Iridium-Catalyzed Asymmetric Isomerization ofPrimary Allylic AlcoholsMantilli, L., Gerard, D., Torche, S., Besnard, C., Mazet* C. Angew. Chem. Int. Ed.,2009, 48, 1-6

1,n-Glycols as Dialdehyde Equivalents in Iridium-CatalyzedEnantioselective Carbonyl Allylation and Iterative Two-Directional Assembly of 1,3-PolyolsLu, Y., Kim, I. S., Hassan, A., Del Valle, D. J., Krische* M. J. Angew. Chem. Int.Ed., 2009, 48, 1-5

Dr. Clément Mazet - University of Geneva

•PhD research with Prof. Lutz H. Gade at the Univ. ofStrasbourg

•Postdoc in 2003 with Andreas Pfaltz (Basel Switzerland)

•Awarded Marie Curie International Outgoing Fellowship in2006 for work carried out in the Jacobsen Lab.

Asymmetric Isomerization

R2

R1

OH

IrNCy3P

(cod)

BArF4

(0.25-5.0 mol%)

R2

R1

O*1 min H2, THF

degassed, 23 oC

Ir

H

THF

H

NP

THF

Mazet et al. Tetrahedron Letters 2009, 50, 4141

Asymmetric Isomerization

OH

(5.0 mol%)

O*1 min H2, THF

degassed, 23 oC

[Ir]

P N

O

Ph

Ph

(cod) iPr

BArF4

PIr

N

(cod)

PhPh

BArF4

IrNP

(cod)Me2N

O

O

BArF4

O

PIr

NCyCy

(cod)

BArF4

PIr

N

O

R1

R1

(cod)

R2

a R1 = Cy ; R2 = iPr

b R1 = tBu ; R2 = iPr

c R1 = Cy ; R2 = CH2Ph

d R1 = tBu ; R2 = CH2Ph

e R1 = Cy ; R2 = Ph

f R1 = tBu ; R2 = Ph

g R1 = 1-Ad ; R2 = Ph

h R1 = Cy ; R2 = tBu

i R1 = tBu ; R2 = tBu

j R1 = 1-Ad ; R2 = tBu

Asymmetric Isomerization

IrN

O

R1

R1

(cod)

R2

f R1 = tBu ; R2 = Ph

g R1 = 1-Ad ; R2 = Ph

j R1 = 1-Ad ; R2 = tBu

R4

R3

OH

(0.25-5.0 mol%)

R4

R3

O*1 min H2, THF

degassed, 23 oC

25% ee18% convgR4 = MeR3 = C6H6

34% ee30% convfR4 = C6H6R3 = Me

98% ee88% conv jR4 = C6H6R3 = Cy99% ee80% convgR4 = C6H6R3 = tBu90% ee>99% convgR4 = 4-MeO-C6H6R3 = iPr

Proposed Mechanism

Ir

P N

Ir

H

THF

H

NP

THF

R2

R1

OH

Ir

H

OH

NPIr

H

OH

NPR2R1

H

R2

R1

H

!"C=C

(E)

OHR2

R1H

OR2

R1H

Ir

H

P N

HO

H

H

R2

R1

Ir

P N

H

H

R2

R1

HO

H

R1

R2

OH

(Z)

Ir

OH

NP R2

R1

H

H

Ir

OH

H

NP R2

R1H

H

Conclusion

Development of bis-Hydride Iridium Catalyst for AsymmetricOlefin Isomerizations

Substrate scope very limited, not tolerant to unbranched alkylsubstituents

Products generated are equivalent to asymmetric protonation of α,β− aldehydes

Michael J. Krische

B.S. Univ. of California at Berkely 1989 - Advisor HenryRapoport

Fulbright Fellow, Helsinki University 1990

Ph.D. Stanford University 1996 - Advisor Barry Trost

NIH Post-Doc., Université Louis Pasteur - Advisor Jean-MarieLehn

Joined the Faculty at Univ. of Texas at Austin in 2003

Enantioselective Carbonyl Allylation

Me

Me

B

Me

)2

Me

OH

Ph

OH

74% Yield93% ee

81% Yield96% ee

Brown, J. Am. Chem. Soc. 1983, 2092

O

B

On-C11H23

OH

Ph

OH

i-PrO2C

i-PrO2C

86% Yield79 % ee

78% Yield71% ee

Roush, J. Am. Chem. Soc. 1985, 8186

Me Me

Me

O

O

B

Ph

Me

OH

Ph

OH

86% Yield86% ee

90% Yield36% ee

Hoffmann, Angew. Chem., Int. Ed. 1978, 768

Ph H

O

Ti(Oi-Pr)4 (10 mol%)(R)-BINOL (10% mol%)

DCM, -78 oCSnBu3

Ph

OH 88% Yield90% ee

Umani-Ronchi J. Am. Chem. Soc. 1993, 7001Keck J. Am. Chem. Soc. 1993, 8467

Ph H

O

DCM, -78 oCSiCl3

Ph

OH 85% Yield87% ee

PH

H

O

N

Me

CH2)2

Denmark J. Am. Chem. 2001, 9488

Iridium Catalyzed Transfer Hydrogenative Allylation of Allylic Alcohols.

OAcOH

R

[Ir(cod)Cl]2 (2.5 mol%(R)-Cl,MeO-BIPHEP (5 mol%)

Cs2CO3 (20 mol%)

m-NO2BzOH (10 mol%)

THF (0.2 M)

100 oC, 20 hrs

R

OH

10 equiv. cinnamyl alcohol 72%, 91% eegeraniol 76%, 86% eenonan-1-ol 72%, 91% eeisobutanol 83%, 94% ee

IrP P

O

O

NO2

Napth Napth

X-ray

Ir

P

PO

O

NO2Napth

OR

H

Krische J. Am. Chem. Soc. 2008, 130, 14891

Iterative Two-directional Synthesis of 1,3-Polyol

OH OH O

H

O

H

Not Isolable

OH OH

OH OH[{Ir(cod)Cl}2] (5 mol%)

(S)-Cl,MeO-biphep (10 mol%)

Cs2CO3 (40 mol%)

4-Cl-3-NO2-BzOH (20 mol%)

dioxane (0.2 M), 90 oC, 3 days

OH OH

(S,S)

70% Yield ! 99% ee, ! 30:1 d.r.

AcO

10 equiv.

OH OH OH OH

OH OH OH OH

Me Me Me

51% Yield ! 99% ee, ! 30:1 d.r.

(R)-Cl,MeO-biphep (10 mol%)48% Yield

! 99% ee, ! 30:1 d.r.

65% Yield ! 99% ee, 18:1 d.r.

66% Yield ! 99% ee, ! 19:1 d.r.

Two-Directional Chain Elongation Strategy

OH OH

(S,S)

O OOH OH

(S,S)

Me Me1) PPTS (10 mol%)

(MeO)2CMe2 (15 equiv)

DCM (0.1 M), 25 oC

2) O3, 1:1 DCM/MeOH

(0.1 M) -78 oC

then NaBH4, -78 oC

O OOH OH

(S,S)

Me Me

OAc

+

O OOH OH

Me Me

O OOH OH

Me Me

(R) (R)(S) (S)

(S) (S) (S) (S)

[{Ir(cod)Cl}2] (5 mol%)(R)-Cl,MeO-biphep (10 mol%)

Cs2CO3 (40 mol%)

4-Cl-3-NO2-BzOH (20 mol%)

THF (0.2 M), 110 oC, 48 hrs

(S)-Cl,MeO-biphep (10 mol%)

As Above

75% yield, ! 20:1 d.r.14% mono-allylation

81% yield, ! 20:1 d.r.12% mono-allylation

Proposed Catalytic Mechanism

R

OH

Krische J. Am. Chem. Soc. 2008, 130, 14891

OIrIII

Ln O

O

R

H H

NO2

OIrIII

Ln

O

O

R

H

NO2

H

O

O

LnIrI

NO2

OAc

Ir

OO

H

Me

O

OLn

OIrIII

Ln

O

NO2

OIrIII

Ln

O

NO2

OAc

OIrIII

Ln

O

NO2

OR

Proposed Catalytic Mechanism - 2

R

OH

Krische J. Am. Chem. Soc. 2008, 130, 14891

OIrIII

Ln O

O

R

H H

NO2

OIrIII

Ln

O

O

R

H

NO2

HO

IrI

Ln

O

NO2

OAc

HOAc

OAc

OIrIII

Ln

O

NO2

OAc

OIrIII

Ln

O

NO2

OIrIII

Ln

O

NO2

OAcO

IrIII

Ln

O

NO2

OR

Extension of MethodologyOH

OH

OH

OH

[{Ir(cod)Cl}2] (5 mol%)(S)-Cl,MeO-biphep (10 mol%)

Cs2CO3 (40 mol%)

4-Cl-3-NO2-BzOH (20 mol%)

dioxane (0.2 M), 90 oC, 3 days

AcO

10 equiv.

68% Yield! 99% ee, ! 30:1 d.r.

OH OH OH OHAs Above 56% Yield! 99% ee, ! 30:1 d.r.

OH OH OHOH

72% Yield! 99% ee, ! 30:1 d.r.

[{Ir(cod)Cl}2] (5 mol%)(S)-Cl,MeO-biphep

(10 mol%)

AcO

O

Me

OPMBHO

NHPh

O

Me

OTBS

BryostatinA Ring

Krische, Org. Lett. ASAP

Conclusions

Two directional assembly of of 1,3-polyols.

Although long reaction times, yields and selectivitiesmore than compensate.

Iridium catalyst used for transfer hydrogenativecoupling of allyl acetate.