1

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

2

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

3

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

4

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

5

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

6

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

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