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Synlett 2005(12): 1848-1852  
DOI: 10.1055/s-2005-871930
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Phenol or Carbinol Glycosidation of 17β-Estradiol and Derivatives Thereof

Matteo Adinolfi, Alfonso Iadonisi*, Alessandro Pezzella, Alessandra Ravidà
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Via Cynthia 4, 80126 Napoli, Italy
Fax: +39(081)674393; e-Mail: iadonisi@unina.it;
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Publication History

Received 26 April 2005
Publication Date:
07 July 2005 (online)

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Abstract

Unprecedented regioselective glycosidations of 17b-estradiol and nitro substituted derivatives thereof either at the phenol or carbinol position is reported. In the former case, glycosyl bromides or iodides were employed as the donors in a base promoted reaction conducted under two-phase conditions. In the latter case, glycosyl trichloroacetimidate donors were used in combination with the mild activation of 4 Å acid washed molecular sieves.

Key words

steroids - glycosidation - regioselectivity - zeolites - phase-transfer

18

Typical Procedure of Phenol Glycosidation of Estradiol.
An aqueous solution of NaOH (5%, 4 mL) was added at r.t. to a suspension of 17β-estradiol (27 mg, 0.1 mmol) and TBAB (32 mg, 0.1 mmol) in CH2Cl2 (2 mL) and the system kept under stirring for 10 min. A solution of crude iodide9 1 (0.15 mmol) in CH2Cl2 (2 mL) was then added. After the consumption of the donor (ca 4 h, TLC analysis), the mixture was repeatedly extracted with CH2Cl2 and the collected organic phases dried and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether-EtOAc from 7:3 to 6:4) to yield pure glycoside 3 (45 mg, 75% yield).
Compound 3: [α]D +51.9 (c 0.7, CH2Cl2). 1H NMR (200 MHz, CDCl3): indicative signals at δ = 7.21 (1 H, d, J 1,2 = 8.2 Hz, H-1 estradiol), 6.77 (1 H, dd, J 2,4 = 2.4 Hz, H-2 estradiol), 6.72 (1 H, d, H-4 estradiol), 5.47 (1 H, dd, J 1,2 = 7.8 Hz, J 2,3 = 10.4 Hz, H-2 Gal), 5.44 (1 H, br d, J 3,4 = 3.6 Hz, H-4 Gal), 5.08 (1 H, dd, H-3 Gal), 4.99 (1 H, d, H-1 Gal), 4.30-4.08 (2 H, m, H2-6 Gal), 4.04 (1 H, br t, J 5,6a = J 5,6b = 6.4 Hz, H-5 Gal), 3.73 (1 H, t, J = 8.0 Hz, H-17 estradiol), 2.18, 2.06, 2.06, 2.01 (12 H, 3 × s, 4 × -COCH3), 0.77 (3 H, s, CH3 estradiol). 13C NMR (50 MHz, CDCl3): δ = 170.3, 170.1, 169.4 (-COCH3), 154.9, 138.3, 135.5 (aromatic C), 126.4, 116.9, 114.3 (aromatic CH), 99.9 (C-1 Gal), 81.8 (C-17 estradiol), 70.9, 70.9, 68.7, 67.0 (C-2, C-3, C-4, and C-5 Gal), 61.4 (C-6 Gal), 20.6 (4 × -COCH3), 11.0 (CH3 estradiol). Other signals of estradiol at δ = 50.0, 44.0, 43.2, 38.7, 36.7, 30.6, 29.7, 27.1, 26.2, 23.1. MALDI-TOF MS: for C32H42O11 (602.3) m/z = 625. 5 [M + Na]+.

19

Typical Procedure of Carbinol Glycosidation of Estradiol.
Freshly activated 4 Å AW 300 MS (ca 500 mg in pellets) were added to a mixture of donor 13 (28 mg, 0.053 mmol) and 17β-estradiol (16 mg, 0.059 mmol). The mixture was suspended under argon with anhyd dichloroethane (1 mL) at 0 °C and then the temperature was allowed to rise spontaneously. The mixture was left overnight under stirring at r.t. and then filtered on a short plug of silica gel. The residue was purified by silica gel chromatography (eluent: toluene-EtOAc, 8:2) to afford monoglycoside 14 (16 mg, 47% yield), unreacted estradiol, and then diglycoside 15 (9 mg, 32%).
Compound 14: [α]D +16.4 (c 0.6, CH2Cl2). 1H NMR (400 MHz, CDCl3): indicative signals at δ = 7.14 (1 H, d, J 1,2 = 8.4 Hz, H-1 estradiol), 6.63 (1 H, dd, J 2,4 = 2.4 Hz, H-2 estradiol), 6.56 (1 H, d, H-4 estradiol), 5.13 (1 H, t, J 2,3 = J 3,4 = 9.6 Hz, H-4 Glc), 5.06 (1 H, t, J 2,3 = 9.6 Hz, H-3 Glc), 4.85 (1 H, dd, J 1,2 = 8.0 Hz, H-2 Glc), 4.58 (1 H, d, H-1 Glc), 4.26 (1 H, dd, J 6a,5 = 5.2 Hz, J 6a,6b = 12.3 Hz, H-6a Glc), 4.15 (1 H, dd, J 6b,5 = 2.8 Hz, H-6b Glc), 3.81 and 3.78 (6 H, 2 × s, 2 × -OCH3), 3.70 (1 H, m, H-5 Glc), 3.63 (1 H, t, J = 8.4 Hz, H-17 estradiol), 2.10 and 2.05 (6 H, 2 × s, 2 -COCH3), 0.75 (3 H, s, CH3 estradiol). 13C NMR (50 MHz, CDCl3): δ = 170.6 and 169.4 (2 × -COCH3), 155.1 and 154.5 (2 × -OCO2CH3), 153.3, 138.2, 126.5 (aromatic C), 126.4, 115.2 and 112.6 (aromatic CH), 101.6 (C-1 Glc), 90.7 (C-17 estradiol), 76.6, 75.2, 71.6, 68.7 (C-2, C-3, C-4, and C-5), 62.1 (C-6), 55.3 and 55.2 (-OCO2CH3), 20.8 and 20.6 (4 × -COCH3), 11.5 (CH3 estradiol). Other signals of estradiol at δ = 49.6, 43.9, 43.3, 38.5, 37.2, 29.5, 28.8, 27.1, 26.3, 23.1. MALDI-TOF MS: for C32H42O13 (634.3) m/z = 657.4 [M + Na]+.
Compound 15: [α]D +26.6 (c 0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3): indicative signals at δ = 7.18 (1 H, d, J 1,2 = 8.4 Hz, H-1 estradiol), 6.75 (1 H, dd, J 2,4 = 2.4 Hz, H-2 estradiol), 6.71 (1 H, d, H-4 estradiol), 5.20-5.00 (6 H, overlapped signals, H-3 and H-4 phenol and carbinol Glc, H-1 and H-2 phenol Glc), 4.84 (1 H, dd, J 1,2 = 8.0 Hz, H-2 Glc), 4.57 (1 H, d, H-1 Glc), 4.28-4.10 (4 H, overlapped signals, H2-6 carbinol and phenol Glc), 3.84 (1 H, m, H-5 phenol Glc), 3.82, 3.80, 3.78, 3.77 (12 H, 4 × s, 4 × -OCH3), 3.70 (1 H, m, H-5 carbinol Glc), 3.64 (1 H, t, J = 8.4 Hz, H-17 estradiol), 2.09, 2.07, 2.05, 2.04 (12 H, 4 × s, 4 × -COCH3), 0.73 (3 H, s, CH3 estradiol). 13C NMR (50 MHz, CDCl3): δ = 170.6 and 169.3 (-COCH3), 155.1 and 154.5 (-OCO2CH3 and C-3 estradiol), 138.2, 135.4 (aromatic C), 126.4, 117.2, 114.5 (aromatic CH), 101.6 (C-1 carbinol Glc), 99.1 (C-1 phenol Glc), 90.6 (C-17 estradiol), 76.6, 75.2, 74.8, 71.6, 71.5, 68.7, 68.3 (C-2, C-3, C-4, and C-5, phenyl and carbinol Glc), 61.9 (C-6, phenyl and carbinol Glc), 55.3
(-OCO2CH3), 20.6 and 20.5 (-COCH3), 11.4 (CH3 estradiol). Other signals of estradiol at δ = 49.6, 43.9, 43.2, 38.3, 37.1, 29.6, 28.8, 27.0, 26.1, 23.1. MALDI-TOF MS: for C46H60O24 (996.4) m/z = 1019.3 [M + Na]+.