total synthesis of...
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Total Synthesis of (-)-Mersicarpine
Guillaume Lapointe, January 21th 2010
Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T.. J. Am. Chem. Soc. 2010, ASAP.
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Indole Alkaloids
- Indole alkaloids isolated from the flowering Kopsia species (Malaysia)
- Features of mersicarpine: - Atypical tetracyclic structure - Nitrogen atom at 3-position of indoline - Seven membered cyclic amine - Adjacent to the imine: quaternary carbon / hemiacetal
- Three synthesis reported so far, in which two involves a radical approach
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Kerr’s Approach to (±)-Mersicarpine
- Key strategy: Mn(OAc)3-Mediated malonic radical cyclization onto the indole
(1) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561-4564. (2) Magolan, J.; Carson, J. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437-1440.
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Kerr’s Total Synthesis of (±)-Mersicarpine
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Kerr’s Total Synthesis of (±)-Mersicarpine
- First total synthesis
- Involved Mn(OAc)3-mediated radical cyclization of a diketone into a indole
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Zard’s Formal Synthesis of (±)-Mersicarpine
- Key strategy: Intermolecular radical addition-radical cyclization cascade
Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11, 2800-2803.
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Zard’s Formal Synthesis of (±)-Mersicarpine
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Fukuyama’s Total Synthesis of (-)-Mersicarpine
Retrosynthetic analysis
- Construction of the indole skeleton via a Sonogashira coupling and a gold(III) catalyzed cyclization
-Eschenmoser-Tanabe-type fragmentation
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Fukuyama’s Total Synthesis of (-)-Mersicarpine
O1) Ph NH2 , toluene, reflux
2) CO2Me , 65 oC, 3 days
83%, 99% ee after recryst.
OCO2Me
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Eschenmoser-Tanabe Fragmentation
α,β-Epoxyketone fragment to alkyne and a ketone, passing throught the corresponding hydrazone
In the present paper, formation of hydrazones failed from 10 – Warkentin’s procedure worked
NCO2Me
O
HNH2N
OPb(OAc)4 CO2Me
O
NN
O
HN
CO2Me
O
NN
CO2MeO
NN
CO2Me
O
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Fukuyama’s Total Synthesis of (-)-Mersicarpine
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Fukuyama’s Total Synthesis of (-)-Mersicarpine
+ side product
- Yield of 1 not reproductible, always side product present
- Treatment with 18O2 after hydrogenation: 18O incorporated
- Potential side product arising from autooxidation of product 2 to19
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Autooxidation of the Enamine 2
Addition of a reductant after oxidation may solve the problem!
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Fukuyama’s Total Synthesis of (-)-Mersicarpine
- First enantioselective synthesis
- Done in 10 steps from ketoester 9, 13% overall yield
- Interesing indole ring construction, and Eschenmoser-Tanabe like rearrangement