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ISBN: 978-604-913-012-0 Tiiu ban: cdc chdt co hogt linh sinh hqc TONG HOP MOT SO DAN CHAT PYRANONAPTHOQUINON Nguyen Van Tuyen, Nguyen Due Vinh, Vu Thi Thu Ha va Dang Thi Tuyet Anh Vien Hda hoe, Vien Khoa hoc va Cdng nghe Viet Nam Abstract: Naturally occurring pyranonaphthoquinones are of special interest due to their important physiological activities. In continuation of our synthetic efforts towards physiologically active psychorubrin derivatives, we now report here a convenient synthesis of psychorubrin derivatives in four steps with a good yield from 1,4naphthoquinone. LMuDau Cac chdt khang sinh thien nhien thudc Idp chat pyranonaphthoquinon la nhiing chat thudc khung lH-naphtho[2,3-c]pyran-5,10-dion. Cac chdt nay chii yeu dugc tim tbay trong cac vi khudn, vi ndm va trong thuc vat [1]. Mot sd pyranonaphthoquinon cd boat tinh khang khudn, khang ndm, chdng sdt ret, virut va chdng ung thu (bioreductive alkyllating agents) [2,3]. Vi du diln hinh vl ldp chdt nay la elutherin (1), nanomycin A (2) va frenolycin B (3) (hinh 1) [4-5]. Psychombrin (4) la hgp chat pyranonaphthoquinon tu nbien cd hoat tinh chdng ung thu, chdng sdt ret va da dugc chiet tach tu Psychotrla rubra [6]. Do cd hoat tinh sinh hoc ly thii nen ldp chat nay rat dugc cac nha hda hoc nghien ciiu tdng hgp. Gan day, Brimble M. A. va cac cdng sir da nghien cuu tdng hgp (-H) eleutherin la cac dan chat ciia ldp chat pyranonaphthoquinon va nghien ciiu boat tinh sinh hoc ciia ehiing. Ket qua nghien ciiu cho thay cac chat nay cd boat tinh lie che topoisomerase 11 va boat tinh gay doe te bao [7]. OH O 1 (eleutherin) O COOH 2 (nanaomycin) 3 (frenolycin) 4 (Psychorubrin) Hinh 1 Trudc day, chiing tdi ciing da xay dung phuang phap mdi, hieu qua tdng hgp psychorubrin (4) qua phan lin^ Grubs metathesis [8]. Tilp tuc hudng nghien ciiu tdng hgp cac chat pyranonaphthoquinon nham muc dich tim kilm cac chdt cd hoat tinh sinh hoc, trong bai bao nay chiing tdi thdng bao ket qua tdng hgp mot vai dan chdt pyranonaphthoquinon tir nguyen lieu 1,4-pyranonaphthoquinon. II. Ket qua va Thao luan Qua trinh tdng hgp 2-phenoxymethyl-l,4-pyranonaphtboquinon (6) duge tiln hanh nhu md ta trong so dd 1. 1,4-Napbthoquinon (5) phan umg vdi axit phenoxyaeetic trong sir cd mat ciia amonium persulfat va bae nitrat, d nhiet do 70°C, trong khoang thdi gian 3 h nhan dugc san pham 6 vdi hieu sudt cao (85%) [9]. 194 Hoi nghi Khoa hqc ky niem 35 ndm Vien Khoa hqc vd Cong nghe Viet Nam - Hd Noi 10/2010 1,5 equiv. phenoxyaeetic axil 1,5 equiv. (NH^),S,08 0,29 equiv. AgNOj, CH3CN H,0,700C,3 h 1.5 equiv. Br 1.5 equiv. Et3N,CH3CN 40°C, 4h 1,1 equiv. EtjN toluen, dun h6i 1 u 7a R= CHCCHj), (93%) 7b R = 4-F-C6H4(89%) 8a R= CH(CH3)2 (86%) 8 b R = 4-F-Cf,H4(83%) Sadd I Tiep theo qua trinh tdng hgp chat 7a,b dugc thue hien theo phan iing cdng Maicon. Pyridium ylid dugc dieu che khi cho mudi ciia pyridin tac dung vdi trietylamin, ylid tao ra tham gia phan img vdi quinon (6) tao thanh san pham 7a,b vdi bieu suat cao [9,10]. Phan iing vdng hda ndi phan tir ciia quinon 7a,b dugc thuc hien bang each cho tac dung ciia chat nay vdi mot duang lugng ciia trietylamin, va dugc dun hdi luu trong toluen, trong khoang 2 b, nhan dugc pyranonaphthoquinon (8a,b) vdi bieu suat tuong iing la 86% va 87% [9,10]. 10 equiv. EtjSiH 10 equiv. CF3COOH, CH2CI2, rt 9a R= CH(CH3), (62%) 9bR=4-F-C6H4 (66%) 8a R= CH(CH3), 8bR = 4-F-C6H4 Sodd 2 Phan ling tdng hgp cac chat pyanonapbtboquinon (9a,b) (so dd 2) dugc thuc bien khi cho 3,4-dehydropyranonaphthoquinon (8a,b) tac dung vdi axit trifloaxetic vdi sir cd mat ciia trietylsilan du, trong dung mdi diclometan, d nhiet do phdng nhan dugc cac chat 9a va 9b vdi hieu xudt tuong img la 62% va 66%. 195 ISBN: Tiiu ban: cdc chat co hogt tinh sinh hqc 978-604-913-012-0 CF3COOH 8a R= CH(CH3)2 8b R = 4-F-C6H4 Et3SiH Et3Si H lla,b Sodd 3 Co che ciia phan iing nay cd the dugc gia thiet nhu md ta t^ong so dd 3. Dudi tac dung ciia axit CF3COOH cac chat 8a,b dugc proton hda tao thanh oxonium trung gian lla,b. Tiep theo chat tmng gian nay phan img vdi anion H" tao thanh san pham 9a,b. Tdm lai, chiing tdi da nghien cuu thanh cdng phuang phap don gian, hieu qua tdng hgp cac dan chat ciia pyranonaphthoquinon 9a va 9b tir 1,4- naphthoquinon (5) qua bdn bude phan ling. III. Thuc nghiem 1. Thiet bj nghien cuu Phd cdng hudng tir proton ' H - N M R (500 MHz) va caebon '^C-NMR (125MHz) dugc do tren may cdng hudng tir hat nhan Avance 500 (Bruker, CHLB Dire). Phd khdi lugng dugc do tren may khdi phd MS 5989B (Helwlett Packard, My), Phd IR dugc do tren may quang phd hdng ngoai FTIR Impact 410 (CHLB Dire). 2. Tong hup Tong hup 2-phenoxymetyl-l,4-naphthoquion (6) Nhd giot tir tir (khoang 1 h) dung dich eiia 32,8 g (14 mmol) ciia (NH4)2S202 trong 300 ml nude vao hon hgp phan iing gdm 15 g (96 mmol) 1,4- naphthoquinone (5), 22,2 g (144 mmol) ciia phenoxyaeetic axit, 4,89 g (28 mmol) AgN03, 300 ml nude va 300 ml acetonitril da dugc dun ndng din 70°C. Phan iing tilp tuc duy tri d nhiet do nay khoang 30 phut, sau do lam lanh bang da mudi dl tiia san phdm phan img. San pham tiia ra dugc loc va rira nhieu lan vdi nude. San pham sau dd dugc hda tan trong CH2CI2, lge qua Celite va lam khan bang dung dich MgS04, loai bd dung mdi nhan dugc 17 g san pham 6 (85%)) [9]. San phdm la chdt rdn mdu vang, dnc: 160-161 °C. ' H - N M R (500 MHz, CDCI3) 6: 8,06-8,12 (2H, 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' 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 = 196 Hoi nghi Khoa hqc ky- niem 35 ndm \ 'ien Khoa hqc vd Cong nghe Viet Nam - Hd Noi 10/2010 2,1 Hz, CH2-O). '^C-NMR (125 MHz. CDCI3) 5: 184,65 (0=0); 184,56 (0=0); 157.76 (C-2); 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'); 126,73 (C-8'); 121,68 (C-5'); 114.67 (C-5' va C-2'); 76.58 (CH2-O). IR (KBr) : 1662, 1625, 1598, 1497, 1338, 1246, 1056, 944, 898, 782 cm"'. MS (m/z): 264 [M^]. Tong hop 3-isobutyl-17/-naptho [2,3-c] pyran-5,10-dion (8a) Nhd giot dung dich 2 g (18,94 mmol) ciia Et3N trong 10 ml toluen vao dung dich phan ling gdm 1 g (2,87 mmol) 2-(oxo-3-methylbutyI)-3-phenoxymetbyI-l,4-naphthoquinon (7a) va 20 ml toluen. Hdn hgp phan iing dugc dun hdi luu trong 2 b, sau dd lam lanh va ehilt san pham bang EtOAc. Dich chiet dugc rira bang nude, lam khan bang MgS04, sau dd cdt loai dung nidi nhan dugc san pham thd. San pham dugc lam sach tren cot sdc ki Si02 nhan dugc san phdm (8a) vdi hieu sudt 86% [10]. San phdm la chdt dang ddu mdu hdng. ' H - N M R (500 MHz, CDCI3) 6 1,21 (6H, d, J = 7 Hz, 2XCH3); 2,55 (IH, sextet, J = 7 Hz, (CH3)2H); 5,18 (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 (m/z): 254 [M^]. Tong hop 3-(4-florophenyl)-liy-naptho[2,3-c] pyran -5,10-dion (8b) Nhd giot dung dich 2 g (18,94 mmol) ciia Et3N trong 10 ml toluen vao dung dich phan img gdm Ig (2,5 mmol) 2-(2-(4-fluoro phenyI)-2-oxoethyI)3-phenoxymethyl-l,4naphthoquinon (7b) ya 20 ml toluen. Hon hgp phan iing dugc dun bdi luu trong 2 h, sau dd lam lanh va ehilt san pham bdng EtOAc. Dich ehilt dugc rira bdng nude, lam khan bdng MgS04, sau dd lai cat loai dung mdi nhan duge san phdm thd. San phdm dugc lam sach tren cot sdc ki Si02 nhan dugc san phdm (83%) [9]. San phdm la chdt rdn mdu hdng, dnc: 190-192 °C. 'H 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 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 (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 = 268 Hz, CF), 160,9 (C-1), 138,2 (Cquat), 134.0 (0-7), 133.2 (C-8), 132.7 (Cquat), 131.7 (Cquat), 128.8 (Cquat), 128,5 (C-3'), 127,6 (C-5'), 126,5 (C-6), 126,0 (C-9), 123,3 (Cquat), 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, 1588, 1547, 1497, 1335, 830, 714 cm"'; MS, (m/z): 306 (M^ 2), 243 (3), 210 (7), 154 (19); 144 (10); 98 (100). Tong hop 3-isopropyl-3,4-dihydro-l/^-naphtho[2,3-c]pyran-5,10-dion (9a) Nhd giot 0,5 ml CF3COOH va 0,5ml (C2H5)3SiH vao hon hgp gdm 96 mg (0,375 mmol) 3-isopropyl-3,4-dihydro-l//-naphtho[2,3-c]pyran-5,10-dion (8a) trong 5 ml CH2CI2. Phan ling dugc khuay qua dem d nhiet do thudng. Khi phan irng kit thiic dung mdi dugc cdt loai d ap suat thap, chiet san pham bang CH2CI2, dich ehilt dugc rira bdng nude din trung tinh va, sau dd lam khan bang Na2S04, cat loai dung mdi nhan dugc san phdm thd. San phdm thd dugc lam sach tren cot sdc ky vdi chdt hdp phu Si02 vdi he dung mdi hexan/EtOAc (98/2) nhan dugc san pham 9a vdi hieu sudt 62%. San phdm la chdt rdn mdu vang nhat, mp: 136137°C. 'H-NMR (500MHz, CDCI3) 6: 1,03 (6H, dd, J =7Hz, 2xCH3); 1,83-1,88 (IH, m, HI,); 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, H-3); 4,49 (IH ddt, J,=0,5Hz, J2= 3Hz, J3= 19, H-la); 4,89 (IH, dd, J,= 3Hz, J2= I9Hz, HIb); 7,74 (2H, m, H-7 va H-8): 8,06-8,11 (2H, m, H-6 va H-9). '^C-NMR (125MHz, CDCI3) 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 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 142,89 (C-11 va C-12); 183,47 va 183,95(0-5 va C-10). IR (KBr): 1660; 1590; 1333; 1293; 1175; 795; 699 cm"'. MS {m/z): 256 [M^] 197 Tiiu ban: cdc chdl co hogt tinh sinh hqc ISBN: 978-604-913-012-0 T6ng hop 3-(4-fluorophenyI)-3,4-dihydro-l/f-naphtho[2,3-c]pyran-5,10-dion (9b) Nhd giot 0,5 ml CF3COOH va 0,5 ml (C2H5)3SiH vao hon hgp gdm 9 mg (0,03 mmol) 3-(4-fluorophenyl)-3,4-dibydro-I//-naphtho[2,3-c]pyran-5,10-dion (8b). va 5 ml CH2CI2. Phan ling dugc khuay qua dem d nhiet do thudng. Kbi phan iing kit thiic dung mdi dugc cat loai d ap sudt thdp, phdn cdn lai dugc chiet san pham bang CH2CI2. rira bdng nude den trung tinh va, sau dd lam khan bang Na2S04, cat loai dung mdi nhan dugc san phdm thd. San pham thd dugc lam sach tren cot sdc ki Si02 vdi he dung mdi bexan/EtOAc (98/2) nhan dugc san phdm 9b (66%). San phdm la chdt rdn mdu vang nhat, mp: 149-150°C. ' H - N M R (500 MHz, 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 (IH, dd, J,=3Hz, J2=10Hz, H-3); 4,71 (IH, ddt, J,=3Hz, J2=19Hz, H-la); 5,01 (IH, dd, 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'); 7,737,76 (2H, m, H-7 va H-8); 8,08-8,12 (2H, m, H-6 va H-9). '^C-NMR (I25MHz, CDCI3) 6: 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 06'); 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 (04'); 183,32 va 183,56 (C-5 va C-10). IR (KBr): 1656; 1592; 1302; 1255; 1095, 842; 701 cm"'. MS {m/z): 308 [M]^ TAI LIEU THAM KHAO 1. Thomson, "R. H. Naturally Occuring Quinones", 2" ed.; Academic Press: London, 1971, p 282, see also p597. 2. Wang, W.; Li, T.; Milburn, R.; Yates, J.; Hinnant, E.; Luzzio, M. J.; Noble, S. A.; Attardo, G. Biorg Med Chem. Leti, 1998, 8, 1579-1584. 3. Lee, H;. Hong, S. H.; Kim, Y. H. Bioorg Med Chem. Lett. 1996, 6 (8), 933-936. 4. Namta, Y.; Mamyama, K., "Recent Advances In the Synthesis of Qulnonoid Compounds", In The Chemistry of Quinonoid Compounds, Vol. 2, Patai, S., Rappoport, Z., Eds., John Wiley: New York, 1998, 241. 5. Moore, H. W. Science 1977, 197, 527. 6. T. Hayashi, F. T. Smith, K. H. Lee, J. Med. Chem., 1987, 30, 2005-2008. 7. Jonathan Sperry , Isabel Lorenzo-Castrillejo, Margaret A. Brimble, Felix Machin, J Bioorganic & Medicinal Chemistry, 2009, 17, 7131-7137. 8. Nguyen Van Tuyen and Norbert De Kimpe, Tetrahedrron Letter 2004, 45, 3443-3446. 9. Nguyin Van Tuyin va Vu Thi Thu Ha, Tap Chi Khoa hoc va Cdng Nghe, 2007, T45, 5A, 251-254. 10. Nguyin Van Tuyin va Nguyin Thi Phuang Chi, Tap chi duoc hoc, 2007, 375,7, 3235. 198