A Novel Synthesis of 1-Acetyl-4-Isopropenyl-1-Cyclopentene by Chemoselective Cyclization of 4-Methyl-3-(Oxobutyl)-4-Pentenal: An Important Intermediate for Natural Product Synthesis

Abstracts

This article presents the direct oxidation of limonene-oxide 1 with KIO4 in water, which is the best way to obtain the keto-aldehyde 3, an important intermediate in natural product synthesis. The cyclization of keto-aldehyde 3 with acidic Al2O3 proceeds chemoselectively to give ketone 4. These two reactions together increase the overall yield of ketone 4 to about 70% compared to 8% previously reported in the literature¹.

terpenoid chirons; epoxide ring opening; KIO4 oxidation; chemoselective cyclization

Neste artigo apresentamos a oxidação direta do epóxi-limoneno 1 com KIO4 em água como uma melhor alternativa para se obter o ceto-aldeído 3, um importante intermediário na síntese de produtos naturais. O ceto-aldeído 3 é ciclizado com Al2O3-ácido de forma quimosseletiva produzindo, preferencialmente, a cetona 4. Estas duas reações elevam o rendimento total da síntese da cetona 4 para 70% em comparação com 8% pelo método citado na literatura¹.

Article

A Novel Synthesis of 1-Acetyl-4-Isopropenyl-1-Cyclopentene by Chemoselective Cyclization of 4-Methyl-3-(Oxobutyl)-4-Pentenal: An Important Intermediate for Natural Product Synthesis

Fernando de Lima Castro, Renata Xavier Kover, Warner Bruce Kover, and Joel Jones Jr.^*

Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, C.P. 68563, 21945-970 Rio de Janeiro – RJ, Brazil

Neste artigo apresentamos a oxidação direta do epóxi-limoneno 1 com KIO₄ em água como uma melhor alternativa para se obter o ceto-aldeído 3, um importante intermediário na síntese de produtos naturais. O ceto-aldeído 3 é ciclizado com Al₂O₃-ácido de forma quimosseletiva produzindo, preferencialmente, a cetona 4. Estas duas reações elevam o rendimento total da síntese da cetona 4 para 70% em comparação com 8% pelo método citado na literatura¹.

This article presents the direct oxidation of limonene-oxide 1 with KIO₄ in water, which is the best way to obtain the keto-aldehyde 3, an important intermediate in natural product synthesis. The cyclization of keto-aldehyde 3 with acidic Al₂O₃ proceeds chemoselectively to give ketone 4. These two reactions together increase the overall yield of ketone 4 to about 70% compared to 8% previously reported in the literature¹.

Keywords: terpenoid chirons, epoxide ring opening, KIO₄ oxidation_, chemoselective cyclization

Introduction

Terpenes are abundant chiral compounds present in nature and an important source of intermediaries for natural product synthesis^2-3.

Wolinsky by two routes^4-5 prepared ketone 4 (Fig. 2), a natural product first isolated from Spanish Eucalyptus globulus in 1947⁵ and aldehyde 5 (Fig. 4), an important intermediate in several natural product syntheses^6-11(Fig. 1), from limonene-oxide 1 (Scheme 1). The keto-aldehyde 3, intermediate in the Wolinsky approach has also been used in the study of asymmetric cyclizations¹² and chemoselective reduction¹³.

Only two other papers reported the formation of ketone 4: First, in 1977, Wolinsky¹⁴ reported the formation of ketone 4 from

a-Pinene (

Fig. 2) and then, in 1996, Jones and Kover

¹⁵ demonstrated the formation of the enantiomer of ketone

4 by hydrolysis of epoxy-tosylates prepared from (-)-R-Carvone (

Fig. 3), but the first Wolinsky synthesis still remained the route of choice to prepare the ketone

4.

In the original Wolinsky approach which gave a low overall yield for formation of ketone 4, the diol 2 was obtained in 39% yield and the subsequent cyclization of keto-aldehyde 3, proceeded in only 10% yield.

Diol 2 is soluble in water, and thus the reaction is best conducted at low temperature and with occasional shaking to induce the formation of crystals. The isolation of diol 2, as an oil, from water is difficult. Diol 2 is also obtained in its hydrated which complicates its characterization and quantification. Drying the diol adds a tedious but necessary task to the whole process in order to avoid use of excess NaIO₄¹³, even though the periodate cleavage is conducted in aqueous medium.

The cyclization of keto-aldehyde 3 leads to a mixture of ketone 4 and aldehyde 5, which is very difficult to separate by conventional methods. Attempts to purify 4 by distillation led to substantial losses of material even

under reduced pressure. Preparative chromatography was not an alternative since

4 and

5 elute together in all solvent mixtures tested. The chemoselective preparation of aldehyde

5

¹⁶,

via formation of an enamine (

Fig. 4), was reported in the literature

⁴, but a chemoseletive preparation for ketone

4 was still necessary

¹⁷.

Discussion and Results

We wish to report here two modifications of Wolinsky’s approach that solve the problems outlined above and enhance the yields of keto-aldehyde 3 and the ketone 4¹⁷.

First we oxidized limonene-oxide 1 directly with KIO₄ leading to keto-aldehyde 3 in one step and high yield (85%). This avoids preparation of intermediate diol 2, represents economy of time and reagent and solves the problems associated with isolation of diol 2. Although oxidation of epoxides with HIO₄ was reported in the literature¹⁸, it has never been applied to limonene-oxide 1.

Second, continuing our study of cyclization of 1,6 dicarbonyls we cyclized keto-aldehyde 3 with acidic Al₂O₃¹⁹ and verified that the process was highly chemoselective resulting in ketone 4 in high yield (95%).

(+)-R-limonene 7 was initially epoxidized with peracid prepared in situ by mixing ethyl chloroformate and H₂O₂ in dichloromethane (Scheme 2). The desired limonene-oxide 1 was isolated by distillation, as a mixture of diastereomers, in 73% yield. This mixture of epoxides was then treated with an equimolar quantity of KIO₄ in water.

We observed the formation of at least three side products (by HRGC analysis) during the oxidation of limonene-oxide 1 with KIO₄. They were not characterized but could be ascribed to epoxide ring opening products from attack of various nucleophiles present in the reaction medium. Keto-aldehyde 3 was refluxed in hexane over acidic Al₂O₃ while the reaction was monitored by HRGC. Analysis of the product mixture after the total consumption of keto-aldehyde 3 shows a ketone 4 to aldehyde 5 ratio of 4:1 (by integration of peak area). When the reaction was conducted at reflux for prolonged times the ratio of 4 to 5 increased to 8:1 (HRGC) After isolation, analysis of the crude light yellow oil revealed a ratio of 4 to 5 of 14:1. This ratio was determined by comparison of the integrated ¹H-NMR signal of the aldehyde proton present in compound 5 (

d 9.95 ppm), and the vinylic proton present in compound

4 (d 6.68 ppm).

It is not clear if chemoselectivity arises from a simple equilibration of products due to catalysis on the surface of the alumina or if the selectivity arises during the desorption from alumina²⁰.

Conclusion

Ketone 4 was prepared efficiently, selectively, and in high overall yield by comparison with previous routes. Cyclization of aldehyde 3 with acidic Al₂O₃ is shown to be very chemoselective. The direct oxidation of epoxy-limonene 1 with KIO₄ is a novel and better way to obtain keto-aldehyde 3, an important intermediate for natural product synthesis.

Experimental

General

(+)-R-Limonene was distilled prior to use. Solvents and inorganic reagents were used without further purification. Analyses by HRGC were performed on a HP-5890-II gas chromatograph with fid by using a 30 m (length), 0.25 mm (ID) and 25

mm (phase thickness) RTX-5 silica capillary column and H

₂ (flow rate 50 cm s

^-1) as carrier gas (split 1:20). Oven temp.: 70 °C then 10 °C / min to 280 °C (2 min), injector temp.: 200 °C, detector temp.: 280 °C. Mass spectra were obtained on a Hewlett-Packard HP-5896-A HRGC-MS using electron impact (70 ev).

¹H-NMR and

¹³C-NMR were acquired on a Bruker DRX-300 (300 MHz and 75 MHz, respectively) spectrometer for CDCl

₃ solutions with tetramethylsilane as internal standard. IR spectra were recorded on a Perkin Elmer 1600 FT-IR or on a Nicolet 740 FT-IR spectrometers (NaCl film).

Limonene-oxide (1)

To a 1 liter round-bottom flask equipped with a magnetic stirrer were added 25 g (180 mmol) of (R)-(+) limonene, 29 mL (180 mmol) of ethyl chloroformate, 193 mL of 30% H₂O₂, 193 mL of dichloromethane and 178 g of NaHPO₄. The flask and contents were vigorously stirred at room temperature for 48 h (limonene consumption was followed by gas chromatography). Upon consumption of starting material the mixture was separated in a separatory funnel. The aqueous phase was extracted with dichloromethane (3 x 50 mL). The combined organic phases were washed with 1% aqueous sodium sulfite solution until complete decomposition of excess H₂O₂. The presence of H₂O₂ was verified with a standard starch-I₂ test. The organic phase was then washed with water (3 x 75 mL), dried over anhydrous Na₂SO₄, and the solvent was evaporated in a rotatory evaporator. The resulting oil was distilled under reduced pressure (3 mmHg) and a fraction corresponding to compound 1 was collected at 40 °C (20 g, 131.5 mmol, 73% yield). The identity of this fraction was confirmed by analysis by GC/MS and IR, and by comparison to an authentic sample.

4-Methyl-3-(oxobutyl)-4-pentenal (3)

A 250 mL round-bottom flask equipped with a magnetic stirrer was charged with 13 g (85 mmol) of 1,2-limonene oxide (1), followed by addition of a suspension of 19.6 g (85 mmol) of KIO₄ in 200 mL of water. The flask and contents were heated on a steam bath to 55 °C and vigorously stirred for 8 h. The limonene-oxide consumption was followed by gas chromatography. Upon consumption of starting material the mixture was saturated with NaCl and was extracted with ether (3 x 60 mL). The layers were separated and the organic phase was dried over anhydrous Na₂SO₄. The solvent was evaporated in a rotatory evaporator at room temperature. Compound 3 was isolated as an oil (obtained 12 g, 71.4 mmol, 85% yield) that was pure enough to use in the next reaction. This oil was analyzed by GC/MS, IR, ¹H and ¹³C-NMR, and then it was compared with an authentic sample.

¹

H-NMR d (ppm): 1.37-1.60 (m, 2H), 1.46 (s, 3H), 1.95 (s, 3H), 2.3-2.3 (m, 4H), 2.50-2.55 (m, 1H), 4.6(d, 2H), 9.4 (s, 1H).

¹³C-NMR d (ppm): 18.5, 26.2, 29.7, 40.5, 40.6, 47.1, 112, 145, 201, 208. IR (neat) n (cm

^-1) 3050, 2920, 2710, 1710, 1630, 1430, 1360, 1160, 890, 730. MS (%) m/z 150(10), 135(10), 107(30), 67(30), 43(100), (molecular ion m/z 168, not found).

1-Acetyl-4-isopropenyl-1-cyclopentene (4)

To a 500 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser were added 12 g (71 mmol) of aldehyde 3, 300 mL of hexane and 50 g of acidic Al₂O₃. The flask and contents were heated on a steam bath to 65 °C with vigorous agitation. Aldehyde consumption was accompanied by gas chromatography. Upon consumption of starting material the mixture was filtered in a Buchner funnel and washed with CHCl₃ (4 x 50 mL). The organic solution was dried over anhydrous Na₂SO₄ and the solvent was evaporated in a rotatory evaporator at room temperature. Compound 4 was obtained as an oil (10.5 g, 70 mmol, 90% pure by HRGC, 95% yield). This oil was analyzed by GC/MS, IR, ¹H and ¹³C-NMR, and then compared with an authentic sample.

¹

H-NMR d (ppm): 1.7 (s, 3H), 2.29 (s, 3H), 2.35-2.52 (m, 2H), 2.65-2.78 (m, 2H), 2.9-3.1 (m, 1H), 4.18 (d, 2H), 6.68 (s, 1H)

¹³C NMR d (ppm): 20.5, 26.5, 35.3, 38.6, 44.8, 109.4, 143.4, 145.2, 147.4, 196.8. IR (neat) n (cm

^-1) 3050, 2940, 1665, 1606, 1403, 1390, 1260, 870, 810. MS (%) m/z 150 (M

⁺ 60), 135 (80), 107 (50), 91 (60), 65 (20), 43 (100).

Acknowledgments

We thank the CNPq and PADCT for financial support, Prof. C.R. Kaiser and C.P.S Chaves for ¹H and ¹³C-NMR spectrometry and R.M.A. Bento for mass spectrometry.

References

1. Wolinsky, J.; Slabaugh, M.R.; Gibson, T. J. Org. Chem. 1964, 29, 3740.

2. Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach; Pergammon Press: Oxford 1983.

3. For leading examples on the use of terpenes in chiral synthesis, see: (a) Money, T. Nat.Prod.Rep. 1985, 2, 253. (b) Money, T. Studies in Natural Products Chemistry. Stereoselective Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam 1989, vol. IV, Part C, p 625. (c) Thomas, F.; Bessiere, Y. Nat. Prod. Rep. 1989, 6, 291. (d) Corey, E.J.; Cheng, X.M. The Logic of Chemical Synthesis; John Wiley & Sons: New York, 1989. (e) Ho, T.-L. Enantioselective Synthesis: Natural Products from Chiral Terpenes; John Wiley&Sons, New York, 1992.

4. Wolinsky, J.; Barker, W. J.Am.Chem.Soc. 1960, 82, 636.

5. Schmidt, H. Ber.1947, 80, 528.

6. Naemura, K.; Hasegawa, T.; Miyabe, H.; Chikamatsu, H. Bull. Chem. Soc. Jpn. 1992, 65, 203.

7. Lange, G.L.; Neidert, E.E.; Orrom, W.J.; Wallace, D.J. Can. J. Chem. 1978, 56, 1628.

8. Yamasaky, M. J. C. S. Chem. Comm. 1972, 606.

9. Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247.

10. Mehta, G.; Krishnamurthy, N.; Karra, S.R. J. Am. Chem. Soc. 1991, 113, 5765.

11. Meinwald, J.; Jones, T.H. J. Am. Chem. Soc. 1978, 100, 1883.

12. Hiroi, K.; Yamaoka, N.; Kato, F.; Oishi, K. Tetrahedron Lett. 1995, 36, 7251.

13. Nataitis, C.F.; Gribble, G.W. Tetrahedron Lett. 1983, 24, 4287.

14. Wolinsky, J.; Vogel, M.K. J.Org.Chem 1977, 42, 249.

15. Kover, W. B.; Jones Jr, J. J Braz.Chem.Soc. 1996, 7, 257.

16. Lee, E.; Yoon, C.H. Tetrahedron Lett. 1996, 37, 5929. The formation of aldehyde 5 is reported.

17. Kover, R.X; Jones Jr, J.; Kover, W.B. The selective cyclization for compound 3 was reported during the 39^th meeting of the Sociedade Brasileira para o Progresso de Ciência in Brasilia, 1987.

18. Nagarkatti, J.P.; Ashley, K.R. Tetrahedron Lett. 1973, 46, 4599.

19. Aguiar, A.P.; Jones, J.J.; Kover, W.B.; von Holleben, M .L. Tetrahedron 1987, 43, 3199.

20. Interestingly, ketone 4 was calculated to be 0.5 kcal less stable than the aldehyde 5 using MM2 (MacroModel) in a Monte Carlo simulation.

Received: May 22, 1998

Publication Dates

• Publication in this collection
  23 Oct 2002
• Date of issue
  1999

History

• Received
  22 May 1998