Iridium-Catalyzed Selective
Allylic Substitution
2017/5/20 (Sat.)
Literature Seminar

Taiki Fujita (M1)1Introduction

Tsuji, J., et al. tetrahedron lett. 1965, 4387.

Prof. Tsuji found that -allyl Pd complex reacts with malonate anion.

Even today, allylic substitution via -allyl metal complex is used widely.
Total synthesis
allylation
Reaction development
2

Other Metals
Co

Mo

W

Ir, Ru, Rh…..

Roustan, J. L., et al. tetrahedron lett. 1979. 3721.

Trost, B. M. et al. J. Am. Chem. Soc. 1982, 104, 5543.

Trost, B. M. et al. J. Am. Chem. Soc. 1983, 105, 7757.

Regioselectivity

controlling selectivity

retention or inversionof configuration

memory effectoxidative addition

ligandnucleophilic addition

First Mechanistic Studies[Mo]=Lloyd-Jones, G. C., Reamer, R. A. et al. J. Am. Chem. Soc. 2004, 126, 702.
Lloyd-Jones, G. C., Reamer, R. A. et al. Proc. Natl. Acad. Sci. USA. 2004, 101, 5379.

Deuterated Substrate

Lloyd-Jones, G. C., Reamer, R. A. et al. J. Am. Chem. Soc. 2004, 126, 702.
Lloyd-Jones, G. C., Reamer, R. A. et al. Proc. Natl. Acad. Sci. USA. 2004, 101, 5379.

Competition Experiment

Lloyd-Jones, G. C., Reamer, R. A. et al. J. Am. Chem. Soc. 2004, 126, 702.
Lloyd-Jones, G. C., Reamer, R. A. et al. Proc. Natl. Acad. Sci. USA. 2004, 101, 5379.

Nucleophilic Attack with Retention of Conversion

Lloyd-Jones, G. C., Reamer, R. A. et al. Proc. Natl. Acad. Sci. USA. 2004, 101, 5379.

Introduction of Iridium

Takeuchi, R. et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 263.

rac-1a 92% yield, branch/ linear= 98/2,rac-2a 54% yield, branch/ linear= 95/5,

69% ee (R)
43% ee (R)Helmchen, G. et al. Chem. Commun. 1999, 741.

Iridacycle

Hartwig, J. F. et al. J. Am. Chem. Soc. 2003, 125, 14273.

Iridacycle

Hartwig, J. F. et al. J. Am. Chem. Soc. 2003, 125, 14273.

Reactivity

Hartwig, J. F. et al. J. Am. Chem. Soc. 2003, 125, 14273.

Which position is critical for enantio selectivity

Hartwig, J. F. et al. J. Am. Chem. Soc. 2005, 127, 15509.

Achiral Alkyl Group

Hartwig, J. F. et al. J. Am. Chem. Soc. 2005, 127, 15509.

Axial Chirality(Ra, Rc) 96% ee(raca, Rc) 90% ee

Hartwig, J. F. et al. J. Am. Chem. Soc. 2005, 127, 15509.

The Rate of Generating Iridacycle

R1=C12H23
R2=Ph

Hartwig, J. F. et al. J. Am. Chem. Soc. 2005, 127, 15509.

Biphenyl Type

Hartwig, J. F. et al. J. Am. Chem. Soc. 2005, 127, 15509.

The Length of Iridium-Carbon

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Branch Selectivity with Phosphite Ligand

perfect selectivity

Hartwig, J. F. et al. J. Am. Chem. Soc. 2015, 137, 14968.

The Length of Iridium-Carbon

same length…

Hartwig, J. F. et al. J. Am. Chem. Soc. 2015, 137, 14968.

NBO Calculation

Regioselectivity can be well explained by NBO calculation.
CH…O interaction is very important.
Hartwig, J. F. et al. J. Am. Chem. Soc. 2015, 137, 14968.

Enantioselectivity

Kinetic and Thermodynamic Control

at -40℃

Thermodynamically (S,S,S,R) is less stable
than (S,S,S,S).
k2=5.4*10-5
Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Nucleophilic Addition is Very Fast Step

Nucleophilic addition is much fasterthan the conversion of the minor tomajor.

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Compare dr with ee of TM

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

The Importance of Oxidative Addition Step
At -60℃ the conversion does not occurred.
Major=(R,R,R,S)
Minor=(R,R,R,R)

kmajor=1.2*10-4 s-1
kminor= 2.0*10-4 s-1oxidative addition must be criticalfor enantio selectivity.

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Oxidative Addition Step

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Retention or Inversion?

oxidative addition is inversion ofconfiguration.

nucleophilic addition is inversion ofconfiguration.

Toally, allylation is retention ofconfiguration.

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Short Summary

The stereoselectivity of Ir-catalyzed allylic substitution
originates from oxidative addition.

Hartwig, J. F. et al. J. Am. Chem. Soc. 2012, 134, 8136.

Kinetic Resolution

Hartwig, J. F. et al. J. Am. Chem. Soc. 2010, 132, 8918.

Etherification

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2011, 50, 5568.

Brønsted Acid Plays Critical Role

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2011, 50, 5568.

Substrate Scope

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2011, 50, 5568.

Both Enantiomers

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2011, 50, 5568.

Thioetherification

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2012, 51, 8652.

Kinetic Resolution?

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2012, 51, 8652.

Substrate

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2012, 51, 8652.

Proposed Mechanism

Carreira, E. M. et al. Angew. Chem. Int. Ed. 2012, 51, 8652.

Dual Catalysis

Carreira, E. M. et al. J. Am. Chem. Soc. 2017, 51, 8652.
Carreira, E. M. et al. Science. 2013, 340, 1065.

Four Isomers

Carreira, E. M. et al. Science. 2013, 340, 1065.

Controlling Two Stereo Centers

Carreira, E. M. et al. Science. 2013, 340, 1065.

Mechanistic Study

Sunoj, R. B. et al. J. Am. Chem. Soc. 2015, 137, 151722.

Carreira, E. M. et al. J. Am. Chem. Soc. 2017, 139, 3603.

Diastereo Selectivity

Sunoj, R. B. et al. J. Am. Chem. Soc. 2015, 137, 151722.

Carreira, E. M. et al. J. Am. Chem. Soc. 2017, 139, 3603.

Ester Substrate

Hartwig, J. F. et al. J. Am. Chem. Soc. 2017, 139, 87.

Four Isomers

Hartwig, J. F. et al. J. Am. Chem. Soc. 2017, 139, 87.

Snaddon’s Precedent Work

Snaddon, T. N. et al. J. Am. Chem. Soc. 2016, 138, 5214.

Proposed Mechanism

Snaddon, T. N. et al. J. Am. Chem. Soc. 2016, 138, 5214.

Ester and Substrate Scope

Snaddon, T. N. et al. J. Am. Chem. Soc. 2016, 138, 5214.

Recent Development

Kawatsura, M. et al. Chem. Commun. 2007, 298.

Breit, B. et al. Acc. Chem. Res. 2016, 49, 1524.

Summary
Ir-catalyzed allylic substitution shows high enantioselectivity and regioselectivity.

• Basic condition is necessary• Oxidative addition step is the mostcritical for enantioselectivity.
• Nucleophilic attack is much fasterthan oxidative addition• Linear selectivity can be explainedby CH…O weak interaction.
• Only kinetic resolution.

• Acidic condition is necessary。
• Dynamic kinetic resolution canbe also used.
• First diastereo- enantiodivergent allylic substitution.

Even today, Ir-catalyzed allylic substitution is evolving constantly !

Kinetic Experimentk1=2.7*10-4
k2=4.6*10-2
k2 is 170 times bigger than k1. = 3 kcal/ molHartwig, J. F. et al. J. Am. Chem. Soc. 2015, 137, 14968.