Stereoselective Synthesis of New Halogen-containing d-Homoestrone Derivatives

Abstract

The Lewis acid-induced cyclization of the 3-methyl and 3-benzyl ethers of an unsaturated secoestrone aldehyde furnished d-homosteroids containing 16β-oriented halogens on the sterane skeleton.

Key words

Lewis acids - intramolecular Prins reaction - fluorination - stereoselective synthesis - d-homosteroids

References

• 1a Andersen NH. Hadley SW. Kelly JD. Bacon ER. J. Org. Chem.  1985,  50:  4144 
• 1b Ladouceur G. Paquette LA. Synthesis  1992,  185 
• 1c Masse CE. Dakin LA. Knight BS. Panek JS. J. Org. Chem.  1997,  62:  9335 
• 1d Barbero A. Garcia C. Pulido FJ. Tetrahedron  2000,  56:  2739 
• 2a Cheney DL. Paquette LA. J. Org. Chem.  1989,  54:  3334 
• 2b Deguin B. Florent J.-C. Monneret C. J. Org. Chem.  1991,  56:  405 
• 2c McIntosh MC. Weinreb SM. J. Org. Chem.  1991,  56:  5010 
• 2d Peron GLN. Kitteringham J. Kilburn JD. Tetrahedron Lett.  1999,  40:  3045 
• 3a Schäfer H.-J. Baringhaus K.-H. Liebigs Ann. Chem.  1990,  355 
• 3b Molander GA. Cameron KO. J. Am. Chem. Soc.  1993,  115:  830 
• 3c Harmata M. Barnes CL. J. Am. Chem. Soc.  1990,  112:  5655 
• 4a Balog A. Geib SJ. Curran DP. J. Org. Chem.  1995,  60:  345 
• 4b Olah GA. Krishnamurti R. Prakash GKS. Synthesis  1990,  646 
• 4c Snider BB. In: Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Heathcock C. H., Pergamon Press; Oxford: 1991.  Part 2. p.527 
• 5a Noltemeyer M. Tietze LF. Wölfling J. Frank . Schneider G. Acta Cryst. Sect. C  1996,  2258 
• 5b Wölfling J. Frank . Schneider G. Tietze LF. Synlett  1998,  1205 
• 5c Wölfling J. Frank . Schneider G. Tietze LF. Eur. J. Org. Chem.  1999,  3013 
• 6 Schneider G. Bottka S. Hackler L. Wölfling J. Sohár P. Liebigs Ann. Chem.  1989,  263 
• 11 Johns WF. Salamon KW. J. Org. Chem.  1971,  36:  1952 

7

Spectroscopic Data of 16β-Fluoro- d -homoestra-1,3,5(10)-triene-3,17ab-diol-3-methyl ether(6a): ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (s, 3 H, 18-H₃), 2.84 (m, 2 H, 6-H₂), 3.27 (m, 1 H, 17aα-H), 3.78 (s, 3 H, 3-OMe), 4.54 (dm, 1 H, J = 48.5 Hz, 16α-H), 6.63 (d, 1 H, J _4-2 = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J _2-1 = 8.6 Hz, J _2-4 = 2.7 Hz, 2-H) and 7.21 (d, 1 H, J _1-2 = 8.6 Hz, 1-H). ¹³C NMR (100 MHz, CDCl₃): δ = 10.9 (C-18), 25.9 (C-11), 26.6 (C-7), 30.0 (C-6), 30.1 (J = 17.9 Hz, C-15), 34.9 (J = 21.0 Hz, C-17), 36.7 (C-12), 38.8 (C-13), 41.7 (C-8), 43.8 (C-9), 43.9 (J = 10.6 Hz, C-14), 55.2 (3-OMe), 74.6 (J = 11.0 Hz, C-17a), 90.0 (J = 164.1 Hz, C-16), 111.6 (C-2), 113.4 (C-4), 126.2 (C-1), 132.4 (C-10), 137.7 (C-5) and 157.5 (C-3).

8

Typical Procedure for the Synthesis of 16β-Chloro- d -homoestra-1,3,5(10)-triene-3,17a-diol-3-methyl Ether Isomers (7a and 7b): 298 mg (1.00 mmol) of 1 was dissolved in 5 mL of ice-cold CH₂Cl₂ and 0.13 mL (278 mg, 1.1 mmol) of anhydrous SnCl₄ in 2 mL of CH₂Cl₂ was added dropwise during stirring of the mixture under an argon atmosphere for 2 h. The solution was then diluted with water (10 mL) and extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic phases were dried over Na₂SO₄. Evaporation in vacuo and purification by column chromatography (silica gel, CH₂Cl₂) afforded 244 mg (73%) of 7a and 34 mg (10%) of 7b as white solids. 7a: mp 90-92 °C; R_f 0.27 (EtOAc-CH₂Cl₂ = 2: 98); ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (s, 3 H, 18-H₃), 2.85 (m, 2 H, 6-H₂), 3.28 (m, 1 H, 17aα-H), 3.78 (s, 3 H, 3-OMe), 3.90 (m, 1 H, 16α-H), 6.63 (d, 1 H, J _4-2 = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J _2-1 = 8.6 Hz, J _2-4 = 2.7 Hz, 2-H) and 7.21 (d, 1 H, J _1-2 = 8.6 Hz, 1-H). ¹³C NMR (100 MHz, CDCl₃): δ = 10.9 (C-18), 25.9, 26.6, 30.0, 34.5, 36.8, 37.5 (C-13), 38.3 (C-8), 40.5, 43.5 (C-9), 47.0 (C-14), 55.2 (3-OMe), 56.3 (C-16), 77.9 (C-17a), 111.7 (C-2), 113.4 (C-4), 126.3 (C-1), 132.4 (C-10), 137.7 (C-5) and 157.6 (C-3), EI MS m/z (relative intensity): 336(37), 334 (M⁺, 100), 173(13) and 147(7). 7b: mp 92-94 ºC; R_f 0.31 (EtOAc-CH₂Cl₂ = 2: 98); ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (s, 3 H, 18-H₃), 2.84 (m, 2 H, 6-H₂), 3.54 (bs, 1 H, 17aβ-H), 3.78 (s, 3 H, 3-OMe), 4.29 (m, 1 H, 16α-H), 6.63 (d, 1 H, J _4-2 = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J _2-1 = 8.6 Hz, J _2-4 = 2.7 Hz, 2-H) and 7.21 (d, 1 H, J _1-2 = 8.6 Hz, 1-H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.2 (C-18), 26.1, 26.2, 30.0, 34.1, 35.1, 37.4 (C-13), 39.0 (C-8), 39.5, 41.7 and 43.1 (C-9 and C-14), 55.2 (3-OMe), 56.6 (C-16), 76.5 (C-17a), 111.7 (C-2), 113.4 (C-4), 126.2 (C-1), 132.5 (C-10), 137.8 (C-5) and 157.5 (C-3), EI MS m/z (relative intensity): 336(27), 334 (M⁺, 100), 173(10) and 147(5). - C₂₀H₂₇ClO₂. The compounds give correct elemental analyses.

9

Typical Procedure for the Synthesis of 16β-Bromo- d -homoestra-1,3,5(10)-triene-3,17a-diol-3-benzyl Ether Isomers (13a and 13b): A mixture of 375 mg (1 mmol) of secoestrone-3-benzyl ether 2 and 478 mg (1.00 mmol) of anhydrous ZnBr₂ in 5 mL of CH₂Cl₂ was heated for 2 h and then stirred overnight at r.t. The suspension was diluted with water (10 mL) and neutralized with NaHCO₃, the aqueous phase was extracted with CH₂CH₂ (3 × 10 mL) and the combined organic phases were washed with brine and dried over Na₂SO₄. After evaporation in vacuo, the crude product was purified by column chromatography (silica gel, CH₂Cl₂) to give 355 mg (78%) of 13a as a white solid and 31 mg (7%) of 13b as a yellow oil. 13a: mp 103-105 °C; R_f 0.24 (CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃): δ = 0.90 (s, 3 H, 18-H₃), 2.84 (m, 2 H, 6-H₂), 3.27 (m, 1 H, 17aα-H), 4.00 (m, 1 H, 16α-H), 5.02 (s, 2 H, 3-benzyl-CH₂), 6.71 (d, 1 H, J _4-2 = 2.6 Hz, 4-H), 6.79 (dd, 1 H, J _2-1 = 8.6 Hz, J _2-4 = 2.6 Hz, 2-H), 7.19 (d, 1 H, J _1-2 = 8.6 Hz, 1-H), 7.32 (m, 1 H, 4’-H), 7.38 (m, 2 H, 3’-H and 5’-H) and 7.43 (m, 2 H, 2’-H and 6’-H). ¹³C NMR (125 MHz, CDCl₃): δ = 10.9 (C-18), 25.9, 26.5, 29.9, 35.4, 36.8, 38.2 (C-16), 38.3 (C-13), 41.5, 43.5 and 47.4 (C-8 and C-9), 48.1 (C-14), 69.9 (3-benzyl-CH₂), 78.4 (C-17a), 112.5 (C-2), 114.5 (C-4), 126.2 (C-1), 127.4 (2C, C-2’ and C-6’), 127.8 (C-4’), 128.5 (2C, C-3’ and C-5’), 132.6 (C-10), 137.2 (C-1’), 137.6 (C-5) and 156.8 (C-3). 13b: R_f 0.37 (CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (s, 3 H, 18-H₃), 2.83 (m, 2 H, 6-H₂), 3.47 (bs, 1 H, 17aβ-H), 4.42 (m, 1 H, 16α-H), 5.02 (s, 2 H, 3-benzyl-CH₂), 6.71 (d, 1 H, J _4-2 = 2.7 Hz, 4-H), 6.78 (dd, 1 H, J _2-1 = 8.7 Hz, J _2-4 = 2.7 Hz, 2-H), 7.19 (d, 1 H, J _1-2 = 8.7 Hz, 1-H), 7.31 (m, 1 H, 4’-H), 7.37 (m, 2 H, 3’-H and 5’-H) and 7.42 (m, 2 H, 2’-H and 6’-H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.2 (C-18), 26.0, 26.2, 30.0, 34.2, 36.0, 37.3 (C-13), 39.0 (C-16), 40.5, 42.8 and 43.0 (C-8 and C-9), 48.7 (C-14), 69.9 (3-benzyl-CH₂), 76.8 (C-17a), 112.5 (C-2), 114.5 (C-4), 126.2 (C-1), 127.4 (2C, C-2’ and C-6’), 127.8 (C-4’), 128.5 (2C, C-3’ and C-5’), 132.8 (C-10), 137.3 (C-1’), 137.8 (C-5) and 156.8 (C-3), EI MS m/z (relative intensity): 456(12), 454 (M⁺, 13) and 91(100). - C₂₆H₃₁O₂Br. The compounds give correct elemental analyses.

10

Typical Procedure for the Oxidation of 16β-Chloro- d -homoestra-1,3,5(10)-triene-3,17a-diol-3-methyl Ether Isomers. 0.35 mL of Jones reagent (8 N) was added dropwise to 335 mg (1.00 mmol) of pure 7a or a mixture of 7a and 7b in 4 mL of ice-cold acetone, and the solution was stirred until complete conversion (TLC) was achieved (1 h). The solution was next poured into ice-water and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with water, dried over Na₂SO₄ and concentrated in vacuo, and the crude product was purified by column chromatography (silica gel, PE-CH₂Cl₂ = 20:80) to afford 206 mg (62%) of 16a and 104 mg (35%) of 23 as white solids. 16a: mp 130-132 °C; R_f 0.53 (PE-CH₂Cl₂ = 20:80); ¹H NMR (500 MHz, CDCl₃): δ = 1.15 (s, 3 H, 18-H₃), 2.86 (m, 2 H, 6-H₂), 3.76 (s, 3 H, 3-OMe), 4.00 (m, 1 H, 16α-H), 6.62 (d, 1 H, J _4-2 = 2.7 Hz, 4-H), 6.71 (dd, 1 H, J _2-1 = 8.6 Hz, J _2-4 = 2.7 Hz, 2-H) and 7.19 (d, 1 H, J _1-2 = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.8 (C-18), 25.6, 26.6, 29.8, 32.2, 38.4 (C-8), 43.1 (C-9), 46.6 (C-14), 47.2 (C-13), 47.6 (C-17), 55.2 (C-16), 55.8 (3-OMe), 111.8 (C-2), 113.5 (C-4), 126.3 (C-1), 132.0 (C-10), 137.3 (C-5), 157.7 (C-3) and 210.7 (C-17a). - C₂₀H₂₅ClO₂. 23: mp: 159-161 °C, R_f 0.31 (PE-CH₂Cl₂ = 20:80); ¹H NMR (500 MHz, CDCl₃): δ = 1.05 (s, 3 H, 18-H₃), 2.87 (m, 2 H, 6-H₂), 3.77 (s, 3 H, 3-OMe), 5.95 (m, 1 H, 16-H), 6.63 (d, 1 H, J _4-2 = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J _2-1 = 8.6 Hz, J _2-4 = 2.7 Hz, 2-H), 6.88 (m, 1 H, 17-H) and 7.22 (d, 1 H, J _1-2 = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.6 (C-18), 25.9 (2C), 27.2, 29.9, 32.3, 39.3 (C-8), 42.6 (C-9), 44.6 (C-13), 45.5 (C-14), 55.2 (3-OMe), 111.7 (C-2), 113.6 (C-4), 126.3 and 127.8 (C-1 and C-17), 132.2 (C-10), 137.4 (C-5), 147.3 (C-16), 157.7 (C-3) and 205.3 (C-17a). - C₂₀H₂₄O₂. The compounds give correct elemental analyses.