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1、Total Synthesis of Amphirionin 4,-Michael Holmes, Daniel Kwon, Matthew Taron, and Robert Britton演讲小组成员：陈人豪、王兴瑞、黄渊 主讲人：陈人豪,CONTENT,1.合成化合物的结构与活性The structure and activity of synthetic compounds 2.逆合成设计思路Inverse synthetic design thinking 3.中间体的合成synthesis of intermediate 4.Amphirionin-4”s nmr data 5.有
2、关反应的反应条件与机理（附） The reaction conditions and related mechanism,Amphidinium species of marine dinoflagellates,Amphidinium species of marine dinoflagellates have proven to be a rich source of structurally diverse polyketides,1 many of which are characterized by cyclic ethers of various ring sizes and po
3、tent cytotoxic activity (e.g., amphidinolide B2 and amphidinin A3).,Amphidinium,Amphirionin 4 is the compound that we need to synthesize 。Of particular interest is amphirionin-4 (1),4a which demonstrates selective and potent proliferation activity on murine bone marrow stromal ST-2 cells (+950% grow
4、th rate at 0.1 ng/mL).,potent cytotoxic activity 具有很强的细胞毒性,Amphidinium-4,Structure characteristics：the tetrahydrofuranol core.C9-stereocenterthe polyene side chain,Retrosynthetic Analysis for Amphirionin-4 (1),The structure of three key intermediates 三个关键的中间体的结构,we envisioned three key retrosyntheti
5、c disconnections (Scheme 1) . Synthesis of intermediate 16中间体16的合成.Synthesis of intermediate33中间体33的合成Synthesis of intermediate34 中间体34的合成,Synthesis route of compound 12-13 化合物12-13的合成路线,1.TMSCl,NaI,MeCN.rt(46%),2.(COCl)2,DMSO, Et3N,CH2Cl2(70%),Swern oxidation,2.,The synthesis of target intermediate
6、 16 requires the synthesis process of 12-16 合成目标中间体16，需要经过12-16这样一个过程。,1.炔烃的亲电加成反应,Synthesis route of compound 13-14 化合物13-14的合成路线,1. 18(20mol%) NCS,CH2Cl2,Macmilllans catalyst,1.,化合物14-15的合成路线,1. acetone,LDA then14,-78,THF(78%),2. NMe4BH(OAc)3 MeCN,AcOH,-40（79%）,1.Acetone，LDA,THF为醛和酮亲核加成反应2. NMe4BH
7、(OAc)3 为一个具有绝对构型的还原剂，使得羰基被还原成固定构型的羟基。,化合物15-16的合成路线,1. wave，120 MeOH，3h,2.TBSCl imid，CH2Cl2,or Ac2O pyr,1.生成的15在甲醇存在下于微波反应器中加热到120度顺利的环化，得到四氢呋喃结构4。 4的相关的立体化学分析采用1D NOESY光谱，同时相应的（R）和（S）- MTPA酯采用改进的Mosher法确定的4的绝对立体化学构型。Moshers method2.羟基的保护,Scheme 2的总结,Scheme 3. 1,4-Stereoinduction in the NHK Reaction
8、 of Vinyl Iodide 4,1.NozakiHiyamaKishi coupling4和17与乙烯基铬中间物的竞争性结合4的C4上的醇也被作为一个TBS醚进行保护，排除在这个位置上的竞争。加入pro-S TS （见插图）来减少空间位阻作用。 但是最终没有选择这个合成路线的原因是。-OTBS保护基团无法被很好的除去。,中间体34的合成,中间体34的结构,在作者不断尝试的过程中发现，从16-21/20和34-37的合成路线并不能得到目标化合物。,化合物22-23的合成路线,1.Zr(Cp2)Cl2,AlMe3CH2Cl2,-78 to rt,2.I2,THF,-78 to0,1.二氯二茂
9、锆为催化剂，,化合物23-25的合成路线,1.n-BuLi，THF-78,2.B(OPr)3,化合物26的合成,Scheme 4. Synthesis of the Vinyl Halides 23 and 26,1.Zr(Cp2)Cl2,ALMe3,CH2Cl2,-78 to rt 2.I2，THF,-78 to 0 3.n-BuLi,THF,-78/B(O i-Pr)3 4.CHC-TMS,EtMgBr,CuBr,THF,50（74%）,Table 1. Cross-coupling Reactions to Access Diene 30,中间体33的合成路线,1.CrCl2,CHI3,
10、THF,0 2.n-BuLi,B(O i-Pr)3，THF,-78， 3.KHF2,MeCN,H2O,rt 4.t-BuLi,THF,-78 5.Bu3SnCl,Unfortunately, all attempts to remove the TBS protecting group from this material resulted in decomposition.,化合物34-38的合成路线,1.TBAF,THF,0,DMP,NaHCO3,CH2Cl2,0(65%),+,CrCl2,NiCl2DMF,rt(75%,dr4:1),TBAF,THF,0(92%),化合物38-目标化合物
11、的合成路线,1.Zr(Cp2)Cl2,AlMe3,CH2Cl2,-78 to rt,2.I2,THF,-78 to 0(94%),+,3.Pd(PPh3)4,CuTC,DMF,Ph2PO2NBu4,rt(70%),1和2反应其实是为3反应做铺垫。因为stille偶联反应，需要反应物位无H的卤代烃。Stille coupling,Moshers method,(R)-MTPA-OH,DIC,DMAP CH2Cl2,MTPA为Mosher酸，与目标化合物酯化，然后用Mosher法测出目标化合物的绝对构型是否符合要求,Amphirionin 4(1)构型检测,Scheme 6. Completion
12、 of the Synthesis of Amphirionin-4,1HNMR,1H NMR (600 MHz, C6D6) : 6.34 (ddt, J = 1.3, 12.1, 15.1 Hz, 1H), 5.98 (br d, J = 10.7 Hz, 1H), 5.81 (br s, 1H), 5.77 (ddd, J = 6.2, 10.4, 16.5 Hz, 1H), 5.57 (br dt, J = 6.2, 15.2 Hz, 1H), 5.08 (br s, 1H), 5.05 (br s, 1H), 5.02 (ddt, J = 1.8, 1.8, 16.1 Hz, 1H)
13、, 5.00 (br s, 1H), 4.98 (ddt, J = 1.5, 2.0, 9.3 Hz, 1H), 4.92 (br s, 1H), 4.12 (dd, J = 4.8, 7.8 Hz, 1H), 3.75 (br s, 1H), 3.57 (ddq, J = 1.6, 5.8, 6.8 Hz, 1H), 3.47 (ddd, J = 3.8, 4.5, 8.6 Hz, 1H), 3.09 (br s, 1H), 2.82 (br s, 2H), 2.62 (ddd, J = 0.8, 8.8, 14.9 Hz, 1H), 2.25 (ddd, J = 6.8, 6.8, 8.5
14、 Hz, 1H), 2.21 (dd, J = 4.9, 15.2 Hz, 1H), 2.15 (ddd, J = 6.8, 9.9, 19.8 Hz, 1H), 2.10 (t, J = 5.7 Hz, 2H), 2.06 (br t, J = 5.7 Hz, 2H), 1.84 (m, 2H), 1.80 (d, J = 1.0 Hz, 3H), 1.73 (m, 1H), 1.69 (br s, 3H), 1.18 (ddd, J = 2.5, 6.6, 13.4, 1H), 1.12 (d, J = 6.2 Hz, 3H).,用Chemdraw做出来的氢谱图,13CNMR,13C NM
15、R (150 MHz, C6D6) : 150.2, 144.3, 138.7, 138.5, 134.2, 132.15, 132.11, 127.7, 127.4, 126.3, 114.9, 114.8, 112.8, 84.1, 75.2, 73.8, 73.4, 48.8, 43.2, 37.2, 35.0, 34.2, 32.8, 31.6, 22.0, 18.1, 16.4.IR: 3394, 2926, 1641, 1441 cm-1. D(CHCl3, c 0.34): -5.8.,NozakiHiyamaKishi coupling,野崎-桧山-岸反应(Nozaki-Hiy
16、ama-Kishi反应，简称“NHK反应“)是由镍或铬介导的烯丙基或乙烯基卤与醛偶联为醇的反应。,Swern oxidation,Structure：,Macmilllans catalyst,常见的几种催化剂：,Moshers method,测定R-(或者S-)手性试剂与底物反应的产物的1H或者13C-NMR化学位移数据，根据化学位移差值与模型比较来推定底物手性中心的绝对构型。 。,（R)-和(S)-甲氧基三氟甲基苯基乙酸（-methyloxy-trifluoro-methyl-phenyl-acetic acid）简称Mosher酸，缩写MTPA,分别计算出(R)-Mosher酯中(R)R1和(R)R2(S)-Mosher酯中(S)R1和(S)R2 计算RX= (S)- (R),Mosher法规定 1.将为负值-H所在的基团即R1放在Mosher模式图平面的左边 2.将为正值-H所在的基团即R2放在Mosher模式图平面的右边,
