Fourth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-4), www.mdpi.org/ecsoc-4.htm, September 1-30, 2000

[A0099]

Synthetic Studies Toward 1a-Hydroxytestosterone from Testosterone

Hongwu Gao and Jerry Ray Dias*

Department of Chemistry
University of Missouri-Kansas City
5100 Rockhill Rd.
Kansas City, MO 64110-2499
E-mail: [email protected]

Received: 28 July, Uploaded: 31 August

Abstract: Alternative synthetic routes to androst-4-ene-1a,17b-diol-3-one (1a-hydroxytestosterone) have been investigated. Within this objective numerous reported reductions have been reviewed and synthetically evaluated.

Introduction

1a-Hydroxytestosterone is of great interest in the enzyme conversion of androst-4-ene-3,17-dione into the A-ring aromatic estrone. The first synthesis of this compound other than via microbiological methods¹ was accomplished from 5a-androstan-17b-ol-3-one-17-benzoate (dihydrotestosterone benzoate) with nine steps and 3.7% yield.² Since it is desirable to make this compound more readily available for biological experimentation, we report our studies directed toward more efficient synthesis of 1a-hydroxytestosterone.

Retrosynthetic Analysis

1a-Hydroxysteroids can be synthesized by catalytic hydrogenation;^3-9 sodium borohydride reduction;¹⁰ lithium aluminum hydride reduction;^{2, 11} or Birch reduction (lithium metal and ammonium chloride in ammonia-tetrahydrofuran)^11-17 of 1a,2a-epoxide steroids (Fig. 1). Double bonds in a,b-unsaturated keto steroids can be selectively oxidized with alkaline hydrogen peroxide to yield epoxy ketones. The nucleophilic attack of hydroperoxide ion on the D¹-3-ones yield predominantly a-oxiranes because of steric factors. The introduction of D^{1, 2}-double bond can be accomplished by dehydrohalogenation^{2, 18-20} or DDQ^21-28, SeO₂^28-29 dehydrogenation. The D^{4, 5}-double bond can exist before the introduction of 1a,2a-epoxide⁴ or be introduced after the introduction of 1a,2a-epoxide.² For the synthesis of 1a-hydroxytestosterone, the second strategy has been done by Mann and Pietrzak² and the first one has never been attempted. We report our results concerning the second strategy.

Results and Discussion

The first synthetic route is showed in Scheme 1. The 17b-hydroxyl group (1) was first protected by acetate. The reaction was carried out in pyridine with 4-dimethylaminopyridine (DMAP) as the catalyst. Without DMAP, reaction can not be completed even with prolonged time. The D^{1, 2}-double bond was introduced by SeO₂ the dehydrogenation.^28-29 The selective peroxidation of D^{1, 2}-double bond was unsuccessful.

To selectively introduce 1a,2a-epoxide, the second synthetic route was showed in Scheme 2. The preparation of D^{1, 4, 6}-3-ones can be finished one step or two steps (Scheme 3). Oxidation of the D⁴-3-one system preferentially gives the D ^{4, 6}-3-one system over the D^{1, 4}-3-one system because their pP -electronic system of the former is more stable than latter cross-conjugated system. In 1960, Agnello and Laubach²⁹ reported one step synthesis of D^{1, 4, 6}-3-ones by the treatment of D⁴-3-ones with chloranil in sec-amyl or n-amyl alcohols. The follownig research repeated the same reaction with low percent yield (30%).⁴ As a preparative route to D^{1, 4, 6}-3-ones, the anhydrous reaction in benzene at room temperature gives 40-55% of product after chromatography and is inferior to a stepwise (via D^{4, 6} ).^23-24 The principal side reactiion (which also occur in the acid catalyzed reaction of D⁴-3-ones with two moles of DDQ) appears to be

addition of the hydroquinone.^{21, 24} A related reaction involving attack at C-6 was also reported.³⁰ The two step synthesis of D^{1, 4, 6}-3-ones from D⁴-3-ones can be concluded by three ways: 1) The D⁴-3-ones were converted to 3-ethoxy-3,5-dienesteroids and then the reaction of DDQ leads to D^{1, 4, 6}-3-ones;^23-25 2) Treatment of D⁴-3-ones with chloranil in t-butanol^{23, 29} or DDQ in dioxane^31-33 gave the corresponding D^{4, 6}-3-ones. Subsequent dehydrogenation with DDQ in dioxane or benzene gave D^{1, 4, 6}-3-ones; ^{23, 26-29} 3) The D⁴-3-ones were deconjugated by kinetic protonation to give the b,g-unsaturated ketones.^34-35 Treatment of 5-en-3-ones with two equivalents of DDQ in benzene or dioxane gave D^{1, 4, 6}-3-ones.²⁶ Our investigations found that the direct dehydrogenation of 2 to 7 by either DDQ or chloranil proceeded in only low yields and it was very difficult to separate D^{1, 4, 6}-3-ones from dienones. The two step dehydrogenation (via D^{4, 6}-3-ones) gave satisfactory results. Treatment of D^{4, 6}-3-ones 6 with DDQ in dioxane^{23, 26, 29, 33} in 24 hours only gave 30-40% 7. We have found that a separated addition of DDQ and prolonged reaction time (72 hours) is quite essential to improve the yield (68%). Subsequent ester hydrolysis provide the corresponding alcohol 8.

We first repeated the same epoxidation on 8 and found that the overnight reaction^{2, 3} gave a polar side product which may be due to the base open the epoxide. TLC in ethyl acetate-hexane (1:1) showed that the reaction could be accomplished after 1 hour instead of 3 hours.⁴ The following hydrogenation in pyridine over Pd(II)/CaCO₃^{3, 4} on 9 gave 1a,17b-dihydroxy-5b-androstan-3-one (10) even with shorter reaction time (5 hours) (Scheme 4). The orientation of the 5 proton in 10 is presumably mainly b. A similar reduction of cholesta-1a,2a-epoxy-4,6-dien-3-one gave mainly 5b proton.⁵ The TLC (CHCl₃: CH₃OH=9:1) showed that most of reactants can not be reduced with further shorter reaction time (2-3 hours). The pre-hydrogenated 5% Pd(0)/CaCO₃ catalyst can not improve the selectivity. In 1996, Liu and co-workers reported that the selective hydrogenation of 17-substituted 13b-ethyl-11b-hydroxy-gona-4,9-dien-3-ones in Pd(0)/SrCO₃-pyridine media gives the corresponding 11b-hydroxy-gon-4-en-3-ones.³⁶ According to Jeger and Wehrli�s results on 1a,2a-epoxy-17b-3-oxoandrosta-4,6-diene, compound 11 should be synthesized.³⁷ We found that this catalyst gave the same results as Pd(0)/CaCO₃ on reduction of 9. Compared with the 6a,7a-epoxide, the chromium (II) acetate reduction³⁸ on 1a,2a-epoxide gave a complex mixture. Compared with the D^{1, 4}-3-one system, the Wilkinson�s catalyst [chlorotris(triphenylphosphine)rhodium (I)] in our hands did not reduce D^{4, 6}-3-one system.³⁸ In 1956, Howe and McQuillin found that Pd(II)/CaCO₃/Pb (Lindlar catalyst) was effective on selective reduction the terminal bond of a dienone of b-cyperone.³⁹ A similar selective hydrogenation of b-damascenone was reported by Büchi and Wüest in 1971.⁴⁰ We found that this catalyst can only reduce 1a,2a-epoxide within 5 hours reaction. Both D^{6, 7}-double bond and D^{1, 2}-double bond will be reduced with prolonged time. In 1989, Jansen and co-workers^{41, 42} reported that the dienone dienone can be selectively 1,6 reduced with Li-selectride to give enone. Our investigation showed that Li-selectride selectively reduced only the 3-ketone to give the 3b-hydroxy group.

1H NMR Spectra: All the ¹H NMR spectra are summarized in Table 1. The 17a-H show triblet because of coupling with the hydrogens at C-16. After the esterification of 17b-OH, both 17a-H and 18-methyl group shifts downfield from 3.66 to 4.60 ppm and from 0.80 to 0.84 ppm, respectively. The 6,7-dehydrogenation has shielding effect on 4-H from 5.73 to 5.68 ppm. The 1,2-dehydrogenation has deshielding effect on 4-H from 5.73 to 6.02-6.08 ppm. After the epoxidation of 1,2-double bond, 4-H shift back to 5.66 from 6.01-6.04 ppm. After the reduction of 3-ketone, 4-H (from 5.66 to 5.21 ppm), 6-H (from 6.01-6.13 to 5.62 ppm) and 7-H (from 6.01-6.13 to 5.91 ppm) are shielded. In compound 13, 7-H show a double-doublet because the couplings from 6-H and 8-H.

13C NMR Spectra: All the ¹³C NMR spectra are summarized in Table 2. The assignments of these spectra are through comparisons with closely related compounds tabulated by Blunt and Stothers.⁴³ From these tables, we can see: 1) After acetate protection of the 17-hydroxyl group, the 18-methyl group deshielded 0.91 ppm; 2) After the formation of 6(7)-double bond, C-5 shift from 171.04 to 163.46 ppm and C-9 shift from 53.72 to 48.10 ppm. The two more sp² peaks demonstrated the 6(7)-double bond. Compared with C-7, C-6 is in the higher field because it is closer to 4(5)-double bond; 3) After the formation of 1(2)-double bond, C-3 shift up-field (199.48-186 ppm) and C-10 shift down-field (36.57-43.07 ppm). The two more sp² peaks demonstrated the 1(2)-double bond; 4) The reduction of 1a,2a-epoxide deshielding C-1 from 59.44 to 78.12 ppm. 5) After the reduction of D^{4, 5}-double bond, 3-ketone deshield from 194.69 to 210.52 ppm.

Conclusion

The synthesis of 1a-hydroxytestosterone from testosterone via its 1,2,6,7-tetradehydro- and 1a,2a-epoxy-6,7-didehydro-derivatives has been attempted and various problems identified. The characterization of numerous intermediates of this study was accomplished by ¹H NMR, ¹³C NMR and MS.

Experimental Section

Column chromatography was carried out using Grade 62 (60-200 mesh) silica gel and eluted by cyclohexane-ethyl acetate solvent system. Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. ¹H NMR and ¹³C NMR spectra were measured at 250 MHz or 63 MHz (Bruker) in CDCl₃ as solvent and TMS as internal standard. Mass spectra were recorded on a VG20-253 or VGZAB-HS Spectrometer.

17b-Acetoxy-androst-4-en-3-one (2): To a cooled (0⁰C) suspension of 1 (5.0g; 17.36 mmol) in acetic anhydride (5 mL) and pyridine (8 mL), DMAP (0.4g; 3.27 mmol) were added. The reaction mixture was stirred at 25⁰C for 1.5 hr. The solvent was concentrated in vacuo, 50 mL ethyl acetate was added and the solution was washed with 1.0 M HCl, NaHCO₃ and NaCl solution. The organic layer was dried with Na₂SO₄ and solvent was evaporated to afford 5.35g (93.4%) 2 as a colorless crystal, m.p. 128-130⁰C [ref.⁴⁴ m.p. 142-142⁰C]. ¹H NMR (CDCl₃): 0.84 (s, 3H, 18-H₃); 1.19 (s, 3H, 19-H₃); 2.05 (s, 3H, 17-OAc); 4.60 (t, 1H, 17a-H); 5.73 (s, 1H, 4-H).

17b-Acetoxy-androsta-1,4-dien-3-one (3): To a solution of 2 (0.7g, 2.12 mmol) in t-BuOH (50 mL) and acetic acid (1.0 mL) was added SeO₂ (0.3g, 2.7 mmol), and then the reaction mixture was reflux for 20 h. A further SeO₂ (0.3g, 2.7 mmol) was added and the mixture was refluxed for 30h. After cooling, the precipitated Se was removed, the filtrate was evaporated in vacuo, and the residue extracted with ethyl acetate. The extracts were washed with 0.5M Na₂S₂O₃ solution, H₂O and brine. The dried extract was purified by chromatography through silica gel affording 0.47g (67.5%) 3 as a yellow crystal, m.p. 157-159⁰C [ref.²² m.p. 155⁰C]. ¹H NMR (CDCl₃): 0.82 (s, 3H, 18-H₃); 1.24 (s, 3H, 19-H₃); 2.05 (s, 3H, 17-OAc); 4.58 (t, 1H, 17a-H); 6.08 (s, 1H, 4-H); 6.23 (d, 1H, 2-H); 7.05 (d, 1H, 1-H). MS(m/z): 328.2 [M]^+..

Androsta-1,4-dien-3-one-17b-ol (4): Compound 3 (0.4g, 1.22 mmol) was hydrolyzed by treatment with 10% methanolic NaOH solution (15 mL) for 2 hours at rt. After neutralization with 1.0M HCl, the solution was concentrated in vacuo, and the residue was extracted with methylene chloride. The organic layer was washed with aqueous NaHCO₃, water, brine and dried with Na₂SO₄. The solvent was evaporated to afford 4 (0.34g, 97.5%) as colorless crystals, m.p. 160-162⁰C. ¹H NMR (CDCl₃): 0.82 (s, 3H, 18-H₃); 1.25 (s, 3H, 19-H₃); 3.65 (t, 1H, 17a-H); 6.08 (s, 1H, 4-H); 6.23 (d, 1H, 2-H); 7.07 (d, 1H, 1-H). MS(m/z): 286.2 [M]^+..

Androstan-1a,2a;4a,5a-diepoxy-3-one-17b-ol (5): To a solution of 4 (0.1g, 0.35 mmol) in methanol (2 mL) was treated with 10% methanolic NaOH (0.036 mL) and 30% H₂O₂ (0.2 mL) for 3 hours at rt. Sodium sulphite (0.1g) was added, followed by brine (5 mL), and the product was extracted three times with methylene chloride (10 mL). The organic phase was washed with 0.1M HCl, NaCl solution, dried, and evaporated to give the crude epoxide. Further purification of the crude epoxide by column chromatography gave 5 (0.09g, 81%) as colorless crystal, m.p. 189-191⁰C. ¹H NMR (CDCl₃): 0.80 (s, 3H, 18-H₃); 1.25 (s, 3H, 19-H₃); 3.15 (s, 1H, 4b-H); 3.41 (d, 1H, 2b-H); 3.59 (d, 1H, 1b-H); 3.66 (t, 1H, 17a-H). MS(m/z): 318.4 [M]^+..

17b-Acetoxy-androsta-4,6-dien-3-one (6): To a solution of 2 (5.0g, 15.15 mmol) in t-BuOH (60 mL) was added chloranil (4.5g, 18.3 mmol), and then the reaction mixture was reflux for 4 hours. After cooling, the reaction mixture was poured into saturated Na₂CO₃ solution and the products were extracted with CH₂Cl₂. The extracts were washed with 0.5M Na₂S₂O₃ solution and again wiith saturated Na₂CO₃ solution. The dried extract was evaporated and the residue was purified by chromatography through silica gel affording 2.72g (54.7%) 6 as a yellow crystal, m.p. 138-140⁰C. ¹H NMR (CDCl₃): 0.89 (s, 3H, 18-H₃); 1.12 (s, 3H, 19-H₃); 2.06 (s, 3H, 17-OAc); 4.63 (t, 1H, 17a-H); 5.68 (s, 1H, 4-H); 6.11 (m, 2H, 6-H, 7-H). MS(EI): 328.2 [M]^+. (44), 268.2 [M-HOAc]^+. (36), 253.3 [M-HOAc-CH₃]⁺ (14), 136.1 (34), 133.1 (50), 43.0 (100).

17b-Acetoxy-androsta-1,4,6-trien-3-one (7): To a solution of 6 (2.5g, 7.58 mmol) in dioxane (30 mL) was added DDQ (2.22g, 9.78mmol) three times during 72 hours refluxing. After cooling, the solution was filtered and treated in the same manner as used in 6. Chromatography gave 7 (1.7g, 68.4%) as colorless crystals, m.p. 148-150⁰C [ref.⁴⁵ m.p. 151-153⁰C]. ¹H NMR (CDCl₃): 0.92 (s, 3H, 18-H₃); 1.21 (s, 3H, 19-H₃); 2.06 (s, 3H, 17-OAc); 4.62 (t, 1H, 17a-H); 6.02 (m, 2H, 2-H, 4-H); 6.23-6.27 (m, 2H, 6-H, 7-H); 7.06 (d, 1H, 1-H). MS(EI): 326.2 [M]^+. (34), 266.1 [M-HOAc]^+. (17), 251.1 [M-HOAc-CH₃]⁺ (11), 134.1 (34), 133.1(56), 43.0 (100). Androsta-1,4,6-trien-3-one-17b-ol (8) was prepared in similar fashion as 4, m.p. 153-155⁰C [ref.⁴⁶ m.p. 156-158⁰C] (94%). ¹H NMR (CDCl₃): 0.88 (s, 3H, 18-H₃); 1.21 (s, 3H, 19-H₃); 3.69 (t, 1H, 17a-H); 6.01-6.04 (m, 2H, 2-H, 4-H); 6.22-6.27 (m, 2H, 6-H, 7-H); 7.08 (d, 1H, 1-H). MS(m/z): 284.4 [M]^+..

Androsta-1a,2a-epoxy-4,6-dien-3-one-17b-ol (9) was prepared in similar fashion as 5, m.p. 163-165⁰C [ref.⁶ m.p. 169-171⁰C] (80%). ¹H NMR (CDCl₃): 0.87 (s, 3H, 18-H₃); 1.20 (s, 3H, 19-H₃); 3.46 (d, 1H, 2b-H); 3.60 (d, 1H, 1b-H); 3.72 (t, 1H, 17a-H); 5.66 (s, 1H, 4-H); 6.01-6.13 (m, 2H, 6-H, 7-H). MS(EI): 300.2 [M]^+. (100), 267.1 (35), 133.1 (81), 97.1 (93).

5b-Androstan-1a,17b-diol-3-one (10): To a suspension solution of pre-hydrogenated 5% Pd(0)/CaCO₃ catalyst (0.1g)³³ and epoxide 9 (0.1g, 0.33 mmol) in pyridine (8 mL) was bubbled a stream of hydrogen with stirring at rt for 5 h. The catalyst was filtered through a small silica-gel column and washed with pyridine (15 mL). The pyridine removed in a stream of air and the residue was chromatographyed afforded 10 (63mg, 61.8%) as colorless crystal, m.p. 163-165⁰C [ref.⁷ m.p. 168-170⁰C]. ¹H NMR (CDCl₃): 0.76 (s, 3H, 18-H₃); 1.22(s, 3H, 19-H₃); 2.56-2.67 (m, 2H, 2-H); 3.64 (m, 1H, 17a-H); 3.71 (m, 1H, 1b-H). MS(m/z): 306.2 [M]^+..

Androst-4,6-dien-1a,17b-diol-3-one (12): To a suspension solution of 5% Pd(II)/CaCO₃/Pb catalyst (Lindlar catalyst, 0.1g) in pyridine (8 mL), was bubbled with hydrogen for 12 h. Then, the epoxide 9 (0.1g, 0.33 mmol) was added and hydrogen was bubbled for another 5 h. The catalyst was filtered through a small silica-gel column and the pyridine removed in a stream of air. Column chromatography gave 9 (35mg, 35%) and 12 (50mg, 49.7%), m.p. 213-215⁰C. ¹H NMR (CDCl₃): 0.82 (s, 3H, 18-H₃); 1.15(s, 3H, 19-H₃); 3.71 (m, 1H, 17a-H); 4.20 (m, 1H, 1b-H); 5.79 (s, 1H, 4-H); 6.14-6.17 (m, 2H, 6-H, 7-H). MS(m/z): 302.2 [M]^+..

Androsta-1a,2a-epoxy-4,6-diene-1a,3b,17b-triol (13): To a solution of 9 (0.1g, 0.33 mmol) in THF (2 mL) amd HMPA (0.35 mL) was added Li-selectride (0.88 mL, 1.0 M THF solution) at 0⁰C. The reaction mixture was stirred for 10 h at 0⁰C and quenched with water. The product was extracted with ethyl acetate and the combined extracts were washed with brine, dried and evaporated. The residue was purified by column chromatography gave colorless crystal 13 (55 mg, %), m.p. 187-189⁰C. ¹H NMR (CDCl₃): 0.83 (s, 3H, 18-H₃); 1.00 (s, 3H, 19-H₃); 3.33 (d, 1H, 2b-H); 3.54 (d, 1H, 1b-H); 3.67 (t, 1H, 17a-H); 4.51 (broad s, 1H, 3a-H); 5.21 (s, 1H, 4-H); 5.62 (d, 1H, 6-H); 5.91 (dd, 1H, 7-H). MS(EI): 302.2 [M]^+. (1), 286.2 [M-H₂O]^+. (21), 151.2 (5), 122.1 (100), 41.1 (10).

Acknowledgment

We gratefully thank Dr. Timothy Thomas for determining EI mass spectra, and Trevor Avends of Steraloids for the testosterone and suggestion for this investigation.

Table 1. Partial ¹H NMR Spectra

Table 2. ¹³C NMR Spectra of 6-12

Table 2a. ¹³C NMR Spectra of 1-5

Table 2b. ¹³C NMR Spectra of 6-13

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