SARs of 17R-Derivatives of Estradiol
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4475
NMR δ (DMSO-d6) 14.37, 23.38, 26.15, 27.28, 29.15, 30.71,
32.47, 37.30, ∼ 39 (under solvent peaks), 43.29, 47.52, 49.04,
84.45, 112.67, 114.91, 125.97, 128.35, 128.46 (2x), 130.44,
135.65, 136.80 (2x), 137.14, 154.89. Anal. (C25H28O2Cl2) C, H,
Cl.
3,17â-Dih yd r oxy-17r-(2′-n a p h t h ylm et h yl)est r a -1,3,5-
(10)-tr ien e (24): white solid (59% yield); IR υ (film) 3400 (OH);
1H NMR δ (acetone-d6) 1.00 (s, 3H, 18-CH3), 2.80 (m, 2H,
6-CH2), 2.90 and 3.09 (2d, J ) 13.3 Hz, 2H, CH2Naphthyl),
6.56 (d, J ) 2.2 Hz, 1H, 4-CH), 6.63 (dd, J 1 ) 2.6 Hz and J 2
)
8.3 Hz, 1H, 2-CH), 7.14 (d, J ) 8.4 Hz, 1H, 1-CH), 7.42 to 7.86
(m, 7H, CH2Naphthyl), 7.94 (br, 1H, OH phenol); 13C NMR δ
(acetone-d6) 15.27, 24.12, 27.51, 28.57, ∼30 (under solvent
peaks), 32.30, 33.83, 41.16, 43.68, 44.92, 48.19, 50.47, 84.06,
113.76, 116.13, 125.97, 126.52, 127.17, 127.66, 128.42, 128.48,
130.37, 131.21, 132.31, 133.22, 134.50, 138.46, 138.62, 156.10;
LRMS for [MH - H2O]+ 395.3 m/z. Anal. (C29H32O2) C, H.
3,17â-Dih yd r oxy-17r-(3′,4′-d ich lor oben zyl)estr a -1,3,5-
(10)-tr ien e (19): white solid (26% yield); IR υ (film) 3420 (OH);
1H NMR (acetone-d6) 0.98 (s, 3H, 18-CH3), 2.80 (m, 3H, 6-CH2
and 1H of CH2PhCl2), 2.92 (d, J ) 13.5 Hz, 1H of CH2PhCl2),
6.54 (d, J ) 2.7 Hz, 1H, 4-CH), 6.60 (dd, J 1 ) 2.7 Hz and J 2
)
8.5 Hz, 1H, 2-CH), 7.12 (d, J ) 8.4 Hz, 1H, 1-CH), 7.35 (dd, J 1
) 2.0 Hz and J 2 ) 8.4 Hz, 1H, 6′-CH), 7.45 (d, J ) 8.1 Hz, 1H,
5′-CH), 7.62 (d, J ) 1.9 Hz, 1H, 2′-CH), 7.90 (br, 1H, OH
phenol); 13C NMR δ (methanol-d4/CDCl3) 15.05, 23.89, 27.26,
28.44, 30.46, 32.06, 32.86, 40.88, 42.88, ∼49 (under solvent
peaks), 50.56, 83.96, 113.48, 115.48, 126.97, 130.22, 130.56,
131.59, 132.16, 132.33, 133.70, 138.40, 140.73, 155.38; LRMS
for [MH - H2O]+ 413.3 m/z. Anal. Calcd for C25H28O2Cl2: C,
69.60; H, 6.54; Cl, 16.44. Found: C, 69.06; H, 6.64; Cl, 16.95.
3.4. Syn th esis of Com p ou n d 25 (a lk yla tion w ith p h en -
yllith iu m a cetylid e). Phenyllithium acetylide was prepared
at -78 °C and under an argon atmosphere by reacting
phenylacetylene (5.5 mmol) and n-BuLi (5.5 mmol) in dry THF
(20 mL) and HMPA (2.0 mL) as cosolvent. A solution of E1
(300 mg, 1.08 mmol) in dry THF (10 mL) was then added and
the reaction mixture was allowed to return slowly to room
temperature overnight. After addition of water, the aqueous
phase was extracted with EtOAc and the organic layer was
washed with brine, dried over MgSO4, and evaporated to
dryness. The crude residue was purified by chromatography
(hexane/EtOAc, 80:20) to afford a mixture of alkylated com-
pound 25 and unreacted E1. This mixture was then dissolved
in MeOH (20 mL) and treated with NaBH4 (2 equiv) at 0 °C.
After complete reduction of E1 to E2 (2 h), the reaction was
quenched with H2O, MeOH was evaporated under vacuum,
and the products extracted with EtOAc. The organic phase was
dried over MgSO4 and evaporated under vacuum before
purification by chromatography (hexane/EtOAc, 85:15) to give
E2 (49%) and alkylated compound 25 (45%).
3,17â-Dih ydr oxy-17r-(4′-m eth oxyben zyl)estr a-1,3,5(10)-
tr ien e (20): white solid (28% yield); IR υ (film) 3380 (OH); 1H
NMR δ (CDCl3) 0.97 (s, 3H, 18-CH3), 2.64 and 2.88 (2d, J )
14.2 Hz, 2H, CH2PhOCH3), 2.83 (m, 2H, 6-CH2), 3.81 (s, 3H,
PhOCH3), 5.07 (br, 1H,OH phenol), 6.57 (d, J ) 2.7 Hz, 1H,
4-CH), 6.64 (dd, J 1 ) 2.7 Hz and J 2 ) 8.4 Hz, 1H, 2-CH), 6.88
(d, J ) 8.6 Hz, 2H, 3′ and 5′-CH), 7.18 (d, J ) 8.6 Hz, 1H,
1-CH), 7.22 (d, J ) 8.6 Hz, 2H, 2′ and 6′-CH); 13C NMR δ
(acetone-d6) 15.03, 23.76, 27.15, 28.25, ∼30 (under solvent
peaks), 31.89, 33.29, 40.75, 42.25, 44.52, 47.66, 50.12, 55.19,
83.59, 113.44, 116.67 (2x), 115.83, 126.84, 131.89, 131.98,
132.72 (2x), 138.27, 155.71, 158.78; LRMS for [M]+ 392 m/z.
Anal. (C26H32O3) C, H.
3,17â-Dih ydr oxy-17r-(2′-ph en yl-1′-eth yn -1′-yl)estr a-1,3,5-
(10)-tr ien e (25): white solid (45% yield); IR υ (film) 3420 (OH);
1H NMR δ (acetone-d6) 0.95 (s, 3H, 18-CH3), 2.80 (m, 2H,
6-CH2), 6.53 (d, J ) 2.4 Hz, 1H, 4-CH), 6.60 (dd, J 1 ) 2.7 Hz
and J 2 ) 8.4 Hz, 1H, 2-CH), 7.12 (d, J ) 8.4 Hz, 1H, 1-CH),
7.35 (m, 3H, CtCPh), 7.43 (m, 2H, CtCPh), 7.92 (br, 1H, OH
phenol); 13C NMR δ (acetone-d6) 13.43, 23.61, 27.43, 28.21, ∼30
(under solvent peaks), 34.06, 40.03, 40.66, 44.73, 48.46, 50.69,
80.20, 85.51, 95.15, 113.63, 115.96, 124.49, 127.10, 128.84,
129.28 (2x), 131.94, 132.20 (2x), 138.43, 155.93; LRMS for [MH
- H2O]+ 355.3 m/z. Anal. (C26H28O2) C, H.
3.5. Syn t h esis of Com p ou n d 26 (r ed u ct ion of t r ip le
bon d ). As reported for compounds 5 and 11, the catalytic
hydrogenation of alkyne 25 afforded the saturated compound
26, which was purified by chromatography with hexane/EtOAc
(85:15).
3,17â-Dih yd r oxy-17r-(2′-p h en yl-1′-eth yl)estr a -1,3,5(10)-
tr ien e (26): white solid (95% yield); IR υ (film) 3380 (OH); 1H
NMR δ (methanol-d4) 0.93 (s, 3H, 18-CH3), 2.75 (m, 4H, 6-CH2
and CH2Ph), 6.46 (d, J ) 2.5 Hz, 1H, 4-CH), 6.51 (dd, J 1 ) 2.6
Hz and J 2 ) 8.5 Hz, 1H, 2-CH), 7.04 (d, J ) 8.5 Hz, 1H, 1-CH),
7.10 to 7.28 (m, 5H, (CH2)2Ph); 13C NMR δ (acetone-d6) 15.00,
24.11, 27.22, 28.28, ∼30 (under solvent peaks), 30.92, 32.45,
34.51, 40.30, 40.78, 44.54, 47.63, 50.36, 83.11, 113.47, 115.84,
126.13, 126.86, 128.99 (2x), 129.21 (2x), 132.00, 138.32, 144.61,
155.84; LRMS for [MH - H2O]+ 359.2 m/z. Anal. (C26H32O2)
C, H.
4. P r ep a r a tion of 16r- or 16â-Ben zylestr a d iol 27 or 28
(Sch em e 3). 4.1. Alk yla tion of TBDMS-E1 a n d Clea va ge
of TBDMS Gr ou p . Under an argon atmosphere, a solution
of lithium diisopropylamide (LDA) was prepared at 0 °C by
adding n-BuLi (1.17 mmol) to a solution of diisopropylamine
(1.34 mmol) in dry THF (25 mL). After 2 h, the mixture was
cooled at -78 °C and TBDMS-estrone25f (300 mg, 0.78 mmol)
dissolved in dry THF (10 mL) was added dropwise. Benzyl
bromide (267 mg, 1.56 mmol) was added after 1 h and the
mixture was allowed to warm slowly to room temperature
overnight. Then, the mixture was poured into water and
extracted with EtOAc. The combined organic phase was
washed with brine, dried (MgSO4), and evaporated to dryness.
The crude mixture was purified by chromatography (hexane/
EtOAc, 85:15) to give 80% of monobenzyl E1 and 11% of
3,17â-Dih yd r oxy-17r-(4′-b en zyloxyb en zyl)est r a -1,3,5-
(10)-tr ien e (21): white solid (43% yield); IR υ (film) 3330 (OH);
1H NMR δ (CDCl3) 0.97 (s, 3H, 18-CH3), 2.63 and 2.87 (2d, J
) 13.3 Hz, 2H, CH2PhOCH2Ph), 2.82 (m, 2H, 6-CH2), 4.63 (br,
1H, OH phenol), 5.06 (s, 2H, CH2PhOCH2Ph), 6.57 (d, J ) 2.5
Hz, 1H, 4-CH), 6.63 (dd, J 1 ) 2.7 Hz and J 2 ) 8.4 Hz, 1H,
2-CH), 6.95 (d, J ) 8.6 Hz, 2H, 3′ and 5′-CH), 7.18 (d, J )
10.4 Hz, 1H, 1-CH), 7.22 (d, J ) 8.6 Hz, 2H, 2′ and 6′-CH),
7.30 to 7.47 (m, 5H, CH2PhOCH2Ph); 13C NMR δ (CDCl3) 14.51,
23.31, 26.33, 27.49, 29.65, 31.37, 33.69, 39.64, 41.45, 43.84,
46.73, 49.53, 70.03, 83.25, 112.72, 114.55 (2x), 115.29, 126.46,
138.19, 153.52, 157.51; LRMS for [M]+ 468 m/z. Anal. (C32H36O3)
C, H.
3,17â-Dih yd r oxy-17r-(4′-b u t ylb en zyl)est r a -1,3,5(10)-
tr ien e (22): white solid (91% yield); IR υ (film) 3410 (OH); 1H
NMR δ (methanol-d4/CDCl3) 0.90 (t, J ) 7.3 Hz, 3H, Ph-
(CH2)3CH3), 0.91 (s, 3H, 18-CH3), 2.54 (t, J ) 7.8 Hz, 2H,
PhCH2(CH2)2CH3), 2.60 and 2.82 (2d, J ) 13.4 Hz, 2H, CH2-
Ph(CH2)3CH3), 2.78 (m, 2H, 6-CH2), 6.51 (d, J ) 2.5 Hz, 1H,
4-CH), 6.57 (dd, J 1 ) 2.6 Hz and J 2 ) 8.4 Hz, 1H, 2-CH), 7.05
(d, J ) 8.0 Hz, 2H, 3′ and 5′-CH), 7.09 (d, J ) 10.0 Hz, 1H,
1-CH), 7.16 (d, J ) 8.0 Hz, 2H, 2′ and 6′-CH); 13C NMR δ
(CDCl3/methanol-d4) 14.25, 15.12, 23.05, 23.87, 27.25, 28.42,
30.44, 31.99, 32.68, 34.55, 35.94, 40.83, 42.88, 44.74, 47.95,
50.52, 84.10, 113.43, 115.86, 126.94, 128.48(2x), 131.76(2x),
132.42, 136.75, 138.61, 141.10, 155.28; LRMS for [M]+ 418 m/z.
Anal. Calcd for C29H38O2: C, 83.21; H, 9.15. Found: C, 82.71;
H, 9.22.
3,17â-Dih yd r oxy-17r-(4′-ter t-b u t ylb en zyl)est r a -1,3,5-
(10)-tr ien e (23): white solid (77% yield); IR υ (film) 3400 (OH);
1H NMR δ (CDCl3) 0.97 (s, 3H, 18-CH3), 1.33 (s, 9H, tert-butyl),
2.65 and 2.90 (2d, J ) 13.2 Hz, 2H, CH2Ph-t-Bu), 2.84 (m, 2H,
6-CH2), 4.68 (br, 1H, OH phenol), 6.58 (d, J ) 2.4 Hz, 1H,
4-CH), 6.63 (dd, J 1 ) 2.7 Hz, and J 2 ) 8.3 Hz, 1H, 2-CH), 7.17
(d, J ) 8.6 Hz, 1H, 1-CH), 7.22 (d, J ) 8.2 Hz, 2H, 2′ and 6′-
CH), 7.35 (d, J ) 8.2 Hz, 2H, 3′ and 5′-CH); 13C NMR δ
(acetone-d6) 15.25, 24.03, 27.45, 28.52, ∼30 (under solvent
peaks), 31.87, 32.21, 33.61, 34.92, 41.11, 42.92, 44.88, 48.02,
50.38, 83.76, 113.69, 116.08, 125.29 (2x), 127.13, 131.88 (2x),
132.25, 137.35, 138.58, 149.07, 156.05; LRMS for [M]+ 418 m/z.
Anal. (C29H38O2) C, H.