first total synthesis of (±)-strychnine via a [4+2]- cycloaddition /rearrangement cascade
DESCRIPTION
First Total Synthesis of (±)-Strychnine via a [4+2]- Cycloaddition /Rearrangement Cascade. Hongjun Zhang, Jutatip Boonsombat , and Albert Padwa * Org . Lett . 2007, 9, 279-282 . Jixin Liu 2/21/2012 Chem 635. Outline. Brief introduction of Dr. Albert Padwa . Strychnine - PowerPoint PPT PresentationTRANSCRIPT
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First Total Synthesis of (±)-Strychnine via a [4+2]-Cycloaddition/Rearrangement Cascade
Hongjun Zhang, Jutatip Boonsombat, and Albert Padwa*Org. Lett. 2007, 9, 279-282.
Jixin Liu2/21/2012 Chem 635
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Outline
• Brief introduction of Dr. Albert Padwa.• Strychnine• Retrosynthesis• Forwardsynthesis • Summary
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Dr. Albert Padwa
Education:B.A., Columbia University; Ph.D., Columbia University; Postdoctoral Research Fellow, University of Wisconsin. Academic :-William P. Timmie Professor of Chemistry, Emory University-Mentored around 200 Graduate Students and Postdocs-Approximately 820 publications including many reviews and book chapters-Editorial Boards of JACS, JOC, Org. Lett. among others-Served as an Alternate Councilor, Chairman of the Organic Division of the ACS, and has been the President of the International Society of Heterocyclic Chemistry.-Avid Mountain Climber and Runner
Biography: http://www.arkat-usa.org/get-file/18783/
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Strychnine
highly toxic colorless crystalline alkaloid, isolated In 1818.Structure determined by Robert Robinson in 1947.
Fruit of Strychnine
6 stereo centers, 5 of which are included within one saturated 6-membered ring
Completed Total Synthesis first by Woodward (1954), then by many others.
N
O
OH
N
H
H
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Strychnine
N
O
OH
N
H
H
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Padwa Synthesis
Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett. 2007, 9, 279-282Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett. 2007, 9, 279-282
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Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett. 2007, 9, 279-282
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Retrosynthesis
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Forward synthesis Key step
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N
N
O
Me
O
Ac 7
Upon MMFF94 Minimization, Iteration 500; Final Energy: 97.153
N
N
O
Me
O
Ac
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Forward synthesis
O
NMe
O
N
OMe
O
HN
O
N
OMe
DMF, 0 oC
NaH
Me
I
7
toluene, microwave MgI2
N
NO
O
Me
O Me
LiAlH4 NaBH(OAc)3
NH
N
Me
H OH
H N
NO
OH
Me
O MeH
NH
NO
OH
Me
H
20% Pd on Pd(OH)2/C
(Pearlman's catalyst) NH
NH
OHH
OO
IBr
NH
N
OHH
OO
IK2CO3, DMF/H2O
NH
N
OH
Me
H
NaBH4
NaOMe
8
13
14 15
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OHO
O
I
N
O Cl
OOOO
I
SO
OHOO
OHOO
I triphenyl phosphine
N-bromosuccinimide
OO NBr OO
IBr
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NH
NH
OHH
OO
IBr
NH
N
OHH
OO
IK2CO3, DMF/H2O
N
N
OH
OO
I
O O
O
O O
NaBH(OAc)3CH3COOH
N
N
O
OO
I
O O
CH3CN
NMO (N-methyl morpholine-N-oxide)
TPAP (tetra-n-propyl-ammonium perruthenate)
9
N
N
O
O O
H
OMOM
PhOK
t-BuOK, t-BuOH phenol
16
Pd(PPh3)4 THF
14 15
N-methyl morpholine-N-oxide
N+
OO-
tetra-n-propyl-ammonium perruthenate
N+ RuO
OO
O-
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diisopropyl amine
NH
N
N
O
O O
H
OMOM
n-BuLi
Ph2P(O)CH2OMe N
N
O O
H
OMOM
OMe
HCl
55 oC,10 h
Wieland-Gumlich aldehyde
NH HO
OH
N
CH3COOH
AC2O, NaOAcN O
H
N
(+)-strychnine (4)
O
HO
OH
O
HO
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Summary
• a concise synthesis of the Strychnos alkaloid (+)-strychnine• The central step in the synthesis consists of an intramolecular [4+2]
cycloaddition/rearrangement.• Closure of the remaining D-ring was carried out from the aza-tetracyclic
intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto group.
Thank you!