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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.