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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3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


Target structure

EWPC 10 – Regensburg – 19/03/13

Target structure


Target structure1

EWPC 10 – Regensburg – 19/03/13

Target structure

Planarchirality


Target structure2

EWPC 10 – Regensburg – 19/03/13

Target structure

Planarchirality

Enantioselectivity


Target structure3

EWPC 10 – Regensburg – 19/03/13

Target structure

Tunable motif

Planarchirality

Enantioselectivity


Dft calculations

EWPC 10 – Regensburg – 19/03/13

DFT calculations

ΔG

kj.mol-1

BINOL

Dr. Gilles Frison, Ecole polytechnique


Dft calculations1

EWPC 10 – Regensburg – 19/03/13

DFT calculations

ΔG

kj.mol-1

BINOL

Dr. Gilles Frison, Ecole polytechnique


Synthetic strategy

EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy

Functionalizedferrocene

Macrocyclisation

Cross-coupling

Ferrocene-Biaryl

Biaryl


Synthetic strategy1

EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy


Synthetic strategy2

EWPC 10 – Regensburg – 19/03/13

Syntheticstrategy


Synthetic strategy3

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 :


X ray analysis

EWPC 10 – Regensburg – 19/03/13

X-Ray analysis :

P

P

Non C2 symmetric

Dr. Pascal Retailleau


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

EWPC 10 – Regensburg – 19/03/13

  • Ferroceneis asuitabletethering unit

    But

  • In order to synthetise a wholeseries of phosphoricacids :


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

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


New synthetic pathway

EWPC 10 – Regensburg – 19/03/13

New Syntheticpathway

1) Introduction of diversity

Key intermediateallowingeasy variation of substituents


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

EWPC 10 – Regensburg – 19/03/13

New Synthetic pathway

2) Synthesis of an epimeric mixture


New synthetic pathway1

EWPC 10 – Regensburg – 19/03/13

New Syntheticpathway

3) Resolution

SiO2


Catalysis

EWPC 10 – Regensburg – 19/03/13

Catalysis :

1) Preliminaryevaluation

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


Catalysis1

EWPC 10 – Regensburg – 19/03/13

Catalysis :

1) Preliminaryevaluation

yield = 98% ee = 31%

Good catalyticactivity


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Hantzsch ester, R = Et

Ph


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Hantzsch ester, R = Et

Ph


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Ph


3 3 paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

EWPC 10 – Regensburg – 19/03/13

Catalysis :

2) Optimisation

Ph


Conclusion

EWPC 10 – Regensburg – 19/03/13

Conclusion


Conclusion1

EWPC 10 – Regensburg – 19/03/13

Conclusion

Identification of a good tether


Conclusion2

EWPC 10 – Regensburg – 19/03/13

Conclusion

Identification of a good tether

2) Good catalyticactivity


Conclusion3

EWPC 10 – Regensburg – 19/03/13

Conclusion

Identification of a good tether

2) Good catalyticactivity

3) Optimisation of the enantioselectivity


Perspectives

EWPC 10 – Regensburg – 19/03/13

Perspectives

  • New organocatalyticreactions

  • Phosphoramidites and organometalliccatalysis


Aknowledgement

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


Aknowledgement1

EWPC 10 – Regensburg – 19/03/13

Aknowledgement

…and you for listening !


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