Tổng hợp một số dẫn chất Pyranonapthoquinon

Tiiu ban: cdc chdt co hogt linh sinh hqc ISBN: 978-604-913-012-0<br /> <br /> <br /> <br /> TONG HOP MOT SO DAN CHAT PYRANONAPTHOQUINON<br /> <br /> Nguyen Van Tuyen, Nguyen Due Vinh, Vu Thi Thu Ha va Dang Thi Tuyet Anh<br /> Vien Hda hoe, Vien Khoa hoc va Cdng nghe Viet Nam<br /> Abstract:<br /> Naturally occurring pyranonaphthoquinones are of special interest due to their<br /> important physiological activities. In continuation of our synthetic efforts towards<br /> physiologically active psychorubrin derivatives, we now report here a convenient<br /> synthesis of psychorubrin derivatives in four steps with a good yield from 1,4-<br /> naphthoquinone.<br /> <br /> LMuDau<br /> Cac chdt khang sinh thien nhien thudc Idp chat pyranonaphthoquinon la nhiing chat<br /> thudc khung lH-naphtho[2,3-c]pyran-5,10-dion. Cac chdt nay chii yeu dugc tim tbay trong<br /> cac vi khudn, vi ndm va trong thuc vat [1]. Mot sd pyranonaphthoquinon cd boat tinh khang<br /> khudn, khang ndm, chdng sdt ret, virut va chdng ung thu (bioreductive alkyllating agents)<br /> [2,3]. Vi du diln hinh vl ldp chdt nay la elutherin (1), nanomycin A (2) va frenolycin B (3)<br /> (hinh 1) [4-5]. Psychombrin (4) la hgp chat pyranonaphthoquinon tu nbien cd hoat tinh chdng<br /> ung thu, chdng sdt ret va da dugc chiet tach tu Psychotrla rubra [6]. Do cd hoat tinh sinh hoc<br /> ly thii nen ldp chat nay rat dugc cac nha hda hoc nghien ciiu tdng hgp.<br /> Gan day, Brimble M. A. va cac cdng sir da nghien cuu tdng hgp (-H) eleutherin la cac<br /> dan chat ciia ldp chat pyranonaphthoquinon va nghien ciiu boat tinh sinh hoc ciia ehiing. Ket<br /> qua nghien ciiu cho thay cac chat nay cd boat tinh lie che topoisomerase 11 va boat tinh gay<br /> doe te bao [7].<br /> OH O<br /> <br /> <br /> <br /> <br /> O COOH<br /> 4 (Psychorubrin)<br /> 1 (eleutherin) 2 (nanaomycin) 3 (frenolycin)<br /> Hinh 1<br /> Trudc day, chiing tdi ciing da xay dung phuang phap mdi, hieu qua tdng hgp<br /> psychorubrin (4) qua phan lin^ Grubs metathesis [8]. Tilp tuc hudng nghien ciiu tdng hgp cac<br /> chat pyranonaphthoquinon nham muc dich tim kilm cac chdt cd hoat tinh sinh hoc, trong bai<br /> bao nay chiing tdi thdng bao ket qua tdng hgp mot vai dan chdt pyranonaphthoquinon tir<br /> nguyen lieu 1,4-pyranonaphthoquinon.<br /> <br /> II. Ket qua va Thao luan<br /> Qua trinh tdng hgp 2-phenoxymethyl-l,4-pyranonaphtboquinon (6) duge tiln hanh<br /> nhu md ta trong so dd 1. 1,4-Napbthoquinon (5) phan umg vdi axit phenoxyaeetic trong sir cd<br /> mat ciia amonium persulfat va bae nitrat, d nhiet do 70°C, trong khoang thdi gian 3 h nhan<br /> dugc san pham 6 vdi hieu sudt cao (85%) [9].<br /> <br /> <br /> <br /> 194<br />  Hoi nghi Khoa hqc ky niem 35 ndm Vien Khoa hqc vd Cong nghe Viet Nam - Hd Noi 10/2010<br /> <br /> <br /> <br /> 1,5 equiv. phenoxyaeetic axil<br /> 1,5 equiv. (NH^),S,08<br /> <br /> 0,29 equiv. AgNOj, CH3CN<br /> H,0,700C,3 h<br /> <br /> <br /> <br /> 1.5 equiv.<br /> Br<br /> 1.5 equiv. Et3N,CH3CN<br /> 40°C, 4h<br /> <br /> <br /> <br /> <br /> 1,1 equiv. EtjN<br /> <br /> toluen, dun h6i 1 u<br /> <br /> <br /> 7a R= CHCCHj), (93%)<br /> 8a R= CH(CH3)2 (86%) 7b R = 4-F-C6H4(89%)<br /> 8 b R = 4-F-Cf,H4(83%)<br /> <br /> <br /> Sadd I<br /> <br /> Tiep theo qua trinh tdng hgp chat 7a,b dugc thue hien theo phan iing cdng Maicon.<br /> Pyridium ylid dugc dieu che khi cho mudi ciia pyridin tac dung vdi trietylamin, ylid tao ra<br /> tham gia phan img vdi quinon (6) tao thanh san pham 7a,b vdi bieu suat cao [9,10]. Phan iing<br /> vdng hda ndi phan tir ciia quinon 7a,b dugc thuc hien bang each cho tac dung ciia chat nay<br /> vdi mot duang lugng ciia trietylamin, va dugc dun hdi luu trong toluen, trong khoang 2 b,<br /> nhan dugc pyranonaphthoquinon (8a,b) vdi bieu suat tuong iing la 86% va 87% [9,10].<br /> <br /> <br /> 10 equiv. EtjSiH<br /> <br /> 10 equiv. CF3COOH,<br /> CH2CI2, rt<br /> <br /> <br /> 8a R= CH(CH3), 9a R= CH(CH3), (62%)<br /> 8bR = 4-F-C6H4 9bR=4-F-C6H4 (66%)<br /> <br /> <br /> Sodd 2<br /> <br /> Phan ling tdng hgp cac chat pyanonapbtboquinon (9a,b) (so dd 2) dugc thuc bien khi<br /> cho 3,4-dehydropyranonaphthoquinon (8a,b) tac dung vdi axit trifloaxetic vdi sir cd mat ciia<br /> trietylsilan du, trong dung mdi diclometan, d nhiet do phdng nhan dugc cac chat 9a va 9b vdi<br /> hieu xudt tuong img la 62% va 66%.<br /> <br /> <br /> <br /> <br /> 195<br /> Tiiu ban: cdc chat co hogt tinh sinh hqc ISBN: 978-604-913-012-0<br /> <br /> <br /> <br /> <br /> CF3COOH<br /> <br /> <br /> <br /> <br /> 8a R= CH(CH3)2<br /> Et3SiH<br /> 8b R = 4-F-C6H4<br /> <br /> <br /> <br /> <br /> Et3Si H<br /> <br /> lla,b<br /> <br /> <br /> Sodd 3<br /> <br /> Co che ciia phan iing nay cd the dugc gia thiet nhu md ta t^ong so dd 3. Dudi tac dung<br /> ciia axit CF3COOH cac chat 8a,b dugc proton hda tao thanh oxonium trung gian lla,b. Tiep<br /> theo chat tmng gian nay phan img vdi anion H" tao thanh san pham 9a,b.<br /> Tdm lai, chiing tdi da nghien cuu thanh cdng phuang phap don gian, hieu qua tdng<br /> hgp cac dan chat ciia pyranonaphthoquinon 9a va 9b tir 1,4- naphthoquinon (5) qua bdn bude<br /> phan ling.<br /> <br /> III. Thuc nghiem<br /> 1. Thiet bj nghien cuu<br /> Phd cdng hudng tir proton ' H - N M R (500 MHz) va caebon '^C-NMR (125MHz) dugc<br /> do tren may cdng hudng tir hat nhan Avance 500 (Bruker, CHLB Dire). Phd khdi lugng dugc<br /> do tren may khdi phd MS 5989B (Helwlett Packard, My), Phd IR dugc do tren may quang<br /> phd hdng ngoai FTIR Impact 410 (CHLB Dire).<br /> 2. Tong hup<br /> Tong hup 2-phenoxymetyl-l,4-naphthoquion (6)<br /> Nhd giot tir tir (khoang 1 h) dung dich eiia 32,8 g (14 mmol) ciia (NH4)2S202 trong<br /> 300 ml nude vao hon hgp phan iing gdm 15 g (96 mmol) 1,4- naphthoquinone (5), 22,2 g<br /> (144 mmol) ciia phenoxyaeetic axit, 4,89 g (28 mmol) AgN03, 300 ml nude va 300 ml<br /> acetonitril da dugc dun ndng din 70°C. Phan iing tilp tuc duy tri d nhiet do nay khoang 30<br /> phut, sau do lam lanh bang da mudi dl tiia san phdm phan img. San pham tiia ra dugc loc va<br /> rira nhieu lan vdi nude. San pham sau dd dugc hda tan trong CH2CI2, lge qua Celite va lam<br /> khan bang dung dich MgS04, loai bd dung mdi nhan dugc 17 g san pham 6 (85%)) [9]. San<br /> phdm la chdt rdn mdu vang, dnc: 160-161 °C. ' H - N M R (500 MHz, CDCI3) 6: 8,06-8,12 (2H,<br /> m, H-5 va H-8); 7,73-7,76 (2H, m, H-6 va H-7); 7,28-7,34 (2H, m, H-2' va H-6'); 7,17 (1H'<br /> dd, J = 4,3 Hz va J = 2,1 Hz, H-4'); 6,97-7,02 (3H, m, H-3', H-3 va H-5'); 5,06 (2H, d, J =<br /> <br /> 196<br />  Hoi nghi Khoa hqc ky- niem 35 ndm \ 'ien Khoa hqc vd Cong nghe Viet Nam - Hd Noi 10/2010<br /> <br /> <br /> 2,1 Hz, CH2-O). '^C-NMR (125 MHz. CDCI3) 5: 184,65 (0=0); 184,56 (0=0); 157.76 (C-2);<br /> 146,17 (C-r); 134,12 (C-7); 133,96 (C-6); 133,79 (C-4'); 132 (C-q); 129,70 (C-l' va C-6');<br /> 126,73 (C-8'); 121,68 (C-5'); 114.67 (C-5' va C-2'); 76.58 (CH2-O). IR (KBr) : 1662, 1625,<br /> 1598, 1497, 1338, 1246, 1056, 944, 898, 782 cm"'. MS (m/z): 264 [M^].<br /> Tong hop 3-isobutyl-17/-naptho [2,3-c] pyran-5,10-dion (8a)<br /> Nhd giot dung dich 2 g (18,94 mmol) ciia Et3N trong 10 ml toluen vao dung dich phan<br /> ling gdm 1 g (2,87 mmol) 2-(oxo-3-methylbutyI)-3-phenoxymetbyI-l,4-naphthoquinon (7a)<br /> va 20 ml toluen. Hdn hgp phan iing dugc dun hdi luu trong 2 b, sau dd lam lanh va ehilt san<br /> pham bang EtOAc. Dich chiet dugc rira bang nude, lam khan bang MgS04, sau dd cdt loai<br /> dung nidi nhan dugc san pham thd. San pham dugc lam sach tren cot sdc ki Si02 nhan dugc<br /> san phdm (8a) vdi hieu sudt 86% [10]. San phdm la chdt dang ddu mdu hdng. ' H - N M R (500<br /> MHz, CDCI3) 6 1,21 (6H, d, J = 7 Hz, 2XCH3); 2,55 (IH, sextet, J = 7 Hz, (CH3)2H); 5,18<br /> (2H, s, H-I); 6,63 (IH, s, H-2), 7,68-7,75 (2H, m, H-7, H-8); 8,07-8,11(2H, m, H-6, H-9). MS<br /> (m/z): 254 [M^].<br /> Tong hop 3-(4-florophenyl)-liy-naptho[2,3-c] pyran -5,10-dion (8b)<br /> Nhd giot dung dich 2 g (18,94 mmol) ciia Et3N trong 10 ml toluen vao dung dich phan<br /> img gdm Ig (2,5 mmol) 2-(2-(4-fluoro phenyI)-2-oxoethyI)3-phenoxymethyl-l,4-<br /> naphthoquinon (7b) ya 20 ml toluen. Hon hgp phan iing dugc dun bdi luu trong 2 h, sau dd lam<br /> lanh va ehilt san pham bdng EtOAc. Dich ehilt dugc rira bdng nude, lam khan bdng MgS04,<br /> sau dd lai cat loai dung mdi nhan duge san phdm thd. San phdm dugc lam sach tren cot sdc ki<br /> Si02 nhan dugc san phdm (83%) [9]. San phdm la chdt rdn mdu hdng, dnc: 190-192 °C. 'H<br /> NMR (CDCI3) 6: 8,09-8,12 (2H, m, H-6 and H-9), 7,80 (2H, dd, J = 5,4 va J= 6,7 Hz, H-2' va<br /> H-6'), 7,66-7,78 (2H, m, H-8 va H-7); 7,10 (2H, dd, J, = 5,4 Hz, J2= 6,7 Hz, H-3' va H-5'); 6,66<br /> (IH, s, H-4); 5,31 (2H, s, H-1); '^0 NMR (CDCI3) 5: 182,1 (0=0), 181,7 (0=0), 164,2 (d, J =<br /> 268 Hz, CF), 160,9 (C-1), 138,2 (Cquat), 134.0 (0-7), 133.2 (C-8), 132.7 (Cquat), 131.7<br /> (Cquat), 128.8 (Cquat), 128,5 (C-3'), 127,6 (C-5'), 126,5 (C-6), 126,0 (C-9), 123,3 (Cquat),<br /> 115,9 (0-2'), 115,6 (C-6'), 93,4 (C-4), 63,5 (C-1); IR (KBr) : 1657 (0=0), 1647 (0=0), 1640,<br /> 1588, 1547, 1497, 1335, 830, 714 cm"'; MS, (m/z): 306 (M^ 2), 243 (3), 210 (7), 154 (19);<br /> 144 (10); 98 (100).<br /> Tong hop 3-isopropyl-3,4-dihydro-l/^-naphtho[2,3-c]pyran-5,10-dion (9a)<br /> Nhd giot 0,5 ml CF3COOH va 0,5ml (C2H5)3SiH vao hon hgp gdm 96 mg (0,375<br /> mmol) 3-isopropyl-3,4-dihydro-l//-naphtho[2,3-c]pyran-5,10-dion (8a) trong 5 ml CH2CI2.<br /> Phan ling dugc khuay qua dem d nhiet do thudng. Khi phan irng kit thiic dung mdi dugc cdt<br /> loai d ap suat thap, chiet san pham bang CH2CI2, dich ehilt dugc rira bdng nude din trung<br /> tinh va, sau dd lam khan bang Na2S04, cat loai dung mdi nhan dugc san phdm thd. San phdm<br /> thd dugc lam sach tren cot sdc ky vdi chdt hdp phu Si02 vdi he dung mdi hexan/EtOAc (98/2)<br /> nhan dugc san pham 9a vdi hieu sudt 62%. San phdm la chdt rdn mdu vang nhat, mp: 136-<br /> 137°C. 'H-NMR (500MHz, CDCI3) 6: 1,03 (6H, dd, J =7Hz, 2xCH3); 1,83-1,88 (IH, m, H-<br /> I,); 2,33 - 2,41(1H, m, H-4a), 2,71-2,76( Ih, ddt, J,= 3Hz, J2= 19Hz, H-4b); 3,20-3,24(IH,m,<br /> H-3); 4,49 (IH ddt, J,=0,5Hz, J2= 3Hz, J3= 19, H-la); 4,89 (IH, dd, J,= 3Hz, J2= I9Hz, H-<br /> Ib); 7,74 (2H, m, H-7 va H-8): 8,06-8,11 (2H, m, H-6 va H-9). '^C-NMR (125MHz, CDCI3)<br /> 6: 18,03 va 18,50 (C-2' va C-2'); 25,20 (C-4); 32,082 (C-1); 63,81 (C-1); 78,69(0-3); 126,09<br /> va 126,45 (C-6 va C-9); 131,11 (C-13 va C-14); 133,68 va 133,72 (C-7 va C-8); 142,41 va<br /> 142,89 (C-11 va C-12); 183,47 va 183,95(0-5 va C-10). IR (KBr): 1660; 1590; 1333; 1293;<br /> 1175; 795; 699 cm"'. MS {m/z): 256 [M^]<br /> <br /> <br /> <br /> 197<br /> Tiiu ban: cdc chdl co hogt tinh sinh hqc ISBN: 978-604-913-012-0<br /> <br /> <br /> T6ng hop 3-(4-fluorophenyI)-3,4-dihydro-l/f-naphtho[2,3-c]pyran-5,10-dion (9b)<br /> Nhd giot 0,5 ml CF3COOH va 0,5 ml (C2H5)3SiH vao hon hgp gdm 9 mg (0,03 mmol)<br /> 3-(4-fluorophenyl)-3,4-dibydro-I//-naphtho[2,3-c]pyran-5,10-dion (8b). va 5 ml CH2CI2.<br /> Phan ling dugc khuay qua dem d nhiet do thudng. Kbi phan iing kit thiic dung mdi dugc cat<br /> loai d ap sudt thdp, phdn cdn lai dugc chiet san pham bang CH2CI2. rira bdng nude den trung<br /> tinh va, sau dd lam khan bang Na2S04, cat loai dung mdi nhan dugc san phdm thd. San pham<br /> thd dugc lam sach tren cot sdc ki Si02 vdi he dung mdi bexan/EtOAc (98/2) nhan dugc san<br /> phdm 9b (66%). San phdm la chdt rdn mdu vang nhat, mp: 149-150°C. ' H - N M R (500 MHz,<br /> CDCI3) 6: 2,61-2-68 (IH, m, H-4a); 3,05 (IH, ddt, Ji=0,5, J2 = 2.5Hz, J3= 19Hz, H-4b); 4,59<br /> (IH, dd, J,=3Hz, J2=10Hz, H-3); 4,71 (IH, ddt, J,=3Hz, J2=19Hz, H-la); 5,01 (IH, dd,<br /> Ji=2,5Hz, J2= 19Hz, H-Ib); 7,06-7,11 (2H, m, H-2', 6'); 7,39 - 7,42 (2H, m, H-3', 5'); 7,73-<br /> 7,76 (2H, m, H-7 va H-8); 8,08-8,12 (2H, m, H-6 va H-9). '^C-NMR (I25MHz, CDCI3) 6:<br /> 29,56 (C-4); 63,98 (C-1); 74,66 (C-3); 115,59 (0-3' va C-5'), 126,22 va 126,55 (C-2' va 0-<br /> 6'); 127,63 va 127,69 (C-6 va C-9); 131,92 va 132,05 (C-13 va C-14); 133,83 va 133,30 (0-<br /> 4'); 183,32 va 183,56 (C-5 va C-10). IR (KBr): 1656; 1592; 1302; 1255; 1095, 842; 701 cm"'.<br /> MS {m/z): 308 [M]^<br /> <br /> <br /> TAI LIEU THAM KHAO<br /> 1. Thomson, "R. H. Naturally Occuring Quinones", 2" ed.; Academic Press: London,<br /> 1971, p 282, see also p597.<br /> 2. Wang, W.; Li, T.; Milburn, R.; Yates, J.; Hinnant, E.; Luzzio, M. J.; Noble, S. A.;<br /> Attardo, G. Biorg Med Chem. Leti, 1998, 8, 1579-1584.<br /> 3. Lee, H;. Hong, S. H.; Kim, Y. H. Bioorg Med Chem. Lett. 1996, 6 (8), 933-936.<br /> 4. Namta, Y.; Mamyama, K., "Recent Advances In the Synthesis of Qulnonoid<br /> Compounds", In The Chemistry of Quinonoid Compounds, Vol. 2, Patai, S.,<br /> Rappoport, Z., Eds., John Wiley: New York, 1998, 241.<br /> 5. Moore, H. W. Science 1977, 197, 527.<br /> 6. T. Hayashi, F. T. Smith, K. H. Lee, J. Med. Chem., 1987, 30, 2005-2008.<br /> 7. Jonathan Sperry , Isabel Lorenzo-Castrillejo, Margaret A. Brimble, Felix Machin, J<br /> Bioorganic & Medicinal Chemistry, 2009, 17, 7131-7137.<br /> 8. Nguyen Van Tuyen and Norbert De Kimpe, Tetrahedrron Letter 2004, 45, 3443-3446.<br /> 9. Nguyin Van Tuyin va Vu Thi Thu Ha, Tap Chi Khoa hoc va Cdng Nghe, 2007, T45,<br /> 5A, 251-254.<br /> 10. Nguyin Van Tuyin va Nguyin Thi Phuang Chi, Tap chi duoc hoc, 2007, 375,7, 32-<br /> 35.<br /> <br /> <br /> <br /> <br /> 198<br />