Design, synthesis, and discovery of stilbene derivatives based on ...

4484 M. Jung et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4481–4486OOCH 3aClRcROOCH 3ClH 3 COH 3 CO14OH13fH 3 COH 3 CO2a: R= CH 2 OH3a: R= CHO15a : Ec:ZbOOCH 3geHOHO4a: R=Cl12: R=I13: R=P + Ph 3 I -d15bOOCH 3Scheme 2. Reagents <strong>and</strong> conditions: (a) DIBAL-H, 78°C, CH 2 Cl 2 ,N 2 , 91%; (b) PCC, 0 °C, CH 2 Cl 2 ,N 2 , 90%; (c) (CH 3 O) 2 P(O)CH 2 CO 2 CH 3 ,NaOCH 3 , MeOH, 91%; (d) NaI, N 2 , acetone, reflux, 90%; (e) TPP, NaOCH 3 , MeOH, 91%; (f) n-BuLi, THF, 0 °C, 12 h, 62%; (g) BBr 3 ,CH 2 Cl 2 ,0°C,28%.R 1 OOOR 2cOORdHOORR 1 OOHOb16 : R 1 =R 2 = H17 : R 1 =R 2 = CH 318 : R 1 =CH 3 , R 2 =Ha19a (99%; R=diethyl amine)19b (72%; R=aniline)20a (26%; R=diethyl amine)20b (26%; R=aniline)Scheme 3. Reagents <strong>and</strong> conditions: (a) CH 2 N 2 ,Et 2 O, 0 °C, 40%; (b) 1 N-LiOH, THF/H 2 O (1/1), rt, 90%; (c) HOBt, EDC, amine, CH 2 Cl 2 , rt; (d)BBr 3 ,CH 2 Cl 2 ,0°C.R 2R 329a : R 1 =R 3 =H, R 2 =OCH 329b : R 1 =H, R 2 =R 3 =OCH 329c : R 1 =R 2 =OCH 3 , R 3 =HR 1aNO 2NO 230a (89% : R 1 =R 3 =H, R 2 =OH)30b (79% : R 1 =H, R 2 =R 3 =OH)30c (80% : R 1 =R 2 =OH,R 3 =H)Scheme 4. Reagents <strong>and</strong> conditions: (a) BBr 3 ,CH 2 Cl 2 ,0°C, 2 h.<strong>stilbene</strong> derivative 15b 8,13 [28% yield, a yellow solid:R f = 0.47 (hexane/ethyl acetate, 1/1, v/v);1 H NMR(500 MHz, CD 3 OD) d 7.72 (d, 1H, J = 16.00 Hz, trans,vinyl H), d 7.60–7.55 (m, 4H, aromatic H), d 7.20 (d,J = 16.00, 1H, trans, vinyl H), d 7.07 (s, 1H, aromaticH), d 6.98 (d, 1H, J = 16.50, vinyl H), d 6.94 (d, 1H,J = 9.00, aromatic H), d 6.80 (d, 1H, J = 8.50, aromaticH), d 6.70 (d, 1H, J = 8.50, aromatic H), d 6.55 (d, 1H,J = 16.50 trans vinyl H), d 3.82 (s, 3H, –OCH 3 ). IR t max3413, 3020, 1634, 1439, 1251 cm 1 . HRMS (MALDI-TOF): m/z 297.0743 ([M+H] + , obsd), 296.1049 (calcdfor C 18 H 16 O 4 ).Similarly, demethylation <strong>of</strong> 15c (Z-form) provided28a 14 (Fig. 2) in 54% yield. Reduction <strong>and</strong> followingoxidation <strong>of</strong> the ester group <strong>of</strong> compound (trans form)6 <strong>and</strong> its cis-form, with subsequent amide coupling <strong>and</strong>deprotection afforded, 11b (60%) as a green solid. 1 HNMR (250 MHz, CD 3 OD); d 7.93–7.89 (d, 2H,J = 8.39Hz, aromatic H), d 7.71–7.60 (m, 4H, aromaticH), d 7.41-7.33 (m, 3H, aromatic H), d 7.20–7.17(m,2H, aromatic H, vinyl CH), d 7.07–6.91 (m, 2H, aromaticH, vinyl CH), d 6.78–6.75 (d, 1H, J = 8.2Hz, aromaticH). IR t max 3442, 1646, 1600, 1525, 1441 cm 1 .HRMS (MALDI-TOF): m/z 354.1351 ([M+Na] + ,obsd), 331.1208 (calcd for C 21 H 17 NO 3 ) <strong>and</strong> 27a(Fig. 2) in 20% yields.For preparation <strong>of</strong> dihydroxycinnamic acid <strong>derivatives</strong>,protection <strong>of</strong> 3,4-dihydroxycinnamic acid, 16, <strong>and</strong> selectivehydrolysis <strong>of</strong> 17 <strong>and</strong> subsequent amide formation <strong>of</strong>18 provided compounds 19a in 99% yield <strong>and</strong> 19b in72% yield as the known procedure, 10 respectively(Scheme 3). Final demethylation 15 <strong>of</strong> 19a, 19b by theboron tribromide in CH 2 Cl 2 cleanly afforded <strong>stilbene</strong><strong>derivatives</strong> 20a <strong>and</strong> 20b (26% yields, E-form: d 6.55 (d,1H, J = 15.6 Hz, trans vinyl CH), <strong>and</strong> d 7.52 (d, 1H,J = 15.6 Hz, trans, vinyl CH)).Similarly, demethylation <strong>of</strong> nitro <strong>stilbene</strong>s 29a–c by theboron tribromide 15 in CH 2 Cl 2 cleanly afforded <strong>stilbene</strong><strong>derivatives</strong> 30a–c in 79–89% yields (Scheme 4). 30c:R f = 0.13 (hexane/ethyl acetate, 2/1, v/v), E-form d7.65 (d, 1H, J = 16.2 Hz, trans, vinyl CH), d 7.76 (d,1H, J = 16.2 Hz, trans vinyl CH). IR t max 3437,1633, 1529, 1346. HRMS (MALDI-TOF): m/z303.0775 ([M+H] + , obsd), 302.0539 (calcd forC 14 H 10 N 2 O 6 ).To examine the structure-activity relationships <strong>of</strong> dihydroxy<strong>stilbene</strong> compounds on PTP1B, a variety <strong>of</strong>