5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Me O O Background/Introduction: HO H H H HO Me 1. Isolated from a myriad of sources, including, but not limited to ants, N frogs, fungi, and trees. Me N HO H N N 2. A host of effects including, but not limited to, harvest failures, edemas, Me Me necrosis, and rashes. elaeokanine C 3. A host of activities including, but not limited to, phytotoxic, insecticidal, Me Me N antibacterial, and fungicidal. allopumiliotoxin 267A myrmicarin 215A 4. It is unclear what defines the limits of the family, however scores of rhazinilam H H natural products contain the core structure shown below. A sampling Me HO H is provided at the end of the handout. HO 5. The ring is numbered as shows below. N N OH Me Me N 8 1 Me 7 9 2 Me Me OH 6 N Me Me 4 myrmicarin 215B myrmicarin 217 5 3 allopumiliotoxin 339B Me Me OH OH H H Me OH H Syntheses Discussed (in order): H H OAc Me H OH OH N N HO O N Me N Me N H Me swainsonine N nuphar alkaloids Me H2N N indolizidine 223AB slaframine N indolizidine 209D indolizidine 223A serratinine Me tashiromine O Me Me HO H H HO H HO H OH H OH OH Me H Me N N N Me N N OH N H OH OH Me Me OH Me Me lentiginosine O pumiliotoxin 323A lepadiformine pumiliotoxin 307A pumiliotoxin 251D gephyrotoxin O OH OH O H H OH H Me H HO H H N H Me N H N N Me OH N HO H N Me H castanospermine H N H Me securinine gephyrotoxin indolizomycin O alkaloid 205B indolizidine 167B HO ipaldibine Me Me Me 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Gallagher, Tetrahedron Lett. 1995, 36, 6957. Barluenga, J. Org. Chem. 1999, 64, 3736. OTMS O OH O O ZnCl , THF, Me 2 pip. TMS – 80 to 25 ºC; Me + N NH N N slaframine CbzHN 30% CbzHN NaHCO ; N Ar 3 O Ar O O SiO2, 51% OMe nuphar alkaloids Marsden, Synlett, 2005, (16), 2528. Kibayashi, J. Am. Chem. Soc. 2000, 122, 4583. O Mechanism? HO H H 1. H2, Pd/C TFA OMOM 2. Na(Hg), Na HPO tashiromine NHOH 2 4 N 3. MsCl, TEA, DMAP 85% N Bu4NIO4 TMS O O 77% O N 4, KOtBu, THF O 69% Knapp, J. Org. Chem. 1992, 57, 4802. OMOM SePh OAc N H (TMS)3SiH, OAc lepadiformine O AIBN, PhH, MOMO N 16 hrs, N THPO THPO O 76% O slaframine Wightman, Tetrahedron, 1998, 54, 9429. Me Me Somfai, Tetrahedron. 1995, 51, 9747. O TBDPSO O TBDPSO Me Tol., ! Me H + Mechanism? O 92% O N+ N N LDA, THF, O- O – 78 ºC, Me CO t-Bu Me 1. TBAF 2 O H N CO2t-Bu Me 2. MsCl, Pyr. Me 98% H lentiginosine OH O 3. H2, Pd/C indolizidine 209D N 76% 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Goti, Tetrahedron Lett. 1994, 35, 949. Rumeson, Tetrahedron Lett. 1999, 40, 1661. H EtO 1. TMSCH MgCl OTBDPS 1. PhH, RT, H OTBDPS 2 EtO2C 7 days, 75% O (2 equiv), CeCl3 N N + OTBDPS OTBDPS N+ N 2. HCl, 86% - 2. xylenes, O O O 140 ºC, 45% Me Me Mechanism? indolizidine 167B Mechanism? lentiginosine Mariano, Tetrahedron. 2005, 61, 8888. Saegusa, Tetrahedron Lett. 1983, 24, 2881. N NHAc AcN 1. HClO4, h" H AcO OAc BnO OTBS Me3N 2. Ac2O, Pyr. TMS CsF MeO N MeO N 42% 71% gephyrotoxin Mechanism? OBn OTBS H RCM swainsonine Mechanism? OTHP OTHP castanospermine NAc 63% See "Pyridinium Photochemistry" Baran Group Meeting. Weinreb, J. Am. Chem. Soc. 1982, 104, 7065. Jefford, Helv. Chim. Act. 1986, 69, 2048. OTBS OTBS N2 DCB, ! O O H Rh(OAc)2 N N ipalbidine MeO C 82% MeO C slaframine 2 2 N 89% N OAc O O Ph Ph Angle, J. Org. Chem. 1997, 62, 8549. Tetrahedron Lett. 1993, 34, 3985. Honda, Org. Lett. 2004, 6, 87. O 1. TIPSOTf, O 1. Hoveyda- 1. NBS, AIBN O O O TEA H Grubbs H 2. TFA Me indolizidine 167B 2. LAH N N NBoc 2. CrO3, N 3. K2CO3 Bn 79% Bn Boc OH Me2Pyrazole 45% Me Mechanism? Me 57% securinine 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Montgomery, J. Am. Chem. Soc. 1999, 121, 6098. Trauner, Org. Lett. 2005, 7, 5207. O O MOM MOM Me N Pd(OAc)2, Me Me K2CO3, 47% N Me TESH, Me I Cy2P Me Ni(COD)2, 1. HF•Pyr rhazinilam N N N N 2. Li, NH PBu3, 95% 3 NMe2 O OTES 81% CO2Me CO2Me H H Me OBn Me OBn allopumiliotoxin 267A Movassaghi, Org. Lett. 2005, 7, 4423. OTf Pd dba , XPhos, Tol. O See "Nickel in Synthesis" Baran Group Meeting. 2 3 t-BuO2C OMe K3PO4, 60 ºC, 95% Me O Me Me Mori, Tetrahedron. 1998, 54, 1153. Tetrahedron Lett. 1997, 38, 3931. OMe O N Me NH OMe Me Me t-BuO H H myrmicarin 215A OMe Ni(COD)2, TESO myrmicarin 215B myrmicarin 217 N N elaeokanine C PPh3, TESH, 74% O O O Kibayashi, J. Am. Chem. Soc. 1992, 114, 10653. Me Me BnO H BnO H CrCl2, HO Sames, J. Am. Chem. Soc. 2002, 124, 6900. ibid. 2000, 122, 6321. NiCl2, O N N allopumiliotoxin 339A O DMF R R Ph I 79% R N 1. TfOH N H2N Me Pt 2. TFE, 70 ºC Back, Org. Lett. 1999, 1, 261. J. Org. Chem. 2000, 65, 4543. Me Me Mechanism? H 3. KCN Me Me H 4. NH OH Me 1. DCM 2 N rhazinilam + Ts N 40% Ts N Cl HN 2. LDA 94% Me indolizidine 167B 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Inubushi, J. Chem. Soc. Chem. Commun. 1974, 827. O'Doherty, Org. Lett. 2006, 8, 1609. Mechanism? O OTBS AcO AcO O OH NBS, H2O H H Me Me 1. LiBH4 OTBS NCS, 2. TsCl, Pyr. 0 ºC, 84% HO O H2N Name? N CuCl2 3. KOAc, 25% Mechanism? swainsonine AcO 20% AcO CO2Et CO2Et Me OAc Kibayashi, Angew. Chem. Int. Ed. 2002, 41, 3017. OAc O BnO OAc HCO2H, Tol/THF, N serratinine OBn BOC NHBOC 0 ºC, 2 h, 88% HCO2 N Me See "Nitrogen Centered Radicals" Baran Group Meeting. Mechanism? Me Baskaran, Org. Lett. 2003, 5, 583. J. Org. Chem. 2004, 69, 3093. lepadiformine H H EtAlCl2, Kirihara, Tetrahedron. 1999, 55, 2911. NaBH 4 indolizidine 167B PIFA, TfOH, N OH N3 indolizidine 209D O MeOH, rt, 67% O 54% HO Me Mechanism? MeO2CN MeO2CN MeO2C Ma, Org. Lett. 2005, 7, 705. indolizidine 223AB N M e CO2Me CO Et CO Et 2 NH2 2 K2CO3 Overman, Tetrahedron Lett. 1988, 29, 901. + MeCN Me Cl HO Me Me Me N H HO I H2CO, CSA, H Me 80% Me MeCN, NaI, Mechanism? HN I N 100 ºC, 82% pumiliotoxin 307A pumiliotoxin 323A indolizidine 223A R Mechanism? R 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Overman, J. Am. Chem. Soc. 1984, 106, 4192. ibid. 1981, 103, 1851. Smith, Org. Lett. 2005, 7, 3247. J. Org. Chem. 2006, 71, 2547. TsN HO Me 1. H2CO Me 1, tBuLi, Et O, – 78 H HO 2 2. CSA, H S S 3 to – 45 ºC, 1 hr; 2, OTBS pumiliotoxin 251D S Me pumiliotoxin 307A 1 Me Et2O, – 78 to – 25 ºC, S TBS R HN EtOH, ! N pumiliotoxin 323A NHTs TMS 60% Me 5 hrs; 3, HMPA/Et O, 2 TBSO R O 2 – 78 to 0!ºC, 56% Me TBSO Mechanism? Overman, J. Org. Chem. 1992, 57, 1179. indolizidine 223AB Me Me HO 1. H2CO HO H H S H S H O 2. TsOH, 20% or O S 1. LHMDS, TMSCl, S Me HN N N THF, – 78 ºC N 2. LDA, TMSCl H H 3. TMSOTf, 56% H H Me 2. Grubbs 2, PhH, allopumiliotoxin 267A 65 ºC, 81% allopumiliotoxin 339B O Me O Me O Li • HO Me alkaloid 205B H 1. H Me OMe O Denmark, J. Am. Chem. Soc. 1999, 121, 3046. HN 2. TsOH N 3. HCl, 45% O OXc O N O X c , MAPh; Mechanism? t-Bu O Overman, J. Am. Chem. Soc. 1980, 102, 1454. Si !, PhH, NaHCO3 H H t-Bu O NO O MeO O 2 44% O TsOH, BnO Si MeO H OMe H H Mechanism? t-Bu N N t-Bu PhH, ! Me BnO Me 79% 1. K2OsO2(OH)4, K2CO3, Ph Ph H2O, NaHCO3, K3Fe(CN)6, 1. BnBr, CHCl3, !; NaOH AlMe tBuOH, (DHQD)2AQN 2. NaBH4 OH 2. TsCl, Pyr., 100% Ph X H H 2 c BnO BnO MAPh O OX H H Me HO O c H CH3(OEt)3 H N NBn EtO2C NBn Me 1. H2, Ran-Ni, acid, TsO ! castanospermine 160 psi, Meoh, 73% H 55% O O Si perhydrogephyrotoxin 2. HF, MeOH, 88% t-Bu t-Bu 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Danishefsky, J. Am. Chem. Soc. 1990, 112, 2003. ibid. 1993, 115, 30. O O 1. NaBH4 2. HCl, MeOH CO2Me + O N 3. TiCl4, N PPh3 MeO2C O O TMS N2 1. Lawesson's S 2. NaOH O O N 3. NMM, N H H iBuOCOCl MeO2C 4. CH2N2, 65% Rh(OAc)2 66% SH 1. Ra-Ni, Name? MeO O Me2CO TEOCCl N N 2. Me3OBF4 H 30% H 3. NaBH Mechanism? 4 HO H 1. H2O2, O 1. mCPBA, 84% NaOH, 97% N N 2.