Nghiên cứu cải tiến phương pháp tổng hợp furoquinolin ancaloit -fagarin

Recently, some of the furoquinoline alkaloids were found to have an interesting biological activity, for example, anti-cancer, antiplatelet aggregation and antifungal activities. The interesting biological activity made these compounds 1-13 attractive targets in organic chemistry. A novel generally applicable synthesis of furoquinolines is described. The condensation of 2- methoxy aniline and malonic acid in the presence of POCl3 gave 2,4-dichloro-8- methoxyquinoline. Then, treatment of this compound with sodium methoxide in methanol under reflux afforded 4,8-dimethoxyquinoline. Thus, -fagarine was synthesized by lithiation of 2,4,8- trimethoxy quinoline followed by treatment of the organolithium compound with ethylene oxide, and then by oxidation and cyclization.
Nội dung trích xuất từ tài liệu:
Nghiên cứu cải tiến phương pháp tổng hợp furoquinolin ancaloit -fagarinT¹p chÝ Hãa häc, T. 42 (3), Tr. 348 - 352, 2004 Nghiªn cøu c¶i tiÕn ph ¬ng ph¸p tæng hîp furoquinolin ancaloit -fagarin §Õn Tßa so¹n 25-3-2004 NguyÔn V¨n TuyÕn, NguyÔn V¨n Hïng ViÖn Hãa häc, ViÖn Khoa häc v# C«ng nghÖ ViÖt Nam Summary Recently, some of the furoquinoline alkaloids were found to have an interesting biological activity, for example, anti-cancer, antiplatelet aggregation and antifungal activities. The interesting biological activity made these compounds 1-13 attractive targets in organic chemistry. A novel generally applicable synthesis of furoquinolines is described. The condensation of 2- methoxy aniline and malonic acid in the presence of POCl3 gave 2,4-dichloro-8- methoxyquinoline. Then, treatment of this compound with sodium methoxide in methanol under reflux afforded 4,8-dimethoxyquinoline. Thus, -fagarine was synthesized by lithiation of 2,4,8- trimethoxy quinoline followed by treatment of the organolithium compound with ethylene oxide, and then by oxidation and cyclization. I - Më ®Çu R1 OMe R1 OMe 2 O R Furoquinolin ancaloit l líp chÊt thiªn nhiªntån t¹i phæ biÕn trong chi Haplophyllum v O N O R3 N ODictamnus thuéc hä cam quÝt (Rutaceae). Do cã R2 R4ho¹t tÝnh sinh häc lÝ thó, vÝ dô, c¸c furoquinolin OMe1 - 7 (h×nh 1) t¸ch ®3îc tõ Vepris punctata [1] 1®Òu cã ho¹t tÝnh g©y ®éc trªn dßng tÕ b o ung Rth3 buång trøng A2780. C¸c furoquinolin 6 - 9 R2 O N®B t¸ch ®3îc tõ Acronychia laurifolia cã ho¹t R3tÝnh g©y ®éc tÕ b o trªn c¸c dßng tÕ b o ung th3cña ng3êi [2]. C¸c hîp chÊt 6, 7, 8 v 13 ®3îc 1 R1 = OMe, R2 = H; 2 R1 = R2 = OMet¸ch tõ Melicope confuse [3a] v dictamnin (10), 3 R1 = H, R2 = OMe; 4 R1 = R2 = H -fagarin (11) v haplopin (12) t¸ch tõ Toddalia 5 R1 = R2 = R3 = R4 = Hasiatica [3b] ®Òu cã ho¹t tÝnh chèng kÕt tô tiÓu 6 R1 = R4 = H, R2 = R3 = OMe (kokusaginin)cÇu. Ngo i ra, c¸c chÊt evolitrin (8) v 10 t¸ch 7 R1 = R2 = H, R3 = R4 = OMe (skimianin)®3îc tõ Evodia luna-ankenda cã ho¹t tÝnh g©y 8 R1 = R2 = R4 = H, R3 = OMe (evolitrin)ng¸n ¨n ®èi víi lo i s©u b3ím h¹i thuèc l¸ 9 R2 = R4 = OMe, R1 = R3 = H (macolusidin)Spodoptera lieura [4]. C¸c chÊt 10 v 12 ®3îc 10 R1 = R2 = R3 = H (dictamnin)x¸c ®Þnh cã ho¹t tÝnh k×m hBm nÊm g©y bÖnh 11 R1 = R2 = H, R3 = OMe ( -fagarin)Cladosporium cucumerium [5]. V× cã ho¹t tÝnh 12 R1 = H, R2 = OH, R3 = OMe (haplopin)sinh häc lÝ thó nh3 ®B nªu trªn nªn líp chÊt n y 13 R1 = R3 = H, R2 = OH (confusamelin)rÊt ®3îc quan t©m nghiªn cøu. H×nh 1348 TiÕp tôc nh÷ng c«ng tr×nh cña chóng t«i vÒ 3. Tæng hîp 3(2-hi®r«xyetyl)-2,4,8-trimetoxy-nghiªn cøu t×m kiÕm c¸c chÊt cã ho¹t tÝnh sinh quinolin (23)häc tõ c©y cá, còng nh3 viÖc nghiªn cøu tæng Dung dÞch 15,1 mmol (6 ml) cña n-BuLihîp c¸c hîp chÊt thiªn nhiªn cã ho¹t tÝnh sinh (2,5 M trong hexan) ®3îc nhá giät tõ tõ v o hçnhäc cao, trong c«ng tr×nh n y chóng t«i th«ng hîp cña 2,4,8-trimetoxyquinolin (13,7 mmol, 3b¸o ph3¬ng ph¸p hiÖu qu¶ tæng hîp mét ®¹i g) trong THF (150 ml) ë 0oC. Hçn hîp ph¶n øngdiÖn cña líp chÊt n y, ®ã l -fagarin. ®3îc duy tr× ë nhiÖt ®é n y trong kho¶ng 1,5 giê, sau ®ã etylen oxit tõ b×nh chøa ®3îc ®3a II - thùc nghiÖm v o hçn hîp ph¶n øng. Hçn hîp ®3îc khuÊy ë 0oC trong vßng 30 phót sau ®ã duy tr× ë nhiÖt ®é Phæ céng h3ëng tõ proton (300 MHz) v phßng trong 2 giê. Hçn hîp ph¶n øng ®3îc xö lÝcacbon-13 (75 MHz) ®3îc ®o trªn m¸y Varian víi n3íc ®¸. Pha h÷u c¬ ®3îc thu håi, l m khanXL 300. Phæ IR ®3îc ®o trªn m¸y Midac FTIR v lo¹i dung m«i nhËn ®3îc s¶n phÈm th«, sauspectrometer. Phæ khèi l3îng ®3îc ®o trªn m¸y ®ã ...