 10 In a vigorously stirred ethereal solution of grignard reagent at cold, a solution of 9 in anhydrous ether was added slowly under nitrogen. Reflux the solution on a water bath for 1 hour for completion of the reaction. The reaction mixture was then poured into a mixture of approximately 2M H2SO4 at cold. Ether layer was separated out, washed with dilute sodium hydrogen carbonate, followed by water and dried and purified. Preparation of 11 Compound 10 was dissolved in dry pyridine at cold. To this solution para toluenesulfonic acid was then added in small lots with stirring at cold. Stirring was continued for another six hours. The reaction mixture was poured in ice cold water, extracted with ether, washed with dil HCl, followed by water, dried and purified.

Compound 11 was dissolved in dry pyridine and refluxed for 4 hours. After the reaction, it was cooled to room temperature and poured in ice cold water, extracted with ether, washed with dil HCl, followed by water, dried and purified. Acknowledgement One of us (AM) is thankful to UGC, New Delhi for financial support. References 1. (a) F. A. Marques, C. A. Lenz, F. Simonelli, B. H. L. N. S. Maia, A. P. Vellasco, M. N. Eberlin,. J. Nat. Prod. 67: 1939 (2004). (b) T. Amagata, K. Minoura, A. Numata, J. Nat. Prod. 69: 1384 (2006). (c) P. Moosophon, S. Kanokmedhakul, K. Kanokmedhakul, K. Soytong, J. Nat. Prod. 72: 1442 (2009). 2. D D. Diaz, A. Converso, K. B. Sharpless, M. G. Finn, Molecules, 11: 212 (2006). 3. Kuninobu, J. Morita, M. Nishi, A. Kawata, K. Takai, Org. Lett., 12: 2535 (2009). 4. (a) S. J. Spessard, B. M. Stoltz, Org. Lett. 4: 1943 (2002). (b) H. Usuda, M. Kanai, M. Shibasaki, Tetrahedron Lett. 43: 3621 (2002). (c) R. Takagi, T. Nerio, Y. Miwa, S. Matsumura, K. Ohkata, Tetrahedron Lett. 45: 7401 (2004). (d) A. Kuramochi, H. Usuda, K. Yamatsugu, M. Kanai, M.

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Jamonline / 2(2); 2012 / 176–181 Shibasaki, J. Am. Chem. Soc. 127: 14200 (2005). 5. B. A. Carlson, H. C. Brown, Org. Synth. 58: 24 (1978). 6. B. Fell, W. Seide, F. Asinger,

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Tetrahedron Lett. 16: 1003 (1968). 7. Foote, C. S.; Woodward, R. B.

Tetrahedron 20: 687 (1964). 8. C. Taeschler, T. S. Sorensen, J. Org. Chem., 63: 5704 (1998).

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