direct organocatalytic enantioselective mannich reactions ...ccc.chem.pitt.edu/wipf/current...

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Direct Organocatalytic Enantioselective Mannich Reactions of Ketimines: An Approach to Optically Active Quaternary α-Amino Acid Derivatives Wei Zhang, Steen Saaby, and Karl Anker Jorgensen The Danish National Research Foundation: Center for Catalysis Department of Chemistry, Aarhus University Angew. Chem. Int. Ed. 2004, 43, 4476-4478 Michael Rishel @ Wipf Group 1 9/13/2004

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Page 1: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Direct Organocatalytic Enantioselective MannichReactions of Ketimines: An Approach to Optically

Active Quaternary α-Amino Acid Derivatives

Wei Zhang, Steen Saaby, and Karl Anker Jorgensen

The Danish National Research Foundation: Center for CatalysisDepartment of Chemistry, Aarhus University

Angew. Chem. Int. Ed. 2004, 43, 4476-4478

Michael Rishel @ Wipf Group 1 9/13/2004

Page 2: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

The Mannich Reaction

R1

O

R2 H R3

OR4NH2++

R1

R2

X

preformed enol equivalent

preformedimine

NR4

R3Hindirect

direct

R1 R3

R2

O HNR4

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J.; J. Am. Chem. Soc. 2002, 124, 827-833.

Michael Rishel @ Wipf Group 2 9/13/2004

Page 3: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Iminoesters as Useful Electrophiles in Mannich Reactions

EtOH

O

O

tosylisocyanate

[AlCl3]

p-methoxyaniline

sieves

EtOH

N

O

Ts

EtOH

N

O

PMP

Taggi, A. E.; Hafez, A. M.; Leckta, T. Acc. Chem. Res. 2003, 36, 10-19.

EtOOH

O

OHPhCONH2

EtOAcEtO

OH

O

HN O

EtOCl

O

HN Ooxalyl chloride

α-haloglycine

Michael Rishel @ Wipf Group 3 9/13/2004

Page 4: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Lewis Acid Catalyzed Mannich Reactions of α-Imino Esters

OH

NX

O

OLG

HNX

O

-LG

MP P

MP P

OH

NX

O

MP

P

O

HNX

O

HNu

Nu

Taggi, A. E.; Hafez, A. M.; Leckta, T. Acc. Chem. Res. 2003, 36, 10-19.

Michael Rishel @ Wipf Group 4 9/13/2004

Page 5: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Chiral Lewis Acid Catalyzed Mannich Reactions - 1

H

O

EtO

NTs

2-10 mol% cat.

THFor CH2Cl2-78 oC to 0 oC

R

OTMS

O

EtO

NHTs

R

O

95%, 98%ee

P

P

R'

R'

CuClO4

R'

R'

"cat"

R = Ar, AlkR' =p-Me-Ph

(a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-4549. (b) Ferraris, D.; Dudding, T.; Young,B.; Drury, W. J.; Lectka, T. J. Org. Chem. 1999, 64, 2168-2169. (c)Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.; Ryzhkov, Lev.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67-77.

Michael Rishel @ Wipf Group 5 9/13/2004

Page 6: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Chiral Lewis Acid Catalyzed Mannich Reactions - 2

H

O

O

NPMP

5 mol% cat.

DMF, 25 oC

R

OTMS

O

O

NHPMP

R

O

80-95%, 71-90%ee

P

P

R'

R'

Pd

R'

R'P

P

R'

R'

Pd

R'

R'

"cat"

O

O

H

H

22TfO-

R = ArR' =Tol

(a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474-2475. (b) Fujii, A.; Sodeoka, M.; 1999, 40, 8011-8014.

Michael Rishel @ Wipf Group 6 9/13/2004

Page 7: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Chiral Lewis Acid Catalyzed Mannich Reactions - 3

H

O

EtO

N

10 mol% cat.

CH2Cl2, 25 oC

R

OTMS

O

EtO

NH

R

O

77-97%, 90-97%%ee

O

R1

O

R1

NHCu

NH

TfO OTf

PhPh

"cat"

R = Ar, OMe, SEtR' = Ar, Alk

(a) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143-145. (b) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640-5641.

Michael Rishel @ Wipf Group 7 9/13/2004

Page 8: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Chiral Lewis Acid Catalyzed Mannich Reactions - 4

O

PPh2N

Ar

OMeO

OH

+NH

Ar

OH

O OMe

1-5 mol% cat.

THF, MS 3A,

-20 oC, 2-24 h93-98%, 88/12-96/4 de,95-98% ee

Et2Zn, 4eq

OH

OH

"cat"

HO

HO

O

Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc.2003, 125, 4712-4713.

Ph2P

O

Michael Rishel @ Wipf Group 8 9/13/2004

Page 9: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Mannich Reactions by Organocatalysis

H

O

O

NPMP

DMSO, 25 oCO

O

NHPMP

O

47-86%, 11-99%ee, 19:1 dr

O

R2R1

+

NH

OH

O

20 mol%

R1 R2

2-20 h

(a) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (b) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842-1842.

H

O

O

NPMP

DMSO, 25 oCO

O

NHPMP

O

44-78%, 74-92%ee, 5:1-19:1 dr

O

R

+

20 mol%

R2-20 h

H H

NH

OMe

(a) Cordova, A.; Barbas, C. F. Tetrahedron Lett. 2002, 43, 7749-7752. (b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591.

Proposed Transition States

N

H CO2EtR1

PMPR2

N

O

OH N

OO R2

N

R1CO2Et

PMP

H

N

H CO2EtR

H

NMeO

PMP N

HMeO

RN

PMP

CO2Et

Michael Rishel @ Wipf Group 9 9/13/2004

Page 10: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

The Scoop: Mannich Reactions Largely Restricted to IminesDerived From Aldehydes

N

O

OEt

R

PG N

O

OEt

R

PG LA*LA* N

O

OEt

R

LA* PG

Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K. A. Chem. Eur. J. 2003, 9, 6145-6154.

• Imines bearing α-protons are susceptible to form enamines in the presence ofBronstead or Lewis acids.

• The equilibrium of the flexible imine double bond is often shifted towards the Zisomer and thereby render difficult a constrained and rigid bidentate coordination to aLewis acid complex

• A characteristic and fundamental problem related to the use of ketimine substrates issteric hindrance.

• The disubstituted carbon atom of a prochiral ketimine double bond is much lessreactive than the analagous monosubstituted prochiral aldimine, owing to unfavorablesteric interactions during the CC bond forming step.

Michael Rishel @ Wipf Group 10 9/13/2004

Page 11: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Intrinsic Protecting Groups: Their Role in ModulatingKetimine Reactivity

“…By anchoring the nitrogenprotecting group by means ofan aryl substituent, the degreeof rotational freedom, as wellas possible imine double bondisomerization, is minimized,rendering a beneficialpreorganized structure forbidentate Lewis acid activation.Moreover, the problem ofenamine formation is alsocircumvented…”

N

Ar

PG

O

OEtNO

R

O

O

OEtvs.

N

RO

OEt

O

OMe

Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K. A. Chem. Eur. J. 2003, 9, 6145-6154.

OH

R Hunig's base

PMB-isocyanateO

R

O

NHPMB

formic acid

NHO

R

O

O

OEtOH TFA (cat)

Dean-Stark

NO

R

O

O

OEt

O

O

OEt

O

O

OEt

Michael Rishel @ Wipf Group 11 9/13/2004

Page 12: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Lewis Acid Catalyzed Ketimine Alkylation

O

OEt

N

5-10 mol% cat.

CH2Cl2, -78 oC

OR1

OTMSO

O

R R2

+

H2O 5-20 mol%

NHO

O

R

CO2Et

CO2RR2

NO

N N

O

Ph Ph

Zn

2

2 OTf-

Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K. A. Chem. Eur. J. 2003, 9, 6145-6154.

cat.

Boc2O, DMAP

MeCN, RT, 17 h

Cs2CO3

MeOH, RT, 2h O O

CO2EtBocHN

RR2

Michael Rishel @ Wipf Group 12 9/13/2004

Page 13: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

O

OEt

N OO

O

+ NHO

O

CO2Et

CHOiPr

iPr

H

chiral amine

1a 2a

+

4a

NHO

O

CO2Et

CHOiPr

3a

Table 1: Direct organocatalytic asymetric Mannich reaction of ketimine 1a with 2a.

Entry Catalyst(mol%)

T[ºC]

2a[equiv]

Solvent Yield[a]

[%]3a/4a[b] ee[c]

[%]1 5a (30) 0 5 CH2Cl2 84 1:8 822 5b (30) 0 5 CH2Cl2 11 >20:1 73 5c (30) 0 5 CH2Cl2 trace >20:1 –4 5d (30) 0 5 CH2Cl2 39 >20:1 805 5e (5) 0 5 CH2Cl2 56 15:1 866 5e (5) 0 5 CH2Cl2 73 2:1 887 5e (5) 0 5 Et2O 74 19:1 908 5e (5) 0 2 Et2O 99 >20:1 919 5e (5) -24 2 Et2O 51 17:1 9210 5e (2) 0 2 Et2O 93 18:1 91[a] Combined yield of the two isolated diastereomeric products. [b] The diastereomericratio was determined by 1H NMR spectroscopic analysis of the crude product mixture.[c] The ee of the major product was determined by HPLC on a Daicel Chiralpak AScolumn.

NH

CO2H NH

CO2MeNH

Ph

OHPh N

H

Ar

OHAr

Ar = 3,5 xylyl

NH

N

5a 5b 5c 5d 5e

Zhang, W.; Saaby, S.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2004, 43, 4476-4478

Michael Rishel @ Wipf Group 13 9/13/2004

Page 14: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

O

OEt

N OO

O

+

R4H

1a-f 2a R4 = iPr

2b R4 = Me

2c R4 = allyl

NHO

O

CO2Et

CHO

R4

3a-h

R1

R2

R3

5e (5 mol%)

0 oC, 20 h

Table 2. Reaction of ketimines 1a-f with aldehydes 2a-c under the optimized reactionconditions

Entry Imine Solvent R1 R2 R3 R4 Product Yield[%][a]

3/4[b] ee[%][c]

1 1a Et2O H H H iPr 3a 99 >20:1 912 1b Et2O H H Me iPr 3b 98 6:1 893 1c Et2O H H OMe iPr 3c 95 9:1 864 1d Et2O H H F iPr 3d 97 19:1 835 1e Et2O H OMe H iPr 3e 90 >20:1 876 1f Et2O –C4H4– H iPr 3f 93 >20:1 847 1a CH2Cl2 H H H Me 3g 72 5:1 958 1a CH2Cl2 H H H allyl 3h 82 4:1 98[a] Combined yield of the two isolated diastereomeric products. [b] The diastereomericratio was determined by 1H NMR spectroscopic analysis of the crude product. [c] The eevalue of the major product (with R configuration at the quaternary center) wasdetermined by HPLC on a Chiral stationary phase (see Supporting Information fordetails).

Zhang, W.; Saaby, S.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2004, 43, 4476-4478

Michael Rishel @ Wipf Group 14 9/13/2004

Page 15: Direct Organocatalytic Enantioselective Mannich Reactions ...ccc.chem.pitt.edu/wipf/Current Literature/Mike_3.pdfR3 5e (5 mol%) 0 oC, 20 h Table 2. Reaction of ketimines 1a-f with

Conclusions

• The first organocatalytic, enantioselective Mannich reaction ofketimines and unmodified aldehydes based on the concept of intrinsicprotecting group anchoring has been reported.

• Catalysis is achieved by the addition of simple chiral amines (2-5mol%) providing optically active quaternary α-amino acid derivativesin high yields (72-99%) and good optical purities (83-98% ee).

• Through careful selection of the amine catalyst, the diastereoselectivityof the reaction can be controlled.

Michael Rishel @ Wipf Group 15 9/13/2004