河豚毒素的合成VIP

Synthesis of Tetrodotoxin H N N H OH OH H2N HO O O O HO O H 中井 良雄 H N N H OH OH H2N HO O O O HO O H 1909? ? 1964-5 ? (Hirata-Goto, Tsuda, Woodward) 1970 ?(Furusaki-Tomie-Nitta) 1972 ? (Kishi, Y. Harvard University ) 2003 ? (Isobe, M. Nagoya University) 2003 ? (Du Bois, J. Stanford University) 2004 ? (Isobe, M.) About Tetrodotoxin (TTX)-1 ? ?Na ? ? ? ? ? ? O O dioxa-adamantane About Tetrodotoxin (TTX) -2 ? ? ? ?dioxa-adamantane? ? ? ? ? ?pKa = 8.7? ? ? ? ? H N N H OH OH H2N HO O O O HO O H N H N H OH OH H2N HO O O O O TTXanhydro-TTX H N N H OH OH H2N HO OH O O HO O H TTX (lactone) H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 Isobes synthesis H N N H OH OH H2N O O O O HO O H H overman rearrangement ring-opening of epoxide Diels-Alder 8a 4a 5a 8 Grignard 10 6 H N N H OH OH H2N O O O O HO O H H 8a Du Bois synthesis Stereospecific C-H amination 5 6 Stereospecific C-H amination 8 aldol 10 methylenation H N N H OH OH H2N O O O O HO O H H 8a Baeyer-Villiger oxidation Beckmann rearrangement Kishis synthesis ring-opening of epoxide Diels-Alder 9 10 4a 7 5 6 H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 Retrosynthetic Analysis Kishi Synthesis (1972) Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Sugiura, S.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5127-5128. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5129-5132. H N N H OH OH H2N O O O O HO O H H 5 10 4 9 8a O AcO O AcO AcHN OAc OAc 4 5 10 9 O 6 7 O AcO AcHN OAc O O 10 4 9 7 6 O O AcHN 9 10 4 OO CH3 N H HAc 8a 9 10 4 4a OO CH3 N CH3HO 8a 4a H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 Baeyer-Villiger oxidation intramolecular epoxide-opening cyclization Diels-Alder Beckmann rearrangement Retrosynthetic Analysis Kishi Synthesis (1972) Kishi, Y. et al. J. Am. Chem. Soc. 1972, 94, 9217-9219.;ibid 1972, 94, 9219-9221. Kishi, Y. et al. Tetrahedron Lett. 1970, 59, 5127-5128.;ibid 1970, 59, 5129-5132. OO CH3 N H HAc 8a 9 10 4 4a OO CH3 N CH3HO 8a 4a H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 Diels-Alder Beckmann rearrangement AB H N N H OH OH H2N O O O O HO O H H 5 10 4 9 8a O AcO O AcO AcHN OAc OAc 4 5 10 9 O 6 7 O AcO AcHN OAc O O 10 4 9 7 6 O O AcHN 9 10 4 TTX CD OO CH3 N CH3HO 8a4a SnCl4 CH3CN rt 83% OO CH3 H3C N OH H 4a 8a 1. MsCl, Et3N, quant. 2. H2O, reflux, 61% OO CH3 H3C N MsO H H OO CH3 NHH3C NH3C N O H H H2O OO CH3 N H H 4a 8a 9 10 4 5 6 7 8 H3C O D C Retrosynthetic Analysis Kishi Synthesis (1972) H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 AB H N N H OH OH H2N O O O O HO O H H 5 10 4 9 8a O AcO O AcO AcHN OAc OAc 4 5 10 9 O 6 7 O AcO AcHN OAc O O 10 4 9 7 6 O O AcHN 9 10 4 6 7 5 TTX C AcHN O O O AcO 11 O H O AcHN OH O O O H Cl H O AcHN C O 9 10 4 6 7 5 8 O AcHN HO O 5 10 AcHN O O O AcO 8 11 SeO2 xylene 180 C quant. 6 7 1. NaBH4, MeOH, 0 C (quant.) 2. mCPBA, ClCH2CH2Cl additive, 90 C, (95%) 3. acetylation, (quant.) 4. aq. TFA, 70 C then Ac2O, Py, 80% AcHN O AcO OAc O O 11 B 10 AcHN O O O 10 O 8 1. CrO3, aq. Py, 50 C (90%) 2. ethylene glycol BF3? ?OEt2(cat.), CH2Cl2, (quant.) 1. Al(OiPr)3, iPrOH 2. acetylation, 95% (2 steps) 1. NaBH4, 0 C, 96% 2. mCPBA, CSA 75% 8 Retrosynthetic Analysis Kishi Synthesis (1972) AB H N N H OH OH H2N O O O O HO O H H 5 10 4 9 8a O AcO O AcO AcHN OAc OAc 4 5 10 9 O 6 7 O AcO AcHN OAc O O 10 4 9 7 6 TTX Baeyer-Villiger oxidation intramolecular epoxide-opening cyclization AcHN O AcO OAc O O B 10 AcHN O AcO OAc O OEt EtO 10 9 o-Cl2C6H4 reflux AcHN O AcO OAc O EtO 9 mCPBA K2CO3 CH2Cl2 AcHN O AcO OAc O EtO O AcOH rtAcHN EtO O H AcHN EtO HO AcOH AcHN OEt HO AcO AcHN OEt O H O Me HO AcHN OEt AcO HO H2O O AcO AcHN OAc O O AcO 70% (4 steps) 10 9 (EtO)3CH, CSA (cat.) EtOH, 80 C then acetylation H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 KOAc AcOH 90 C O AcO AcHN OAc O O H AcO O 7 6 O AcO AcHN OH OAc OAc quant. O AcO O 9 10 4 7 6 O AcO AcHN OAc O O AcO 10 7 O AcO AcHN OAc O O AcO O 10 9 4 quant. O O AcO AcHN OH OAc OAc AcO O 7 6 mCPBA CH2Cl2 rt H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 O AcO AcHN OAc OAc O AcO O 8a A 1. Ac2O, CSA (cat.) 100 C, quant. 2. high vacuum 290-300 C 80% Retrosynthetic Analysis Kishi Synthesis (1972) A H N N H OH OH H2N O O O O HO O H H 5 10 4 9 8a O AcO O AcO AcHN OAc OAc 4 5 10 9 O 6 7 8a TTX O AcO AcHN OAc OAc O AcO O 8a Et3O+-BF4(Xs.) Na2CO3 CH2Cl2 92% H2N 8a AcN SEt SEt N H 8a AcN SEt NH3 CH2Cl2 /MeOH rt AcNH2 O AcO N H OAc OAc O AcO O AcN NH2 20% (3 steps) 4 OsO4 THF -20 C AcO N H OAc OAc O AcO O AcN NH2 OH OH O N H 8a AcN NHAc NaIO4 aq THF, 0 C then NH4OH aq MeOH AcO N H OAc OAc O AcO O AcN NH2 OH O NH4OH 25% (4 steps) H N N H OH OH H2N O O O O HO O H H D,L-tetrodotoxin Retrosynthetic Analysis Kishi Synthesis (1972) H N N H OH OH H2N O O O O HO O H H 5 10 4 9 8a O AcO O AcO AcHN OAc OAc 4 5 10 9 O 6 7 O AcO AcHN OAc O O 10 4 9 7 6 O O AcHN 9 10 4 OO CH3 N H HAc 8a 9 10 4 4a OO CH3 N CH3HO 8a 4a H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 Baeyer-Villiger oxidation intramolecular epoxide-opening cyclization Diels-Alder Beckmann rearrangement Retrosynthetic Analysis Isobe Synthesis (2004) Nishikawa, T.; Urabe, D.; Isobe, M. Angew. Chem. Int. Ed. 2004, 43, 4782-4785. Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Fukuda, Y.; Isobe, M. Tetrahedron 2001, 57, 3875-3883. Nishikawa, T.; Asai, M.; Isobe, M. Tetrahedron 2001, 57, 4543-4558. Nishikawa, T.; Asai, M.; Isobe, M. J. Am. Chem. Soc. 2002, 124, 7847-7852. first asymmetric synthesis see, Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798-8805. H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 H N N H OH OH H2N O O O O HO O H H 7 10 4 8a O N H OH OTES O O O O O AcO TES TES 5 6 8a 9 10 7 Cl3C O H O O NH TESO TESOOH 5 6 8a 8 7 9 11 Cl3C O Me H HO O O H H 8a 8 7 94a 4 5 O O O 8a 4a 4 9 H Overman rearrangement NH 8a 9 O CCl3 intramolecular epoxide-opening cyclization Retrosynthetic Analysis Isobe Synthesis (2004) Nishikawa, T. and Isobe, M. et. al. Tetrahedron 2001, 57, 3875-3883. H N N H OH OH H2N O O O O HO O H H 7 10 4 8a O N H OH OTES O O O O O AcO TES TES 5 6 8a 9 10 7 Cl3C O H O O NH TESO TESOOH 5 6 8a 8 7 9 11 Cl3C O Me H HO O O H H 8a 8 7 94a 4 5 O O O 8a 4a 4 9 P Q TTX RS O O O levoglucosenone P O O O Br 8a 4a 4 9 Me BF3? ?OEt2 CH3CN 0 C to rt O O O Br Me H O O O Br H + Me 15:1 76% 8a4a 9 8 7 6 5 O O O Me F3B ? ?+ ? ?- NaBH4 MeOH, 0 C O HO O Br Me H Me H HO O O H H 8a 8 7 94a 4 5 R 74% (2 steps) TFA Ac2O 0 C O HO O Br Me H Ac2O Ac2O O AcO Br Me H OAc O AcOBr Me H 85% (2 steps) AcO OAc H 8a 4a 4 9 Zn-Cu DMF-H2O rt O Me H AcO OAc H 81% AcO 1. LiAlH4, Et2O 2. CSA, acetone MeOOMe Br2, 0 C CH2Cl2 then Et3N 91% 4 Retrosynthetic Analysis Isobe Synthesis (2004) Nishikawa, T. and Isobe, M. et. al. Tetrahedron 2001, 57, 3875-3883.; ibid 2001, 57, 4543-4558. J. Am. Chem. Soc. 2002, 124, 7847-7852. H N N H OH OH H2N O O O O HO O H H 7 10 4 8a O N H OH OTES O O O O O AcO TES TES 5 6 8a 9 10 7 Cl3C O H O O NH TESO TESOOH 5 6 8a 8 7 9 11 Cl3C O Me H HO O O H H 8a 8 7 94a 4 5 P Q TTX R Overman rearrangement Overmann Rearrangement ? ? ? ?trichloroacetimidate? ? ? ?trichloroacetamide? ? ? ? ? thermal rearrangement ? ? NO H RR CCl3 R1R3 O R2 1 2 3 HN CCl3 R1R3 O R2 HN CCl3 3 1 2 Hg(II)-catalyzed rearrangement R1R3 O R2 HN CCl3 HgX2 Hg R1R3 O R2 N CCl3 Hg XH R1R3 O R2 HN CCl3 + HgX2 R1R3 OH R2 Cl3CCN base (cat.) 1 2 3 R1R3 O R2 1 2 3 HN CCl3 heat or metal cat. R1R3 O R2 HN CCl3 metal cat. : Hg(OCOCF3)2etc 3 1 2 3,3 trichloroacetimidate trichloroacetamide Overman, L. E. JACS, 1974,96, 597-599. Me H HO O O H H R 8a DBU CCl3CN CH2Cl2 0 C Me H H H H O NH Cl3C O OH 8a K2CO3 xylene reflux Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M.J. Org. Chem. 1998,63, 188-192. Me H O O NH O 8a 9 CCl3 92% (2 steps) 8 5 11 H H O Cl3C HN O O Me Me H PyHBr3 K2CO3 CH2Cl2 0 C DBU DMF rt Me H O O HN Cl3CC O Br Br 91% Me H O O Br N O Cl3C H 8 Me H O O N O Cl3C H 8 8a SN2 N O H Br Me B: B: Me H O O N O Cl3C H 8 8a p-TsOH Py? ?H2O 70 C mCPBA Na2HPO4 CH2Cl2 rt Me H O O HN Cl3CC O HO 71% (2 steps) 8 OH H O O mCPBA Ti(OiPr)4 CH2Cl2 reflux Me H O O HN Cl3CC O HO OH 90% Me H O O HN Cl3CC O HO O 98% 7 O H O O O Me H Ti L2 OiPr Morgans, D. J., Jr.; Sharpless, K. B. Traynor, S. G. J. Am. Chem. Soc. 1981, 103, 462-464. 7 H N N H OH OH H2N O O O O HO O H H 7 10 4 8a 8 6 Me H O O HN Cl3CC O HO OH 7 8 O I O O HO IBX DMSO 60 C IBX: o-iodoxybenzoic acid Me H O O HN Cl3CC O O O 1. LiAlH(t-BuO)3 LiBr, THF, -78 C 2. NaBH4 CeCl3 ? ?7H 2O MeOH, -78 C Me H O O HN Cl3CC O HO OH 80% (3 steps) 8a 8 7 11 1. TESOTf, Py, CH3CN, rt, 86% 2. SeO2, PNO, dioxane, reflux 3. NaBH4, CeCl3 ? ?7H 2O, MeOH 46% (2 steps) H O O HN Cl3CC O TESO TESOOH Q 8 7 11 8a H N N H OH OH H2N O O O O HO O H H 7 10 4 8a 8 6 11 NO PNO: pyridine N-oxide Frigerio, M.;* Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022. Retrosynthetic Analysis Isobe Synthesis (2004) Nishikawa, T. and Isobe, M. et. al. Angew. Chem. Int. Ed. 2004, 43, 4782-4785. H N N H OH OH H2N O O O O HO O H H 7 10 4 8a O N H OH OTES O O O O O AcO TES TES 5 6 8a 9 10 7 Cl3C O H O O NH TESO TESOOH 5 6 8a 8 7 9 11 Cl3C O P Q TTX intramolecular epoxide-opening cyclization 1. TESOTf, 2,6-lutidine, CH2Cl2, 0 C, 2. mCPBA, Na2HPO4, CH2Cl2, rt, 83% (2) 3. O3, CH2Cl2, -78 C then Et3N, 90% H O O HN Cl3CC O TESO TESOOH Q 8a H O O HN O Cl3CC O TESO TESOOTES O 9 5 6 1. EtMgBr, THF, 0 C, 88% dr (4 : 1) 2. Ac2O, DMAP, Py, rt 3. TBAF, THF, -10 C 91% (2 steps) TMSH H O O HN Cl3CC O OR TESOOTES O AcO R = TES 9 10 KMnO4 NaIO4 NaHCO3 aq t-BuOH 50 C 30% H2O2 NaHCO3 MeOH rt H O O HN Cl3CC O OR TESOOTES O AcO O HO2C 10 9 H O O HN Cl3CC O OR TESOOTES O HO O O 5 10 O N H OH OR O O O O O HO TES TES Cl3C O 5 11 9 10 R = TES and H 1. TESOTf, 2,6-lutidine CH2Cl2, -40 C 2. Ac2O, Py O N H OH OTES O O O O O AcO TES TES Cl3C O 64% (4 steps) 9 P O O O O OH 9 5 6 RH Mn OO OO MnO4 O Mn O RH OO MnO2 OO RH Mn O O O O OO R H Mn O O O O OO RO Lee, D. G.; Chang, V. S. J. Org. Chem. 1979, 44, 2726-2730. OH O R CO2+ MnO4 Oxidation of Alkynes by Potassium Permanganate Retrosynthetic Analysis Isobe Synthesis (2004) Nishikawa, T. and Isobe, M. et. al. Angew. Chem. Int. Ed. 2004, 43, 4782-4785. H N N H OH OH H2N O O O O HO O H H 7 10 4 8a O N H OH OTES O O O O O AcO TES TES 5 6 8a 9 10 7 Cl3C O PTTX Retrosynthetic Analysis Isobe Synthesis (2004) Nishikawa, T. and Isobe, M. et. al. Tetrahedron 2001, 57, 3875-3883. H N N H OH OH H2N O O O O HO O H H 7 10 4 8a O N H OH OTES O O O O O AcO TES TES 5 6 8a 9 10 7 Cl3C O H O O NH TESO TESOOH 5 6 8a 8 7 9 11 Cl3C O Me H HO O O H H 8a 8 7 94a 4 5 O O O 8a 4a 4 9 P Q TTX RS intramolecular epoxide-opening cyclization Overman rearrangement O O O O Cl OH2N O H O O Me Me 8a Me Me 9 10 1 4 5 H N N H OH OH H2N O O O O HO O H H 4 4a 7 8a 9 10 1 Retrosynthetic Analysis Du Bois Synthesis (2003) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511. H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 O O Me Me O O Me Me NMe2 PivO O 5 H 10 9 8a 4 8 6 O O Me Me TBSO O O PivO H O N2 5 6 8 8a 10 9 O O O H Me Me H TBSO O O OBn O 8a OBn+ 8 9 10 4 Stereospecific C-H insertion Stereospecific C-H amination methylenation O O O O Cl OH2N O H O O Me Me 8a Me Me 9 10 1 4 5 H N N H OH OH H2N O O O O HO O H H 4 4a 7 8a 9 10 1 Retrosynthetic Analysis Du Bois Synthesis (2003) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511. H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 O O Me Me O O Me Me NMe2 PivO O 5 H 10 9 8a 4 8 O O Me Me TBSO O O PivO H O N2 5 6 8 8a 10 9 O O O H Me Me H TBSO O O OBn O 8a OBn+ 8 9 10 4 X Y TTX W Z Stereospecific C-H insertion Insertion by carbene RH+ CH2 RCH2H order tertiary secondary primary C-H insertion H C H H C H H H H C H H 1. a simple one-step mechanism (three-center cyclic transition state) RH+CH2R+CH2 R + 2. a free-radical process RCH2H H CH2H O O PivO H O O Me Me O O Me Me 77% (2 steps) C O O Me Me TBSO O O PivO C O H 5 6 O O O H Me Me H TBSO 8 7 Z OO OBn O OBn NaOAc THF O O Me Me TBSO O O HO H OBn O 10 : 1 8 7 6 8a4a 9 10 1. PivCl, Py, THF 85% (3 steps) 2. H2, Pd-C, THF MeOH, rt, 88% 3. (COCl)2, cat. DMF then, CH2N2, CH2Cl2, 63-70% O O Me Me TBSO O O PivO H O N2 5 6 Y Rh2(HNCOCPh3)4 (1.5 mol%) CCl4 C O O Me Me TBSO O O PivO H O Rh C H NNCH Rh-carbene C-H insertion 1. NH3? ?BH3, CH2Cl2/MeOH 75% (2 steps) 2. H2, (1200 psi) Rh-C (5 mol%) TFA/MeOH OH OH HO O O PivO OH H H H 8a 4a 9 OH OH HO O O HO PivO H 8a 9 4a 8 p-TsOH THF OMeMeO O O PivO H O O Me Me O O Me Me 4 10 1. Me2NH, THF 83% 2. cat. TPAP, NMO, 4 MS, CH2Cl2, 94% O O Me Me O O Me Me O NMe2 PivO O H Zn (2 eq) CH2I2, TiCl4, cat. PbCl2 THF O O Me Me O O Me Me NMe2 PivO O H 72% X 4 methylenation CH2I2+Zn (2 eq) Pb (cat.) THF CH2(ZnI)2 O TiCl4 O TiCl3 C H2 ZnI ClZnI OTiCl2 CH2 O O O O Cl OH2N O H O O Me Me 8a Me Me 9 10 1 4 5 H N N H OH OH H2N O O O O HO O H H 4 4a 7 8a 9 10 1 Retrosynthetic Analysis Du Bois Synthesis (2003) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511. H N N H OH OH H2N O O O O HO O H H 1 2 3 4 4a 5 6 7 8 8a 9 10 11 O O Me Me O O Me Me NMe2 PivO O 5 H 10 9 8a 4 8 X TTX W O O Me Me O O Me Me NMe2 PivO O 5 H X Ph2Se (cat.) PhIO2 Py(excess) C6H5Cl 100 C O O Me Me O O Me Me NMe2 PivO O O H 70% 1., CuI, THF 2. t-BuNH2 ? ?BH 3, ClCH2CH2Cl2 70% (2 steps) MgBr O O Me Me O O Me Me O PivO Me2N OH H 4a 4 5 9 10 1. t-BuCO2H, C6H5Cl 200 C 2. NaOMe, THF/MeOH O O O O Me Me HO O O Me Me 10 9 78% (2 steps) NCl3C O CO CH2Cl2, rt ON H O Cl3C O Zn MeOH 93% O O O O Me Me O O O Me Me H2N O 1. O3, then NaBH4 CH2Cl2/MeOH, 83% 2. MeSO2Cl, Py, ClCH2CH2Cl 86% O O O O Me Me Cl OH2N O H O O Me Me Kocovsky, P.Tetrahedron Lett. 1986,27, 5521-5524. 8a 4a O O O O Cl OH2N O H O O Me Me 8a Me Me 9 10 1 4 5 H N N