Total Synthesis of Palytoxin O NH 2 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 OHHO OH Me OH HO Me OH OH OH HO OH OH OHOH MeOO Me OH Armstrong, R.W.; Beau, J.M.; Cheon, S.H.; Christ, W.J.; Fujioka, H.; Ham, W.H.; Hawkins, L.D.; Jin, H.; Kang, 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.; White, J.B.; Yonaga, M. J.Am.Chem.Soc., 1989, 111, 7525; Armstrong, R.W.; Beau, J.M.; Cheon, S.H.; Christ, W.J.; Fujioka, H.; Ham, W.H.; Hawkins, L.D.; Jin, H.; Kang, 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.; White, J.B.; Yonaga, M. ibid, 1989, 111, 7530; Suh, 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 Chris 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 = <5μg Vasoconstriction and Hemolysis http://www.nlm.nih.gov/medlineplus/ency/imagepages/8983.htm http://www.physiology.rwth-aachen.de/user/martin/DuUndDeinBlut/Bl- Terminologie-d.html 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.edu/pubinfo/012103.php ? 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—Japan 1 ? Moore—Hawaii 2 ? 64 stereogenic centers ? 115 carbon backbone ? One of the longest contiguous carbon chains in a natural product ? There are about 2 71 different stereoisomers ? Y. Kishi succeeded in elucidating the complete structure of palytoxin in 1982 and then completed the synthesis in 1994 3 1 Uremura, D.; Ueda, K.; Hirata, Y.; Naoki, H.; Iwashita, T. Tetrahedron Lett. 1981, 22, 2781 2 Moore, R.E.; Bartolini, G. J. J. Am. Chem. Soc. 1981, 103, 2491 3 Kishi et al. Notable Reactions ? NiCl 2 /CrCl 2 -catalyzed coupling reaction between vinyl iodides and aldehydes (NHK Coupling). ? Pd(0) catalyzed and thallium hydroxide assisted synthesis of cis-trans conjugated dienes from vinyl iodides and vinyl boronic acids. ? New Methods for the construction of N-acyl vinylogous ureas NiCl 2 /CrCl 2 Coupling 1 R X + H R' O CrCl 2 , DMF 25°C R R' OH X=I, Br i.e. 1 I Me + H O O CrCl 2 , DMF 25°C Me OH O ?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 1 Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281. NiCl 2 /CrCl 2 Coupling Cont. ? Problem: Reaction didn’t always work. The success of the Cr(II) coupling depended on the batch of the CrCl 2 . ?Possible Reasons: ? Quality of CrCl 2 ? NO! Homemade CrCl 2 reagent didn’t help ?Possible contaminant in the CrCl 2 ? Yes!! Kishi examined the effect of transition metals on the reaction and found that NiCl 2 had an effect. NiCl 2 /CrCl 2 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. NiCl 2 = Catalytic amount CrCl 2 = Excess Kishi et al. J. Am. Chem. Soc. 1986, 108, 5644 NiCl 2 /CrCl 2 Coupling Cont. Transmetalation X Ni-X Cr(III) RCHO R OH Cr(III) Ni(II)Ni(0) 2Cr(II)2Cr(III) X= I, Br, OTf Oxidative Addition Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. NiCl 2 /CrCl 2 Coupling Cont. O t-BuPh 2 SiO I H Me OC(O)t-Bu Me H H CrCl 2 (excess) NiCl 2 (0.5%) DMSO/Me 2 S (73%) OHC O t-BuPh 2 SiO H HO Me H OC(O)t-Bu Me H H H Me H Me H H Me Me O Me HO OHC H (+)- ophiobolin C Rowley, M.; Tsukamoto, M.; Kishi, Y.; J. Am. Chem. Soc. 1989, 111, 2735 Notable Reactions ? NiCl 2 /CrCl 2 -catalyzed coupling reaction between vinyl iodides and aldehydes ? Pd(0) catalyzed and thallium hydroxide assisted synthesis of cis-trans conjugated dienes from vinyl iodides and vinyl boronic acids. ? New methods for the construction of N-acyl vinylogous ureas Retrosynthesis O NH 2 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 OHHO OH Me OH HO Me OH OH OH HO OH OH OHOH MeOO Me OH 1 Retrosynthesis II O N-TEOC OTBS O O O O OH H O TBSO OTBS OTBS OTBS OTBS TBSO Me Ph 3 P CH(SEt) 2 I OTBS OTBS OTBSI OCPh 2 (C 6 H 4 -p-OMe) Wittig Rxn. NiCl 2 /CrCl 2 Coupling 8 9 10 Matteson Rxn.; Suzuki Coupling OAc O OTBS OTBS OTBS O OTBS TBSO OTBS OTBS H OTBS TBSO I MeO O O OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB OTHP HO NH 2 N H HO O SePh O OMe OBz OBz BzO Me O OBz HO O O O Me Me Me OTBS PPh 3 I Me OAc O MeO TBS MeO NiCl 2 /CrCl 2 Coupling Amide Bond Formation Wittig Rxn.; Hydrog. 12 13 14 15 16 HWE 11 Wittig Rxn.; Hydrog. Synthesis I O OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB OTHP HO O O Me Me Me OTBS PPh 3 I 1.(COCl) 2 , DMSO; then Et 3 N 2.n-BuLi, THF, -78°C; then aldehyde from 14 3.H 2 , 10% Pd/C 4.TBAF, THF, 25°C O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me OH THPO 17 14 13 88% Synthesis II O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me OH THPO 17 1.MsCl, Et 3 N, 0°C 2.NaI, 2-butanone, 60°C 3.Ph 3 P, DMF, 110°C O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me PPh 3 THPO 18 I O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me THPO O OO BzO Me OBz OBz OMe BzO 20 O OMe OBz OBz BzO Me O OBz HO O O OMe OBz OBz BzO Me O OBz O O 12 19 (COCl) 2 DMSO; then Et 3 N 100% 1.18, n-BuLi, THF, -78°C; then add 19 2.H 2 , 10% Pd/C 62% from 12 Synthesis III O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me THPO O OO BzO Me OBz OBz OMe BzO 20 O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O O OO BzO Me OBz OBz OMe BzO 21 1.PPTS, MeOH/Et 2 O 42°C 2.(COCl 2 ), DMSO; then Et 3 N Synthesis IV O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O O OO BzO Me OBz OBz OMe BzO 21 Me OAc O MeO I TBS MeO 15 CrCl 2 , NiCl 2 (0.11%) DMSO/THF (1:3), 32°C (68-82%) O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OO BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OH 22 Synthesis V O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OO BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OH 22 O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OH OH BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OAc 23 1.Ac 2 O, 4-DMAP, pyr. 2.PPTS, MeOH/Et 2 O 40°C 97% Synthesis VI O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OH OH BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OAc 23 RuCl 2 (PPh 3 ) 3 25°C (72-81%) O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OH O BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OAc 24 What we have so far O NH 2 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 OHHO OH Me OH HO Me OH OH OH HO OH OH OHOH MeOO Me OH Synthesis VII TEOC = C(O)CH 2 CH 2 SiMe 3 O N-TEOC OTBS O O O O OH H O TBSO OTBS OTBS OTBS OTBS TBSO Me Ph 3 P CH(SEt) 2 I 89 (COCl) 2 , DMSO; then Et 3 N LDA (0.4M THF) THF/HMPA (5:1) 25°C (ylide formation) (60-80%) O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O CH(SEt) 2 25 ≥8:1 cis:trans Synthesis VIII O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O CH(SEt) 2 25 I 2 , NaHCO 3 , (CH 3 ) 2 CO/H 2 O (19:1) 0°C (98%) O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O O 26 OTBS OTBS OTBSI OCPh 2 (C 6 H 4 -p-OMe) 10 CrCl 2 , NiCl 2 (0.11%) DMSO/THF (3:1) (90%) O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OCPh 2 (4-MeOPh) HO OTBS OTBS OTBS 27 Synthesis IX O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O O HO OTBS OTBS OTBS 27 1.PDC, DMF, 0°C 2.Ph 3 P=CH 2 , hexanes/THF (2:1), 0°C 3.PPTS, MeOH/CH 2 Cl 2 4.(COCl) 2 , DMSO; then Et 3 N (80% overall) O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O O OTBS OTBS OTBS 28 C OMe Synthesis X O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O O OTBS OTBS OTBS 28 LiCH[B(OCH 2 CH 2 CH 2 O)] 2 -TMEDA THF, 0°C; then EtOAc, brine/1N HCl O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OTBS OTBS OTBS B OH HO 29 8-10:1 trans:cis Synthesis XI O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OTBS OTBS OTBS B OH HO 29 OAc O OTBS OTBS OTBS OTBS TBSO OTBS OTBS H OTBS TBSO I MeO O 11 1.Pd(PPh 3 ) 4 (cat.), TlOH; then add 11 2.LiCH 2 P(O)(OMe) 2 THF, -78°C O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OTBS OTBS OTBS O O P OTBS OTBS OTBS H OTBS OAc OTBS OTBS TBSO OTBS TBSO O O MeO OMe 30 Taking Inventory O NH 2 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 OHHO OH Me OH HO Me OH OH OH HO OH OH OHOH MeOO Me OH Haven’t made this connection yet Synthesis XII O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OH O BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OAc 24 O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OTBS OTBS OTBS O O P OTBS OTBS OTBS H OTBS OAc OTBS OTBS TBSO OTBS TBSO O O MeO OMe 30 NaH, THF; then add 24 1.LiBH 4 , EuCl 3 , MeOH/Et 2 O (1:1) 2.Ac 2 O, 4-DMAP, pyr., 0°C (75-80%) O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OTBS OTBS OTBS O O OTBS OTBS OTBS H OTBS OAc OTBS OTBS TBSO OTBS TBSO OAc O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OAc BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OAc 31 Synthesis XIII O NH-TEOC OTBS O O O TBSO OTBS OTBS OTBS OTBS TBSO Me O O OTBS OTBS OTBS O O OTBS OTBS OTBS H OTBS OAc OTBS OTBS TBSO OTBS TBSO OAc O O Me O Me OPMB H OPMBPMBO OPMB OPMB PMBO OPMB OPMB OPMB Me O OAc BzO Me OBz OBz OMe BzO MeO O OTBSMe OAc OAc 31 O NH 2 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 HO OH OH Me OH H OHHO OH Me OH HO Me OH OH OH HO OH OH OHOH MeO Me OH 32 1.DDQ, t-BuOH/CH 2 Cl 2 /pH7, 25°C then Ac 2 O, 4-DMAP, pyr., 25°C 2.HClO 4 (1.18N)/THF, 25°C 3.LiOH(0.08N), H 2 O/MeOH/THF, 25°C 4.TBAF, THF, 22°C; then in DMF/THF, 22°C 5.AcOH/H 2 O, 22°C Synthesis XIV O NH 2 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 OH OH Me OH H OHHO OH HO Me OH OH OH HO OH OH OHMe Me OH 33 32 AcOH O Me HO O Synthesis XV…the end NH 2 N H HO O SePh 16 33 1.pyr. (62%) 2.oxaziridine A (43%) 3.hν (cis→trans ? isomerization) O NH 2 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 OHHO OH Me OH HO Me OH OH OH HO OH OH OHOH MeOO Me OH Me Me N S O O O A: Camphor Sulfonyl Oxaziridine 1 O Me HO O R Summary ? NHK coupling was utilized to bring together key connections in the molecule. ? Strategically picked protecting groups allowed the manipulation of the molecule. ? The total synthesis as well as structure elucidation of palytoxin was a great achievement. The End