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 Bharadwaj October 26, 2004
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Proline As a Catalyst in Organic Synthesis · Why Proline is a Good Catalyst? Possible Reasons Proline is the only natural amino acid with a secondary amine functionality, which raises
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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. 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.