Taming Data Chaos: Simplify Data Integration with DataDirect Data
Transcript of Taming Data Chaos: Simplify Data Integration with DataDirect Data
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