藥用天然產(chǎn)物全合成四川大學(xué)博士考試

1、 課程主要內(nèi)容：課程主要內(nèi)容： 課程講授藥用天然產(chǎn)物全合成，著重強(qiáng)調(diào)天然 產(chǎn)物骨架的有效構(gòu)建方法，如何從小分子片斷 或從結(jié)構(gòu)相關(guān)的、資源豐富的天然產(chǎn)物合成結(jié) 構(gòu)復(fù)雜的天然藥物。授課內(nèi)容包括如下四個(gè)部 分：1) 藥用吲哚生物堿的合成；2)頭孢類抗生 素合成及新藥研發(fā)的一般程序；3) 藥用大環(huán)多 肽的合成；4) 異戊二烯類天然產(chǎn)物的生物合成。 syntheses of natural medicines 秦勇教授秦勇教授, 王光明教授，鄧金根教授，張國(guó)林教授王光明教授，鄧金根教授，張國(guó)林教授 syntheses of natural medicines 秦勇教授秦勇教授, 王光明教授，鄧金根教授，

2、張國(guó)林教授王光明教授，鄧金根教授，張國(guó)林教授 課程進(jìn)度安排課程進(jìn)度安排: 第一周：藥用吲哚生物堿慨述。第二周至第三 周：長(zhǎng)春花堿的合成。第四周：馬錢子堿和利 血平的合成。第五周至第八周：頭孢類抗生素合 成及新藥研發(fā)的一般程序。第十周：天然環(huán)肽 的分離、純化和結(jié)構(gòu)鑒定。第十一周：環(huán)肽的 合成方法學(xué)。第十二周至第十三周：藥用天然 環(huán)肽的合成。第十四周：c5單元的合成及組合。 第十五周：?jiǎn)屋?、倍半萜和二萜的合成。第?六周至第十七周：二倍半萜、三萜和類胡蘿卜 素的合成。 syntheses of natural medicines general introduction of indole alk

3、aloids 1.structurally most diverse natural product, over 5000 has been identified 2.most from plant kingdom, also from fungi，insects and mammals 3.long historic usage: traditional chinese medicines; poisons for hunting, murder; euphoriants, psychedelics and stimulants in religious activities; drug a

4、buse-serious social problem 4.human interest-pharmacological activities, lead compounds to synthetic analogue-drugs isolated in 1958 from cathrathus roseus: 1) nobel, r. l. et al. ann. n.y. acad. sci. 1958, 76, 882; 2) svoboda, g.h. et al. j. am. pharm. assoc. sci. ed. 1959, 48, 659. strong toxicity

5、 and side effects combined usage with other anticancer reagents: methotrexate, daunomycin, cyclophosphamide in the middle of 1960s was used in clinic for treatment of nonmalignant disease and malignant disease: hodgkins lymphoma, testicular cancer, bladder cancer; melanoma, lung cancer, breast cance

6、r l1210 rcc-2 colon microtuble leukemia adenocarcinoma assembly ic50 (nm) 0.4 3 300 safe drug-sar on vinblastine leading to navalbine n h n oh coome n me n meooac oh coome h vinblastine n h n oh coome n me n meooac oh coome h navalbine syntheses of natural medicines structural summaries of medicinal

7、 indole alkaloids n h n oh coome n me n meooac oh coome h vinblastine (長(zhǎng)春花堿） n h n oh coome n n meooac oh coome h vincristine (長(zhǎng)春花新堿） cho anticancer agents syntheses of natural medicines structural summaries of medicinal indole alkaloids n h nh o o indirubin （靛玉紅） “當(dāng)歸龍惠丸” n h n h oo indigo (靛蘭） “當(dāng)歸龍

8、惠丸” antileukemia 0.05% syntheses of natural medicines structural summaries of medicinal indole alkaloids blood pressure lowing agents n h n meooc reserpine (利血平） meo h h ome o o ome ome ome h n h n o h meooc me h ajamalicine（阿嗎堿） h n h n h oh h oh ajamaline (阿嗎靈） syntheses of natural medicines struc

9、tural summaries of medicinal indole alkaloids n h n n o o amauromine antibiotic, vasodilator h nh hh h nh nme hooc lysergic acid （麥角酸） n n oh oh o o h h bipolaramide antibiotic syntheses of natural medicines structural summaries of medicinal indole alkaloids n h n h meo ibogaine n h n h ibogamine n

10、h n ome h 18-methoxycoronaridine coome n h n h coronaridine coome antiaddictive syntheses of natural medicines structural summaries of medicinal indole alkaloids n n o o strychine n o n me n h n o nomopfungin (communesin b) h n n me n n perophoramidine 2 h h synthetic challenge molecules n n o o str

11、ychine （箭毒） h h n h n meooc reserpine (利血平） meo h h ome o o ome ome ome h n h n oh coome n me n meooac oh coome h vinblastine (長(zhǎng)春花堿） synthesis of vinblastine n h n oh coome n me n meooac oh coome h vinblastine (長(zhǎng)春花堿） n h n oh coome n me n meooac oh coome h vindoline p. potier et al. j. am. chem. soc

12、. 1979, 101, 2243； m. e. kuehne et al. j. org. chem. 1991, 66, 1560； p. magnus et al. j. am. soc. chem. 1992, 114, 10232； t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 synthesis of vinblastine p. potier et al. j. am. chem. soc. 1979, 101, 2243 n h n coome catharanthine mcpba cl coooh n h n co

13、ome o (cf3co)2o n h n coome o o cf3 n me n meooac oh coome h vindoline n h n coome cf3coo- n me n meooac oh coome h vindoline cf3coo- h synthesis of vinblastine p. potier et al. j. am. chem. soc. 1979, 101, 2243 n h n coome cf3coo- n me n meooac oh coome h h- n h n coome n me n meooac oh coome h h2/

14、pd/c n h n coome n me n meooac oh coome h n h n coome n me n meooac oh coome h o mcpba synthesis of vinblastine p. potier et al. j. am. chem. soc. 1979, 101, 2243 n h n coome n me n meooac oh coome h o polonovski n h n+ coome n me n meooac oh coome h h n h n coome n me n meooac oh coome h n h n coom

15、e n me n meooac oh coome h o tl(oac)3 ac2o aco- synthesis of vinblastine p. potier et al. j. am. chem. soc. 1979, 101, 2243 n h n coome n me n meooac oh coome h o nabh4 n h n coome n me n meooac oh coome h oh synthesis of vinblastine catharanthine synthesis n h n coome catharanthine b. m. trost et a

16、l. j. org. chem. 1979, 44, 2054; m. honaoka et al. tetrahydron lett. 1980, 21, 3285; g. buchi et al. j. am. chem. soc. 1970, 92, 999. catharanthine synthesis b. m. trost et al. j. org. chem. 1979, 44, 2054 catharanthine synthesis b. m. trost et al. j. org. chem. 1979, 44, 2054 catharanthine synthesi

17、s b. m. trost et al. j. org. chem. 1979, 44, 2054 n h n oboc pdcl h hpdcl n h n oboc nabh4 n h n oboc meli n h n oh f3ccooh n so3 dmso/et3n n h n o etmgcl n h n oh h+ catharanthine racemic synthesis of vinblastine m. e. kuehne et al. j. org. chem. 1991, 66, 1560 n me n meooac oh coome h vindoline h

18、b- n n otms ots ph coome n me n meooac oh coome h n n otms ots ph coome synthesis of vinblastine m. e. kuehne et al. j. org. chem. 1991, 66, 1560 ooh oh o oh oh o o o o o nabh4 sharpless asym. epoxidation mgcl /cui ome ome o3/pph3 or me2soso4/o n o h2o2/m+ o o oh oh naio4 ho ho coome coome ti(oipr)4

19、 4 a melecular sieves + t-buooh synthesis of vinblastine m. e. kuehne et al. j. org. chem. 1991, 56, 513 o o o n h n coome ph + n h n coome ph o o diels-alder n h n o o ph coome n h n o o ph coome + n h n coome n me n meooac oh coome h oh 1.1 : 1 synthesis of vinblastine m. e. kuehne et al. j. org.

20、chem. 1996, 61, 1175 o o o n h n coome + n h n coome r* o o diels-alder n h n o o ph coome n h n o o ph coome + fe me ph2p 3 ：1 synthesis of vinblastine m. e. kuehne et al. j. org. chem. 1991, 56, 513 martin e. kuehne et al. j. org. chem. 2001, 66, 1560 o o o n h n coome + n h n coome r* o o diels-a

21、lder n h n o o r* coome n h n o o r* coome + fe 9 : 1 synthesis of vinblastine m. e. kuehne et al. j. org. chem. 1991, 56, 513 n h n o o ph coome n h n ohoh ph coome n h n ohots ph coome n h n otms ots ph coome n n otms ots ph coome cl hcl ts2o et3n tmsotf et3n t-buocl et3n synthesis of vinblastine

22、m. e. kuehne et al. j. org. chem. 1991, 56, 513 n n otms ots ph coome cl n me n meooac oh coome h vindoline h b- n n otms ots ph coome agbf4 n me n meooac oh coome h n n otms ots ph coome et3n kbh4/acoh n me n meooac oh coome h n h n otms ots ph coome synthesis of vinblastine m. e. kuehne et al. j.

23、org. chem. 1991, 56, 513 n me n meooac oh coome h n h n otms ots ph coome bu4nf n me n meooac oh coome h n h n o- ots ph coome n me n meooac oh coome h n h n o ph coome n me n meooac oh coome h n h n+ ho ph coome synthesis of vinblastine m. e. kuehne et al. j. org. chem. 1991, 56, 513 n me n meooac

24、oh coome h n h n+ ho ph coome h2/pd/c n me n meooac oh coome h n h n ho coome synthesis of vinblastine p. magnus et al. j. am. soc. chem. 1992, 114, 10232 oh oh o oh oh phs o o phs sharpless asm. epoxidation ho ho coome coome ti(oipr)4 4 a melecular sieves + t-buooh phsna ome h+ meo ome n h n coome

25、o o n me n meooac oh coome h synthesis of vinblastine p. magnus et al. j. am. soc. chem. 1992, 114, 10232 o o phs o o s o ph o o s o ph aco o o s o ph ho meo- mcpba ac2o/acona k2co3/meoh o o o n h n coome o o synthesis of vinblastine p. magnus et al. j. am. soc. chem. 1992, 114, 10232 n h n coome o

26、o o o o n h n s coome + n h n ssnotf coome n h n s coome o o oh n h n s coome o o ots sn(otf)2 n et ts2o/et3n synthesis of vinblastine p. magnus et al. j. am. soc. chem. 1992, 114, 10232 n h s coome o o ots n h n s coome o o n h n coome o o n h n coome o o dbu raney nickel h2/pd/c synthesis of vinbl

27、astine p. magnus et al. j. am. soc. chem. 1992, 114, 10232 n h n coome o o pno2-phch2cocl n n h n+ coome o o r o n h n coome o o r o n me n meooac oh coome h vindoline h b- n h n o o r n me n meooac oh coome h o coome synthesis of vinblastine p. magnus et al. j. am. soc. chem. 1992, 114, 10232 n h n

28、 o o r n me n meooac oh coome h o coome h+ n h hn oh oh n me n meooac oh coome h coome py./so3 n h hn o oh n me n meooac oh coome h coome n h n+ coome n me n meooac oh coome h oh vinblastine h2/pd/c synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 n +h n ots otfa et ns c

29、oome n me n meooac oh coome h vindoline h b- n h n ots otfa et ns meooc n me n meooac oh coome h synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 n +h n ots otfa et ns meooc otbdps et ome o o n boc oh thpo ncs otbdps et otes ome o tmso + etcooh ohc otbdps et synthesis of

30、 vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 etcoohet n o obn o nc n o obn o et nc oh et nc otbdps et ohc otbdps et pivcl hn o bn o buli o cl cn (oipr)ticl3 ipr2net2 nabh4 tbdpscl imidazole dmf dibal-h tbdmscl tmscl/tescl cl o cl o synthesis of vinblastine t. fukuyama et al. j.

31、am. soc. chem. 2002, 124, 2137 ohc otbdps et otbdps et n ho otbdps et +n o- otbdps et n o otbdps et o oh otbdps et oh o o nh2oh naclo 1,3-dipolar diels-alder zn/acoh mcpba baeyer-villiger otbdps et oh o oselectivity synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 otbdps

32、 et oh o o meoh k2co3 otbdps et oh meo o hotescl imidazole dmf otbdps et otes meo o ho otbdps et otes meo o tmso tmscl imidazole dmf synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 otbdps et otes ome o tmso ho ncs o tsoh thpo ncs thpo n h s otbdps et otes ome o tmso n h

33、 othp otbdps et otes ome o tmso + lda nli thpo n r . thpo n r . h. otbdps et otes ome o tmso n boc othp boc2o dmap et3n o o o o o n n o o cl ph bu3snh synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 otbdps et oh ome o ho n boc oh otbdps et otes ome o tmso n boc othp aco

34、h tscl bu2sno et3n otbdps et ots ome o ho n boc ots nahco3 dmf otbdps et ome o o n boc ots synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 otbdps et ome o o n boc oh nsnh2 dead pph3 otbdps et ome o o n boc nhns o2ns o o nh2 o o n n o o etet mitsunobu reaction k2co3 n bo

35、c n otbdps oh et ns coome tfa n h n oh oh et ns coome tscl n h n ots oh et ns coome synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 otbdps et ome o o n boc oh nsnh2 dead pph3 otbdps et ome o o n boc nhns o2ns o o nh2 o o n n o o etet mitsunobu reaction k2co3 n boc n otb

36、dps oh et ns coome tfa n h n oh oh et ns coome tscl n h n ots oh et ns coome mitsunobu reaction synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 n h n ots oh et ns coome tfaa pridine n h n ots otfa et ns coome tbuocl n h n ots otfa et ns coome cl cl+ n +h n ots otfa et n

37、s coometfa n me n meooac oh coome h vindoline h b- n h n ots otfa et ns meooc + n me n meooac oh coome h synthesis of vinblastine t. fukuyama et al. j. am. soc. chem. 2002, 124, 2137 n h n ots otfa et ns meooc n me n meooac oh coome h et3n/meoh n h n ots oh et ns meooc n me n meooac oh coome h hs oh

38、 dbu n n n h n h ots oh et meooc n me n meooac oh coome h nahco3 n h n meooc n me n meooac oh coome h ho et synthesis of vindole n me n meooac oh coome h vindoline albert padwa et al. organic lett. 2004, aug. asap d. boger et al. j. am. chem. soc. 2002, 124, 11292; t. fukuyama et al. j. am. soc. che

39、m. 2002, 124, 2137; m. e. kuehne et al. j. org. chem. 1987, 52, 347; h. repoport et al. j. am. chem. soc.1987, 109, 1603; g. buchi et al. j. am. chem. soc. 1975, 97, 6880 synthesis of vindole albert padwa et al. organic lett. 2004, aug. asap -n2 n me n meo o o coome o 3+2 n me n meo o coome h o vind

40、oline o n me n meo o o coome o o n2 rh(i) o synthesis of vindole d. boger et al. j. am. chem. soc. 2002, 124, 11292 n o n n o obn cl cl 180 0c 4+2 -n2 n me n meo obn o coome o n n coome n me n meo obn o coome o 3+2 n me n meoobn o coome h o vindoline n me meo synthesis of vindole m. e. kuehne et al.

41、 j. org. chem. 1987, 52, 347 n h nh coome o oh cl h h meo + n h n coome meo oh n h meo n oh coome h n h meo n coome h pph3/ccl4(phse)2o n h meo n coome h oh n h meo n coome h oh o mcpba n h meo n coome h oac ho nabcnh3 ac2o h woodward synthesis of reserpine woodward, r. b. j. am. chem. soc. 1956, 78

42、, 2023 woodward, r. b. j. am. chem. soc. 1956, 78, 2657 n h n meooc reserpine (利血平） meo h h ome o o ome ome ome h n h n meooc meo h h ome oac o n h meooc n meooc meo h h ome oac n h nh2 meo meooc meooc h ome oac ohc + meooc o o o o coome + retrosynthetic analysis woodward synthesis of reserpine wood

43、ward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 meooc o o o o coome + o o coome h h h h h h h h al(oi-pr)3 i-proh oh o h h h o meerwein-ponndorf-verley reduction r1 r2 o al oipr o oipr h r1 r2 o al oipr o oipr h i-proh r1 r2 oh h al(oi-pr)3 o + h- h- back br2 oh o h h h o br o o

44、h h h o br o o h h o naome meo- -br- meo- diels-alder reaction rule: electron-deficient diene +electron rich dienophile; electron-deficient dienophile +electron rich diene. gwe1 gwe2 coome gwe2 ewg1 coome h h h h h meooc ewg2 gwe1 h h h gwe1 ewg2 coome gwe2 ewg1 h h h h h meooc ewg2 gwe1 h h h + coo

45、me endo-adduct: cis-dienophile + trans-diene; trans-dienophile + cis-diene diels-alder reaction rule meooc o o o o coome + o o coome h h h h h h h h exo-adduct: trans-dienophile + trans-diene; cis-dienophile + cis-diene; cis-dienophile + trans-diene gwe1 gwe2 coome gwe2 ewg1 meooc h h h h ewg1 gwe2

46、h h + h coome h gwe1 ewg2 coome gwe2 ewg1 coome h h h h ewg1 gwe2 h h + h coome h woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 o o h h o meo- o o h h o ome h nbs h2so4 h2o o o h h o ome h br h2o o o h h o ome h br ho o o h h o ome h br o h2c

47、r2o7 o o h h o ome h br o zn h+ o ho h h o ome h br o zn zn/acoh woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 o ho h h o ome h br o zn o ho h h o ome h br o zn h h+ oh ho h h o ome h br o zn acoh oh ho h h o ome h ho oh ho h h o ome h o -aco

48、znbr woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 oh ho h h o ome h o ch2n2 oh meo h h o ome h o ac2o oac meo h h o ome h o oac meo h h o ome h o oh oh oac meo h h o ome h o o oh oac meo h h o ome h o o ome oso4 naclo3 naio4 ch2n2 mes o o n

49、me n o naoh woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 n h meooc n meooc meo h h ome oac n h nh2 meo oac meo h h o ome h o o ome + phme nabh4 n h n meooc meo h h ome oac o n h n+ meooc meo h h ome oac cl n h n+ meooc meo h h ome oac nabh4

50、n h n meooc meo h h ome oac h woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 n h n meooc meo h h ome oac h n h n meooc reserpine (利血平） meo h h ome o o ome ome ome h epi n h n meooc meo h h ome oac h epi n h n coome h h h oac ome ome n h n coom

51、e meo ome oac h h h koh n h n cooh meo ome oh h h h dcc/pyr n h n meo ome o h h h o n+ n meo ome o h h o t-bucooh xylenes h h h+ h t-bucoo- n h n meo ome o h h o h h+ n+ n meo ome o h h o h h h n h n meo ome o h h o h -h+ woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956,

52、 78, 2023; 1956, 78, 2657 n c n n c n o n n n n cdi dic dcc rcooh+n c n n c h n o o r roh n c h n oh rcoor + h n c h n o activation of carbonic acid woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 n h n meooc meo h h ome oac h epi n h n meo ome

53、 o h h o h n h n meooc meo h h ome oac h n h n meo ome oh h h o h meo woodward synthesis of reserpine woodward, r. b. et al. j. am. chem. soc. 1956, 78, 2023; 1956, 78, 2657 n h n meo h h ome o h naome n h n meooc meo h h ome oh h ome ome ome o cl pyr n h n meooc meo h h ome o h ome ome ome o racemi

54、c n h n meooc meo h h ome o h ome ome ome o (-)-reserpine meme o s (+)-camphorsulfonic acid resolution o ooh o synthesis of reserpine sparks, s. m.; gutierrez, a. j.; shea, k. j. j. org. chem. 2003; 68 (13), 5274-5285; sparks, s. m.; shea, k. j.; org. lett.2001; 3(15), 2265-2267 woodward synthesis o

55、f strychnine woodward, r. b. et al. j. am. chem. soc. 1954, 76, 4749 n n o o strychine h h n n o o h n n o ho h n n o ohh n n o ohh o n n o oh o n nh o oh o h n nh o o me h rearrangment allylic rearrangment reduction organometallic addition oxidation h woodward synthesis of strychnine woodward, r. b

56、. et al. j. am. chem. soc. 1954, 76, 4749 n nh o o me h n nac o oh n nac o o ome oh oh n nac o o ome o ome n nac o o ome o ome h h h n nso2ar o o ome o ome h n h nso2ar meooc o ome o ome h h n ac nso2ar meooc o ome o ome h h dieckmann keto reduction epimization lactom formation deprotection ketoliza

57、tion woodward synthesis of strychnine woodward, r. b. et al. j. am. chem. soc. 1954, 76, 4749 n ac nso2ar meooc o ome o omeh n ac nso2ar o omeh ome ome n nso2ar o ome ome ome n n o ome ome ome h b- so2-ar cl n n o ome ome ome h imine formation n nh2 ome ome h n n ome ome h n ome ome h nhnh2 o ome om

58、e fisher indole synthesis c-c bond formation c-c bond formation + woodward synthesis of strychnine woodward, r. b. et al. j. am. chem. soc. 1954, 76, 4749 n ome ome h nhnh2 o ome ome fisher indole synthesis + polyphosphoric acid n h ome ome n n h ome ome n h 3, 3-rearrangment n h2 ome ome nh ome ome

59、 hn nh2 ome ome h2n nh2 -nh3 -h+ woodward synthesis of strychnine woodward, r. b. et al. j. am. chem. soc. 1954, 76, 4749 n ome ome h n ome ome h nme2 cho/hnme2 h2o-dioxane acoh mei n ome ome h n+me3 n ome ome h cn nacn lialh4 n ome ome h nh2 etocho o n ome ome h n oet o p-tscl/pyr n n o ome ome ome

60、 h b- so2-ar cl n nso2ar o ome ome ome n nso2ar o ome ome ome sole product woodward synthesis of strychnine woodward, r. b. et al. j. am. chem. soc. 1954, 76, 4749 n nso2ar o ome ome ome n h nso2ar o ome ome ome h n ac nso2ar o ome ome ome h ac2o/pyr nabh4 o3/acoh n ac nso2ar o ome coome coome h n h