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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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