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Proline As a Catalyst in Organic Synthesis
Lead References:Dalko, P. I.; Moison, L.; Angew. Chem. Int. Ed. 2004, 43, 5138-5175.Notz, W.; Tanaka, F.; Barbas, C.F. Acc. Chem. Res., 2004, 37,580-591.List, B. Acc. Chem. Res. 2004, 37, 548-557.List, B. Tetrahedron 2002, 58, 5573-5590.
Ashwin BharadwajOctober 26, 2004
Why Proline is a Good Catalyst? Possible Reasons
Proline is the only natural amino acid with a secondary amine functionality, which raises thepKa value and better nucleophilicity as compared to other amino acids.
It can act as a nucleophile to carbonyl groups(iminium intermediate) or Michael acceptors(enamines).
It can be regarded as a bifuctional catalyst
The high stereoselectivity possibly due to its formation of organized transition states with many hydrogen bonding frameworks.
Proline is not the only molecule to promote catalysis, but it still seems to be one of the best in the diversity of transformations
Transformations Covered:Aldol Reactions
Mannich ReactioonsDiels Alder Reactions
Michael ReactionsOther Transformations
NH
O
OH
Modes of Proline Catalysis
NH
N
N N
CO2H
CO2HCO2-
O
H MO
H
Metal CatalysisBifunctional Cataysis
MeR R
Iminium Catalysis Enamine Catalysis
Initial Findings
O
O
MeR
O3 mol % L-proline
DMF, 20h, rt
OR
OHO
R= Me, 100%, 93% eeR= Et 71%, 99% ee
OR
Me
O
O
3 mol % L-proline
DMF, 72h, rt52%
O
Me
OH
O
74% eeUse of protic solvents diminishes selectivity
Other amino acids used lead to poor yield and selectivity
Hajos, J.; Parrish, D.; J. Org. Chem. 1974, 39, 1615.Eder, U.; Sauer, G.; Weichert, R.; Angew. Chem. Int. Ed, 1971, 10, 496.
Initial Studies on Catalyst Structure
O
O
MeMe
ONMe
O
OH
DMF
Me
HO
O
H
Me
O
racemic
"major product"
O
O
MeMe
O
O
O
MeMe
O
NH
O
OMe
DMF
DMF
O
Me
OH
O
O
racemic
NH
CO2Hno reaction
Hajos, J.; Parrish, D.; J. Org. Chem. 1975, 39, 1615.
L-Proline even in preliminary investigations showed the most promise!!!
Transtion States: Two Views
N
H
H
H O
OHO
Me
O
Houk, 2001-2003
1) N-H---O Hydrogen bond does not lower energy of T.S.
2) Favorable O--H----O Hydrogen bond
3) Reaction first order in Proline (kinetic data)
N-O2CH
Me
O
ON
CO2-
H
Agami 1986
1) Favorable enamine bond
2) N-H- anti to carboxylate
3) Second order in proline
Agami, C. Bull. Soc. Chim. Fr. 1988, 3, 499. Hoang, L.; Bahmanyar, S.; Houk, K.N., List, B. J. Am. Chem. Soc. 2003, 125, 16.
General Cycle: An Enamine Mediated Catalytic Cycle with L-Proline
R2
O
R1
NH
CO2H
R1
N
R2
CO2HYX
electrophile(aldehyde, ketone,....)
NO
O
R2R1
Y
X
H
N+O
O-
R2R1
Y
X
H
R1 XO
R2
YH
+ H2O
It is believed that exceptional enantioselectivity is due to proline to promote formation of highy organized transition stateswith an array of hydrogen bonding frameworks.
In all proline mediated reactions, proton transfer from amine or acid to alkoxide or imide is essential for charge stabalization of bond forming events
Initial Study: Two Good Catalysts
Me Me
O
H
O+
R
L- proline, 30 mol%
DMSO, 4h trMe
O OH
R
Me
O OH
NO2
Me
O OH
Me
O OH
Br
Me
O OH
R
Me
O OHCl
Me
O OH
Me
Me
NH
S
NH
Me Me
CO2H
O
OH1 2
DMTC
1: 68%, 76% ee2: 60%, 86% ee
1: 62%, 60% ee2: 60%, 89% ee
1: 74%, 65% ee2: 65%, 87% ee
1: 97%, 96% ee2: 61%, 94% ee
1: 54%, 77% ee2: 60%, 88% ee
1: 94%, 69% ee2: 71%, 74% ee
2 is a good catalyst for aromatic aldehydes but the reaction rate is slower
List, B.; J. Amer. Chem. Soc. 2000, 122, 2395.
Direct Asymmetric Aldol Reaction: Ketones and Aldehydes
R1
OR2 +
H R3
O (S)-Proline
10-30 mol%DMSO or DMF
rt, 2-72h
R1 R3
O
R2
OH
Me
O OH
62%, 72% ee
Me
O OH
Me
Me Me
O OH
Me
O OH O OH
Me
Me
97%, 96% ee
Me
Me
OH
85%, 99%ee
60%, > 20:1 dr, >99%ee 77%, 2.5 d.r, 95% ee
List.B.; Lerner, R.A.; Barbas, C.F. J. Amer. Chem. Soc. 2000, 122, 2395-2396List, B.; Pojarliev, P.; Castello, P. Org. Lett. 2001, 3, 573-575.
H
OX
General Scheme:
enantioselective
catalyst HH
O
Y
+
O
X
OH
Y
Enantioselective Aldehyde Aldol: Elusive
H
OMe
10 mol%
catalyst, DMF, 4°C H
O
Me
OHMe
Proline Catalyzed Aldehyde Aldol Dimerization
80% yield, 4:1 anti syn, 99% ee
Enantioseletive aldol coupling of nonequivalent aldehydes is formidable
Propensity for aldehydes to polymerize
Two discrete components must occur: a nucleophilic component and an electrophilic component
Problem solved for nonequivalent aldehydes solved by syringe pump addition to propionaldehyde
H
OR1 10 mol%
catalyst, DMF, 4°C H R2
O
R1
OH
Proline Catalyzed Aldehyde Aldol Dimerization
donor
H R2
O+
acceptor
H
O
Me
OHMe
H
O
Me
OH
H
O
Me
OH
H
O
Me
OH
H
O
Me
OHMe
H
O
Bu
OHMe
H
O
Bn
OHMe
80%, 4:1, 99% ee 88%, 3:1, 97% ee 87%, 14:1, 99% ee 81%, 3:1, 99% ee
87%, 24:1, 99% ee 80%, 24:1, 99% ee 87%, 14:1, 99% ee
Me
Me
Me
Me Me
MacMillan, D.W.C.; Northrup, A. B.; J. Am. Chem. Soc. 2002, 124, 6798-6799.
Intramolecular Aldol Reactions
OHC CHO
R1R
(S)-Proline
10 mol%, CH2Cl2
OHCOH
R
R1
OHCOH
OHCOH
OHCOH
OHCHO
OHCOH
Me Me
MeMe
95%, 10:1 dr, 99% ee 75%, >20:1 dr, 97% ee 74%, >20:1 dr, 98 ee%
95%, 10:1 dr, 99% ee88%, 1:1 dr, 99% ee
Me
MeMe
Angew. Chem., Int. Ed. Engl. 2003, 42, 2785-2788,
HMe
(S)-ProlineH
OH
Me
O
82% yield, 24:1 anti syn, 99% ee
OMe
Me
O
H+Me
Me
1) (R)-Proline
2) TBSOTf
40:1 dr99% ee
61%
H
OH
Me
OMe
Me
O
O
Me
Me MeOH
Prelactone B1) OtBu
OTMS
, BF3
2) HCl
1) H22) TBSOTf3) LiBH44) Swern
74%
N O
OO
Me
Me
Bn
N O
OO
MeBn
1) MgCl2, NaSbF6, Et3N
MeH
O
2) MeOH, TFA, 77%, 15:1 dr
Synthesis of Prelactone B
Pihko, P.M.; Erkkila, A.; Tetrahedron Lett. 2003, 44, 6798-6799.
OH
Slight Catalyst Modification: α,α−-Disubstituted Aldol Products
H
OMe
R
+X
OHC NH
N
5 mol%
TFA, DMSOrt
H
O
Me R
OH
H
O
Me Me
OH
H
O
Me Me
OH
H
O
Me Me
OH
H
O
Me Et
OH
H
O
Me Pr
OH
H
O
Me
OH
nonyl
X
NO2 CN Br
NO2 NO2 NO2
Anti/Syn ratio quite modest in the general range from 1:2:1 to 5.3:1.
Mase, N.; Tanaka, F.; Barbas, C.F. Angew. Chem. Int. Ed. 2004, 43, 2420-2423.
92%, 96% ee 95%, 92% ee 80%, 95% ee
91%, 96/68% ee92%, 89/66% ee96%, 91/68% ee
Anti-Diols from Hydroxyacetone
Me
O
OHH R
O+
(S)-Proline (20 mol%)
DMSORMe
O
OH
OH
c-hexMe
O
OH
OH
i-PrMe
O
OH
OH
Me
O
OH
OH
Me
O
OH
OH
PhMe
O
OH
OH
2-naphthMe
O
OH
OH
t--BuMe
O
OH
OH
Me
O
OH
OH
Ph
Me
Cl
OO
MeMe
40-95%
> 99% ee>20:1 anti:syn
> 99% ee>20:1 anti:syn
> 95% ee>20:1 anti:syn
> 67% ee3:2 anti:syn
83% ee1:1 anti:syn
62% ee3:1 anti:syn
38% ee1.7:1 anti:syn
40% ee2:1 anti:syn
Notz, W.; Sakithivel, K; Bui, T.; Barbas, C.F.; J. Amer. Chem. Soc. 2001, 123, 5260-5267.
Acetaldehyde: A Trimerization
Me H
O 50 mol%, L-Proline
THF, 0°C, 5 hr, 10%3
H
O
Me
OH
15%
Mechanism:
HN
CO2H
+Me H
O -H2O
+H2ON
CO2
Me
H
N
CO2HH
Me H
O
N
CO2HHO
MeMannich Condensation
Me H
OH
O
Me
OHHN
CO2H
+
Cordova, A.; Notz, W.; Barbas, C.F. J. Org. Chem. 2002, 67. 301-303.
Aldehyde Aldol to Activated Carbonyls
H
OR +
EtO2C CO2Et
O 20 mol% L-Proline
CH2Cl2, 3 hr, rtH CO2Et
OHCO2Et
O
R
H CO2Et
OHCO2Et
O
MeH CO2Et
OHCO2Et
O
EtH CO2Et
OHCO2Et
O
i-Pr
H CO2Et
OHCO2Et
O
allylH CO2Et
OHCO2Et
O
n-Hex
H CO2Et
OHCO2Et
O
Ph
Yields range from 90-97%and enantioselectivities range from 84-90% exceptfor R= Ph where it is 0.
Chem. Comm. 2002, 620.
N
R
H
HH
H O
OO
EtO2C CO2Et
H
Aldol Reaction MechanismR2 Me
O NH
O
OH
++ H2O
- H2OR2
Me
N+
O-O
H R2
Me
N
OHO
H
R1CHO
N
H O
O
H
H
R2
MeO
HR1
H
Calculated T.S.
Points: synclinal approach of aldehyde R1 in pseudoequatorial position Calculations in DMSO C-H----O ; 2.4 A
Me
N
OHO
H
R2
R1
OH
+ H2O
- H2OR2
R1
OH
NH
O
OH
+
Me
O
R2N
OO-O
H
R1
MeH
metal-free Zimmeraman-Traxler model
List, B.; J. Am. Chem. Soc. 2000, 122, 2395.List, B. Houk, K. J. Am. Chem. Soc. 2003, 125, 2475.
Possible Transition State: Mannich vs. Aldol
O
HR+ N
X
CO2H
N
X
Me
Me
H O
O
R
O
H
H
Aldol
Selectivity of electrophileprobably depends on non-bonding interactions
Mannich
N
X
Me
H O
O
R
N
H
H
MeO
R Me
O
X
NHAr
R Me
O
X
OH
Direct Three -Component Mannich Reaction
R1
O
R2
+H R3
O
NH2
OMe
+(S)-Proline
5-35 mol%DMSO
R3R1
O NHPMP
R2
Me
O NHPMP
35%, 96% ee
Me
O
Me
NHPMPMe Me
O NHPMP
Me
O NHPMP
OHNO2
Me
O
Me
NHPMPMe
OH
Me
O NHPMP
Me
Me
56%, 70% ee 80, 90% ee
57%, 17:1 dr, 65% ee56%, >20:1 dr, >99% ee 90%, 93% ee
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J.Am. Chem. Soc. 2002, 124, 827-833
Functionalized α-Amino AcidsO
R1 R2
L-proline
20 mol%, DMSOrt
H
NPMP
CO2Et+
O
R1 R2
NHPMP
CO2Et
Me
O
Et
NHPMP
CO2Et Me
O
Me
NHPMP
CO2Et
O
Me Me
NHPMP
CO2Et
O NHPMP
CO2Et Me
O NHPMP
CO2Et
O
F
NHPMP
CO2Et
O
OH
NHPMP
CO2Et
72%, >19:1, 98% ee 47%, >19:1, >99% ee82%, 95% ee
81%, >19:1, >99% ee 79%, >19:1, >99% ee 77%, 61% ee
62%, >19:1, 99% ee
Cordova, A.; Notz, W.; Zhong, G.; Betancort, J.; Barbas, C. J. Am. Chem. Soc. 2002, 124, 1842.
Mannich Reaction Continued: Anti Products
H
OR + OEt
O
NPMP
H20 mol%, DMSO
NH
OMe
H
O
R
NHPMPOEt
O
H
O
Et
NHPMPOEt
O
H
O
i-Pr
NHPMPOEt
OH
O
n-Bu
NHPMPOEt
O
H
O
t-Bu
NHPMPOEt
O
H
O
n-Pent
NHPMPOEt
OH
O
Hex
NHPMPOEt
O
The dr for all of these products are >10:1 to 19:1 except when R=Et (1:1)ee generally ranges from 75-92% ee, however the yields are only moderate.
44% 52% 54%
57% 78% 65%
Tetrahedron Lett. 2002, 43, 7749.
proposed transition state
N
H
OMe
R
N
CO2Et
MeO
HR
HH
Mannich Applications: One Pot Cyanation
H
O
R
+H CO2Et
NPMP
1) L-Proline
THF, rt, 16-20h
2)Et2AlCN
NC CO2Et
OH
R
HNPMP
NC CO2Et
OH
i-Pr
HNPMP
NC CO2Et
OH
Bn
HNPMP
NC CO2Et
OH
(CH2)3OTBS
HNPMP
40%, 94% ee 62%, >99% ee 42%, >99% ee
Watanabe, S.; Cordova, A.; Tanaka, F.; Barbas, C.F. Org. Lett. 2002, 4, 4519-4522
Method for constructing three contiguous stereocenters
One-Pot Oxime Formation and Allylation
H
O
R
+H CO2Et
NPMP 1) L-Proline
THF, rt, 16-20h H CO2Et
O
R
HNPMP
H CO2Et
O
R
HNPMP
BnONH2HClDioxane and Pyridine
H CO2Et
N
R
HNPMPBnO
up to 78% yieldand 99% ee
OO
R NHPMP
In, THF/H2O (9:1)Br
dr = 1:1- 2:1up to 99% ee
Cordova, A.; Barbas, C.F.; Tetrahedron Lett. 2003, 1923-1926Bui, T.; Barbas, C.F. Tetrahedron Lett. 2000, 41, 6951-6954.
Asymmetric α-Amination of Aldehydes
R1
OR2
R1= H, alkylR2=alkyl, benzyl
+ NNBnO2C
CO2Bn
(S)-Proline
10 mol% thenNaBH4
NCO2Bn
R2
HNCO2Bn
HO
NCO2Bn
HNCO2Bn
HO NCO2Bn
HNCO2Bn
HON
CO2BnBu
HNCO2Bn
HO
NCO2Bn
Me
HNCO2Bn
HONCO2Bn
Bn
HNCO2Bn
HO
MeMe
Me99%, 96%ee93%, 95% ee
94%, 97% ee
97%, 96% ee95%, 96% ee
N
O
O
NR2 CO2Bn
NBnO2C H
Aminoxylation of KetonesO
R2R1NO
Ph+ (S)-Proline (10-30 mol%)
DMSO, 2-3h rt
O
R2R1
O
R2R1
ONHPh NPh
OH
7-11% eeup to 99% ee
O/N selectivity >100:1 to 8:22
OO
NHPh
OO
NHPh
OO
NHPh
OO
NHPh
O
OO
NHPh
NMe
OO
NHPh
All of these products formed in 70-85% yield and greater than 99% ee.
Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem. Int. Ed. 2004, 43, 1112-1115.
O
Me Me
O
Aminooxylation of Aldehydes
H
OR
5 mol% L-proline
CHCl3, 4°CH
OO
RNH
PhNO
Ph+
NH
X
N
O
OO
H
H
Possible Transition State
Basicity of nitrogen allows O-nucleophilic addition
Oxidation of Aldehydes with Nitrosobenzene
H
OR
5 mol% L-proline
CHCl3, 4°C H
OO
RNH
PhNO
Ph+
H
OO
MeNH
Ph
H
OO
n-BuNH
Ph
H
OO
i-PrNH
Ph
H
OO
PhNH
PhH
OO
BnNH
Ph
H
OO
NH
PhH
OO
(CH2)3OTIPSNH
Ph
88%, 97% ee
79%, 98% ee
85%, 99% ee
95%, 97% ee 60%, 99% ee
76%, 98% ee99%, 96% ee
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808.
Asymmetric Conjugate Addition
R1
O
R2
+R4 NO2
R3
(S)-Proline
10-20 mol%DMSO, rt
R1 NO2
R2
R3
R4
O
MeNO2
PhO
MeNO2
ONO2
PhO
97%, 7% ee 95%, 19%ee, 10:1 dr 94%, 23% ee, >20:1 dr
List, B.; Martin, H.J. Org. Lett. 2001, 2, 2423
Catalyst modification improves ee
OHC
R1
R2
NO2
+
R1, R2 = alkyl, aryl NH N
O
THF, rtH
NO2
R1
R2O
56-78% ee, syn/anti 98:2
20 mol%
Alexakis, A.; Andrey, O. Org. Lett. 2002, 3611-3614. Alexakis, A.; Bernardelli, G. Org. Lett. 2003, 5, 2559-2561.
Tandem Mannich-Michael Reaction
NH
N
O
Me+NH
NL-Proline (50 mol%)
DMSO, 7dH
O
76%, 92% ee
NH
NNH
NH
General Scheme:
Me
O
R+
R
O
L-Proline (3 mol%)
DMSO/H2O
51-98%7-92% ee
Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5, 4301-4304.
Tandem Process: Much longer Reaction Time
Amine-Catalyzed Activation Modes: Diels-Alder
Iminium-activation of dienophile
R
O
R
NR'R' O
R
Enamine-activation of diene
R
O
R1
R'NH
R'
dienophile
N
R1
R'R'
diene
R2NO2
NR'R'
R2 R1NO2
R2 R1NO2
O
R
NO2
+ Me
O
R1
proline
THF or MeOH rt, 32%-75%
O
NO2
R1R
O
NO2
R1R
R = Ph, 4-MeOC6H4, 1-naphtyl, 2-CF3C6H4R1= Ph, 2-thienyl, 2-furyl
Me
O
R
2
proline
THF or H2O 25-40°C, 5-60h
47-80%
O
RR
O
RR
OMe OMe
R = Ph, 4-MeOC6H4, 1-naphtyl, 2-furyl, CO2Me
Enantioselectivities generally poor between11-47%
Ramachary, D.B.; Chowdari, N.D.; Barbas, C. Tetrahedron Lett. 2002, 6743-6746.Thayumanavan, R.;Dhevalapally, B.; Sakthivel, K.; Tanaka, F, Barbas, C.F. Tetrahedron Lett. 2002, 3817-3820
Diels Alder Reactions
A New Amine Catalyst
O
H
NH
O
PhMe
Me
+N
H
NMe
Me
MeO
Ph
Condenstion to the imminium ion lowers LUMO and allows catalysis
O
H + Lewis Acid
O
H + RNH
R•HCl
O
HLA
NR
R
A LUMO-lowering strategy:a reduction in π-bond activation
Ahrendt, K.A.; Borths, C.J.; Macmillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243-4244.
Macmillan Diels-Alder Variation
R O
H
+20 mol% cat
23°C
CHO
X
R
X
endo adduct
CHOCHO
84%, 89% ee
Ph
90%, 83% eeCHO
Me
Me
75%, 90% eeexo:endo 1:5
CHO
OAc
72%, 85% eeexo:endo 1:11
CHO
82%,94% eeexo:endo 1:14
O
CHOMe
Ph
Ph75%,96% eeexo:endo 35:1
catalyst:NH
O
PhMe
Me
•HCl
Ahrendt, K.A.; Borths, C.J.; Macmillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243-4244.
SN2 Alkylation: With Proline
OHC IEtO2C CO2Et
(S)-Proline (10%)
NEt3, > 75%
OHC
EtO2CCO2Et
ca. 20% ee
OHC I
EtO2C
EtO2C
(S)-Proline (10%)
NEt3, > 75% EtO2C CO2Et
OHCca. 60% ee
Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450.
SN2 Alkylation Continued: Slight Catalyst Modification, Nice Improvement
General Scheme:
OHCY
XNH
MeCO2H
NEt3, - 30°C24h CHCl3
Y
OHC10 mol%
EtO2CEtO2C
OHC
BnO2CBnO2C
OHC OHC
TsN
OHC
EtO2CCO2Et
OHC
EtO2CCO2Et
92%, 95% ee 94%, 95% ee 94%, 96% ee
52%, 91% ee 70%, 86% ee
Vignola, N.; List, B. J. Amer. Chem. Soc. 2004, 126, 450-451.
Other Applications: Oxidations and Reductive Cleavage
(S)-Proline (10 mol%)Cu(OAc)2 (5 mol%)
PhCO3t-Bu, EtCO2H16h
O
OMe
39%, 61% ee
Levina, A.; Muzart, J.; Tetrahedron: Asymmetry 1995, 6, 147-156.
MeO (S)-Proline
ZrCl4, NaBH4, THFr.t., 3h
MeOH
rac 60%, 44%ee
Laxmi, Y.R.S.; Iyengar, D.S.; Synth. Commun. 1997, 27, 1731-1736
Conclusions
Proline is a versatile organic catalyst capable of promoting a variety of useful transformations including many which are enantioselective
Both enantiomers of proline are available which allows some flexibility
Catalyst: inexpensive, commercially available, non-toxic(Green Chemistry), recoverable
Many of the transformations discussed can be run at room temperature, even with wet solvents.Generally they are operationally simple processes.
Conditions are however specific per transformation(solvent, time, catalyst loading)