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Total Synthesis of (+)- Fastigiatine. Gretchen Peters February 10 , 2011. Shair Research Group. Total synthesis and chemical biology Focus of syntheses: “naturally occurring complex molecules that challenge the state-of-the-art of organic synthesis” - PowerPoint PPT Presentation
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Total Synthesis of (+)-Fastigiatine
Gretchen PetersFebruary 10, 2011
Total synthesis and chemical biology
Focus of syntheses: “naturally occurring complex molecules that challenge the state-of-the-art of organic synthesis”
Complexes that are unique structurally and biologically
Shair Research Group
http://www.chem.harvard.edu/research/faculty/matthew_shair/research/research.html
Found in plants (clubmosses) Members have been found to have
cardiovascular and neuromuscular effects Used for homeopathic remedies
Lycopodium alkaloids
N
NMe
Me
O Me
N
N
Me
Me
O
H
N
Me
N
N
H
(-)-himeradine A lycodine (+)-fastigiatine
http://findarticles.com/p/articles/mi_g2603/is_0004/ai_2603000497/
Retrosynthesis
N
NMe
Me
O MeHN
NR
Me
R'HN
NR
MeH
H
R'
NH2O
O
R'
NHR
Me
NR
PO OO
P2N XR' Li
O OM
Me
Mannich
1,4 Addition
Condensation
Protection
NH
EtO OO
NBoc
TMSEO OO
a. KHTMSEOH
b.Boc2O
1 2
Cuperate Addition
NBoc
TMSEO OO
O OCuLi·LiI
Me
tBu
O O
Me
NBoc
OOOTMSE
2 3
Alkylation, Decarboxylation
OO
Me NBoc
OO
OTMSE
O O
Me
NBoc
OOOTMSE
Cl
a. Cs2CO3
I(CH2)3Cl
OO
Me NBoc
ON3
b. NaN3,NaIc. TBAF, DBU
3 4
5
Addition of Li-enolate
O O
Me
NNs
ON3
OLi
OtBu
O O
Me
NNs
ON3
OtBuO
O O
Me
N3OtBu
O
O
NHNs
PPh3
O O
Me
NHNs
HNO
tBuO
5
67
Intramolecular Aza-Wittig
RN
PPh3
R
NO
tBuO
NN RNNNPh3PNN
NPh3P R
NPh3P
R
OtBu
O
O
R
N
OOtBu
OPPh3
R
N
OtBu
O
PPh3
O
O O
Me
NHNs
HNO
tBuO
6
7
Reactive Amine Wanted to remove
protecting group and induce addition
Free amine too reactive
Added on to a,b unsaturated ketone to form five-membered ring
O O
Me
NHNs
HNO
tBuO
7
Acid catalyzed cyclization
O O
Me
NHNs
HNO
tBuO
NHNs
CO2tBu
Me
HN
ONHNs
CO2tBu
Me
HN
OH
HCl
7 8 9
Mannich Reaction
NHMe
CO2tBu
Me
HN
OH
H+
NHMe
CO2tBu
Me
HN
OH
CO2tBu
Me
HN
MeN
HOH
CO2tBu
Me
HN
NMe
H2O
CO2tBu
Me
HN
NMe
CO2tBu
Me
HN
NMe
9
10
First synthesis of (+)-fastigiatine
15 step synthesis with 30% overall yield
Conclusions
N
NMe
Me
O Me
Chem 647 classmates
Dr. Davis
Acknowledgements
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