Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Background/Introduction:

1. Isolated from a myriad of sources, including, but not limited to ants, frogs, fungi, and trees.2. A host of effects including, but not limited to, harvest failures, edemas, necrosis, and rashes.3. A host of activities including, but not limited to, phytotoxic, insecticidal, antibacterial, and fungicidal.4. It is unclear what defines the limits of the family, however scores of natural products contain the core structure shown below. A sampling is provided at the end of the handout.5. The ring is numbered as shows below.

N

1

2

345

6

7

89

Syntheses Discussed (in order):

N

H

slaframineH2N

OAc

N

H

tashiromine

OHN

H

Me

indolizidine 209D

N

HMe

O

nuphar alkaloids

N

Me

OH

lepadiformine

N

H OH

OH

lentiginosine

NH

H

H

OH

gephyrotoxin

N

H

indolizidine 167B

Me

N

H

castanospermine

OH

HO

OH

HO

N

O

HMe

HO ipaldibine

N

O

O

H

H

securinine

N

H

allopumiliotoxin 267AMe

MeHO

HO

MeN

O

MeH

HO

elaeokanine C

N

NH

Me

O

rhazinilam

N

H

myrmicarin 217

Me

Me

N

H

myrmicarin 215A

Me

Me

N

H

myrmicarin 215B

MeMe

N

H

allopumiliotoxin 339B

Me

MeHO

HO

Me

OH

OH

Me

HO

N

serratinine

O

Me

OH

indolizidine 223A

N

H

Me

Me

MeN

OHH OH

OH

swainsonine

N

H

Me

indolizidine 223AB

Me

N

H

pumiliotoxin 307A

Me

MeHO

OH

Me

pumiliotoxin 323A

N

H

Me

MeHO

OH

OH

MeN

H

pumiliotoxin 251DMe

MeHO

Me

NH

H

H

MeOH

gephyrotoxin

N

H

alkaloid 205B

HH

Me

Me

Me

N

OH

indolizomycin

O

MeMe

H

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Gallagher, Tetrahedron Lett. 1995, 36, 6957.

Marsden, Synlett, 2005, (16), 2528.

Knapp, J. Org. Chem. 1992, 57, 4802.

Somfai, Tetrahedron. 1995, 51, 9747.

slaframineN

O

CbzHN

O

O

N

O

CbzHN

O

pip.

30%

N

HO

O

TFA

85% N

H

O

tashiromine

N

OAc

O

SePh

THPO

H (TMS)3SiH,AIBN, PhH,

16 hrs, 76%

N

O

THPO

OAc

slaframine

N

Me

CO2t-Bu

LDA, THF, – 78 ºC,

98%NH

CO2t-BuMe

indolizidine 209D

Barluenga, J. Org. Chem. 1999, 64, 3736.

Kibayashi, J. Am. Chem. Soc. 2000, 122, 4583.

Wightman, Tetrahedron, 1998, 54, 9429.

Me

OTMS

N

OMe

Ar

NTMS

+

ZnCl2, THF,– 80 to 25 ºC;

NaHCO3;SiO2, 51%

NH

OH

Me

O Ar

nuphar alkaloids

Mechanism?N+

O

O

O-

Me

MeTBDPSO

+

Tol., !

92%N

O

O

Me

Me

O

TBDPSOH

1. TBAF2. MsCl, Pyr.3. H2, Pd/C 76%N

O

O

Me

Me

HOHlentiginosine

NHOH

O

Bu4NIO4

77% NO

OMOM

O

1. H2, Pd/C2. Na(Hg), Na2HPO4

3. MsCl, TEA, DMAP

4, KOtBu, THF 69%

NOlepadiformine

HMechanism?

OMOM

MOMO

TMS

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Goti, Tetrahedron Lett. 1994, 35, 949.

Saegusa, Tetrahedron Lett. 1983, 24, 2881.

Weinreb, J. Am. Chem. Soc. 1982, 104, 7065.

Angle, J. Org. Chem. 1997, 62, 8549. Tetrahedron Lett. 1993, 34, 3985.

Rumeson, Tetrahedron Lett. 1999, 40, 1661.

Mariano, Tetrahedron. 2005, 61, 8888.

Jefford, Helv. Chim. Act. 1986, 69, 2048.

Honda, Org. Lett. 2004, 6, 87.

Mechanism?

N+

OTBDPS

OTBDPS

-O

+

1. PhH, RT, 7 days, 75%

2. xylenes, 140 ºC, 45%

N

OH OTBDPS

OTBDPS

lentiginosine

TMSN

OTHP

Me3N

N

OTHP

H

MeO MeO

gephyrotoxin

Mechanism?

CsF

71%

HN

OTBS

MeO2C

OOAc

DCB, !

82%N

OTBS

MeO2C

O

slaframine

NBn

O

Me

O1. TIPSOTf, TEA

2. LAH 79%

NBn

MeOH

indolizidine 167B

Mechanism?

N

EtOEtO2C

OMe

1. TMSCH2MgCl (2 equiv), CeCl3

2. HCl, 86%

N

OMe

H

indolizidine 167BMechanism?

N 1. HClO4, h"

2. Ac2O, Pyr. 42%

NHAc

OAcAcO

AcN

OTBSBnO

RCM

63%NAc

OBn OTBSH

swainsoninecastanospermine

See "Pyridinium Photochemistry" Baran Group Meeting.

Mechanism?

NPh

N2

O

NPh

O

ipalbidineRh(OAc)2

89%

NBoc

O

MeH

N

OH

Boc

1. Hoveyda- Grubbs

2. CrO3, Me2Pyrazole 57%

1. NBS, AIBN2. TFA

3. K2CO3

45%securinine

O

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Montgomery, J. Am. Chem. Soc. 1999, 121, 6098.

Mori, Tetrahedron. 1998, 54, 1153. Tetrahedron Lett. 1997, 38, 3931.

Sames, J. Am. Chem. Soc. 2002, 124, 6900. ibid. 2000, 122, 6321.

Trauner, Org. Lett. 2005, 7, 5207.

Movassaghi, Org. Lett. 2005, 7, 4423.

Kibayashi, J. Am. Chem. Soc. 1992, 114, 10653.

Back, Org. Lett. 1999, 1, 261. J. Org. Chem. 2000, 65, 4543.

See "Nickel in Synthesis" Baran Group Meeting.

N

Me OBn

OTESH

N

Me OBn

O

MeMe

H

Me

Me

TESH, Ni(COD)2,

PBu3, 95%

allopumiliotoxin 267A

1. HF•Pyr

2. Li, NH3

81%

N

O

H

N

O

HTESO

Me

Ni(COD)2,

PPh3, TESH,74%

elaeokanine C

Me

O

N

N

PhO

NR

Pt

Me

Me

Me

Me

N

H2N1. TfOH2. TFE, 70 ºC

3. KCN4. NH2OH 40%

Me

rhazinilam

N

N

Me

O

CO2Me

MOM

I

Pd(OAc)2,K2CO3, 47%

Cy2P

NMe2

N

N

Me

O

CO2Me

rhazinilam

t-BuO2C

OTf

OMe

OMe

t-BuO

O N

OMe

OMe

Me

O

Me

Pd2dba3, XPhos, Tol.K3PO4, 60 ºC, 95%

NH

MeO

Me

myrmicarin 215Amyrmicarin 215Bmyrmicarin 217

N

RI

O

MeBnO H

N

MeBnO H

R

HOCrCl2,NiCl2,

DMF79%

allopumiliotoxin 339A

MOM

HNCl

HMe

Ts+ N

H

Me

Ts

1. DCM

2. LDA 94% indolizidine 167B

Mechanism?

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Inubushi, J. Chem. Soc. Chem. Commun. 1974, 827.

Baskaran, Org. Lett. 2003, 5, 583. J. Org. Chem. 2004, 69, 3093.

Ma, Org. Lett. 2005, 7, 705.

O'Doherty, Org. Lett. 2006, 8, 1609.

Kibayashi, Angew. Chem. Int. Ed. 2002, 41, 3017.

Kirihara, Tetrahedron. 1999, 55, 2911.

Overman, Tetrahedron Lett. 1988, 29, 901.

AcO

Me

AcO

H

CO2Et

H2NNCS,

CuCl220%

AcO

Me

AcO

H

CO2Et

N

1. LiBH4

2. TsCl, Pyr.

3. KOAc, 25%

N

OAc

Me

OAcOAc

serratinine

O

HEtAlCl2, NaBH4

54%

N

H

HO

indolizidine 167Bindolizidine 209DN3

Mechanism?

Mechanism?

Me Cl

Me

NH2

I

CO2Et

+

K2CO3

MeCN

80%

N

CO2Et

Me

Me

indolizidine 223A

Mechanism?

O OH

OTBS

NBS, H2O

0 ºC, 84% O

O

HO

OTBS

swainsonine

Name?Mechanism?

OBn

NHBOC

O

Me

HCO2H, Tol/THF,

0 ºC, 2 h, 88%

N

BnO

HCO2Me

BOC

lepadiformine

Mechanism?

MeO2CN

O

MeO2CN

OH

Me

PIFA, TfOH, MeOH, rt, 67%

NCO2Me

M eMeO2C

indolizidine 223AB

pumiliotoxin 307Apumiliotoxin 323A

HN

MeHO

R

H

N

MeHOH

I

R

H2CO, CSA, MeCN, NaI,

100 ºC, 82%

Mechanism?

See "Nitrogen Centered Radicals" Baran Group Meeting.

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Overman, J. Am. Chem. Soc. 1984, 106, 4192. ibid. 1981, 103, 1851.

Overman, J. Org. Chem. 1992, 57, 1179.

Overman, J. Am. Chem. Soc. 1980, 102, 1454.

Smith, Org. Lett. 2005, 7, 3247. J. Org. Chem. 2006, 71, 2547.

Denmark, J. Am. Chem. Soc. 1999, 121, 3046.

Mechanism?

HN

MeHOH

N

MeHOH

R

1. H2CO2. CSA,

EtOH, ! 60%TMS

R

pumiliotoxin 251Dpumiliotoxin 307Apumiliotoxin 323A

HNMe

MeHOH

N

MeHOH

1. H2CO2. TsOH, 20% or

2. LDA, TMSCl3. TMSOTf, 56%

O O

1.

2. TsOH3. HCl, 45%

•Li

OMe

HN

Me

HO

N

MeHOH

O

allopumiliotoxin 267Aallopumiliotoxin 339B

HN

Me

OMe

TsOH,

PhH, !79%

N

H

BnOH H

Me

O

1. BnBr, CHCl3, !; NaOH2. NaBH4

NBn

H

BnOH H

Me

OH

CH3(OEt)3

acid, !55%

NBn

H

BnOH H

MeEtO2C

perhydrogephyrotoxin

BnO

MeO

MeO

S S

TBS

O

TBSO

Me

Me

TsN

13

2

SS

TBSO

Me

NHTs

Me

OTBS

1, tBuLi, Et2O, – 78 to – 45 ºC, 1 hr; 2,

Et2O, – 78 to – 25 ºC,

5 hrs; 3, HMPA/Et2O, – 78 to 0!ºC, 56%

indolizidine 223AB

N

SS

MeOMe

H

HH

N

SS

O

H

HH

Me

1. LHMDS, TMSCl, THF, – 78 ºC

2. Grubbs 2, PhH, 65 ºC, 81%

alkaloid 205B

SiOt-Bu

Ot-Bu NO2

OXc

Ph

Ph

AlMe

2

MAPh

, MAPh;

!, PhH, NaHCO3

44%

NOO

O

SiO

OXc

H

t-But-Bu

1. K2OsO2(OH)4, K2CO3, H2O, NaHCO3, K3Fe(CN)6, tBuOH, (DHQD)2AQN2. TsCl, Pyr., 100%

NOO

O

SiO

OXc

H

t-But-Bu

Ph

Xc

HO

TsO1. H2, Ran-Ni, 160 psi, Meoh, 73%

2. HF, MeOH, 88%

castanospermine

Mechanism?

Mechanism?

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Danishefsky, J. Am. Chem. Soc. 1990, 112, 2003. ibid. 1993, 115, 30.

O

O

ON PPh3

CO2Me

+ N

O

OMeO2C

1. NaBH4

2. HCl, MeOH

3. TiCl4,

TMS

N

O

MeO2C H

1. Lawesson's2. NaOH

3. NMM, iBuOCOCl4. CH2N2, 65%

N

S

H

O

N2

NH

O

1. Ra-Ni, Me2CO

2. Me3OBF4

3. NaBH4

NH

MeO

NH

O

TEOCCl

30%

TEOC

H

Name?

1. H2O2, NaOH, 97%

2. H2NNH2, AcOH, 52%

NH

TEOC

HO

1. mCPBA, 84%

2. TBSOTf, TEA3. O3, NaHCO3

4. MeOCH=PPh3

76%

NH

TEOC

TBSO

OMe

O1. O2; PPh3, 2.

3. Ac2O

Li

PhO2S

Me

MeN

HTEOC

HOO

MeMe

SO2Ph

AcO1. Na-Hg, 53%2. HIO4

3. TPAP, 74%4. TBAF, 29%

indolizomycin

See Classics I, Chapter 27

Rh(OAc)2 66%

Name? Mechanism?

Mechanism?

Mechanism?

SH

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Other Indolizidine Containing Natural Products:

N

Me

H

Me

monomorine

N

H

myrmicarin 237A/B

Me

OMe

indolizidine 207A

N

HMe

N

H

uniflorine A

OH

HO

OH

HO

OH

N

H

indolizidine 205A indolizidine 235B'

Me

N

HMe

indolizidine 233D

N

HMe

indolizidine 209B

N

HMe

Me

N

Me

H

Me

indolizidine 195B

indolizidine 221I

N

H

Me

indolizidine 223J

N

HMe

indolizidine 235B''

N

HMe

Me

Me

Me

indolizidine 249H

N

HMe

MeMe

Me

Me

indolizidine 263D

N

HMe

Me

Me

Me

Me

indolizidine 203A

N

HMe

indolizidine 209I

N

H

Me

Me

indolizidine 217B

N

H

Me

N N

H H

indolizidine 231C indolizidine 219F

N

H

indolizidine 223V

Me Me

N

H

indolizidine 233D

Me

N

Me

H

dendroprimine

Me

N

H

indolizidine 259B

Me

Me

Me

N

H

indolizidine 223I

Me

Me

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Other Indolizidine Containing Natural Products:

N

H

pumiliotoxin 237A

Me

Me

MeHO

N

H

pumiliotoxin 225F

MeHO

MeHO

N

H

pumiliotoxin 209F

MeMe

MeHO

N

H

pumiliotoxin 321

Me

OMe

Me

MeHO

Me

N

H

pumiliotoxin 277B

Me

MeHO

Me

O

N

H

pumiliotoxin 305B

Me

MeHO

Me

O

Me

N

H

allopumiliotoxin 323B'

Me

OH

Me

MeHO

Me

HO

N

H

allopumiliotoxin 341A

MeHO

HO

O

OH

HMe

N

H

allopumiliotoxin 339A

Me

OH

Me

MeHO

Me

HO

OH

N+

stgellattamide A

H

Me

HN

O

Me Me

Me

Me

N+

stgellattamide C

H

Me

HN

O

N+

stgellattamide B

H

Me

HN

O

Me

Me

MeMe

MeMe

Me

Me

N

O

H

MeOsecoantofine

OMe

MeO

N

O

H

HOphyllostemine

OMe

HO

N

O

H

MeO

septicine

OMe

MeO

OMe

N

H

MeO

HO

OMeunnamed

OH

N+

MeO

MeO

OMe

tylophoridicine D

N

MeO

MeOantofine

OMe

H

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Other Indolizidine Containing Natural Products:

N+

H

MeO

HO

OMeunnamed

OH

O-

N+

MeO

MeO

OMe

dehydrotylophorine

OMe

N

MeO

MeO tylophorine

OMe

H

OMe

N

MeO

MeO isotylocrebrine

H

OMe

MeO

N+

MeO

MeOficuseptine

H

OMe

MeO

OMe

O-

OH

N

MeO

MeOtylocrebrine

OMe

H

MeO

N

HOH

MeO

MeO

OMe

N

HOH

MeO

MeO

OMe

O-methyltylophorinidinetylophorinine

N

HOH

MeO

HO

OMe

N

HOH

HO

MeO

OMe

tylophorinidinetylophoridicine E

N

H

MeO

HO

OMe

tylophoridicine A

N

H

MeO

MeO

OMe

deoxypergularinine

NH

H

H

OH

dihydrogephyrotoxin

N

O

O

H

H

phyllanthine

MeO

N

O

O

H

H

virosecurinine

N

O

O

H

H

allosecurinine

N

O

O

H

H

viroallosecurinine

N

H

allopumiliotoxin 323B''

Me

OH

Me

MeHO

Me

HO

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Other Indolizidine Containing Natural Products:

N

NH

Me

O

rhazinal

NAc

N H Me

H

OMe

aspidospermine

NMe

N H Me

H

vindoline

OAc

OH

CO2MeMeO

N

OMeOH

HO

N

OHOMe

HO

N

OMeO

O

erythraline erysonine erythramine

N

O

Me

O

H

H H

elaeocarpine

N

O

Me

O

H

H H

isoelaeocarpine

N

OH

Me

O

H

HO H

isoelaeocarpicine

N

O

MeH

elaeokanine A

N

N

N

Me

H

MeMe

H

O

Me

MeHH

H

Me

myrmicarin 663

N Me

O

Cl

cylindricine A

N Me

O

OH

cylindricine B

N

N

H

H

H

Me Me

MeMe

NNH

H

H

MeMe

Me

Me

N

Me

Me

myrmicarin 430

myrmicarin 645

N

OH

O

CO2H

CO2H

A58365

N

Me

N

OH OH

chilocorine D

N

secu'amamine A

HO

OOH

N

pantocin A

O

H2N

ONH2

CONH2

CO2H

HO

N

serratezomine A

O

O

Me

H

N

H

HH

Me

Me

alkaloid 261C

N

grandisine A

O

O

H

H

H

Me

MeO

N

grandisine B

H

N

O

Me

N

HH

OH

HO

O

O

lycorine

NH

OH

HO

O

O

ambellineOMe

N+N

H

H

Me

Me

HO

O

fluorocurine

Indolizidine AlkaloidsRichter5/10/06

Baran Group Meeting

Other Indolizidine Containing Natural Products:

N

NH

H

CO2Me

Me

vincadifformine

N

N

O

Me

aspidoalbine

OH

MeO

O

H

N

N

H

pleiocarpineMeO2C

N

NH

H

tuboxenine

Me

MeO2C

N

N

H

kopsineHO

MeO2C

O

N

N

H

fruticosineHO

MeO2C

O

N

N

H

neblinine

MeO

HH

O

N

NH

H

OMeH

O

beninine

N

NH

H

vincatine

O

CO2Me

Me

N

NH

H

pandoline

H

H

OH

Me

NH

condylocarpine

N

Me

H

H

CO2Me

N

NH

H

tubifolidine Me

H

N

NH

H

CO2Me

akuammicineMe

H

H

N

N

H

tsilanine

Me

H

O

HHO

MeO

N

N

H

strychnine

OH

HH

O

N

NH

O

O

CO2Me

Me

H

H

H

mitraphylline

N

OMeOMe

HO

erysodine

N

O

OMeO

erythroidine

N O

N

O

O

Mecamptothecin

N

O

Me

H

H

H

O

elaeokanine E

N

N

HH

HH

Ocamoensidine

N

O

O

NMe

H

HO

MeO

MeO

MeO

Ocancentrine

N

N+

MeH

H

H

N

N+

Me

Me

Me HH

H

dihydrotoxiferine

Other Indolizidine containing natural products (that I didn't feel like drawing):

vinblastinetoxiferine Ialkaloid Ecalebassinespeciophyllinealkaloid Halkaloid G

vincristinecurarine Ialkaloid Fpteropodineuncarine Falkaloid Aisopteropodine

N

O

MeO2C H

MeMe

daphniyunnine

N

Me

HO

OH

himandrine