3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids
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[3,3] Paracyclophanes as Planar Chiral Scaffolds for the Synthesis of New Phosphoric Acids. PowerPoint PPT Presentation


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EWPC 10 – Regensburg – 19/03/13. [3,3] Paracyclophanes as Planar Chiral Scaffolds for the Synthesis of New Phosphoric Acids. Jérémie Stemper. Dr. J.F. Betzer Dr. A. Voituriez Dr. A. Marinetti. EWPC 10 – Regensburg – 19/03/13. Phosphoric acids as organocatalysts.

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[3,3] Paracyclophanes as Planar Chiral Scaffolds for the Synthesis of New Phosphoric Acids.

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EWPC 10 – Regensburg – 19/03/13

[3,3]Paracyclophanes as Planar Chiral Scaffolds for the Synthesis of New Phosphoric Acids.

Jérémie Stemper

Dr. J.F. Betzer

Dr. A. Voituriez

Dr. A. Marinetti


EWPC 10 – Regensburg – 19/03/13

Phosphoricacids as organocatalysts

Brønsted basic site

Bifunctionalcatalyst

Brønstedacidic site

Steric and electroniceffects

*

Terada, M. Bull. Chem. Soc. Jpn. 2010,Vol. 83, 101-119


EWPC 10 – Regensburg – 19/03/13

Phosphoricacids as organocatalysts

First examples of catalysiswithchiral phosphoricacids by Teradaand

Akiyamain 2004 :

Yields up to 99%

e.e. up to 95%

Yields up to 99%

e.e. up to 96%

Syn/anti ratio up to 100:0

Terada, M. et al., J. Am. Chem. Soc.2004, 17, 5356

Akiyama, T. et al., Angew. Chem. Int. Ed. 2004, 12, 1566


EWPC 10 – Regensburg – 19/03/13

Phosphoricacids as organocatalysts

A wide range of syntheticalyusefull transformations is possible underphosphoricacidscatalysis :

List, B. et al.,Top. Curr. Chem.2010, 395

Terada, M. et al., Synthesis2010, 12, 1929


EWPC 10 – Regensburg – 19/03/13

Most representativechiral phosphoricacidsfromthelitterature:

List, Wang, 2010

Terada, Akiyama, 2004

Akiyama, Charette, 2005

Central chirality

Axial chirality

Terada, M. et al., J. Am. Chem. Soc.2004, 17, 5356

Akiyama, T. et al., Angew. Chem. Int. Ed. 2004, 12, 1566

List, B. et al., J. Am. Chem. Soc. 2010, 132, 17370

Wang, Y. et al., J. Org. Chem. 2010, 75, 8677

Akiyama, T. et al., Adv. Syn. Catal. 2005, 347, 1523

Charette, A. B. et al., Adv. Syn. Catal. 2006, 348, 2363


EWPC 10 – Regensburg – 19/03/13

Most representativechiral phosphoricacidsfromthelitterature:

List, Wang, 2010

Terada, Akiyama, 2004

Akiyama, Charette, 2005

Central chirality

Axial chirality

1 example by Enders in 2012

Planarchirality ?

Enders, D. D. et al.,Chirality2012 , 215


EWPC 10 – Regensburg – 19/03/13

Target structure


EWPC 10 – Regensburg – 19/03/13

Target structure

Planarchirality


EWPC 10 – Regensburg – 19/03/13

Target structure

Planarchirality

Enantioselectivity


EWPC 10 – Regensburg – 19/03/13

Target structure

Tunable motif

Planarchirality

Enantioselectivity


EWPC 10 – Regensburg – 19/03/13

DFT calculations

ΔG

kj.mol-1

BINOL

Dr. Gilles Frison, Ecole polytechnique


EWPC 10 – Regensburg – 19/03/13

DFT calculations

ΔG

kj.mol-1

BINOL

Dr. Gilles Frison, Ecole polytechnique


EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy

Functionalizedferrocene

Macrocyclisation

Cross-coupling

Ferrocene-Biaryl

Biaryl


EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy


EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy


EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy

Heptane : THF : NEt3 : TFA

40:60:0.3:0.5 1mL/min

(±)

Resolution by chiral HPLC

(+) 6.45 min

(-) 14.33 min

[α]D= + 931 (c=1.0, CHCl3)

Column : Chiralpak ID

Stationary phase :


EWPC 10 – Regensburg – 19/03/13

X-Ray analysis :

P

P

Non C2 symmetric

Dr. Pascal Retailleau


EWPC 10 – Regensburg – 19/03/13

  • Ferroceneis asuitabletethering unit

    But

  • In order to synthetise a wholeseries of phosphoricacids :


EWPC 10 – Regensburg – 19/03/13

  • Ferroceneis a suitabletethering unit

    But

  • In order to synthesizea wholeseries of phosphoricacids :

Introduction of arylsubstituentsat alaterstepof the reactionsequence

Easierresolution of the enantiomers


EWPC 10 – Regensburg – 19/03/13

New Syntheticpathway

1) Introduction of diversity

Key intermediateallowingeasy variation of substituents


EWPC 10 – Regensburg – 19/03/13

New Synthetic pathway

2) Synthesis of an epimeric mixture


EWPC 10 – Regensburg – 19/03/13

New Syntheticpathway

3) Resolution

SiO2


EWPC 10 – Regensburg – 19/03/13

Catalysis :

1) Preliminaryevaluation

Rueping, M. et al.,Angew. Chem. Int. Ed. 2006, 45, 3683


EWPC 10 – Regensburg – 19/03/13

Catalysis :

1) Preliminaryevaluation

yield = 98% ee = 31%

Good catalyticactivity


EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Hantzsch ester, R = Et

Ph


EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Hantzsch ester, R = Et

Ph


EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Ph


EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Ph


EWPC 10 – Regensburg – 19/03/13

Conclusion


EWPC 10 – Regensburg – 19/03/13

Conclusion

Identification of a good tether


EWPC 10 – Regensburg – 19/03/13

Conclusion

Identification of a good tether

2) Good catalyticactivity


EWPC 10 – Regensburg – 19/03/13

Conclusion

Identification of a good tether

2) Good catalyticactivity

3) Optimisation of the enantioselectivity


EWPC 10 – Regensburg – 19/03/13

Perspectives

  • New organocatalyticreactions

  • Phosphoramidites and organometalliccatalysis


EWPC 10 – Regensburg – 19/03/13

Aknowledgement

ANR-11-BS07-002-01 : CHIRACID

Dr. A. Marinetti

Dr. J.F. Betzer

Dr. A. Voituriez

Dr. X. Guinchard

Kévin Isaac

Yang Zhang

Julien Pastor

KeihannYavari

Maxime Gicquel

Paul Aillard

Valérian Gobé

Dr F. Nuter

Cristallography

Dr. Pascal Retailleau

HPLC

Odile Thoison

Suzanna Ramos

Franck Pelissier

ComputationalChemistry

Dr. G. Frison


EWPC 10 – Regensburg – 19/03/13

Aknowledgement

…and you for listening !


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