A convenient procedure for the synthesis of 3beta-hydroxy-6-oxo-5alpha-steroids: aplication to the synthesis of laxogenin

Abstracts

A convenient pathway to obtain 3beta-hydroxy-6-oxo-5alpha-steroids from 3beta-acetoxy delta5-steroids is reported; the methodology was applied to the synthesis of laxogenin (7), substance that behaves as a plant growth hormone. This is an alternative way to produce an important functionality found in many examples of naturally occurring steroids. The developed procedure uses inexpensive reagents and can be carried out in four steps. The oxidizing and acidic steps used in this methodology did not affect the labile spiroketal side chain present in diosgenin (16).

laxogenin; diastereoselective epoxidation; 3beta-hydroxy-6-oxo-5alpha-steroids

Uma rota conveniente para a síntese de 3beta-hidroxi-6-oxo-5alfa-esteroides a partir de delta5-esteroides é descrita tendo sido aplicada para a síntese da laxogenina, substância que apresenta atividade como hormônio de crescimento vegetal. O método é uma alternativa para instalar este grupo funcional importante encontrado em esteróides naturais. O processo descrito utiliza reagentes baratos e pode ser executado em quatro etapas. As etapas de oxidação e de tratamento ácido não afetam a cadeia lateral espirocetálica presente na diosgenina (16).

ARTICLE

A convenient procedure for the synthesis of 3b-hydroxy-6-oxo-5a-steroids. Application to the synthesis of laxogenin

Martín A. Iglesias-Arteaga^I,*; Eva M. Símuta-Lopez^II; Sergio Xochihua-Moreno^II; Omar Viñas-Bravo^II; Sara Montiel Smith^II; Socorro Meza Reyes^II; Jesús Sandoval-Ramírez^II,*

^IDepartamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México - D. F., México

^IIFacultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla - Pue., México

ABSTRACT

A convenient pathway to obtain 3b-hydroxy-6-oxo-5a-steroids from 3b-acetoxy D⁵-steroids is reported; the methodology was applied to the synthesis of laxogenin (7), substance that behaves as a plant growth hormone. This is an alternative way to produce an important functionality found in many examples of naturally occurring steroids. The developed procedure uses inexpensive reagents and can be carried out in four steps. The oxidizing and acidic steps used in this methodology did not affect the labile spiroketal side chain present in diosgenin (16).

Keywords: laxogenin, diastereoselective epoxidation, 3b-hydroxy-6-oxo-5a-steroids

RESUMO

Uma rota conveniente para a síntese de 3b-hidroxi-6-oxo-5a-esteroides a partir de D⁵-esteroides é descrita tendo sido aplicada para a síntese da laxogenina, substância que apresenta atividade como hormônio de crescimento vegetal. O método é uma alternativa para instalar este grupo funcional importante encontrado em esteróides naturais. O processo descrito utiliza reagentes baratos e pode ser executado em quatro etapas. As etapas de oxidação e de tratamento ácido não afetam a cadeia lateral espirocetálica presente na diosgenina (16).

Introduction

The 3b-hydroxy-6-oxo moiety is present in different naturally occurring steroids.¹ The brassinosteroid teasterone (1),² the steroid glycoside osladin (2),³ lactones as chiogralactone (3)⁴ and dendrosterone (4),⁵ and steroidal alkaloids like petisidine (5)⁶ and petisine (6)⁷ are some examples of naturally occurring steroids bearing such functionality (Figure 1).

Recently, we have synthesized laxogenin (7), a steroidal sapogenin isolated from Smilax sieboldi⁸ and its C-23 substituted derivatives 8 and 9 and reported that they have shown plant growth promoting activity similar of that of brassinosteroids (Figure 2).⁸ In that report, a protocol based on Brown's hydroboration for the introduction of the 3b-hydroxy-6-oxo moiety was developed.

The 5b,6b-epoxy moiety has been previously used for the preparation of 6-oxosteroids. In particular, Henbest and Wrigley reported⁹ that treatment of 5,6b-epoxy-5b-cholestan-3b-ol acetate with BF₃·Et₂O led to the corresponding 3b-acetoxy-5-fluoro-6b-hydroxy-5a-steroid which was oxidized to 3b-acetoxy-5-fluoro-5a-cholestan-6-one using Jones reagent. More recently, an extension of this procedure to stigmasterol has been used to obtain brassinosteroid analogues bearing the 5a-fluoro-6-oxo moiety.⁹

Owing our interest on steroids bearing such functionality, and after some reports on the highly stereoselective b-epoxidation of D⁵-steroids using biphasic systems involving potassium permanganate and metal salts,¹⁰ we envisaged the b-epoxidation of the C5-C6 double bond followed by the regioselective oxirane ring opening as the key steps for the introduction of an oxygen atom at position C-6. This led us to an alternative protocol for the synthesis of 3b-hydroxy-6-oxo steroids.

Results and Discussion

Treatment of cholesteryl acetate, in a mixture of CH₂Cl₂, tert-butyl alcohol and H₂O, with KMnO₄ and Fe₂(SO₄)₃ resulted in the highly diasteroselective b-epoxidation of the C5-C6 double bond; only traces of the a-epoxide could be detected in the ¹H NMR spectra. Regioselective opening of the b-oxirane ring with aq. HBr led to the bromohydrin 11 as sole product.

Treatment of the bromohydrin 12 with Jones reagent, supported on silica gel, led the bromoketone 13 (Scheme 1). In this way, manipulation of the reaction was rapidly effectuated and permitted a better treatment for wastes.

We also studied this three-reaction sequence without isolation of the intermediate epoxide 11 and bromohydrin 12; this resulted in a very fast and convenient protocol for the conversion of cholesteryl acetate into the bromoketone 13 (75% overall yield for the consecutive three steps). Treatment of 13 with zinc in refluxing acetic acid yielded the acetylated ketone 14, which on saponification afforded the desired 3b-hydroxy-5a-cholestan-6-one (15).

The same one-pot synthetic sequence was applied to diosgenin acetate (16) to produce laxogenin (7). Under these strong oxidizing and acidic media, the labile spiroketal side chain of diosgenin resulted unchanged (Scheme 2).

Experimental

NMR spectra were registered in CDCl₃ on a Varian Mercury spectrometer at 400 MHz for ¹H or 100 MHz for ¹³C. Chemical shifts (d) are expressed on ppm downfield from TMS. Melting points were obtained on a Gallenkamp MFB 595 apparatus and were not corrected.

5,6b-Epoxy-5b-cholestan-3b-ol acetate (11)

KMnO₄ (2 g) and Fe₂(SO₄)₃.nH₂ O (1 g) were finely grounded in a mortar, H₂O (0.2 mL) was added and the mixture was placed in a round bottom flask containing CH₂Cl₂ (5 mL). A solution of cholesteryl acetate (10) (428 mg, 1 mmol) in CH₂Cl₂ (5 mL) was added followed by addition of tert-butyl alcohol (0.5 mL). After 20 min of stirring at room temperature, the mixture was filtered through a pad of celite, and eluted with 30 mL of CH₂Cl₂. The crude filtrate was washed with H₂O (5x15) mL, dried (anhydrous Na₂SO₄) and evaporated to afford 427 mg (96%) of the desired epoxide 11; mp 110-111 ºC, lit.¹¹ 111-112 ºC; ¹H NMR d 4.76 (m, H-3), 3.07 (d. J 2.4 Hz, H-6), 2.03 (s, CH₃COO-3), 1.0 (s, CH₃-19), 0.89 (d, J_21-20 6.8 Hz, CH₃-21), 0.86 (d, J 6.4 Hz, CH₃-26 and CH₃-27), 0.64 (s, CH₃-18); ¹³C NMR d 29.76 C-1, 27.25 C-2, 71.28 C-3, 38.02 C-4, 62.47 C-5, 63.55 C-6, 36.71 C-7, 32.49 C-8, 56.13 C-9, 35.03 C-10, 21.99 C-11, 39.78 C-12, 42.28 C-13, 50.97 C-14, 24.23 C-15, 28.21 C-16, 56.13 C-17, 11.85 C-18, 17.11 C-19, 35.76 C-20, 18.7 C-21, 36.15 C-22, 23.85 C-23, 39.51 C-24, 28.06 C-25, 22.64 C-26, 22.90 C-27, 21.41 CH₃COO-3, 170.24 CH₃COO-3.

5-Bromo-5a-cholestan-3b,6b-diol 3-acetate (12)

A solution of the epoxide 11 (445 mg, 1 mmol) in CH₂Cl₂ (15 mL) was vigorously shaken for 5 min in a separatory funnel with 5 mL of 48% HBr. The organic layer was washed with H₂O (5x 15 mL), dried (anh. Na₂SO₄) and evaporated to afford 510 mg (97%) of the bromohydrin 12; mp 174-175 ºC, lit.¹² 177-179 ºC; ¹H NMR d 5.47 (m, H-3), 4.18 (s, H-6), 2.03 (s, CH₃COO-3), 1.31 (s, CH₃-19), 0.90 (d, J_21-20 6.6 Hz, CH₃-21), 0.86 (d, J 6.4 Hz, CH₃-26 and CH₃-27), 0.67 (s, CH₃-18); ¹³C NMR d 35.16 C-1, 26.43 C-2, 72.17 C-3, 38.42 C-4, 86.73 C-5, 75.68 C-6, 34.62 C-7, 30.64 C-8, 47.44 C-9, 41.30 C-10, 21.39 C-11, 39.78 C-12, 42.72 C-13, 55.73 C-14, 24.16 C-15, 28.29 C-16, 56.10 C-17, 12.32 C-18, 18.15 C-19, 35.83 C-20, 18.78 C-21, 36.18 C-22, 23.90 C-23, 39.51 C-24, 28.10 C-25, 22.67 C-26, 22.93 C-27, 21.50 CH₃COO-3, 170.30 CH₃COO-3.

3b-Acetoxy-5-bromo-5a-cholestan-6-one (13)

A mixture of Jones reagent (2.5 mL) and silica gel (5 g) was stirred until an homogeneous orange powder was formed. CH₂Cl₂ (15 mL) was added followed by the addition of a solution of the bromohydrin 12 (526 mg, 1 mmol) in CH₂Cl₂ (10 mL); the mixture was stirred for 20 min, filtered through an small pad of silica gel and the eluent was evaporated to afford 414 mg (79%) of the bromoketone 13; mp 157-158 ºC (decomp.), lit.¹³ 162 ºC (decomposition); ¹H NMR d 5.32 (m, H-3), 3.15 (dd, J_{7ax-7eq, 7ax-8ax} 14.85, 12.1 Hz, H-7a), 2.38 (ddd, J_4eq-4ax 14.3, J_4eq-3ax 4.2, J_4eq-2eq 1.5 Hz, H-4eq), 2.28 (dd, J_7ax-7eq 15, J_7eq-8ax 5.5 Hz, H-7e), 2.03 (s, CH₃COO-3), 0.99 (s, CH₃-19), 0.90 (d, J_21-20 6.2 Hz, CH₃-21), 0.86 and 0.85 (d, J 6.6 Hz, CH₃- 26 and 27), 0.65 (s, CH₃-18); ¹³C NMR d 30.43 C-1, 26.09 C-2, 70.92 C-3, 34.84 C-4, 79.61 C-5, 203.67 C-6, 40.45 C-7, 36.24 C-8, 47.26 C-9, 42.69 C-10, 21.79 C-11, 39.51 C-12, 43.03 C-13, 55.93 C-14, 23.84 C-15, 28.10 C-16, 56.16 C-17, 12.18 C-18, 14.59 C-19, 35.71 C-20, 18.72 C-21, 36.10 C-22, 23.84 C-23, 39.28 C-24, 28.07 C-25, 22.65 C-26, 22.90 C-27, 21.36 CH₃COO-3, 170.04 CH₃COO-3.

3b-Acetoxy-5-bromo-5a-cholestan-6-one (13) via a three steps procedure: b-epoxidation, oxirane-opening, alcohol-oxidation

KMnO₄ (6 g) and Fe₂(SO₄)₃.nH₂ O (3 g) were finely grounded in a mortar, H₂O (0.6 mL) was added and the mixture was placed in a round bottom flask containing CH₂Cl₂ (45 mL). A solution of cholesteryl acetate (10) (1.284 g, 3 mmol) in CH₂Cl₂ (45 mL) was added followed by addition of tert-butyl alcohol (1.5 mL). After 20 min of stirring at room temperature, the mixture was filtered through a pad of celite and eluted with 30 mL of CH₂Cl₂. The crude filtrate was washed with H₂O (5x25 mL) and vigorously shaken for 5 min in a separatory funnel with 15 mL of 48% HBr, washed with H₂O (5x 30 mL) and added to a stirred mixture of silica gel-supported Jones Reagent (prepared from 2.5 mL of Jones reagent and 5 g silica gel as described for the oxidation of 12) and CH₂Cl₂ (30 mL). The mixture was stirred for 20 min, filtered through a small pad of silica gel and the eluent was evaporated to afford 1.178 mg (75%) of the bromoketone 13, identical as described above.

3b-Acetoxy-5a-cholestan-6-one (14)

A mixture of the bromoketone (524, 1 mmol), zinc powder (262 mg, 4 mmol) and acetic acid (10 mL) was stirred under reflux for 2 h. AcOEt (50 mL) was added and the mixture was washed with saturated NaCl solution (5x15 mL), 10% NaHCO₃ solution (3x20 mL) and H₂O (5x15 mL). The organic layer was dried with Na₂SO₄ and evaporated to afford 436 mg (98%) of the acetylated ketone 14; mp 126-127 ºC, lit.¹⁴ 128-129 ºC; ¹H NMR d 4.67 (m, H-3), 2.03 (s, CH₃COO-3), 0.91 (d, J_21-20 6.6 Hz, CH₃-21), 0.87 and 0.86 (d, J 6.6 Hz, CH₃-26 and CH₃-27), 0.77 (s, CH₃-19), 0.66 (s, CH₃-18); ¹³C NMR d 36.32 C-1, 26.75 C-2, 72.78 C-3, 26.04 C-4, 56.01 C-5, 210.40 C-6, 46.58 C-7, 37.85 C-8, 53.73 C-9, 40.87 C-10, 21.28 C-11, 39.38 C-12, 42.89 C-13, 56.59 C-14, 23.89 C-15, 27.97 C-16, 56.38 C-17, 11.94 C-18, 12.96 C-19, 35.62 C-20, 18.56 C-21, 36.00 C-22, 23.73 C-23, 39.38 C-24, 27.93 C-25, 22.48 C-26, 22.74 C-27, 21.39 CH₃COO-3, 170.56 CH₃COO-3.

3b-Hydroxy-5a-cholestan-6-one (15)

A mixture of the acetylated ketone 14 (445 mg, 1 mmol), KOH (0.5 g) and MeOH (50 mL) was gently warmed for 15 min, H₂O (15 mL) was added, most of the MeOH was evaporated and the mixture was extracted with AcOEt (2x20 mL). The organic layer was washed with brine (3x15 mL) and H₂O, dried with MgSO₄ and evaporated to afford 412 mg (98%) of the hydroxylated ketone 15; mp 141-142 ºC, lit.¹⁵ 142-143 ºC; ¹H NMR d 3.57 (m, H-3), 0.91 (d, J_21-20 6.6 Hz, CH₃-21), 0.87 and 0.86 (d, J 6.6 Hz, CH₃-26 and CH₃-27), 0.75 (s, CH₃-19), 0.66 (s, CH₃-18); ¹³C NMR d36.65 C-1, 30.61 C-2, 70.44 C-3, 29.97 C-4, 56.72 C-5, 210.87 C-6, 46.70 C-7, 37.92 C-8, 53.83 C-9, 40.96 C-10, 21.53 C-11, 39.44 C-12, 42.93 C-13, 56.66 C-14, 23.99 C-15, 28.03 C-16, 56.02 C-17, 12.06 C-18, 13.21 C-19, 35.68 C-20, 18.67 C-21, 36.07 C-22, 23.84 C-23, 39.44 C-24, 28.02 C-25, 22.60 C-26, 22.86 C-27.

(25R)-3b-Acetoxy-5-bromo-5a-spirostan-6-one (17)

Application of the described one-pot b-epoxidation, oxirane-opening, alcohol-oxidation procedure to diosgenin acetate (16) (1.370 g, 3 mmol) afforded 1.208 mg (73%) of the bromoketone 17; mp 229-230 ºC (petroleum ether/AcOEt), lit.¹⁶ 230-233 ºC; ¹H NMR d 5.31 (m, H-3), 4.42 (ddd, J_16-17 J_16-15 7.3 Hz, H-16), 3.48 (ddd, J_26ax-26eq 11, J_26eq-25ax 4.8, J_26eq-24eq 1.8 Hz, H-26eq), 3.59 (dd, J_26ax-26eq J_26ax-25ax 11 Hz, H-26ax), 3.18 (dd, J_7ax-7eq 11.7, J_7ax-8ax 15 Hz, H-7a), 2.40 (ddd, J_4ax-4eq 14.7, J_4eq-3ax 5.3, J_4eq-2eq 1.8 Hz, H-4a), 2.31 (dd, J_7ax-7eq 15, J_7eq-8ax 5.1 Hz, H-7b), 2.03 (s, CH₃COO-3), 1.01 (s, CH₃-19), 0.97 (d, J_20-21 7 Hz, CH₃-21), 0.79 (d, J_25-27 7 Hz, CH₃-27), 0.76 (s, CH₃-18); ¹³C NMR d 30.40 C-1, 36.05 C-2, 70.82 C-3, 34.80 C-4, 79.37 C-5, 203.21 C-6, 40.50 C-7, 35.74 C-8, 47.29 C-9, 42.68 C-10, 21.62 C-11, 39.25 C-12, 40.99 C-13, 55.88 C-14, 31.38 C-15, 80.34 C-16, 61.90 C-17, 16.55 C-18, 14.68 C-19, 41.60 C-20, 14.58 C.21, 109.14 C-22, 31.44 C-23, 28.80 C-24, 30.29 C-25, 66.83 C-26, 17.22 C-27, 170.02 CH₃COO-3, 21.35 CH₃COO-3

(25R)-3b-Acetoxy-5a-spirostan-6-one (18)

1.103 g (2 mmol) of the bromoketone 17 were reduced as described for 13 to afford 756 mg (80%) of the ketone 20; mp 223-224º (petroleum ether/AcOEt), lit.¹⁶ 222-224 ºC; ¹H NMR d 4.66 (m, H-3), 4.41 (m, H-16), 3.47 (ddd, J_26ax-26eq 11, J_26eq-25ax 4.2, J_26eq-24eq 1.8 Hz, H-26eq), 3.36 (dd, J_26ax-26e J _26ax-25ax 11 Hz, H-26ax.), 2.03 (s, CH₃COO-3), 0.97 (d, J_21-20 6.97 Hz, CH₃-21), 0.79 (d, J_27-25 6.97 Hz, CH₃-27), 0.78 (s, CH₃-19), 0.78 (s, CH₃-18). ¹³C NMR d 36.35 C-1, 26.84 C-2, 72.66 C-3, 26.16 C-4, 56.35 C-5, 209.63 C-6, 46.68 C-7, 37.38 C-8, 53.71 C-9, 40.95 C-10, 21.36 C-11, 39.44 C-12, 40.92 C-13, 56.42 C-14, 31.58 C-15, 80.32 C-16, 61.96 C-17, 16.49 C-18, 13.18 C-19, 41.60 C-20, 14.56 C-21, 109.14 C-22, 31.34 C-23, 28.77 C-24, 30.29 C-25, 66.81 C-26, 17.21 C-27, 170.31 CH₃COO-3, 21.41 CH₃COO-3.

(25R)-3b-Hydroxy-5a-spirostan-6-one, laxogenin (7)

473 mg (1 mmol) of the ketone 18 were hydrolyzed as described for 14 to afford 422 mg (98%) of laxogenin (7); mp 210-211 ºC (petroleum ether/AcOEt), [a]_D²⁵ - 83 (c 1.1, CHCl₃); lit.¹⁷ 210-212 ºC; [a]_D²⁵- 86 (c = 1.0, CHCl₃); ¹H NMR d 4.41 (m, H-16), 3.57 (m, H-3), 3.47 (ddd, J_26ax-26eq 11, J_26e-25ax 4.2 and J_26eq-24eq 1.8 Hz, H-26e), 3.36 (dd, J_26ax-26eq and J_26ax-25ax 11 Hz, H-26ax.), 0.97 (d, J_21-20 6.97 Hz, CH₃-21), 0.79 (d, J_27-25 6.97 Hz, CH₃-27), 0.78 (s, CH₃-19), 0.78 (s, CH₃-18); ¹³C NMR d 36.59 C-1, 30.56 C-2, 70.27 C-3, 29.91 C-4, 56.70 C-5, 210.39 C-6, 46.68 C-7, 37.33 C-8, 53.79 C-9, 40.90 C-10, 21.36 C-11, 39.46 C-12, 40.90 C-13, 56.39 C-14, 31.53 C-15, 80.31 C-16, 61.91 C-17, 16.43 C-18, 13.26 C-19, 41.55 C-20, 14.50 C-21, 109.11 C-22, 31.29 C-23, 28.71 C-24, 30.21 C-25, 66.75 C-26, 17.14 C-27.

Conclusions

A convenient procedure to generate 3b-hydroxy-6-oxo-5a-steroids from D⁵-unsaturated steroids has been accomplished through a four steps process; the three first steps can be effectuated in a one-pot manner. Each step has been performed obtaining a good overall yield.

Acknowledgments

We are indebted to CONACyT, Mexico, for financial support via grant 35235-E and the scholarships granted to S.X.M and O.V.B. We also want to acknowledge Professor Benjamín Ruiz for laboratory facilities at the Facultad de Química of UNAM.

References

1. Hill, R. A.; Makin, H. L. J.; Kirk, D. N.; Murphy, G. M., eds.; Dictionary of Steroids, Chapman and Hall: London, 1991.

2. Adam, G.; Marquardt, V.; Phytochemistry 1986, 25, 1787.

3. Jizba, J.; Herout, V.; Collect. Czech. Chem. Commun. 1967, 32, 2867.

4. Takeda, K.; Shimaoka, A.; Iwasaki, M.; Minato, H.; Chem. Pharm. Bull. 1965, 13, 691.

5. Behr, D.; Berg, J. E.; Karlsson, B.; Leander, K.; Pilotti, A. M.; Wiehager, A. C.; Acta Chem. Scand. (B) 1975, 29, 401.

6. Nakahatov, I.; Nabiev, A.; Shakirov, R.; Yusonov, S.; Khim. Prir. Soedin 1983, 6, 747. (CA 100: 188749)

7. Nakahatov, I.; Nabiev, A.; Shakirov, R.; Khim. Prir. Soedin. 1981, 4, 616. (CA 96: 65672x)

8. Okanishi, T.; Akahor, A.; Yasuda, F.; Chem. Pharm. Bull. 1965, 13, 545; Iglesias-Arteaga, M. A.; Perez Gil R.; Perez Martinez C. S.; Coll Manchado, F.; J. Chem. Soc., Perkin Trans. 1 2001, 261.

9. Henbest, H. B.; Wrigley, T. I.; J. Chem. Soc. 1957, 4765; Ramírez, J. A.; Gros, E. G.; Galagovsky, L. R.; Tetrahedron 2000, 56, 6171.

10. Syamala, M. S.; Das, J.; Baskaran, S.; Chandrasekaran, S.; J. Org. Chem. 1992, 57, 1928; Parish, E. J.; Li, H.; Li, S.; Synth. Commun. 1995, 25, 927; Hanson, J. R.; Hitchock, P. B.; Liman, M. D.; Nagaratnam, S.; Manickavasagar, R.; J. Chem. Res. (S) 1995, 220; Parish, E. J.; Li, S.; J. Chem. Res. (S) 1996, 288; Parish, E. J.; Li, S.; J. Org. Chem. 1996, 61, 5665; Salvador, J. A. R.; Sáe Melo, M. L.; Campos Neves, A. S.; Tetrahedron Lett. 1996, 37, 687; Salvador, J. A. R.; Hanson, J. R.; J. Chem. Res. (S) 2002, 576. The authors became aware that, after submission of the present paper, a different and convenient method for b-epoxidation of D⁵-steroids using Co(II) salts and molecular oxygen had been published: Silvestre, S. M.; Salvador, J. A. R.; Clark, J. H.; J. Mol. Catal. A: Chemical 2004, 219, 143.

11. Chakravorty, P. N.; Levin, R.; J. Am. Chem. Soc. 1942, 64, 2317.

12. James, D. R.; Shoope. C. W.; J. Chem. Soc. 1954, 4224.

13. Heilbron, I. M.; Jones, E. H. R.; Spring, F. S.; J. Chem. Soc. 1937, 801.

14. Fonken, G. J.; Miles, H. M.; J. Org. Chem. 1963, 28, 2432.

15. Dodson, R. G.; Riegel, B.; J. Org. Chem. 1948, 13, 424.

16. Bowers, A.; Denot, E.; Cuéllar Ibáñez, L.; Cabezas, M. E.; Ringold, H. J.; J. Org. Chem. 1962, 27, 1862.

17. Elks, J. In Rodd's Chemistry of Carbon Compounds; Coffey, S., ed., Elsevier Publ. Co.: Amsterdam, 1971, ch. 18.

Received: June 24, 2004

Published on the web: March 30, 2005

Publication Dates

• Publication in this collection
  18 July 2005
• Date of issue
  June 2005

History

• Accepted
  30 Mar 2005
• Received
  24 June 2004