fe/cr- and co/cr- mediated catalytic asymmetricccc.chem.pitt.edu/wipf/current...
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Fe/Cr- and Co/Cr- Mediated Catalytic Asymmetric 2-Haloallylations of Aldehydes
Kurosu, M.; Lin, M.-H.; Kishi*, Y.
Harvard University J. Am. Chem. Soc. 2004, 126, 12248-12249.
New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents
Namba, K.; Kishi*, Y. Harvard University
Org. Lett. 2004, 6, 5031-5033.
Br
X
X = Br, I
+R
O
H
HNSO2
Bn
O
N
t-Bu
5-10 mol%
CrBr3, TEA
Fe(TMHD)3 or CoPc
2,6-lutidine
Mn, TMSCl
R
XTMSO
90 - 93% ee
R4
R4
R3
HNSO2
R2
O
N
R1
CrCl2 or CrBr3/ Cp2ZrCl2
Yield: 83 - 98%
up to 90% ee
R1
O
H
R2
IBr
I
+
R1
OH
R2
R1
OH I
10 mol%
David @ Wipf Group 1 1/15/2005
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Organochromium (III) Reagents in C-C Bond Formation
Unique Features of the Nozaki-Hiyama-Kishi (NHK) Reactions:
- High Chemoselectivity favoring additions to aldehydes - Excellent Compatibility with an array of other electrophilic groups - Low Basicity (chiral centers α to the reacting aldehyde are not racemized, free hydroxy groups are in
some cases compatible with the reaction conditions)
- The High Stability of the emerging O-Cr(III) bond constitutes a formidable driving force (synthetic tool for the formation of highly strained ring systems)
For a Review on C-C Bond Formations Involving Organochromium (III) Reagents see: Fürstner, A. Chem. Rev. 1999, 99, 991.
R YCrX2
(II)
RCrX2
(II)
R CrX2
(III) ER E
R M
CrX3
(III) TRANSMETALATION
NOZAKI-HIYAMA-KISHI APPROACH
David @ Wipf Group 2 1/15/2005
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NHK Reactions: Background (I)
Stoichiometric NHK Reactions
- Nozaki-Hiyama (1977-1983): - Kishi and Nozaki-Takai (1986):
Traces of Nickel salts exert a catalytic effect on the formation of the C-Cr(III) bond:
X
O
R H
+
OH
R R2R2
NiX2 0.1-1.0%
Ni(II)
Ni(0)
2 Cr(II)2 Cr(III)
XR2
NiXR2
(II)Cr(III)
CrX2R2
(III)
O
R H
OH
RR2
> 2 eq. CrCl2
O
R H +> 2 eq. CrCl2
OH
R R1XR1
R1 = allyl- , propargyl- , alkenyl- , alkynil-, aryl-
David @ Wipf Group 3 1/15/2005
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NHK Reactions: Background (II)
Addition of Alkylchromium (III) Reagents to Aldehydes
- Takai - Utimoto (1989):
O
R H +
> 2 eq. CrCl2OH
R R1XR1
R1 = alkyl-
cat. CoPc or Vitamin B12
XR1 Co(III)R1 R1 Cr(III)R1
O
R H
OH
R R1
Cr(II)
Co(II)Co(I)
Cr(II)Cr(III)
C12H25ClC9H19Br
PhCHOCrCl2
DMF
cat NiCl2
cat CoPc
C12H25
OH
Ph
68%
C9H19
OH
Ph
82%
+ +
David @ Wipf Group 4 1/15/2005
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NHK Reactions: Background (III)
Catalytic NHK Reactions
- Fürstner-Shi (1996):
A Problem:
With low catalyst-loading, coupling reactions smoothly progress only to a certain degree but not to completion due to the formation of TMS-enol ethers of aldehydes
O
R H +
cat. CrCl2
OH
R R1XR1
R = allyl- , propargyl- , alkenyl- , alkynil-, aryl-
> 2 eq. Mn
> 2 eq. TMSCl
X
CrX32 CrX2
MnMnX2
CrX2
OCrX2
R
O
R H
TMSX
OTMS
R
CrX3
David @ Wipf Group 5 1/15/2005
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NHK Reactions: Background (IV)
Catalytic Asymmetric NHK Reaction - Cozzi - Umani Ronchi (1999): - Kishi (2002): - Paterson - Berkessel (2003): - Nakada (2003):
O
NNH
R1
O2S
R2
R3
R4
Nucleophiles Used:
XX
R R X
Y = (70 - 90)%, de = (75 - 90)%
Nucleophiles Used:
X
Y = (77 - 98)%, ee = (89 - 96)%
NH
O N
R1
O
N
R1
X
Y = (20 - 93)%, ee = (51 - 98)%
N
OH
N
HO
Y = (54 - 78) %, ee = (54 - 90)%
Nucleophiles Used:
XX
R
N OH
N OH
H
H
Y = (40 - 67) %, ee = (65 - 89)%
Nucleophiles Used:
Cl
David @ Wipf Group 6 1/15/2005
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Fe/Cr- and Co/Cr- Mediated Catalytic Asymmetric 2-Haloallylations of Aldehydes (I)
Catalytic Asymmetric Allylations of Aldehydes
X
R3
R2
R2
R1
O
+
O
NNH
t-Bu
O2S
Bn
CrCl3 3THF
TEA 8 mol% Mn 120 mol%
2,6-lutidine 200 mol% TMSCl 250 mol%
1.
2. aq. AcOH
R3
R2 R2
R1
OH
Br
Br
Me
Me
I
Me
O
MeH
O
TBDPSOH
OH
Me
BrOH
OTBDPS
OH
OTBDPS
Me Me
OH
OTBDPS
Me
93% yield, 93% ee
90% yield, 92% ee
94% yield, 94% ee
91% yield, 93% ee
H
4 mol%
5 mol%
THF 0 oC 36h
2.5 eq.
David @ Wipf Group 7 1/15/2005
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Fe/Cr- and Co/Cr- Mediated Catalytic Asymmetric 2-Haloallylations of Aldehydes (II)
Catalytic Asymmetric 2-Haloallylations of Aldehydes
Br
Br
O
Me
O
TBDPSO
O
TBSO
O
EtS
SEt
O
O
Me
Ph
O
Ph
O
OH
Me
Br
OH
OTBDPS
Br
OH
OTBS
Br
OH
SEt
SEt
Br
OHBr
OH
Me
Br
Ph
OHBr
Ph
OHBr
H
H
H
H
H
H
H
H
75% yield, 93% ee
75% yield, 92% ee
60% yield, 91% ee
70% yield, 90% ee
70% yield, 90% ee
75% yield, 87% ee
75% yield, 83% ee
86% yield, 84% ee
Br
I
Br
Cl
O
TBDPSOH
OH
OTBDPS
I
OH
OTBDPS
Cl
50% yield, 93% ee [with Fe(TMHD)3]
63% yield, 93% ee [with CoPc]
45% yield, 90% ee [with Fe(TMHD)3]
63% yield, 93% ee [without Fe or Co salt]
Br
X
R
O
+
O
NNH
t-Bu
O2S
Bn
CrBr3
TEA 90 mol% Mn 600 mol%
2,6-lutidine 220 mol% TMSCl 300 mol%
1.
2. aq. AcOH or TBAF
X
R
OH
Fe(TMHD)3 or CoPc
H
11 mol%
10 mol%
2 mol%
THF 0 oC 20h
2.2 eq.
David @ Wipf Group 8 1/15/2005
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Fe/Cr- and Co/Cr- Mediated Catalytic Asymmetric 2-Haloallylations of Aldehydes (III)
Proposed Mechanism
X
BrX
M
X
Cr(III)BrS / ligand
O
R H
X
R
OCr(III)BrS / ligand
M
Mn(II) or Cr(III) Mn(0) or Cr(II)
``low-valent M``
CrBr3
Fe/Mn or Co/Mn
ligand, TEACr(II)BrS / ligand
M : Fe or Co
S : THF or 2,6-lutidine
ligand :
O
NNH
t-Bu
O2S
Bn
David @ Wipf Group 9 1/15/2005
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New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents (I)
Is It Possible to Improve the Fürstner Catalytic Cycle?
Yes, Cp2ZrCl2 Can Replace TMSCl !
X
CrX32 CrX2
MnMnX2
CrX2
OCrX2
R
O
R H
TMSX
OTMS
R
CrX3
OCrX2
R
ML
ML
R
?
David @ Wipf Group 10 1/15/2005
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New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents (II)
Cr Mediated Couplings
O
H
Br
2.0 eq
OH
O
NNH
t-Bu
O2S
Bn
CrCl3 3THF 10 mol%
TEA 11 mol%
11 mol%
Mn 300 mol%
2,6-lutidine 11 mol%
THF
0 oC 15-24 h
Br
2.0 eq
Me
Me OH
Me Me
94% yield, > 90% ee
97% yield, > 90% ee
Cp2ZrCl2 100 mol%
David @ Wipf Group 11 1/15/2005
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New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents (III)
Ni/Cr Mediated Couplings
O
H
OH
O
NNH
t-Bu
O2S
CrCl2 10 mol%
11 mol%
Mn 200 mol%
CH3CN
rt 12 h
92% yield, 86% ee
Cp2ZrCl2 100 mol%
NiCl2(dppp) 0.5 - 5 mol%
LiCl 200 mol%
Proton Sponge 100 mol%
IMe
2.0 eq
Me
I
2.0 eq
MeOH
92% yield, ee not reported
Me
2.0 eq
Me
I
HOMe
79% yield, ee not reported
2.0 eq
Me
I OH
97% yield, ee not reported
Me
2.0 eq
ICO2Me
OH
96% yield, ee not reported
MeO2C
3.0 eq
I
OH
97% yield, ee not reported
David @ Wipf Group 12 1/15/2005
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New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents (IV)
Fe/Cr- and Co-Cr- Mediated Couplings
O
H
OH
O
NNH
t-Bu
O2S
CrBr3 10 mol%
11 mol%
Mn 300 mol%
THF
0 oC 15 h
84% yield, 90% ee
Bn
Cp2ZrCl2 100 mol%
CoPc 0.2 mol%
2,6-lutidine 11 mol%
TEA 100 mol%
2.5 eq
2.5 eq
92% yield, ee not reported
2.5 eq
HO
98% yield, ee not reported
2.5 eq
MeOH
83% yield, ee not reported
Me
2.5 eq
86% yield, ee not reported
IBr
BrBr OH
I
Br
Br
Cl HO
I
David @ Wipf Group 13 1/15/2005
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New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents (V)
Examples Selected from the Ongoing Halichondrin Program: Usefulness of the New Catalytic Cycle
O
NNH
t-Bu
O2S
CrBr3 10 mol%
11 mol%
Mn 300 mol%
THF
0 oC 24 h
Bn
Cp2ZrCl2 100 mol%
CoPc 0.2 mol%
2,6-lutidine 21 mol%
TEA 11 mol%
2.6 eq
90% yield, 91% ee
BrBr
O
HTBDPSO +
OH
OTBDPSBr
(When TMSCl is used: 75%, 92% ee)
O
Me
O
H
O
TBS
O
O
MeMe
+
I
CO2Me
O
NNH
t-BuO2S
23 mol%
93% yield, dr = 15 / 1
(When TMSCl is used: 82%, 12 / 1)
Me
CrCl2 20 mol%
Mn 200 mol%
CH3CN
rt 24 h
Cp2ZrCl2 100 mol%
NiCl2(dppp) 2 mol%
LiCl 200 mol%
Proton Sponge 23 mol%
2,6-lutidine 130 mol%
O
Me
OH
O
TBS
O
O
MeMe CO2Me
2.0 eq
David @ Wipf Group 14 1/15/2005
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New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents (VI)
Proposed Catalytic Cycle
1/2 Mn(II) 1/2 Mn (0)
Cr
Cl O(THF)
N N
OS
OR
Cr(II) - ligand complex
Cr
Cl O(THF)
N N
OS
OR
Cl
Cr(III) - ligand complex
Cr
Cl O(THF)
N N
OS
OR
R1
Cr
Cl O
N N
OS
OR
R1
XR1
R2CHO
THF
H
R2
Cr
Cl O
N N
OS
OR
(THF)OH
R2
R1
(Cp)2Zr(Cl)2
O
R2R1
Zr(Cl)(Cp)2
David @ Wipf Group 15 1/15/2005
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Summary
Fe/Cr and Co/Cr Mediated Catalytic Asymmetric 2-Haloallylation of Aldehydes
- A novel class of (transition metal)-Cr mediated process has been applied in a new kind of allylation reaction (2-haloallylation) of aldehydes
- The new 2-haloallylation process has been successfully realized in a catalytic and
asymmetric fashion
- The coupling reactions furnish products that are valuable synthetic intermediates in organic synthesis
New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents
- The use of Cp2ZrCl2 in place of TMSCl has resulted in the discovery of a new catalytic cycle for NHK reactions
- With the new catalytic cycle higher yields of the coupling products are obtained
- No additional desilylation step is required at the end of the coupling process
David @ Wipf Group 16 1/15/2005
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Future Work
Fe/Cr and Co/Cr Mediated Catalytic Asymmetric 2-Haloallylation of Aldehydes
- An investigation of the Scope and Limitations of this new class of reaction is required
as well as a detailed Mechanistic Investigation. (What is the role of 2,6-lutidine? Why the 2-chloroallylation reaction works better without Fe or Co salts? What is the exact role of Fe and Co?)
Catalytic Asymmetric NHK reactions
Ligand Optimization is still needed
David @ Wipf Group 17 1/15/2005