A Three-Step Route to a Tricyclic Steroid Precursor

Abstract

2-Alkyl cyclohexenones are useful intermediates for organic synthesis. The Wittig reaction of a series of aldehydes with (cyclopropylmethyl)triphenylphosphonium bromide delivered the corresponding alkenyl cyclopropanes. UV irradiation in the presence of Fe(CO)₅ converted the alkenyl cyclopropanes to the 2-substituted cyclohexenones. This approach enabled a three-step synthesis of the tricyclic core of estrone methyl ether.

Introduction

Estrone 1 and estradiol 2 (Eq. 1), important hormones that control the menstruation cycle of mammals, are an attractive research area due to their high biological activity and many pharmaceutical applications. A variety of synthetic strategies have been published for the synthesis of estrone and its derivatives.¹ The first total synthesis of estrone was published in 1948 by Anner and Miescher.^1a The tricyclic phenanthrenone core 3 played a key role in that synthesis and is a potentially useful intermediate for steroid syntheses.²

(1)

We envisioned (Scheme 1) that aldehyde 4a could be homologated to the corresponding alkenyl cyclopropane by Wittig reaction with the commercially available (cyclopropylmethyl)-triphenylphosphonium bromide 5.³ UV irradiation of the alkenyl cyclopropane 6a so prepared in the presence of Fe(CO)₅ under a CO atmosphere⁴ would then lead to the corresponding cyclohexenone 7a. Acid catalyzed cyclization would then deliver the tricyclic ketone 3, in just three steps from the commercial aldehyde 4a.

Scheme 1.

Results and Discussion

2-Alkyl cyclohexenones are important intermediates for target-directed synthesis.⁵ While several methods have been developed to prepare such cyclohexenones, these routes tend to be either low yielding or multi-stepped.⁶ There were two challenges to be overcome in developing the route to 2-alkylcyclohexenones outlined in Scheme 1: Development of the Wittig reaction, and optimization of the Fe-mediated cyclocarbonylation.

Development of the Wittig Reaction

We initially performed the Wittig reaction utilizing one equivalent of commercial (cyclopropylmethyl)triphenylphosphonium bromide and one equivalent of potassium t-butoxide at cryogenic temperatures. This protocol led to modest yields, with some unreacted aldehyde. During optimization, we found that increasing both base and phosphonium salt to a slight excess increased conversion. While maintaining the slight excess of phosphonium bromide, we doubled the amount of base, which led to complete conversion and high yields. Finally, we found that the reaction could be carried out at room temperature. The products (Table 1) were isolated as a mixture of both the Z and E isomers of the alkenyl cyclopropane, which was of no consequence for the subsequent cyclocarbonylation.

Table 1. Wittig Reaction and Carbonylation.

Entry	Aldehyde	Wittig Yield (%)	Cyclohexenone	Carbonylation Yield (%)
1		93		89
2		84		89
3		78		86
4		98		72a,b
5		89		86
6		88		85

^aAutocooling in Rayonet was turned off.

^bFor a previous preparation of 3d, see ref 8.

Optimization of the Fe-Mediated Cyclocarbonylation

We initiated carbonylation studies using the conditions that we had previously developed.⁶ We found that using less than one equivalent of Fe(CO)₅ reduced the conversion rate, while adding greater than two equivalents did not lead to significantly higher conversions. Increasing the concentration of the solution typically lowered conversion. We did find that the conversion and yield improved when the mixture was agitated periodically, providing for an exchange between the product and starting material forming the thin film that was being irradiated. We maintained a CO atmosphere in each of the runs, even though CO is formed during the irradiation of the Fe(CO)₅.

During the carbonylation of 6d, we observed a significantly lower conversion of the alkenyl cyclopropane to the cyclohexenone 7d. It was our hypothesis that the steric bulk of the molecule hindered the carbonylation. When we ran the photolysis without autocooling and so warmer, the conversion improved significantly. This two-step conversion appears to be a versatile and convenient way to prepare 2-alkyl cyclohexenones from the corresponding aldehydes.⁷

Cyclization of the Enone

We envisioned (Scheme 2) that a variety of Lewis acids could effect the cyclization of the enone 3.^5b,9 We initiated our studies with BF₃·OEt₂ and TiCl₄. While both Lewis acids were efficient in forming the tricyclic ring, BF₃·OEt₂ was milder in its reaction with the cyclohexenone, leading to less decomposition and thus higher yield. We found that by adding the Lewis acid slowly at 0°C, we could also minimize decomposition.

Scheme 2.

The tricyclic ketone was approximately a 1:1 mixture of trans and cis diastereomers 3 and 8. As had been described², the trans diastereomer 3 could be separated by fractional crystallization. Alternatively, the two diastereomers could be efficiently separated by column chromatography. The isolated cis diastereomer 8 could then be epimerized to the 1:1 mixture by heating to reflux with K₂CO₃ in THF. Using this approach, one could prepare gram quantities of the crystalline trans ketone 3.

Conclusion

We expect that the aldehyde to 2-alkyl cyclohexenone conversion described here will make such cyclohexenones more readily available as intermediates for target-directed synthesis. We also envision that this facile new preparation of the ketone 3 will facilitate future steroid syntheses.

Experimental

1-(4-Cyclopropylbut-3-enyl)-3-methoxybenzene 6a

Potassium t-butoxide (1.0 M solution in THF, 50 mL, 50 mmol) was added over 20 min to a suspension of (cyclopropylmethyl)triphenylphosphonium bromide (10.0 g, 25 mmol) in 25 mL of dry THF at 0°C. The external cooling was removed and the mixture was stirred for 30 min. The aldehyde 4a (3.28 g, 20 mmol) was added, and the solution was stirred at rt for 1 h. The mixture was quenched with 1N HCl (50 mL) and then partitioned between water and EtOAc (3 × 100 mL). The combined organic extract was dried (MgSO₄) and concentrated. The residue was chromatographed to give the alkenyl cyclopropane 6a (3.76 g, 93% yield, 77:23 Z/E) as an oil. TLC R_f = 0.62 (9:1 hexanes/EtOAc), ¹H NMR (Z) δ 7.19 (t, J = 7.8 Hz, 1H), 6.72-6.84 (m, 3H), 5.33-5.38 (m, 1H), 4.76 (t, J = 10.8 Hz, 1H), 3.79 (s, 3H), 2.61-2.72 (m, 2H), 2.44-2.52 (m, 2H), 1.44-1.53 (m, 1H), 0.63-0.72 (m, 2H), 0.27-0.31 (m, 2H); ¹³C NMR (Z) δ CH₃: 55.1 CH₂: 36.2, 29.4, 6.8 CH: 134.5, 129.2, 127.0, 120.9, 114.2, 111.0, 9.5 C: 159.6, 143.8; ¹H NMR (E) δ 7.19 (t, J = 7.8 Hz, 1H) 6.72-6.84 (m, 3H), 5.52-5.57 (m, 1H), 5.01 (dd, J = 15.2, 8.4 Hz, 1H), 3.79 (s, 3H), 2.61-2.72 (m, 2H), 2.25-2.32 (m, 2H), 1.30-1.36 (m, 1H), 0.63-0.72 (m, 2H), 0.27-0.31 (m, 2H); ¹³C NMR (Z) δ CH₃: 55.1 CH₂: 36.1, 29.4, 6.4 CH: 134.4, 129.2, 127.2, 120.9, 114.2, 111.0, 9.5 C: 159.6, 143.8; IR 2935, 1598, 1487, 1455, 1258 cm^-1; MS m/z (%) 202 (M, 30), 137 (65), 121 (100); HRMS: Calcd for C₁₄H₁₈O 202.1358, obsd 202.1360.

2-(3-Methoxyphenethyl)cyclohex-2-enone 7a

To the alkenyl cyclopropane 6a (202 mg, 1.0 mmol) in 15 mL of 2-propanol (0.075 M) was added Fe(CO)₅ (392 mg, 2.0 mmol). The reaction vessel was purged with CO, a CO balloon was attached, and the mixture was photolyzed for 8 h at room temperature in a Rayonet apparatus (300 nm) set for autocooling. The reaction was halted every 2 hours to agitate the tube inside the larger tube, after which photolysis was restarted. At the end of the irradiation, DBU (304 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature for 1 h under nitrogen. The mixture was diluted with 40 mL of EtOAc and filtered through a small pad of packed silica gel and then subsequently concentrated. The residue was chromatographed to give 2 mg of unreacted 2a and 202 mg of 7a (89% yield based on 6a not recovered) as an oil. TLC R_f = 0.17 (9:1 hexanes/EtOAc), ¹H NMR δ 7.16 (t, J = 8.4 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.81 (t, J = 9.2 Hz, 1H), 6.73 (m, 1H), 6.61 (m, 1H), 3.78 (s, 3H), 2.68 (m, 2H), 2.45 (m, 4H), 2.28 (m, 2H), 1.98 (m, 2H); ¹³C NMR δ CH₃: 55.4 CH₂: 38.7, 35.1, 31.7, 26.1, 23.1 CH: 149.6, 129.2, 121.0, 114.1, 111.2 C: 199.4, 159.5, 143.7, 139.2; IR 3442, 2960, 1734, 1206, 1099 cm^-1; MS m/z (%) 230 (M, 8), 221 (7), 163 (15), 135 (95), 107 (100); HRMS: Calcd for C₁₅H₁₈O₂ 231.1385, obsd 231.1391.

7-Methoxy-2,3,4,4a,10,10a-hexahydrophenanthren-1(9H)-one 3 and 8

BF₃·OEt₂ (1.0 M solution in CH₂Cl₂, 2 mL, 2 mmol) was added over 5 min to cyclohexenone 7a (230 mg, 1.0 mmol) in 5 mL of dry CH₂Cl₂ (0.20 M) at 0°C. The solution was stirred at rt for 3 h, quenched with water (5 mL), and then partitioned between water and methylene chloride. The combined organic extract was dried (MgSO₄) and concentrated. The residue was chromatographed using 80:20 PE:MTBE as an elution solvent to give the phenanthrenone 3 (92 mg, 40% yield) as a solid and phenanthrenone 8 (90 mg, 38% yield, 78% yield overall) as an oil. The cis diastereomer 8 (85 mg, 0.37 mmol) was then heated to reflux with a suspension of K₂CO₃ (690 mg, 5 mmol) in dry THF (2 mL) overnight to epimerize the phenanthrenone to a 1:1 mixture of diastereomers. For phenanthreone 3: mp = 106-109°C, TLC R_f = 0.45 (8:2 hexanes/EtOAc (double elution)). ¹H NMR δ 7.23 (d, J = 9 Hz, 1H), 6.75 (dd, J = 9, 3 Hz, 1H), 6.66 (d, J = 3 Hz, 1H), 3.78 (s, 3H), 2.84 (m, 2H), 2.73 (td, J = 12, 3 Hz, 1H), 2.61 (m, 1H), 2.41-2.53 (m, 2H), 2.35 (td, J = 12, 3 Hz, 1H), 2.18-2.30 (m, 2H), 1.86 (tdd, J = 13, 5, 4 Hz, 1H), 1.61-1.77 (m, 2H); ¹³C NMR δ CH₃: 55.2 CH₂: 44.3, 30.5, 29.3, 26.3, 21.7 CH: 138.0, 113.8, 112.0, 52.7, 44.3; C: 212.0, 157.8, 138.0, 131.2, 126.9; IR 1720, 1615 cm^-1; MS m/z (%) 230 (M, 100), 213 (55), 187 (30), 160 (25), 135 (43); HRMS: Calcd for C₁₄H₁₈O 230.1307, obsd. 230.1302; For phenanthrenone 8: TLC R_f = 0.42 (8:2 hexanes/EtOAc (double elution)), ¹H NMR δ 7.05 (d, J = 9 Hz, 1H), 6.75 (dd, J = 9, 3 Hz, 1H), 6.62 (d, J = 3 Hz, 1H), 3.78 (s, 3H), 2.84 (m, 2H), 2.73 (td, J = 12, 3 Hz, 1H), 2.61 (m, 1H), 2.41-2.53 (m, 2H), 2.35 (td, J = 12, 3 Hz, 1H), 2.18-2.30 (m, 2H), 1.86 (tdd, J = 13, 5, 4 Hz, 1H), 1.61-1.77 (m, 2H); ¹³C NMR δ CH₃: 55.6 CH₂: 38.8, 30.7, 29.0, 24.5, 22.6 CH: 129.7, 113.6, 112.7, 50.6, 40.4; C: 214.4, 157.8, 137.0, 131.2, 126.9; IR 1720, 1615 cm^-1; MS m/z (%) 230 (M, 100), 213 (4), 187 (40), 159 (35), 147 (31), 121 (19); HRMS: Calcd for C₁₄H₁₈O 230.1307, obsd 230.1302.

Supplementary Material

1_si_001. Supporting Information Available.

General experimental procedures, experimental procedures for 2b-2f and 3b-3f, details of the photochemical apparatus and spectroscopic data. This material is available free of charge via the Internet at http://pubs.acs.org.