progress toward the total synthesis of ergot...
TRANSCRIPT
Progress Toward the TotalSynthesis of Ergot Alkaloids:
Cody TimmonsWipf Group12/23/2006
University of Pittsburgh
Cody Timmons @ Wipf Group 1 1/1/2007
Ergot Alkaloids
NMe
HN
H
CO2R
NMe
HN
H
CH3
Lysergic acid subclass Clavine subclass
Cody Timmons @ Wipf Group 2 1/1/2007
Ergot Alkaloids
NMe
HN
H
CO2R
NMe
HN
H
CH3
Lysergic acid subclass Clavine subclass
Common tetracycliccore
Cody Timmons @ Wipf Group 3 1/1/2007
NMe
HN
H
CO2R
NMe
HN
H
CH3
Lysergic acid subclass Clavine subclass
Ergot Alkaloids
Tryptophan subunit
Cody Timmons @ Wipf Group 4 1/1/2007
Lysergic Acid Compounds
NMe
HN
H
CO2H
Lysergic acid
NMe
HN
H
CONEt2
Lysergic acid diethylamide (LSD)
Cody Timmons @ Wipf Group 5 1/1/2007
Clavine Compounds
NHMe
HN
H
Chanoclavine-I
OH
HN
H
Agroclavine
NMe
CH3
HN
H
Elymoclavine
NMe
OH
H H H
Cody Timmons @ Wipf Group 6 1/1/2007
HistoryErgotism
(aka St. Anthony’s Fire)
Disease resulting from eatingcereal grains (esp. rye) infectedwith ergot fungus
Ergot on a head of grain
Cody Timmons @ Wipf Group 7 1/1/2007
HistoryErgotism
(aka St. Anthony’s Fire)
Last epidemic: 2001-Ethiopia
Cause of Salem Witch Trials?
Symptoms include: convulsions, vomiting, hallucinations, gangrene, insanity, and death
Cody Timmons @ Wipf Group 8 1/1/2007
Physiological Effects• Ergolines: bind serotonin
receptors…induce mood swings,vomiting, vasoconstriction,gangrene, convulsions
• Historical uses: abortive agent,controlling maternal bleeding,hallucinogen, treatment ofParkinson’s disease, migraine
NH2
HN
Serotonin(5-hydroxytryptamine)
OH
HN
H
Ergoline Skeleton
NMe
X
Cody Timmons @ Wipf Group 9 1/1/2007
Literature Highlights:Lysergic Acid
BzN
CO2H1) SOCl2
2) AlCl3BzN
O
1) Br2
2)O O
NHMe
BzN
O
NMe
OO
1) HCl
2) NaOMe
HN
NMe
O
1) NaBH4
2) SOCl2 / SO2
HN
NMe
Cl
1) NaCN / HCN
2) hydrolysis3) Raney Ni
HN
NMe
CO2H
Woodward, 1954, 1956:
JACS, 1954, 76, 5256.JACS, 1956, 78, 3087.
Cody Timmons @ Wipf Group 10 1/1/2007
Literature Highlights:Lysergic Acid
Szantay, 2004 (resolution of Uhle’s ketone):
JOC, 2004, 69, 5993.
HN
NMe
O
H
(-)-dibenzoyl-L-tartaric acid
38%
HN
NMe
O
H
HN
NMe
CO2H
H
Cody Timmons @ Wipf Group 11 1/1/2007
Literature Highlights:Lysergic Acid
Hendrickson, 2004:
OL, 2004, 6, 3.
HN
B(OH)2
+N
CO2Me
CO2Me
Cl
Pd(PPh3)4 / Na2CO3
EtOH
HN
N
CO2Et
CO2Et
HN
N
CHO
CO2Et
NaOH
HN
N
CO2Et
OH
HN
NMe
CO2H
Cody Timmons @ Wipf Group 12 1/1/2007
Literature Highlights:Clavine Alkaloids
Oppolzer, 1983:
HN
CO2Me
1) Me2NH, CH2O
2) MeI, KCN
HN
CO2Me
CN
Raney Ni
NaH2PO2
HN
CO2Me
CHO
1) MeNHOH
2) LAH
HN
NMe
O
H
H
OH
1) Raney Ni
2) Boc2O3) NaIO4
HN
N(Boc)MeCHO
H
H Ph3PCO2Me
1)
2) TFA3) DIBAL
NHMe
HN
H
Chanoclavine
OH
H
Tet., 1983, 39, 3695.
Cody Timmons @ Wipf Group 13 1/1/2007
NSEt
O O
O
BzN
Ac2O/TsOH
BzN
O
N
O
SEt
N
HN
N
O
BzN
H
H
Costaclavine
Literature Highlights:Clavine Alkaloids
Padwa, 2000:
JOC, 2000, 65, 2368.
Cody Timmons @ Wipf Group 14 1/1/2007
Synthetic Trend
Indole core present in starting materials
NMe
HN
H
R
X
HN
Y
Cody Timmons @ Wipf Group 15 1/1/2007
Acknowledgments
• Prof. Peter Wipf• Dr. Anthony Cuzzupe
– (synthesis of D-A precursor,initial D-A studies)
• Wipf Group members
Cody Timmons @ Wipf Group 16 1/1/2007