Site-Selective Synthesis of 3,17-Diaryl-1,3,5,16-estratetraenes

Abstract

A straightforward, site-selective arylation of the bis(triflate) of estrone by Suzuki–Miyaura reactions has been developed. Monoarylation occurs selectively at the D-ring with good to excellent yield. Such products were exemplarily employed for the synthesis of estrones containing two different aryl substituents.

Key words

palladium - site selectivity - steroids - Suzuki–Miyaura reaction

• References and Notes

• 1 Shi J, Shigehisa H, Guerrero CA, Shenvi RA, Li C.-C, Baran PS. Angew. Chem. Int. Ed. 2009; 48: 4328
• 2a Aoki S, Watanabe Y, Sanagawa M, Setiawan A, Kotoku N, Kobayashi M. J. Am. Chem. Soc. 2006; 128: 3148
• 2b Watanabe Y, Aoki S, Tanabe D, Setiawan A, Kobayashi M. Tetrahedron 2007; 4074
• 2c Aoki S, Watanabe Y, Tanabe D, Setiawan A, Arai M, Kobayashi M. Tetrahedron Lett. 2007; 48: 4485
• 2d Aoki S, Watanabe Y, Tanabe D, Arai M, Suna H, Miyamoto K, Tsujibo H, Tsujikawa K, Yamamoto H, Kobayashi M. Bioorg. Med. Chem. 2007; 15: 6758
• 2e Sato Y, Kamiyama H, Usui T, Saito T, Osada H, Kuwahara S, Kiyota H. Biosci. Biotechnol. Biochem. 2008; 72: 2992
• 2f Solum EJ, Cheng J.-J, Sørvik IB, Paulsen RE, Vik A, Hansen TV. Eur. J. Med. Chem. 2014; 85: 391
• 3a Nicolaou KC, Sun Y.-P, Peng X.-S, Polet D, Chen DY.-K. Angew. Chem. Int. Ed. 2008; 47: 7310
• 3b Lee HM, Nieto-Oberhuber C, Shair MD. J. Am. Chem. Soc. 2008; 130: 16864
• 4 Inhoffen HH, Holhlweg W. Naturwissenschaften 1938; 26: 96
• 5a Schang LM, Vincent AV. US 20120135954, 2012
• 5b Ivanov A, Boldt S, un Nisa Z, Shah SJ. A, Ehlers P, Villinger A, Schneider G, Wölfling J, Rahman Q, Iqbal J, Langer P. RSC Adv. 2016; 6: 11118
• 6a Möller G, Duluca D, Gege C, Rosinus A, Kowalik D, Peters O, Droescher P, Elger W, Adamski J, Killisch A. Bioorg. Med. Chem. Lett. 2009; 19: 6740
• 6b Nussbaumer P, Billich A. Med. Res. Rev. 2004; 24: 539
• 6c Geisler J, Lonning PE. Cancer Res. 2005; 11: 2809
• 6d Woo LW. L, Leblond B, Purohit A, Potter BV. L. Bioorg. Med. Chem. 2012; 20: 2506
• 6e Suwandi LS, Agoston GE, Shah JH, Hanson AD, Zhan XH, LaVallee TM, Treston AM. Bioorg. Med. Chem. Lett. 2009; 19: 6459
• 6f Solum EJ, Cheng J.-J, Sylte I, Vik A, Hansen TV. RSC Adv. 2015; 5: 32497
• 7 Govan JM, McIver AL, Riggsbee C, Deiters A. Angew. Chem. Int. Ed. 2012; 51: 9066
• 8a Jopp S, Liesegang M, Ehlers P, Frank E, Schneider G, Wölfling J, Langer P. Tetrahedron Lett. 2018; 59: 26
• 8b Jopp S, Wallaschkowski T, Ehlers P, Frank E, Schneider G, Wölfling J, Mernyak E, Villinger A, Langer P. Tetrahedron 2018; 74: 2825
• 8c Jopp S, Liesegang M, Ehlers P, Frank E, Schneider G, Wölfling J, Villinger A, Langer P. Synlett 2017; 28: 2647
• 8d Ivanov A, Ejaz SA, Syed JA, Shah P, Ehlers A, Villinger E, Frank G, Schneider J, Wölfling J, Iqbal P, Langer P. Bioorg. Med. Chem. 2017; 25: 949
• 8e Riebe S, Jopp S, Ehlers P, Frank E, Schneider G, Wölfling J, Villinger A, Langer P. Tetrahedron Lett. 2017; 58: 2801
• 9 Sun Q, Jiang C, Xu H, Zhang Z, Liu L, Wang C. Steroids 2010; 75: 936

For arylation at position 3, see:
• 10a Tran H, McCallum T, Morin M, Barriault L. Org. Lett. 2016; 18: 4308
• 10b Wang X.-Y, Song HX, Wang S.-M, Yang J, Qin H.-L, Jiang X. Tetrahedron 2016; 72: 7606
• 10c Iranpoor N, Panahi F, Jamedi F. J. Organometal. Chem. 2015; 781: 6
• 10d Li X.-J, Zhang J.-L, Geng Y, Jin Z. J. Org. Chem. 2013; 78: 5078
• 10e Chen H, Huang Z, Hu X, Tang G, Xu P, Zhao Y, Cheng C.-H. J. Org. Chem. 2011; 76: 2338
• 10f Guan B.-T, Wang Y, Li B.-J, Yu D.-G, Shi Z.-J. J. Am. Chem. Soc. 2008; 130: 14468
• 10g Lipshutz BH, Petersen TB, Abela AR. Org. Lett. 2008; 10: 1333
• 10h Ciattini PG, Morera E, Ortar G. Tetrahedron Lett. 1993; 33: 4815

For arylation at position 17, see:
• 11a Lei C, Yip YJ, Zhou JS. J. Am. Chem. Soc. 2017; 139: 6086
• 11b Li J, Knochel P. Angew. Chem. Int. Ed. 2018; 57: 11436
• 11c Hamze A, Brion J.-D, Alami M. Org. Lett. 2012; 14: 2782
• 11d Sun C.-L, Wang Y, Zhou X, Wu Z.-H, Li B.-J, Guan B.-T, Shi Z.-J. Chem. Eur. J. 2010; 16: 5844
• 12 Holt DA, Levy MA, Ladd DL, Oh H.-J, Erb JM, Heaslip JI, Brandt M, Metcalf BW. J. Med. Chem. 1990; 33: 937
• 13 Onefold Suzuki–Miyaura Reaction of 1 – General Procedure Arylboronic acid (0.60 mmol), K₃PO₄ (0.60 mmol, 127 mg), Pd(OAc)₂ (5 mol%, 2.2 mg), and cataCXium A® (10 mol%, 7.2 mg) were weighed into a pressure tube under argon. Compound 1 (0.20 mmol, 107 mg) was dissolved in toluene (4 mL) and added to the pressure tube. The reaction was stirred at 100 °C for 20 h. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate (3 × 10 mL). The crude products 3a–j were purified by column chromatography. 17-(4-Methylphenyl)-3-(trifluoromethylsulfonyloxy)-13β-estra-1,3,5(10),16-tetraene (3b) Compound 3b was synthesized according to the general procedure using 4-methylphenylboronic acid (0.60 mmol, 82 mg) and purified via column chromatography (heptane/dichloromethane, 10:1); yield 90 mg (95%); [α]_D ²⁸ –24.9 (CHCl₃, β = 1.5 mg mL^–1). ¹H NMR (300 MHz, CDCl₃): δ = 1.07 (s, 3 H, CH₃), 1.48–1.59 (m, 1 H, CH_Alkyl), 1.67–1.82 (m, 4 H, CH_Alkyl), 1.99–2.26 (m, 3 H, CH_Alkyl), 2.29–2.40 (m, 6 H, CH₃ + CH_Alkyl), 2.94–2.97 (m, 2 H, CH_Alkyl), 5.92 (dd, ³ J = 3.19 Hz, ³ J = 1.74 Hz, 1 H, C=CH), 7.00–7.06 (m, 2 H, CH_Ar), 7.15 (d, ³ J = 7.91 Hz, 2 H, CH_Ar), 7.30–7.37 (m, 3 H, CH_Ar). ¹³C NMR (75 MHz, CDCl₃): δ = 16.6, 21.1 (CH₃), 26.4, 27.3, 29.5, 31.2, 35.4 (CH₂), 36.8, 44.2 (CH), 47.4 (C), 56.7 (CH), 118.1 (C=CH), 118.8 (q, ¹ J = 320.8 Hz, CF₃), 121.1, 126.2, 126.2, 126.9, 128.9 (CH_Ar), 134.2, 136.5, 139.5, 141.2, 147.5 (C_Ar), 154.7 (C=CH). ¹⁹F NMR (282 MHz, CDCl₃): δ = –72.97. IR (ATR): ν = 2930 (w), 2850 (w), 1488 (w), 1416 (s), 1250 (m), 1201 (s), 1139 (s), 925 (s), 886 (m), 836 (m), 797 (s), 700 (w), 599 (s), 511 (w), 486 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 477 (16), 476 (83) [M⁺], 461 (58), 291 (24), 170 (34), 169 (75), 165 (23), 157 (40), 155 (33), 153 (29), 141 (39), 131 (20), 130 (28), 129 (51), 128 (44), 116 (25), 115 (89), 105 (44), 91 (47), 77 (15), 69 (100) [CF₃ ⁺]. HRMS (EI, 70 eV): m/z calcd for C₂₆H₂₇F₃O₃S [M⁺]: 476.16275; found: 476.16212.
• 14 Twofold Suzuki–Miyaura Reaction – General Procedure 4-Methoxyphenylboronic acid (0.60 mmol, 91 mg), K₃PO₄ (0.60 mmol, 127 mg), Pd(OAc)₂ (5 mol%, 2.2 mg), and SPhos (10 mol%, 8.2 mg) were weighed into a pressure tube under argon. Compound 3f (0.20 mmol, 96 mg) was dissolved in toluene (4 mL) and added to the pressure tube. The reaction was stirred at 100 °C for 20 h. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate (3 × 10 mL). The crude product 4a was purified via column chromatography (heptane/dichloromethane, 5:1); yield 64 mg (73%). [α]_D ³⁰= 28.5 (CHCl₃, β = 1.1 mg mL^–1); mp 181–183 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.08 (s, 3 H, CH₃), 1.52–1.60 (m, 1 H, ­CH_Alkyl), 1.70–1.90 (m, 4 H, CH_Alkyl), 2.01–2.22 (m, 3 H, CH_Alkyl), 2.32–2.39 (m, 3 H, CH_Alkyl), 3.00–3.06 (m, 2 H, CH_Alkyl), 3.87 (s, 3 H, OCH₃), 5.92 (dd, ³ J = 3.15 Hz, ³ J = 1.73 Hz, 1 H, C=CH), 6.98–7.06 (m, 4 H, CH_Ar), 7.33–7.42 (m, 5 H, CH_Ar), 7.53–7.56 (m, 2 H, CH_Ar). ¹³C NMR (75 MHz, CDCl₃): δ = 16.6 (CH₃), 26.6, 27.7, 29.6, 31.3, 35.5 (CH₂), 37.2, 44.5 (CH), 47.6 (C), 55.3 (OCH₃), 56.9 (CH), 114.1 (CH_Ar), 115.0 (d, ² J = 21.1 Hz, CH_Ar), 124.0, 125.5 (CH_Ar), 127.0 (C=CH), 127.3, 128.0 (CH_Ar), 128.2 (d, ³ J = 7.72 Hz, CH_Ar), 133.3 (d, ⁴ J = 3.34 Hz, C_Ar), 133.7, 137.0, 138.2, 139.0 (C_Ar), 154.0 (C=CH), 158.9 (C_Ar), 161.9 (d, ¹ J = 245.6 Hz, C–F). ¹⁹F NMR (282 MHz, CDCl₃): δ = –115.92. IR (ATR): ν = 2924 (w), 2904 (w), 2850 (w), 1601 (w), 1508 (m), 1490 (m), 1279 (w), 1244 (m), 1222 (m), 1179 (m), 1038 (m), 843 (m), 807 (s), 647 (w), 556 (m), 521 (w), 504 (w) cm^–1. MS (EI, 70 eV): m/z (%) = 439 (28), 438 (100) [M⁺], 250 (15), 249 (21), 247 (15), 173 (21), 165 (12), 133 (13), 109 (18). HRMS (EI, 70 eV): m/z calcd for C₃₁H₃₁FO [M⁺]: 438.23535; found: 438.23428.
• 15 CCDCs 1882186 and 1882187 contain supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.