Copper-Catalyzed Enantioselective Synthesis of trans-1-Alkyl-2-substituted Cyclopropanes via Tandem Conjugate

Additions-Intramolecular Enolate TrappingHartog, T. D.; Rudolph, A.; Macia B.; Minnaard, A. J.; Feringa, B. L.

J. Am. Chem. Soc. 2010, ASAP.

Short Literature Presentation 10/4/2010

Erika A. Crane

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-Catalyzed Reactions Employing MnO2 as a Stoichiometric Oxidant

Liu, L.; Floreancig, P. E. Org. Lett. 2010, ASAP.

Prof. Dr. Ben L. Feringa

? - 1978: PhD from the University of Groningen with Prof. Dr. Hans Wynberg1978 - 1984: Research Chemist at Royal Dutch Shell1984 - 1988: Organic Chemistry Lecturer at University of Groningen1988 - present: Appointed to Professor and Chair of Organic Chemistry

Meet the P.I.

The Feringa Group is pursuing “new enantioselective catalytic methods for key synthetic transformations and catalytic strategies for the efficient construction of

complex (biological active) chiral molecules”.

And used these ligands to develop the first enantioselective, catalytic 1,4-addition of organometallic

reagents to enones with absolute stereocontrol...

OO

P NMe

Me

They have developed monodenate phosphoramidite ligands for use in

asymmetric catalysis......

Angew. Chem. Int. Ed. Engl. 1996, 20, 2374-2376.

Angew. Chem. Int. Ed. Engl. 1997, 36, 2620-2623.

The Feringa Group is pursuing “new enantioselective catalytic methods for key synthetic transformations and catalytic strategies for the efficient construction of

complex (biological active) chiral molecules”.

And used these ligands to develop the first enantioselective, catalytic 1,4-addition of organometallic

reagents to enones with absolute stereocontrol...

OO

P NMe

Me

They have developed monodenate phosphoramidite ligands for use in

asymmetric catalysis......

Angew. Chem. Int. Ed. Engl. 1996, 20, 2374-2376.

Angew. Chem. Int. Ed. Engl. 1997, 36, 2620-2623.

The Feringa Group also....

– Pioneered low-molecular weight organogels

– Reported the first optical molecular switch in which chirality is controlled by light in 1991

– Has made several advances in the field of molecular motors (light-driven & rotary, speed enhancement, etc.)

–Achieved the first design and synthesis of a light-driven unidirectional rotary motor

Utilizing Chiral Auxillaries/Substrates:

Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254-8256.

Et2ZnCH2I2 90 % yield

94% de92% eeO

OCO2i-Pr

CO2i-PrO

OCO2i-Pr

CO2i-Pr

H

MeMe

Hardee, D. J.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 7536-7537.

Me

O La OTfTfO OTf

OBnO La OTfTfO OTf

OBn

Me

H

epoxide opening semi-pinacol rearrangement

Catalytic Asymmetric Epoxidation–Intramolecular Methylene Transfer:

5 mol% La(OTf)35 mol% 2,6-lutidineO

OBn OBn

O

HLiClO4DCE, 40 °C

72% yield >20:1 dr

MeMe

The Synthesis of Trans-1-alkyl-2-substituted Cyclopropanes

The Synthesis of Trans-1-alkyl-2-substituted Cyclopropanes

Utilizing Chiral Auxillaries/Substrates:

Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254-8256.

Et2ZnCH2I2 90 % yield

94% de92% eeO

OCO2i-Pr

CO2i-PrO

OCO2i-Pr

CO2i-Pr

H

MeMe

Catalytic Asymmetric Epoxidation–Intramolecular Methylene Transfer:

5 mol% La(OTf)35 mol% 2,6-lutidineO

OBn OBn

O

HLiClO4DCE, 40 °C

72% yield >20:1 dr

MeMe

Via Chiral Cyclopropenes:

Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916-8918.

Hardee, D. J.; Lambert, T. H.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 7536-7537.

90% yield 95% eeHH3C(H2C)4

H

N2

OEt

O0.5 mol % 1

CH2Cl2 H3C(H2C)4 H

H CO2Et

H3C(H2C)4

H CO2Et

5% Pd/CaCO3H2, EtOAc92% yield

The “Benchmark Reaction”

Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651-2652.

R2

R1

R3

HO

OB

O

R6 R6

Bu

Et2ZnR5CHI2

DME/DCM

H R5

R2 R3R1 OH

R1-4 = H, substituted alkyl & aryl; R5 = H, Me, phenyl; R6 = CONMe2

! 80% yields91-94% ee

The Synthesis of Trans-1-alkyl-2-substituted Cyclopropanes

Asymmetric Simmons-Smith Cyclopropanation:

In This Paper, A Catalytic, Asymmetric MIRC reaction:

(a Michael addition initiated ring-closure reaction)

ClR1

O

R2MgBrCuI

(R)-TolBINAP

t-BuOMe/CH2Cl24h, – 78 °C

ClR1

R2 OMgBr

R1

OR2

2 h– 78 °C to rt

den Hartog, T.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010, 352, 999-1013.

BrR1

O

1,2SN2' SN2

1,4

4-halocrotonate

potential chemo-, regio- and stereoselectivity issues with the addition of a Grignard reagent!

A Regioselective Grignard Addition to a 4-halocrotonate

den Hartog, T.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010, 352, 999-1013.

BrR1

O

MeMgBrCuBr•SMe2

(R,R)-1R1

O

MeCH2Cl2, – 78 °Crt

Fe

PPh2

Ph2P

NMe2

1, TaniaPhos

4-halocrotonate

potential chemo-, regio- and stereoselectivity issues with the addition of a Grignard reagent!

A Regioselective Grignard Addition to a 4-halocrotonate

1,2SN2' SN2

1,4

den Hartog, T.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010, 352, 999-1013.

BrR1

O

4-halocrotonate

potential chemo-, regio- and stereoselectivity issues with the addition of a Grignard reagent!

A Regioselective Grignard Addition to a 4-halocrotonate

R1X

R2

*

OMgBr

1,2SN2SN2'

1,4

Substrate Screening

Pp-Tol2

Pp-Tol2

(R)-TolBINAP

XSEt

O

CH3(CH2)5MgBr1 mol% CuI

1.5 mol% (R)-TolBINAP

t-BuOMe/CH2Cl24h, – 78 °C

XSEt

Hex O

SEt

OHex+

when X = Cl 83 % yield94% ee

when X = Br < 20 % yield

when X = Cl 87 % yield94% eewith warming to room temperature*

Substrate Screening

ClSEt

O

RMgBr1 mol% CuI

1.5 mol% (R)-TolBINAP

t-BuOMe/CH2Cl24h, – 78 °C

SEt

OR

R % yield % ee

i-Pr

i-Bu

89% 70%

91% 84%

but-3-enyl 88% 94%

(CH2)3Ot-Bu >95% 96%

BnCH2 92% 84%

Ph 50% 26%

Pp-Tol2

Pp-Tol2

(R)-TolBINAP

Substrate Screening

Pp-Tol2

Pp-Tol2

(R)-TolBINAP

ClR1

O

R2MgBr1 mol% CuI

1.5 mol% (R)-TolBINAP

t-BuOMe/CH2Cl24h, – 78 °C

R1

OR

R2 % yield % ee

Me

BnCH2

87% 98%

68% >95%

R1

C11H23

OMe

Prof. Paul Floreancig

B.S. from IndianaPh.D. from Stanford (Wender)Postdoc at Caltech (Dervan)

Meet the P.I. and Past Work

Tu, W.; Floreancig, P. E. Angew. Chem. Int. Ed. 2009, 48, 4567-4571.

MeO

O C6H13

OAc

DDQ, 2,6-Cl2Py

DCE10 min, 77% MeO

O C6H13

O

Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem. Int. Ed. 2008, 47, 4184-4187.

DDQ, 2,6-Cl2Py

LiClO4, DCE58%

Me

MeO

Pr

O

O

OH

OAc Me

MeO

Pr

O

O

OH

OH

neopeltolide

Me

MeO

Pr

O

O

OH

HO O

NO

NH

O

MeO

University of Pittsburgh

Past Work (Cont.)

Liu, L.; Floreancig, P. E. Angew. Chem. Int. Ed. 2010, 49, 5894 –5897.

DDQ, 2,6-Cl2Py

O Me

OAc

Me

MeOH

O Me

MeOH

O

MeMeNO2

78% yield

O Me

OAc

HMeO

O

OMeO Me

H

84% yield

– Only moderate stereocontrol obtained with the usual solvent, DCE–They postulate the more polar MeNO2 is necessary the provide more stabilization for the intermediate oxocarbenium ion

Can This Reaction Be Rendered Catalytic in DDQ?

O

O

Cl

Cl

CN

CN

Cl

Cl

CN

CNOH

OH

product

substrate

oxidant

reduction product

DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone

$526/mol (Aldrich)modest toxicity concerns

HNO3?

FeCl3?

Mn(OAc)3?

PbO2?

Substrate Scope

15 mol % DDQ,MnO2 (6 equiv),

2,6-Cl2Py, MeNO248 h, 79%

O OH

O

HMe

Me

OAc

OTBS OTBSMe

Me

20 mol % DDQ,PbO2 (8 equiv),

2,6-Cl2Py, MeNO248 h, 75%

oxidative cyclization is slower in MeNO2, but the regeneration

of DDQ is much faster

O

OAc

Me

O

Me

O

83% yield

O Me

OAc

Me

MeOH

O Me

MeOH

O

Me

75% yield

All yields were within ~10% of the yields to the corresponding reactions with 2.0 equiv. of DDQ!

Can It Do Other DDQ-Mediated Transformations?

PMB ether deprotection:

Dehydrogenation:

Oxazole Synthesis:

15 mol % DDQ,MnO2 (6 equiv),

MeOH, MeNO2, 60 °C48 h, 90%

O

OMeOH

15 mol % DDQ,MnO2 (6 equiv),

MeNO2, rt24 h, 96%

20 mol % DDQ,MnO2 (6 equiv),

C6H6, 80 °C48 h, 86%

O

N

O

N