《有机合成设计导论》课程教学资源（案例）合成实例 3 Total Synthesis of Palytoxin

Total Synthesis of Palytoxin Armstrong, R.W., Beau, J. M: Cheon, S H; Christ, H;kaloka,H:Ham,WH.Hawkins,LD; Jir WJ McWhorter, w.w., Jr. Mizuno, M, Nakata, M Stutz, A.E., Talamas, F.X.: Taniguchi, M: Tino J.A., Ueda, K, Uenishi, J, White, J B, Yonaga OH M.JAm. Chem. Soc., 1989, 111, 7525: Armstrong, OH JM. Fujioka, H, Ham, W.H., Hawkins, L D; Jin, H Kang, S.H., Kishi, Y, Martinelli, MJ McWhorter, w.w., Jr, Mizuno, M: Nakata, M Me Stutz, A.E., Talamas, F.X.: Taniguchi, M, Ti HO\ J.A., Ueda, K. Uenishi, J: White, J B: Yo M. ibid, 1989, 111, 7530, Suh, E.M., Kishi, Y. ibid. OH 1994,116,11205; Kishi,Y.Chem,Scr.1987,27, OH 573, Kishi,Y. Pure Appl Chem, 1989, 61, 313 HO OH Me oh Me OH OH OH OH OH OH Y Kishi OH OH OH OH HO Chris Hupp Cem852

Total Synthesis of Palytoxin Total Synthesis of Palytoxin O NH2 OH O O OH OH O HO OH OH OH OH OH OH OH HO OH O Me OH OH OH O OH HO OH OH H O OH OH OH HO O O Me O N H N H HO OH OH Me OH H HO OH OH Me OH HO Me OH OH OH HO OH OH O O OH Me OH Me OH Armstrong, R.W.; Beau, J.M.; C heon, S.H.; C hrist, W.J.; F ujioka, H.; Ham, W.H.; Hawkins, L.D.; Jin, H.; Kan g, S.H.; Kishi, Y.; Martinelli, M.J.; McWhorter, W.W., Jr.; Mizuno, M.; Nakata, M.; Stutz, A.E.; Talamas, F.X.; Taniguchi, M.; Tino, J.A.; Ueda, K.; Uenishi, J.; W hite, J.B.; Yonaga, M. J.Am.Chem.Soc., 1989, 111, 7525; Armstrong, R.W.; Beau, J.M.; C heon, S.H.; C hrist, W.J.; F ujioka, H.; Ham, W.H.; Hawki ns, L.D.; Jin, H.; Kan g, S.H.; Kishi, Y.; Martinelli, M.J.; McWhorter, W.W., Jr.; Mizuno, M.; Nakata, M.; Stutz, A.E.; Talamas, F.X.; Taniguchi, M.; Tino, J.A.; Ueda, K.; Uenishi, J.; W hite, J.B.; Yonaga, M. ibid, 1989, 111, 7530; S u h, E.M.; Kishi, Y. ibid, 1994, 116, 11205; Kishi, Y. Chem,Scr. 1987, 27, 573; Kishi, Y. Pure & Appl. Chem, 1989, 61, 313. Y.Kishi Y.Kishi O NH2 OH O O OH OH O HO OH OH OH OH OH OH OH HO OH O Me OH OH OH O OH HO OH OH H O OH OH OH HO O Me O O N H N H HO OH OH Me OH H HO OH OH Me OH HO Me OH OH OH HO OH OH O O OH Me OH Me OH Chris Hupp CEM 852 Hupp CEM 852

What is Palytoxin? One of the most toxic non-peptidic natural products known to man vasoconstrictor Hemolysis agent Lethal dose for a human=<5ug

What is Palytoxin? What is Palytoxin? „ One of the most toxic non-peptidic natural products known to man! „ Vasoconstrictor „ Hemolysis agent „ Lethal dose for a human = <5µg

vasoconstriction and hemolysis Normal blood flow Restricted blood flow R,0 ENG WADAM. http://www.nlm.nih.gov/medlineplus/ency/imagepages/8983.htm http://www.physiology.rwth-aachen.de/user/martin/duunddeinblut/bl- Terminologie-d. html

Vasoconstriction and Hemolysis Vasoconstriction and Hemolysis http://www.nlm.nih.gov/medlineplus/ency/imagepages/8983.htm http://www.physiolog y.rwth-aachen.de/user/martin/Du U n dDeinBlut/Bl￾Ter minologie-d.html

What is Palytoxin? One of the most toxic non-peptidic natural products known to man! Vasoconstrictor a hemolysis agent Lethal dose for a human=<5ug Comes from the soft coral species palythoa Toxica found in a small tidal pool in maui http:/www.rockefeller.edu/pubinfo/012103ph

What is Palytoxin? What is Palytoxin? „ One of the most toxic non-peptidic natural products known to man! „ Vasoconstrictor „ Hemolysis agent „ Lethal dose for a human = <5µg http://www.rockefeller.ed u/pubinfo/012103.ph p ƒ Comes from the soft coral species Palythoa Toxica found in a small tidal pool in Maui

From the Tidal pool to the lab The gross structure was first reported by two groups Hirata--Japanl a Moore--Hawaii2 64 stereogenic centers a 115 carbon backbone One of the longest contiguous carbon chains in a natural product a There are about 27 different stereoisomers Y Kishi succeeded in elucidating the complete structure of palytoxin in 1982 and then completed the synthesis in 1994 Jremura, D. Ueda, K, Hirata, Y; Naoki, H, Iwashita, T. Tetrahedron Lett. 1981, 22, 2781 2Moore. R.E.: Bartolini. G. J J. Am. Chem. Soc. 1981. 103. 2491 Ishi et

From the Tidal Pool to the Lab From the Tidal Pool to the Lab „ The gross structure was first reported by two groups: The gross structure was first reported by two groups: „ Hirata —Japan 1 „ Moore —Hawaii 2 „ 64 stereogenic centers stereogenic centers „ 115 carbon backbone carbon backbone ⇒ One of the One of the longest longest contiguous carbon chains in a natural product contiguous carbon chains in a natural product „ There are about There are about 271 different stereoisomers different stereoisomers „ Y. Kishi succeeded in elucidating the complete Y. Kishi succeeded in elucidating the complete structure of structure of palytoxin palytoxin in 1982 and then completed the in 1982 and then completed the synthesis in 1994 synthesis in 1994 3 1Ure mura, D.; Ueda, K.; Hirata, Y.; Naoki, H.; Iwashita, T. Tetrahedron Lett. 1981, 22, 2781 2Moore, R.E.; Bartolini, G. J. J. Am. Chem. Soc. 1981, 103, 2491 3Kishi et al

Notable reactions NiCl/CrCl2-catalyzed coupling reaction between vinyl iodides and aldehydes( nhk coupling). a Pd(0)catalyzed and thallium hydroxide assisted synthesis of cis-trans conjugated dienes from vinyl iodides and vinyl boronic acids a New methods for the construction of N-acyl vinylogous ureas

Notable Reactions Notable Reactions „ NiCl 2/CrCl 2 -catalyzed coupling reaction between catalyzed coupling reaction between vinyl iodides and aldehydes (NHK Coupling). vinyl iodides and aldehydes (NHK Coupling). „ Pd(0) catalyzed and thallium hydroxide assisted Pd(0) catalyzed and thallium hydroxide assisted synthesis of synthesis of cis -trans conjugated dienes from vinyl conjugated dienes from vinyl iodides and vinyl boronic acids. iodides and vinyl boronic acids. „ New Methods for the construction of N New Methods for the construction of N -acyl vinylogous ureas vinylogous ureas

NiCl/CrCl2 Coupling CrCl. DME OH 25°C R R X=L. Br Le CrCl2, DMF Me OH This carbon-carbon bond forming reaction is highly chemoselective Aldehyde carbonyls are selectively attacked even in the presence of other electrophilic groups e.g. Ketones, esters, and nitriles Gives benzylic or allylic alcohols Takai, K; Kimura, K; Kuroda, T; Hiyama, T, Nozaki, H. Tetrahedron Lett. 1983, 24, 5281

NiCl2/CrCl2 Coupling Coupling 1 R X + H R' O CrCl2, DMF 25°C R R' OH X=I, Br i.e.1 I Me + H O O CrCl2, DMF 25°C Me OH O •This carbon This carbon-carbon bond forming reaction is carbon bond forming reaction is highly chemoselective highly chemoselective • Aldehyde carbonyls Aldehyde carbonyls are selectively selectively attacked attacked even in the presence even in the presence of other electrophilic groups of other electrophilic groups e.g. Ketones, esters, and nitriles e.g. Ketones, esters, and nitriles •Gives benzylic benzylic or allylic allylic alcohols alcohols 1Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281

NiCl2/CrCl Coupling Cont Problem: Reaction didnt always work. The success of the Cr(ll) coupling depended on the batch of the Crc .Possible reasons: Quality of CrCl? NO! Homemade crcl, reagent didnt help .Possible contaminant in the CrCl? YYes! Kishi examined the effect of transition metals on the reaction and found that niCh had an effect

NiCl2/CrCl2 Coupling Cont. Coupling Cont. • Problem: Problem: Reaction didn’t always work. The success Reaction didn’t always work. The success of the Cr(II) coupling depended on the batch of the of the Cr(II) coupling depended on the batch of the CrCl2. •Possible Reasons: Possible Reasons: • Quality of CrCl Quality of CrCl2? NO! Homemade CrCl Homemade CrCl2 reagent didn’t help reagent didn’t help •Possible contaminant in the CrCl Possible contaminant in the CrCl2? Yes!! Kishi examined the effect of transition metals Kishi examined the effect of transition metals on the reaction and found that on the reaction and found that NiCl2 had an effect. had an effect

NiCl2/CrCl Coupling Cont The stereochemistry of the trans or cis iodo olefin is retained Reaction produces diastereomers although a preference for one is usually observed. Has an advantage over conventional carbonyl additions NiCk=Catalytic amount CrCl=Excess Kishi et al. J. Am. Chem. Soc. 1986. 108. 5644

NiCl2/CrCl2 Coupling Cont. Coupling Cont. • The stereochemistry of the The stereochemistry of the trans or cis iodo olefin is retained. olefin is retained. • Reaction produces Reaction produces diastereomers diastereomers although a although a preference for one is usually observed. preference for one is usually observed. • Has an advantage over conventional carbonyl Has an advantage over conventional carbonyl additions. additions. NiCl2 = Catalytic amount = Catalytic amount CrCl2 = Excess = Excess Kishi et al. J. Am. Chem. Soc. 1986, 108, 5644

NiCl/CrCl2 Coupling Cont Transmetalation Cr(lr) Ni-Ⅹ Cr(Il) XEL Br. oti Oxidative Addition RCHO Ni(0) Ni(n)* R 2Cr(Im) OH Takai, K, Tagashira, M, Kuroda, T, Oshima, K; Utimoto, K; Nozaki, H J. Am. Chem. Soc. 1986, 108, 6048

NiCl2/CrCl2 Coupling Cont. Coupling Cont. Transmetalati Transmetalation X Ni-X Cr(III) RCHO R OH Cr(III) Ni(0) Ni(II) 2Cr(III) 2Cr(II) X= I, Br, OTf Oxidative Addition Oxidative Addition Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048