5/10/06 Richter Indolizidine 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 natural products contain the core structure shown below. A sampling H H 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 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 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 OTBDPS OTBDPS EtO 1. TMSCH2MgCl 1. PhH, RT, H EtO C 7 days, 75% O 2 (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. Hoveyda- 1. NBS, AIBN 1. TIPSOTf, O 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. TBSOTf, TEA H H TEOC 2. H2NNH2, TEOC 3. O3, NaHCO3 AcOH, 52% 4. MeOCH=PPh3 Name? Mechanism? 76% 1. O2; PPh3, O HO OTBSO 2. Me PhO S Me Mechanism? 2 N N OMe H H Li TEOC TEOC SO Ph 3. Ac2O 2 1. Na-Hg, 53% AcO 2. HIO4 Me indolizomycin Me 3. TPAP, 74% See Classics I, Chapter 27 4. TBAF, 29% 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting

Other Indolizidine Containing Natural Products: Me Me H H Me H H H OH H OH N Me N HO Me N Me N Me Me Me N OH Me Me N Me HO Me Me O Me Me monomorine uniflorine A myrmicarin 237A/B indolizidine 249H indolizidine 263D indolizidine 223I

Me Me Me Me H H H Me Me H H H

N N N N N N

Me

indolizidine 207A indolizidine 205A indolizidine 235B' indolizidine 203A indolizidine 209I indolizidine 217B

Me Me H H H Me Me Me H H H N N N Me N N N Me Me

indolizidine 233D indolizidine 209B indolizidine 195B indolizidine 231C indolizidine 233D indolizidine 219F

Me Me Me Me H H H H H H Me Me N Me N N N Me N N Me Me Me

indolizidine 221I indolizidine 223J indolizidine 235B'' dendroprimine indolizidine 259B indolizidine 223V 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting

Other Indolizidine Containing Natural Products: H Me N H H Me N Me Me Me H HO H HO H HO H O Me OH HO O Me N+ O + N Me N N N Me Me H Me Me HO Me Me Me Me Me stgellattamide B stgellattamide C pumiliotoxin 237A allopumiliotoxin 341A pumiliotoxin 225F OMe MeO OH HO Me Me Me H HO H HO H HO H H O O N N Me N Me N N

Me HO O Me Me Me Me unnamed HO OMe phyllostemine pumiliotoxin 209F pumiliotoxin 277B pumiliotoxin 305B OMe OMe Me MeO Me HO H MeO HO H HO H H N N OH N OMe N Me O Me Me O Me MeO Me MeO secoantofine OMe septicine Me pumiliotoxin 321 allopumiliotoxin 323B' MeO OMe Me Me HO H H MeO HO N H O Me H N+ N OH N+ N Me MeO Me Me Me Me OMe OH Me MeO allopumiliotoxin 339A stgellattamide A antofine tylophoridicine D 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting

Other Indolizidine Containing Natural Products: MeO HO OH OH MeO OMe OH H H H MeO H N N N+ - O MeO N HO MeO HO unnamed OMe OMe tylocrebrine OMe MeO tylophoridicine E tylophorinidine

OMe MeO MeO OMe MeO H H MeO H N N N+ N HO MeO MeO dehydrotylophorine OMe OMe MeO OMe tylophorine tylophoridicine A deoxypergularinine OMe Me OMe HO MeO H H MeO HO H OH H H MeO N N MeO OH N OH + H Me N Me O- MeO dihydrogephyrotoxin Me allopumiliotoxin 323B'' isotylocrebrine MeO OMe ficuseptine O O OMe O O MeO O OH MeO O O OH O H H H H H H MeO

N N N N N N H H MeO H H tylophorinine MeO O-methyltylophorinidine phyllanthine virosecurinine viroallosecurinine allosecurinine OMe OMe 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting

Other Indolizidine Containing Natural Products: O N H Me N H Me Me NH O Me O Me H OAc N Me O Me OH H H H N H MeO N H CO2Me O N Ac Me H N OMe H H N N Me rhazinal aspidospermine vindoline OH OMe O grandisine A grandisine B alkaloid 261C OMe OH OMe HO HO O O OH OH HO HO N H H N+ Me N N N O O H H erythraline erysonine erythramine N N O O HO Me Me Me H lycorine ambelline OMe fluorocurine Me O O O H H H H H O O OH H Me Me H H H H HO H N N Me N N N Me Me Me Me O elaeocarpine isoelaeocarpine isoelaeocarpicine H H N Me N O N H N CO H H N 2 O Me Me Me Me Me Me H2N HO H H CONH O H O N 2 myrmicarin 663 myrmicarin 645 N O H2 N elaeokanine A Me pantocin A serratezomine A Me O O H OH O OH Me H O CO H OH O H H 2 N Me N Me N N N N N N H Me Cl OH O CO2H Me cylindricine A cylindricine B myrmicarin 430 A58365 chilocorine D secu'amamine A 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting

Me Other Indolizidine Containing Natural Products: H OMe OMe O OMe N N N N O HO H O

H O H O H CO Me N Me MeO N N N 2 H H H N N CO Me OH Me MeO2C 2 O mitraphylline MeO2C erysodine erythroidine vincadifformine aspidoalbine pleiocarpine O H N Me O N H H N N O N H H H O H O O N O H H N N N N H H H MeO C N Me O O 2 H Me Me HO camptothecin elaeokanine E camoensidine fruticosine tuboxenine neblinine MeO N N Me N + H N Me O H O O H cancentrine H H N N O O N N H H H NMe H H Me CO Me MeO C OMe 2 2 beninine vincatine MeO Me H H HO N N kopsine OH H N HO H Me N O N N+ H H MeO2C H dihydrotoxiferine Me MeO Me N N H H H H H O CO2Me CO2Me Me N Other Indolizidine containing H H condylocarpine akuammicine Me Me natural products (that I didn't pandoline N N feel like drawing): N N OH vinblastine vincristine H H daphniyunnine I curarine I HO alkaloid E alkaloid F N N H H H H H H calebassine pteropodine O Me N speciophylline uncarine F N H O O H H H O himandrine alkaloid H alkaloid A Me tubifolidine Me MeO tsilanine alkaloid G isopteropodine