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1、Total Synthesis of Amphirionin Total Synthesis of Amphirionin 4 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CONTENTCONTENT1.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 interm
2、ediate 4.Amphirionin-4”s nmr data 5.有关反应的反应条件与机理（附） The reaction conditions and related mechanismAmphidinium species of marine dinoflagellatesAmphidinium species of marine dinoflagellates have proven to be a rich source of structurally diverse polyketides,1 many of which are characterized by cyclic
3、ethers of various ring sizes and potent 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 ma
4、rrow stromal ST-2 cells (+950% growth rate at 0.1 ng/mL).potent cytotoxic activity 具有很强的细胞毒性AmphidiniumAmphidinium-4-4Structure characteristics：the tetrahydrofuranol core.C9-stereocenterthe polyene side chainR Retrosynthetic Analysis for Amphirionin-etrosynthetic Analysis for Amphirionin- 4 (1)4 (1)
5、The structure of three key intermediates 三个关键的中间体的结构we envisioned three key retrosynthetic 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 12-13Synthesis route of compound 12-13 化合物化合物
6、12-1312-13的合成路线的合成路线1.TMSCl,NaI,MeCN.r t(46%)2.(COCl)2,DMSO, Et3N,CH2Cl2(70%)Swern oxidation2.The synthesis of target intermediate 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,CH2Cl2Macmilllans cataly
7、st1.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(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， 3h2.TBSCl imid， CH2Cl2or Ac2O pyr1.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
8、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 of Scheme 3. 1,4-Stereoinduction in the NHK Reaction of Vinyl Iodide 4Vinyl Iodide 41.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 T
9、S （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 rt2.I2,THF,-78 to01.二氯二茂锆为催化剂，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 26Scheme 4. Sy
10、nthesis of the Vinyl Halides 23 and 261.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 30Table 1. Cross-coupling Reactions to Access Diene 30entryreactantstempcatalystadditiveyield123+
11、2850Pd（PPh3）4CsCO3a10%223+2850Pd（PPh3）4Ba(OH)2a5%323+2850Pd（PPh3）4Ba(OH)2a5%423+2950Pd（PPh3）4CsCO3a5%527+2650Pd（PPh3）4CuI,CsFb5%624+2650Pd（PPh3）4CsCO3c5%725+2650Pd（PPh3）4CsCO3a68%中间体中间体3333的合成路线的合成路线1.CrCl2,CHI3,THF,0 2.n-BuLi,B(O i-Pr)3，THF,-78， 3.KHF2,MeCN,H2O,rt 4.t-BuLi,THF,-78 5.Bu3SnClUnfortun
12、ately, all attempts to remove the TBS protecting group from this material resulted in decomposition.化合物化合物34-3834-38的合成路线的合成路线1.TBAF,THF,0 DMP,NaH CO3,CH2Cl2,0(65%)+CrCl2,NiCl2 DMF,rt(75 %,dr4:1)TBAF,THF, 0(92%)化合物化合物38-38-目标化合物的合成路目标化合物的合成路 线线1.Zr(Cp2)Cl2,AlMe3,CH2Cl2,-78 to rt2.I2,THF,-78 to 0(94%
13、)+3.Pd(PPh3)4,CuT C,DMF,Ph2PO2 NBu4,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 couplingMoshers method(R)-MTPA- OH,DIC,DMAP CH2Cl2MTPA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AmphirioninAmphirionin 4(1) 4(1)构型检测构型检测Scheme 6. Completion of the Synthesis of Scheme 6. Completion of
14、 the Synthesis of Amphirionin-4Amphirionin-41HNMR1H 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
15、 Hz, 1H), 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,
16、6.8, 8.5 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13CNMR13C NMR (150 MHz, C6D6) : 150.2, 144.3, 138.7, 138.5, 134.2, 132.15, 132.11, 127.7, 127.4, 126.
