Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid -...

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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 Atienza Short 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.

Transcript of Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid -...

Page 1: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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.

Page 2: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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

Page 3: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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!

Page 4: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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

Page 5: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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.

Page 6: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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

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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

Page 8: Concise Photochemical Synthesis of the Antimalarial Indole ... · - extracyclic indole alkaloid - biological activity: 4.4 microg/mL against chloroquinine-resistant malaria parasite

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