涂永强有机串联反应课件

有机串联反应研究及其在 有机合成中的应用 涂永强 功能有机分子化学国家重点实验室（兰州大学） 兰州大学化学化工学院 http://www.sklaoc.labs.gov.cn E-mail: tuyq@lzu.edu.cn 有关Tandem （Domino）反应的文献： ——2000-2004年 美国化学会 347篇（CR, JACS, OL, JOC) 德国Wiley公司 294篇 (ANGEW, CEJ, EJOC) 英国皇家化学会92篇 (CSR, CC, OBC) 近期的综述: 1) Chem. Soc. Rev. 2002, 1-11. 2) Chem. Soc. Rev. 2001, 332–339. 3) Chem. Rev. 1999, 99, 3329- 3365; 4) Chem. Rev. 1996, 96, 137-165; 5) Chem. Rev. 1996, 96, 167-176; 6) Chem. Rev. 1996, 96, 195-206; 7) Tetrahedron 1995, 51, 13103-13159; 8) J. Organometa.Chem. 1999, 576, 42-64. 有机化学中的串联（Tandem or Domino）反应 ¾简单的One – Pot 反应： A B+ PCondition 1 C Condition 2 D Condition 3 One-Pot Reaction : 多个反应条件，多次投料，多个化学转化 ¾Tandem 反应： A B+ PCondition C Same Condition D Same Condition Tandem Reaction : 一个反应条件，一次投料，多个化学转化 O O O O O O O O MeO2C O OH X O H O OMe A (1, IC50 = 2 uM) B (2, IC50 = 10 uM) X = O1 (A) 2 (B) X = O O SO3NaX =3 (C) 1）B. C. M. Potts, D. J. Faulkner, J. Am. Chem. Soc., 1991, 113, 6321 2）E. Christine, J. Faulkner, et al., Organic Lett., 2002, 4, 1699 OH O OHOH OHO O OH O OH OH OSBT OSBT SO2Ph EtO OEt OSBT O OSBT + 1 2 3 4 O OH OHOH O OH O OH O OH OH Al(iOPr)3PCC Base α :β = 60: 40 Tetrahedron lett., 2004, 3713. Tetrahedron, 2002, 58, 1697. J. Chem. Soc., Perkin Trans 1., 2002, 565. Organic Lett., 2001, 3, 847. 1）The Tandem Rearrangement and Reduction Reaction of Tertiary α-Hydroxy Epoxide OH O Al(iPrO)3 (1 equiv) iPrOH + OH OH 45 %25 % OH OH* 12 3 MeO O O O N OH Me PretazettineGalanthamine N Me O MeO OH Crinane O O NOHO OMe N Me H (±) - Lycoramine Pentalenene O H O O OH Crinipellin A * * ** * * R O HO O O O O O HO O O Ginkgolide (hypothalmaic inhibitor) * * O R2 OH R1 OH R2 OH R1 R2 O O Al R1 O O HH O O R2 R 1 Al iPrO OiPr OH R2 OH R1 1 2 3 12 3 12 3 ** Al(iPrO)3 - iPrOH major minor C1-C2 anti ab ab C1-C2 syn a route: favor b route: disfavor J. Org. Chem., 1999, 64, 629. Entry Substrate Product syn/anti (C1-C2) Yield (%) (syn/anti) 1 80/20 85 2 72/28 98 3 73/27 95 4 >99/<1 53 5 >99/<1 86 O OH OH OH O Ph OH Ph OH OH O Ph OH Ph OH OH O Ph OH OH Ph OH (80/20) (77/23) (87/13) O OH OH OH A. S. C. Chan etal., J. Am. Chem. Soc., 1997, 119, 9570 OPPh2Ph2PO * OH OH O O O CO2H* * * 3-8 isomer ~ 40% Cis-Trans (major) Cis-Cis (minor) +O HO ( )m ( )n Al(iPrO)3 (1 equiv) iPrOH, reflux OH OH ( )m ( )n OH OH ( )m ( )n * 36-100% de m n Cis-Trans/Cis-Cis Yield (%) 1 1 >99/<1 99 1 2 >99/<1 60 1 3 >99/<1 99 0 1 68/32 80 0 2 76/24 50 0 3 >99/<1 77 Chem. Lett., 1998, 285 n = 0, 1 > 99% d e ( )n ( )n ( )n OH R1 R2 OCOR 1' +3 2 1 1 OCOR R1 R2 OH SmI2 (Cat. 01-0.3 equiv) RCHO (4-8 equiv) Toluene, 80-85 oC R1, R2 = alkyl, aryl R = phenyl, p-C6H4Cl O R2 R1 OH C1-C2 anti C1-C2 anti Angew. Chem. Int. Ed., 2001, 40, 3877. O Ph OH OCOPh Ph OH OCOPh Ph OH OCOPh Ph OH OCO(p_C6H4Cl) Ph OH O Ph OH O Ph OH O Ph OH (80/20) OCOPh OH O O OH O (0/100) OCO(p_C6H4Cl) OH O OH (91/9) (70/30) (87/13) (56/44) Entry Substrate Product SmI2 (equiv) 1/1' Yield (%) (syn/anti) 1 0.15 100 / 0 96 2 0.2 100 / 0 80 3 0.3 100 / 0 70 4 0.25 100 / 0 83 5 0.3 93 / 7 78 6 0.3 74 / 26 85 3 MR3CHO + SmI2 O M R1 OH R2 4 + _ R3CHO O OH R2 R1 1 5 + _ O OH M R2 R1 M = OO R3 R3 I2Sm SmI22 O O R3 O H R1 R2 H + _ 6 O R2 R1 M OH R3 O H H R3O M R1 OH O R2 Si face attack favorable 6 2 C1-C2 anti + _ O R2 R1 M OH R3 O H R1 OCOR3 R2 OH 1 2 3 O M R2 OH O H R3 R2 5 + _ Re face attack unfavorable (not observed) C1-C2 syn R1 OCOR3 R2 OH 1 2 3 7 _ + M HO O R2 H R1 R3 O O R2 R1 OH ( )n R1 ( )n OH R2 * 1 3 2 1 3 2 OH R1 ( )n OH R2 * 1 3 2 OH C1-C2 syn C1-C2 anti major minor RB(OH)2 Cl(CH2)2Cl, RT R = allyl, allenyl + O R1 R2 OH1 3 2 R1 OH R2 * 1 3 2 OH R1 OH R2 * 1 3 2 OH C1-C2 syn C1-C2 anti majorminor Cl(CH2)2Cl, RT + B(OH)2 Angew. Chem. Int. Ed., 2004, 43, 1702. R3 O O R4 R2 R1 B RHO - H2O O B O R4 R2 R3 R1 HO B O OHO R1R2 R3 R4R4 R3 R2 R1 OH O RB(OH)2 R1 ( )n OH R2 * 1 3 2 OH C1-C2 syn R1 OH R2 * 1 3 2 OH C1-C2 anti HO HO * Pentalene-type skeleton OH OH *O HO AllB(OH)2 (i) PDC (ii) SmI2 SmIII O O H 1 2 3Pentalenene O H O O OH Crinipellin A 2) The Tandem Oxidative Rearrangement Reaction of Tertiary α-Hydroxy Epoxide OH O OH O OH O NH[CrO3Cl] 1a 1b enriched 1b + + complex products PCC (1.5 equiv) CH2Cl2, r.t. > 98% de, > 95% yield PCC = + _ Tetrahedron Lett., 2001, 42, 2141 O OH O OH O Ph OH O Ph OH Ph OH Ph O Ph OH Ph O O OH O OH O OH (61/39) (63/37) OHO O O Ph Ph O O Ph O OH (47/53) (69/31) (60/40) (84) (98) (55) Enrtry Substrate Time Recovered a/b Product a/b, ratio ratio, Yield (%) Yield (%) 1 5h 96/4, 53 ___ 2 4.5h 92/8, 42 3 25h 2/98, 25 4 5h 96/4, 54 ___ 5 24h 91/9, 45 NH[CrO3Cl] + _ PICC = NH[CrO3Cl]LCC = + _ NH[CrO3Cl]PCC = + _ N ACC = + H [CrO3Cl] _ 20 40 60 80 100 0 100 200 300 t (min) de of 1b (%) PICC LCC PCC CrO 3 ACC PCC (1.5 equiv) CH2Cl2, r.t. O R1 R2 OH R3 ( )n R1, R2 = alkyl, aryl R3 = Me, H n = 0, 1 R2 O R1 O ( )n R3 O Cr O R2 R1 H R4R3 O O Cl OH PyH+ H R4 O R3 R2 O R1 Cr OCl HO +HPy O O H R1 OH R2 R3 R4 PCC R1 R4 O O R3 R2 Cr OH OH Cl O PyH+ + Synthesis, 2001, 2384 O HO Ph HO Ph O O Ph O O Ph OH Ph O O O nBu Ph OH nBu Ph O O O OH S S O O O Ph Ph OH Ph Ph O O Entry Substrate syn/anti Product Yield (%) Time (h) 1 56/44 71 25 2 70/30 94 18 3 79/21 91 4 4 80/20 67 25 5 77 48 HO O OH HO H2NCH2CH2NHLi HO O Li NHLi H2N AlEt3 * OH OH THF, reflux 3) The Tandem Rearrangement and Reduction Reaction of Secondary α-Hydroxy Epoxide Chem. Comm., 2003, 798 N O OO nBu OH H * Madindoline O HO OH OH * Illudin Algoane OH Br Br Cl HO OAc * OH O R O Al HO Et Et Et R O O AlEt Et HHR H O O Al Et Et HR H H OH R OH AlEt3 H3O + Chem. Commun., 2003, 798 O OH OH OH O OH OH OH O OH Ph OH OH Ph O OH Ph OH OH Ph O OH OH OH Entry Substrate Product Yield (%) Time (h) 1 55 8 2 51 12 3 31 8 4 56 8 5 68 8 OH O R1 OR2 OR3 R1 SmI2 (0.3 eq) RCHO(6.0 eq) Cl(CH2)2Cl T range RT to 70oC 1: R1, R = alkyl, aryl 2: R2 = RCO, R3 = H 2': R2 = H, R3 =RCO Chem. Eur. J. 2003, 9, 4301. [Sm] H OH O H R O [Sm] R1 6 7 H O HO H R O [Sm] R1 8 H O HO H R O [Sm] R1 O [Sm] OHR1 O [Sm] OR1 O H RH O R1 OH [Sm] 3 4 5 RCHO H O O H R H R1 O 2 1 O R1 OH O H OR1 4' SmI2 + RCHO 3 2 1 4) Ring-Opening/Rearrangement of α-Hydroxy Aziridine ZnBr2(1 equiv) CH2Cl2, r.t. R1, R2 = H, alkyl, aryl n = 0, 1 TsN OH R2 R1 ZnBr2 H2O ( )n ( )n *NTs OH R2 R1 NHTs R1 R2 O ( )n >99% de Org. Lett., 2002, 4, 363 NTs OH NTs OH Ph NTs HO NTs Cl OH NTs OH Ph NTs OH NHTs O NHTs Ph H O TsHN O TsHN O NHTs H O Cl H NHTs Ph O Entry Substrate Product Yield (%) Time (min) 1 88 30 2 85 40 3 95 30 4 91 30 5 85 40 6 86 60 NTs HO Lewis acid (1.2 equiv) CH2Cl2, r.t. TsHN O Entry Lewis acid Yield (%) Time (min) 1 AlCl3 40 30 2 ZnCl2 74 60 3 Sn(OTf)2 80 60 4 BF3/Et2O 82 10 5 SnCl4 86 10 6 SmI2 93 40 7 ZnI2 82 60 8 TiCl4 55 10 9 Sc(OTf)3 74 60 10 ZrCl4 76 20 AlEt3/THF,reflux OH NHTs Ph NHTs R3 OH R3 = al kyl, aryl R3 NTs OH Ph NHTs O Synlett., 2003, 623 a The substrates are diastereomerically pure OH Ph NTs OH NHTs Ph OH NTs 60 OH Pr NTs OH NHTs Pr 75 85 11 12 13 14 15 Entry Substratesa Products Yields (%) OH NHTs Ph 80 11a 11b 13a 13b 14a 14b 15a 15b OH 12b OH NHTs O O 12a OH NTs O O NHTs Ph NHTs O 92 5) Application to Total synthesis of Natural Products MeO O O O N OH Me PretazettineGalanthamine N Me O MeO OH Crinane Mesembrine NO OMe MeO MeH O O N OHO OMe N Me H (±) - Lycoramine Pentalenene O H O O OH Crinipellin A * * * * * * * Short Synthesis of alkaloid (±)-Crinane Ar = O O Cl NTs Ar OH ZnBr2 ( Cat .) H Ar O NHTs H 1 2 3 2 steps 2 steps key 1,3-amino ketone intermediate (±)-Crinane N OH H Ar Ts SMEAH N H Ar H (CH3)2N=CH2I THF O O N o-xylene 4 5 cis-3a-Aryloctahydroindole Nuclei Short Synthesis of alkaloid (±)-Mesembring OH OH NNHTs OTBS 1) TBDMSCl, Im 2) PCC 3) ToSNHNH2, n-BuLi, TMEDA then ArCHO OMe OMe CHO OH TBSO Ar PTAB, Cl-T CH3CN, r.t ZnBr2 CH2Cl2 MeOCHPPh3 TBSO H Ar NHTs OMe NHO Ar H OHHClO4(70%) Et2O NHO Ar H NO H Me Ar 1) HCHO(aq), NaBH3CN, ZnCl2 2) PDC TBSO N OH Ts Ar TBSO Ar O NHTs H NaBH3CN TiCl4 TsTs Na,NpH DME NHO Ar H H ArCHO = (±)- Mesembrine Org. Lett., 2003, 13, 2319 The Total Synthesis of alkaloid (±)-Lycoramine RO OH RO X Lycoramine ORO OMe O H OR1 OMe OR1 OMe O Semipinacol rearrangement H 片段-I 片段-II (X = Br)片段-III OHO OMe N Me one-carbon homologation * modified Pictet-Spengler reaction A B C D H * * OTBSO OMe 9 OTBSO OMe O H H H MeO 10 (Z/E = 2:1) OTBSO OMe 11 H OHC OTBSO OMe H X O (±) T OHO OMe H N O Me 12a OHO OMe N Me H O 13 DBU, DMSO 95% MeOCH=PPh3 75% THF/H2O, then KI 91% THF NBS, AIBN (cat.) CCl4, 95oC 71% ((CH2O)n, CF3CO2H Cl(CH2)2Cl 81% 83% 80oC Hg(OCOCF3)2 then MeNH2 LiAlH4 THF 11a ( X = Br ) 12 ( X = NHMe ) TBSO OH OTBS OMe 93% > 99:1 d.r. TBSO Br OTBS OMe O H * * * i-PrOH or t-BuOH, r.t. 6 5 NBS OH Ar Br Org. Lett., 2004, 4691. Galanthamine的全合成 O O NNHTris OTBS OHC O O O OH TBSO O 85% O O OTBS O BrOHC O O O OHC O NBS CH2Cl2 0oC DBU DMSO, 95oC 95% 90% O OO O O O OO O O 1) MeOCH=PPh3, THF, t-BuOK, 98% 2) 0.1eq PTS, Acetone, glycol, 75% 1) L-Selectride, THF, -78oC, 93% 1) LDA, TMSCl, THF, -78oC 2) Pd(OAc)2, Na2CO3, CH3CN Shapiro reaction O O OAc 2) 1N HCl, THF 40oC, 99% O O OHC OAc 3) (Ac)2O, Pyridine, CH2Cl2, DMAP, 80% NBS, AIBN(cat.) CCl4 95oC 1) (CH2O)n, CF3CO2H, Cl(CH2)2Cl 82% then MeNH2 2) LiAlH4 DME, 76% 75% MeHNOC O O N OH Galanthamine O O OH TBSO O Br * 13 steps, Overall yield 12% Org. Lett., 2006, ASAP. 中国专利：200610041682.6 Acknowledgement 赵学智 高栓虎 Xue-Zhi Zhao Shuan-Hu Gao 李德润 王少华 De-Run Li Shao-Hua Wang 李 心Xin Li吴 滨Bin Wu 任世阔Shi-Kuo Ren宋振雷Zhen-Lei Song 胡向东Xiang-Dong Hu樊春安Chun-An Fan 王 飞Fei Wang王保民Bao-Min Wang Natural Science Foundation of China 谢谢 谢谢 ！！ 有机串联反应研究及其在有机合成中的应用 Short Synthesis of alkaloid (?)-Crinane