Post on 23-Dec-2015
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
Outline
• Brief introduction of Dr. Albert Padwa.• Strychnine• Retrosynthesis• Forwardsynthesis • Summary
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/
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
Strychnine
N
O
OH
N
H
H
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
Hongjun Zhang; Jutatip Boonsombat; Albert Padwa; Org. Lett. 2007, 9, 279-282
Retrosynthesis
Forward synthesis Key step
N
N
O
Me
O
Ac 7
Upon MMFF94 Minimization, Iteration 500; Final Energy: 97.153
N
N
O
Me
O
Ac
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
HN
NO
OH
Me
O Me
H
NH
NO
OH
Me
H
20% Pd on Pd(OH)2/C
(Pearlman's catalyst) NH
NH
OHH
OO
I
Br
NH
N
OHH
O
O
I
K2CO3, DMF/H2O
NH
N
OH
Me
H
NaBH4
NaOMe
8
13
1415
OHO
O
I
N
O Cl
OOOO
I
SO
OHO
O
OHOO
I triphenyl phosphine
N-bromosuccinimide
OO N
Br OO
I
Br
NH
NH
OHH
OO
I
Br
NH
N
OHH
O
O
I
K2CO3, DMF/H2O
N
N
OH
O
O
I
O O
O
O O
NaBH(OAc)3
CH3COOH
N
N
O
O
O
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+
O
O-
tetra-n-propyl-ammonium perruthenate
N+ Ru
O
O
O
O-
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
HOOH
N
CH3COOH
AC2O, NaOAcN O
H
N
(+)-strychnine (4)
O
HO
OH
O
HO
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!