Protecting-Group-Free Total Synthesis of (E)- and (Z)- Alstoscholarine
Gerfaud, T.; Xie, C.; Neuville, L.; Zhu, J. Angew. Chem. Int. Ed. 2011, 50, 3954-3957.
Concise Photochemical Synthesis of the Antimalarial Indole Alkaloid Decursivine
Mascal, M.; Modes, K. V.; Durmus, A. Angew. Chem. Int. Ed. 2011, 50, early view.
Roxanne AtienzaShort Literature Presentation
April 18, 2011
Concise Photochemical Synthesis of the Antimalarial Indole Alkaloid Decursivine
Mascal, M.; Modes, K. V.; Durmus, A. Angew. Chem. Int. Ed. 2011, 50, early view.
Mark Mascal
Kyle Modes Asuman Durmus
Decursivine
NH
HN
O
O
HH
O
O
Decursivine- isolated from Rhaphiophora decursiva- extracyclic indole alkaloid
- biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite
Plasmodium flaciparum
Previous Synthesis by Leduc and Kerr 2007
20 steps from p-aminophenol3% overall yield
Mascal Retrosynthesis
OO
Cl Cl
O
HNHN
HO
NH
HN
O
O
HH
O
O
OO
Br
Witkop cyclization
4 steps from piperonyl bromide!
Forward Synthesis
OO
Br
OO
Cl ClO
O
CH3
CH3
OO
Cl ClOH
O
OO
Cl Cl
O
HNHN
HO
NH
HN
O
O
HH
O
O
Cl2CHCO2CHMe2, LHDMS, THF KOH, H2O, MeOH
serotonin, DPPA, collidine, DMF
hv, MeCN
90 %98 %
84 %
72 %
Witkop cyclization
Witkop Reaction
NH
HN
HO
O
O
OCl
Cl
NH
HN
HO
O
O
OCl
Cl
NH
HN
HO
O
O
OCl
hv -Cl-
NH
HN
HO
O
O
OCl
NH
HN
HO
O
O
OCl
-H+
NH
HN
HO
O
O
O
-HCl
Formation of Decursivine
NH
HN
HO
O
O
O
NH
HN
HO
O
O
O
NH
HN
O
O
HH
O
O
H+ -H+
Protecting-Group-Free Total Synthesis of (E)- and (Z)- Alstoscholarine
Gerfaud, T.; Xie, C.; Neuville, L.; Zhu, J. Angew. Chem. Int. Ed. 2011, 50, 3954-3957.
Jieping Zhu
ThibaudGerfaud
ChunsongXie
LucNeuville
Alstoscholarine
HN
N
HCO2MeH
H
OHCMe
- isolated from Alstonia scholaris, traditional medicinal plant in South Asia in 2007
- pentacyclic structurebridged [3.1.3] bicycle, fused indole ring
and pyrrole ring- no known biological activity to date
Alstoscholarine
Retrosynthetic Breakdown
HN
N
HCO2MeH
H
OHCMe
HN
N
HCO2MeH
H OHN
CO2Me
N
O
HO
I
NH2N
O
HO
CO2MeO
HN
O
CO2MeOHCOHC
HN
O
CO2Me
O
O
O
Pictet-Spengler
Pd-catalyzedheteroannulation
heminaminalcyclization
oxidativecleavage
de-racemization
Forward Synthesis
O
O
O
O
OMe
O
OHHN
O
CO2Me
N
O
HO
CO2MeO
(0.05 equiv.), MeOH (10.0 equiv.) in Et2O, rt
2,2'-dipyridyldisulfide, PPh3, THF, rt, then pyrrylmagnesium bromide, THF, -20 °C
1) OsO4 (0.1 equiv.), N-methylmorpholine-N-oxide, tBuOH/THF/H2O (13:9:1), rt 2) NaIO4, acetone/H2O, rt
95 %, 93 % ee 76 %
78 % over two steps
de-racemization
oxidativecleavage
I
NH2 N
O
HO
CO2MeO
HN
CO2Me
N
O
HO
N
NHMeO2CH H
O
N
H HHN H
CO2Me
O
Pd(OAc)2 (0.3 equiv.), DABCO, DMF, 85 °C HCO2H, rt
60 % over two steps
Forward Synthesis
Pd-catalyzedheteroannulation Pictet-
Spengler
ratio 1:5 (undesired to desired)
desired
undesired
The End
N
H HHN H
CO2Me
O N
H HHN H
CO2MeMe
1,1-bis(phenylthio)ethane, [Cp2TiCl2] (10 equiv.), P(OEt)3 (20 equiv.), Mg (12 equiv.) 4 A MS, THF, 70 °C, 6h DMF, POCl3, DCE, rt
N
H HHN H
CO2Me
OHC Me
N
H HHN H
CO2Me
OHCMe
31 % over 2 steps
9 % over 2 steps
Ethylidenation Vilsmeier-Haack