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PROLINE CATALYZED ALDOL, MANNICH,PROLINE CATALYZED ALDOL, MANNICH, AND MICHAEL REACTIONS: AND MICHAEL REACTIONS:
APPLICATION OF ASYMMETRIC ORGANOCATALYSISAPPLICATION OF ASYMMETRIC ORGANOCATALYSIS
SANJIT SANYALDEPARTMENT OF CHEMISTRYMICHIGAN STATE UNIVERSITY
JANUARY 19, 2005
What is What is Organocatalysis?
“ A field of chemistry that pays my mortgage and has gotten me many free dinners.” - David W. C. Macmillan
What is What is Organocatalysis?
“A catalysis field wherein small organic molecules efficiently and selectively catalyze organic transformations.” - David W. C. Macmillan
“Organocatalysis is the catalysis of a reaction with an organic small molecule. By accepted convention, organic small molecule means a molecule without a metal, and not a macromolecule like protein, nucleic acid, or polymer.” - K. N. Houk
“Catalytic reactions mediated by small organic molecule in absence of metals or metal ions.” - Carlos F. Barbas, III
Organocatalysts
NFe
RR
RRR
R12N
Chiral DMAP (Gregory C. Fu)
BOCHNO
HN
O
NH O
HN
O
NH O
HN
O
NH O
HN
Oi-Pr
i-PrOMe
Me Ot-Bu
Ph Met-BuO
MeMeN N
N
NMe
Trt
Peptide-Based Catalyst (Scott J. Miller)
(S)-2-methoxy-methyl -pyrrolidin (SMP)
NH
OMe
5,5-dimethyl thiazoli-dinium-4-carboxylate (DTMC)
NH
S
NH
L-proline
CO2H
acetylquinineN
NHAcO
OMe
N
NH
(-)-cinchonidinea cinchona alkaloid
HO
H2N
O
OH
(S)-phenylalanine
N
ON
Br
H
chiral quaternary ammonium salt
fructose-derived chiral-ketone
O
OO
O
O
O
Classification of Classification of Organocatalysts
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
Type-I : Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.
OO
O
3 mol % L-prolineDMF, 20 ºC, 20 h 100%
O
O OH1 2
93% ee
Type-II : Organic molecules that form reactive intermediates. The chiral catalyst is consumed in the reaction and requires regeneration in parallel catalytic cycle.
Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807–8810.
O
OO
O
O
O
30% H2O2 (3 equiv.) CH3CN-K2CO33 4
30 mol %R2
R1 R3
R2
R1 R3
O
Classification of Classification of Organocatalysts
Type-III : Phase-transfer reactions. The chiral catalyst forms a host-guest complex with the substrate and shuttles between the standard organic solvent and a second phase.
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–12415.
Catalytic Enantioselective Enolate Alkylation :
NPh
Ph OtBu
OEtI N
Ph
Ph OtBu
O
H Et
Catalyst (10 mol %) CsOH•H2OCH2Cl2, -60 ºC, 30 h
5 6
N
ON
Br
H
Chiral quaternary ammonium salt
Type-IV : Molecular-cavity-accelerated asymmetric transformations in which the catalyst may select between competing substrates, depending on size and structure criteria.
HO
NHN
OHO
OH
O
PolymerSellergren, B.; Karmalkar, R. N.; Shea, K. J. J. Org. Chem. 2000, 65, 4009–4027.
O O
BOCHN NO2 1. Polymer
2. Nu
O
BOCHN Nu OH
NO27 8
OH
Type-IType-I Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.
Background Information
Direct Catalytic Asymmetric Aldol Reaction
Direct Catalytic Asymmetric Mannich Reaction
Direct Catalytic Asymmetric Michael Reaction
Background InformationBackground Information
Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7–23.
N
NH
(-)-CinchonidineA cinchona alkaloid
HOCHO1. HCN, Catalyst, CHCl3, rt, 24 h
2. 4N H2SO4, 8.7%COOH
OH
8.9% ee9 (-)-10
Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-29.
AcetylquinineN
NHAcO
OMe
Catalyst
1 mol % Catalyst, toluene
110 ºC, 90%C O
Ph
MeMeOH MeO Me
O
Ph
74% ee (R)
11 12
Background InformationBackground Information
Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 496–497.
Hajos-Parrish-Eder-Sauer-Wiechert Reaction
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
NH
Catalyst
L-proline
CO2H
NH
Catalyst
L-proline
CO2H47 mol % catalyst, 1N HClO4
CH3CN, 80 ºC, 25 h 83%
O
O
Me
O O
O
71% ee13 1514
OO
O
3 mol % catalystDMF, 20 ºC, 20 h 100%
O
O OH
p -TsOHPhH, 15 min 99%
O
O
1695% ee
1 293% ee
Why Why ProlineProline??
Proline is an optically active pyrrolidine derivative.
OO
O O
O OH1 (±)-2
NH
DMF, rt
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.
H2N
pyrrolidinium camphorsulphonic acid
O3S O NH
O
O H
L–proline
Asymmetric carbon is in the same molecule next to the functional groups.
Why Why ProlineProline??
The isoelectric point of proline is at pH 6.30.
The optically active reagent should attach itself at more than one point to a symmetrical compound. (Ogstone’s hypothesis†)
NH
O
O HL–proline O
N O
OOH
‡
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.† Ogstone, A. G. Nature. 1958, 181, 1462–1465.
Why Why ProlineProline??
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
OO
O O
O OH1 2
Solvent, rt
pyrrolidine derivatives
2-(S)-trans-4-hydroxyproline
(±)-2-piperidinecarboxylic acid
(S)-(+)-prolinol
12.1%73% ee
59%14% ee
No Reaction
(S)-proline ethyl ester N-methylproline
traceRacemic
48%Racemic
100%93% ee
NH
L-proline
CO2H
NMe
CO2H
NH
HO
NH
OHHO
O
HN
HO
O NH
CO2Et
(S)-azetidine-2-carboxylic acid
51% 64% ee
HN O
OH
37%19% ee
(S)–phenylalanineH2N
O
OH
How How Proline Proline WorksWorks
Some passive or dynamic interaction is necessary to translate the chiral information via the organization of the transition state for the organocatalyzed enantioselective transformation.
Hydrophobic, Van der Waals, and electrostatic interactions can be considered as passive interactions.
Dynamic binding refers to interactions between catalysts and substrates at the reaction centers, e.g. hydrogen bonding.
OO
NHO2C
Enamine IntermediateO
N OH
OO
B
Enaminium-catalyzed mechanism
‡
OH
HON
O
HO
O
Carbinolamine Intermediate
O
NO H
O H
OH O
ANucleophilic substitution mechanism
‡
How How Proline Proline WorksWorks
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
OO
N
Enamine Intermediate
OO
O CO2HNH
CO2H
O
18O
-H2O16
O
N
CO2H2O18
(exs.)O
18ONH
CO2H
-H2O16
OHOH
RR1
OH , R2NH
-R2NH, H3OR
R1
NR2 H , R2NH
-R2NH, H3OR
R1
NR2
R2CHO-R2CHO
RR1
NR2
R2
O
RR1
NR2
R2
OHH , R2NH
-R2NH, H3O
How How Proline Proline WorksWorks
Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353–2357.
OO
NHO2C
Enamine Intermediate O
N OO
OH
NH
O OH‡
CDual proline enaminium-catalyzed mechanism
Nonlinear Effect Study in the Hajos-Parrish Reaction by Agami & et. al.
% ee of Ketol–A
% ee of proline
O
O OHKetol-A
How How Proline Proline WorksWorks
Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558–569 & references cited therein.
O
N O
OO H
‡
D
Carboxylic acid-catalyzed enamine mechanism
OO
NHO2C
Enamine Intermediate
0 Kcal/mol
O
NO H
O H
OH O
ANucleophilic substitution mechanism
‡
37.9 Kcal/mol
O
N OH
OO
B
Enaminium-catalyzed mechanism
‡
30.5 Kcal/mol
O
N OO
OH
NH
O OH‡
CDual proline enaminium-catalyzed mechanism
30.5 Kcal/mol
Linh, H.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16–17.
How How Proline Proline WorksWorks
% ee of 3
% ee of proline
Absence of Nonlinear Effect in Hajos-Parrish-Eder-Sauer-Wiechert Reaction: (Observed by K. N. Houk and coworkers)
OO
O
(S)-Proline
O
O
O
O
31 2
n a (n = 1)b (n = 2)
-H2O
nOH n
% ee of 16
% ee of proline
How How Proline Proline WorksWorks
Nonlinear Effect Study by Agami & et. al.
% ee of Ketol–A
% ee of proline
Nonlinear Effect Study by K. N. Houk & et. al.
O
N O
OO H
‡
D
Carboxylic acid-catalyzed enamine mechanism
O
N OO
OH
NH
O OH‡
CDual proline enaminium-catalyzed mechanism
Linh, H.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16–17.Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353–2357.
How How Proline Proline WorksWorks
O18–incorporation study by Benzamin List and et. al.
O
N O
OO H
‡
D
Carboxylic acid-catalyzed enamine mechanism
O
NO H
O H
OH O
ANucleophilic substitution mechanism
‡
List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. 2004, 101, 5839–5842.
B C D
O(S)-proline(25 mol %)
3 vol % H2O18 in DMSO, Ar, 4 d
18O 18O
O
O
O
OH
O
NCO2H
O
A (0.1 M) B, 40% C, 50% D, 10%
Type-IType-I
Background Information Direct Catalytic Asymmetric Aldol Reaction
Direct Catalytic Asymmetric Mannich Reaction
Direct Catalytic Asymmetric Michael Reaction
Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.
List, B.; Lerner, R. A.; Barbas III, C. F. Org. Lett. 1999, 1, 59–61.
Aldol Aldol ReactionReaction
Ab 38C2 : 94%L-proline : 83%
O
OO
O
O
15Ab38C2: 96% eeL-proline: 71% ee
List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
OH
NO2
O
20 vol % NO2
ONH
CO2H
30 mol %
DMSO, rt, 4 h68%
OH
1876% ee
Ab 38C2, 90%
>90% ee
OH
NO2
O
20 vol % NO2
O OH
17
Aldol Aldol ReactionReaction
List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
1
2
3
4
5
< 10
< 10
55
< 10
< 10
n. d.a
n. d.
40
n. d.
n. d.
(L)-His, (L)-Val(L)-Tyr, (L)-Phe
NH
CO2H
NH
CO2H
NH
CONH2
NHCO2H
Yield% %eeEntry Catalyst Yield% %eeEntry Catalyst
6
7
8
9
10
S
NH
CO2H
NH
CO2H
NH
HO CO2H
NH
CO2HAcO
NH
CO2HHO
67
68
85
>50
70
73
76
78
62b
74
aNot determinedbOpposite enantiomer
OH
NO2
O
20 vol % NO2
OCatalyst (30 mol %)
DMSO, rt,
OH
18
Aldol Aldol ReactionReaction
Product Yield%
68
62
74
94
54
%ee
76
60
65
69
77
NO2
O OH
O OH
O OH
Br
O OH Cl
O OH
O
ArH
O
20 vol %Ar
OCatalyst (30 mol %)
DMSO, rt,
OH
List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
Proposed Enamine Mechanism
List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
Aldol Aldol ReactionReaction
HN
OHO HO
N
OHO HHO
- HO NO
HOH
NO
HOH
N H
H
R O H
re-facial attack
RCHON
O
OH
R
OH
NO
OHOH
R
OH
HHN
OHO H
R
OOH
OO
N H
R
H O H
si-facial attack
OO
List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–574.
Aldol Aldol ReactionReaction
20 vol%
(L)-proline 30 mol %
DMSO, rt, 2-96 h
O
H
O
R R
OHO
19
81
Entry R Yield% %ee
1 CH2R1 <2 –
2 i-Pr 97 96
3 t-Bu >99
4 p-O2NPh 68 76
HR1
OH , R2NH
-R2NH, H3OH
R1
NR2 H , R2NH
-R2NH, H3OH
R1
NR2
R1CH2CHO-R1CH2CHO
HR1
NR2 O
HR1
NR2 OHH , R2NH
-R2NH, H3O R1R1
Aldol Reactions of α-Unsubstituted Aldehydes
List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–574.
Aldol Aldol ReactionReaction
R = Yield% of 21 (22) %ee solventEntry
1
2
3
4
5
31 (38)29
6770
AcetoneCHCl3
35 (40) 73 Acetone
34 (35) 72 CHCl3
34 (42)23 (46)
7361
AcetoneCHCl3
22 (50) 36 CHCl3
20 vol%
(L)-proline10-20 mol %
rt, 3-7 d
O
H R
O
R
OHO
R
O
21 22
Enone 29 is Formed Via Mannich Reaction-Elimination Sequence
Aldol Aldol ReactionReaction
List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–574.
H R
O
R H
N CO2
N CO2H
R
OO
R
O
R
OH
+ Proline
-H2O
+ Acetone
- Proline
+ Acetone
Proline
21
22
O OH O TBS
21d
1. TBSCl, Imidazole2. KHMDS
N
N
Cl
TfTf
57%
LiCl, THFPd(PPh3)4 (2mol%) 95%
SnBu3
OTBS
TBAF, THF 90%
OTf
23
24
L-proline (20 mol %)
rt, 3 d20 vol%
O
H
O
Kg scale
OH
25(S)-Ispenol
Aldol Aldol ReactionReaction
Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem. Soc. 1994, 116, 8422–8423.
HDERA O
OH
[DERA = 2-deoxyribose-5-phosphate aldolase]
OHOH DERA OH OH
2,4,6-trideoxyhexose
O
H
O
H
O
O O
26
Cordova, A.; Notz, W.; Barbas III, C. F. J. Org. Chem. 2002, 67, 301–303.
NO O
H
H
MeHHO
re-facial attack
‡
L-proline, THF
0 ºC, 5 h(S)
90% ee
Me H
O O
H
OH
273 equiv. 10%
Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799.
H Me 10 mol % (L)-proline
DMF, 4 ºC 80%
HMe
OHMe
2 equiv. 4:1 anti:syn, 99% ee
O O
28
Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799.
Aldol Aldol ReactionReaction
NO
H
H
R2HHO
anti
‡H
R1O
NO
H
HH
syn
HR1
OO
H
R2
‡
Entry R1 R2 Product Yielda% anti:syn %ee
a combined yields of diastereomers
1 Me i-Bu 88 3:1 97
2 Me c-C6H11 87 14:1 99
3 Me Ph 81 3:1 99
4 Bn i-Pr 75 19:1 91
H
O
Me
OH
H
O
Me
OH
H
O
Me
OH
H
O
Bn
OH
10 mol % L-Proilne
DMF, 4 ºC, 11-26 hH R1H R2
OO
H R2
O
R1
OH
29
3 steps, 22% overall yield Pihko, P. M.; Erikkila, A. Tetrahedron Lett. 2003, 44, 7607–7609.
Aldol Aldol ReactionReaction
O
H
O
H
L-proline (10 mol%) DMF, 40 h, 5 ºC
H
O
with crudeTBSOTf, 2,6-lutidine Et2O/CH2Cl2 (1:1) 10 ºC, 2.5 h 61% (two steps)
TBSO
OEt
BF3•Et2O, CH2Cl2 -78 ºC, 65%
EtO
O OH48% HF, H2O, MeCN ( 1:2:17)
4.5 h, rt, 55%
O
O
HO
(-)-Prelactone B
OTBS
OTBS
3031
3233
O
O
HOEtO
O OH OTBSTBSO
OEt
O
H
O
H
Lactonization
(-)-Prelactone B
Aldehyde-aldehyde crossed-aldol
Mukaiyama aldol33
Aldol Aldol ReactionReactionA recent synthesis involves 8 steps, 33% overall yield
Dias, C. L.; Steil, L. J.; Vasconcelos, V. A. Tetrahedron: Asymmetry. 2004, 15, 147–150.
MeH
O
NO
OMe
Bn
O1. MgCl2, NaSbF6
Et3N, TMSCl, rt2. MeOH, CF3CO2H 77%
MeXc
O
Me
OH
dr 15:1
Xc = NO
O
Bn
H2, Pd/C
EtOAc, 99%Me
MeXc
O
Me
OH
1. TBSOTf, THF 2,6-Lutidine, 0 ºC
2. LiBH4, H2O Et2O, 79% (2 steps)
Me
Me
OH
Me
TBSOSwern
-78 ºC, 95%Me
Me
O
Me
TBSO
H
Me
Me Me
TBSO O
OtBu
OHOTMS
OtBu
BF3.OEt2 CH2Cl2-78 ºC, 75%
HCl/THF/H2O
rt, 48 h, 77%
O
MeMe
Me
O
OH
(+)–Prelactone B
95:5aldehyde re-face attackFelkin/1,3-anti
34
33
an enantioselective aldol union of α-oxyaldehyde substrates (Aldol 1). a diastereoselective aldol coupling between tri-oxy substituted butanals and an α−oxyaldehyde enolate (Aldol 2).
Northrup, A. B.; Mangion, F. H.; Macmillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152-2154.
Aldol Aldol ReactionReaction
Aldol 1 Aldol 2H
OX
O
35
H
OOX
H
O
OX
OH
OX
H
OOY O
OYXOOH
XO OH
36 37
Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C. F. J. Am. Chem. Soc. 2001, 123, 5260–5267.
L-proline (20 mol %)
DMSO, rt 62%
anti:syn = >20:1, 99% ee
OH
O
H
O O OH
OH38 39 40
R Solvent Yield% anti:syn ee (%)
Ac DMF 0 - -Bn
PMB
MOM
TBDPS
TIPS
TBS
DMF 73 4:1 98
DMF 64 4:1 97
DMF 42 4:1 96
DMF/Dioxane 61 9:1 96a
DMSO 92 4:1 95
Dioxane 62 3:1 88a
aUsing 20 mol% catalystNorthrup, A. B.; Mangion, F. H.; Macmillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152–2154.
Aldol Aldol ReactionReactionStep 1: Organocatalytic Enantioselective Aldehyde Dimerization
H
OOR H
O OH
OR
10 mol % L-prolinesolvent, rt, 24-48 h
OR
Aldol Aldol ReactionReactionStep 2: Lewis Acid (LA) Mediated Mukaiyama Aldol–Carbohydrate Cyclization
Northrup, A. B.; Macmillan, D. W. C. Science 2004, 305, 1752–1755.
H
O OH
H OAcOTMS
OTIPSTIPSO
MgBr2•Et2O
Et2O, -20 to 4 ºC
O
TIPSO
OHTIPSO
GlucoseOH
OAc
H
O OH
H OAcOTMS
OTIPSTIPSO
MgBr2•Et2O
CH2Cl2, -20 to 4 ºC
O
TIPSO
TIPSO
MannoseOH
OAc
OH
H
O OH
H OAcOTMS
OTIPSTIPSO
TiCl4CH2Cl2, -78 to -40 ºC
O
TIPSO
TIPSO
AlloseOH
OAc
OH
79% yield 10:1 dr, 95% ee
87% yield> 19:1 dr, 95% ee
97% yield> 19:1 dr, 95% ee
42
42
42
43
43
43
44
45
46
H
O OH
OXOXH OY
OTMS
H
O
OXOY
OH OH
OX
TMS O
XOOH
OY
OHXO
oxocarbenium
LA
4 possible carbohydrates36 41 37
Type-IType-I Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.
Background Information Direct Catalytic Asymmetric Aldol Reaction
Direct Catalytic Asymmetric Mannich Reaction
Direct Catalytic Asymmetric Michael Reaction
Mannich Mannich ReactionReaction
Two important requirements : The nucleophilic addition of the proline enamine must be faster to an imine than to an aldehyde.
The imine formation with a primary amine must be faster than the competitive aldol reaction.
R1
O
H R2
O
R3NH2
R1
O
H R2
NR3
Direct
Indirect
Preformedenol equivalent
Preformed imine
R1 R2
O NR3
List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337.
R
O OH
OH R
O
H R
NR1
R1 R
O NR1kaldol
keqR1NH2
-H2O
kMannich
O
Mannich Mannich ReactionReaction
Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 307–310.
Ph OCH3Et2N Ph OCH3
NEt2 (R)-ALB (30 mol %)La(OTf)3.nH2O (30 mo l%)
toluene, 50 ºC, 18 h, MS 3Å 65%
40% ee
O O
47
OO
OOAl
Li
(R)-AlLibis(binapthoxide) ((R)-ALB)
48
List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337.
L-proline (35 mol %)
DMSO, rt, 12 h 50%
94% ee
O
NO2
CHO NH2
OMe
O HN
OMe
48 NO2
syn:anti = 17:1, 65% ee
L-proline (35 mol %)
DMSO, rt, 12 h 57%
ONH2
OMe
O HN
49OH
H
O
OMe
OH
Mannich Mannich ReactionReaction
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827–833.
NO
HH
HX
N
H
R ArO
N N
HRAr
HHO
H
O
NCO2H
X
H
R
ON
H
H
N
MeO
X
H O
R
O
R
syn
(E)-Imine Small (planar) R gives high ee
Enamine si Imine si
N
H
X
H O
O
H Large Rgives high ee
Enamine siAldehyde re
anti
O NHAr
R
O OH
O
Mannich Mannich ReactionReaction
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
R = Yield % dr %ee
p-NO2C6H4 92 20:1 >99
C6H5 83 9:1 93
P-MeOC6H4 88 3:1 61
10 vol%
L-proline (20 mol %)
DMSO, rt, 3-24 h
ONH2
OMe
O HN
OHH
O
R R
OMe
OH
O
OH
RNH2(S)-Proline
Sharpless AA
H
O
R
O
R
O
ROH
NHR
50
Mannich Mannich ReactionReaction
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
OHPh
NHPMPCl3CO OCCl3
O NPMP
Ph
(PMP = paramethoxyphenyl)
76% O NBOC
Ph1. CAN2. BOC2O
80%
CF3CO3H
O NBOCO
Ph
87%
NaBH4, EtOHHO Ph
NHBOC 98%
OO O
O
O
O
O
O
51 52
5354
Synthesis of α-amino acid derivative from the syn-1,2-amino alcohol: an oxydative α−hydroxy ketone(glycol-type) cleavage. an oxidative removal of the aromatic nitrogen substituent.
OHR
HNOxidation
HO2C R
PMPO NH2
Mannich Mannich ReactionReaction
Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 1842–1843.
CO2Et
NHPMP L-proline(20 mol %)
DMSO, 2 h, rt 82%
95% ee
O
H CO2Et
N
55 56
OPMP
(S)
L-proline (5 mol %)
[bmim]BF4, rt, 48 h 30%OH
HOH
OH
>99% ee
OO O
58
Chowdari, N. S.; Ramachary, D. B.; Barbas III, C. F. Synlett 2003, 1906–1909.
N N BF4-
[bmim = 1-butyl-3-methylimidazolium]
[bmim]BF4 =
55
L-proline (5 mol %)
[bmim]BF4, rt, 30 min 99%
CO2Et
NHPMP
>99% ee
O O
57
H CO2Et
NPMP
For an excellent review on room temperature ionic liquids in organic synthesis, seeWelton, T. Chem. Rev. 1999, 99, 2071–2084.
Mannich Mannich ReactionReaction
H H CO2Et
NHPMP L-proline (20 mol %)
DMSO, 8 h, rt 80%iPr iPr
syn: anti = 10:1, 87% ee2 equiv.
O O
59
H CO2Et
NPMP
55
Corodova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 1866–1867.
Catalyst Time(h) Yield% syn:anti %eesyn (anti)
(L)-Proline 3 88 32:1 >99 (31)
SMP 22 40 <1:10 - - (76)
NH
CO2H
L-proline
(S)(S)
H H CO2Et
NHPMP Catalyst (20 mol %)
DMSO, rtnPent nPent
O O
62
H CO2Et
NPMP
55
(S)-2-methoxy-methyl -pyrrolidin(SMP)
NH
OMe
H CO2Et
NHPMP
iPr
1. NaClO2, KH2PO4, 2-methyl-2-butene, t-BuOH/H2O
2. CH2N2, Et2O 89%, two steps
MeO CO2Et
NHPMP
iPrN
PMP
HHCO2Et
iPr LHMDS, THF, -20 ºC
96%
Synthesis of Novel β-lactams :
O O
O
59 60 61
Mannich Mannich ReactionReaction
Corodova,A.; Barbas, C. F. Tetrahedron Lett. 2002, 7749–7752.
N
CO2EtH
PMP NO
OH
H
R
transition state for Proline-catalyzed Mannich reaction
N
HR
CO2Et
NOMe
H
transition state for SMP-catalyzed Mannich reaction
PMP
Chowdari, N.S.; Suri. J. T.; Barbas III, C. F. Org. Lett. 2004, 2507–2510.
L-proline(30 mol %)
DMSO, rt, 6 h
H CO2Et
HNPMP
98% ee
NaClO2NaH2PO4
rt, 2 h 90%
1. NaClO2 NaH2PO4 2 h, rt2. NaOH3. HCl5 min, 80%
HO CO2Et
HNPMP
NPMP
CO2Et
OO
O
O63
64
65
H CO2Et
NPMP
55 94%
H
Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.
Type-IType-I
Background Information Direct Catalytic Asymmetric Aldol Reaction
Direct Catalytic Asymmetric Mannich Reaction
Direct Catalytic Asymmetric Michael Reaction
Michael ReactionMichael Reaction
Role of chiral amine in previous catalytic asymmetric Michael reaction: activate the Michael acceptor via formation of an iminium species (I) act as a base forming a complex with enolate to react with the acceptor (II) activation of ketone donors through formation of an enamine intermediate (III)
Betancort, J. M.; Sakthivel, R. T.; Barbas, C. F. Tetrahedron Lett. 2001, 42, 4441–4444.
O
NuMichael addition
O
Nu
Nu = active methylene center, e.g., malonic acid ester β-keto esters, nitroalkanes, etc.
NR2R'
Nu
I
O
R' EWG
II
NR2
R' EWG
III
:HNR3
Michael ReactionMichael Reaction
Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M. Tetrahedron. 1997, 32, 11223-11236.
ONO2
NH
CO2Rb
5 mol %
24 h, CHCl3, rt 81%
O
NO2
59 % ee65
(R)
Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975–2978.
ONO2
NH
CO2H
5 mol %
additive, CHCl3, rt 88%
O
NO2
(R)
93 % ee
HN
NH
trans-2,5-dimethylpiperazine
additive =
66
Michael ReactionMichael Reaction
Entry Product Yield dr (syn: anti) eea
1
2
3
4
5
6
97% – 7%
10%3:185%
95% 20:1 23%
n. d.bn. d.
n. d. n. d.
87%
92% 20:1 10%
85%
List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–2425. aee of syn diastereomer
bnot determined
ONO2
Ph
ONO2
Ph
ONO2
Ph
ONO2
iPr
ONO2
Ph
SO NO2
O
R R1
20 vol%
R3 NO2
R2
L-proline (15 mol %)
DMSO, rt, 2-24 h
O
R R1
R2
R3
NO2
67 68
Michael ReactionMichael Reaction
a 0.5 mL ofSolvent/mmol of nitrostyerene
Enders, D.; Seki, A. Synlett 2001, 26–29.
EntryProline (equiv.) Solvent Conditions Yield%a %ee
1
2
3
4
5
6
7
8
9
10
11
0.50.5
0.5
0.5
0.2
0.5
0.5
0.5
1.5
0.5
0.5
DMSOMeCN
DMF
DMSO
DMSO
MeOH
EtOH
i-PrOH
MeOH
MeOH
MeOHa
rt, 1.5 drt, 4 d
rt, 7 d
15 ºC, 2 d
rt, 3 d
rt, 3 d
rt, 3 d
rt, 3 d
rt, 3 d
rt, 3 d
rt, 3 d
606
46
62
57
70
32
39
77
68
70
5460
47
5458
71
73
66
73
75
76
O
Ph NO2(L)-proline O
NO2Ph
69
Michael ReactionMichael Reaction
Enders, D.; Seki, A. Synlett 2001, 26–29.
acombined yield of both diastereomers, b5mL solvent/mmol of 2, c0.5mL solvent/mmol of 2
R1
R2
O
Ph NO2 (0.2–1.5 equiv.)
MeOH, rtR1
ONO2
R2
Ph
70 71 72
L-proline
EntryProline (equiv.) Time (d) Yield%a %eede (%)72
1
2
3
4
5
6
syn 0.2b 4 74 88 76
syn 1.5c 3 81 90 73
(S,R) 0.2b 8 44 80 76
(S,R) 1.5c 3 83 80 72
(S,R) 0.2b 4 79 94 57
(S,R) 1.5c 2 99 97 47
R1 R2
Et Me
Et Me
Ph(CH2)2 Me
Ph(CH2)2 Me
–(CH2)4–
–(CH2)4–
Michael ReactionMichael Reaction
Proposed transition state
Enders, D.; Seki, A. Synlett 2001, 26–29.
NO
OR1
R2
N O
O
H
Betancort, J. M.; Barbas III, C. F. Org. Lett., 2001, 3, 3737–3740.
NH N
OCatalyst
R R' time yield% dr(syn/anti)
%ee(syn)
H Ph 3 h 85 90/10 56
iPrCF3
3 d 77 98/2 78
R CHO NO2R' Catalyst 20 mol %
THF, rtOHC NO2
R'
R73
Michael ReactionMichael Reaction
Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611–3614.
NH
N
(R,R)Catalyst
H
O
NO2Ph
Catalyst (15 mol %)HCl (15 mol %)
CHCl3, –25 ºC, 2 d 71%
NO2
O
H
Ph
83% ee(syn: anti) = 95:5
74
Betancort, J. M.; Barbas III, C. F. Org. Lett. 2004, 6, 2527–2530.
NH
N
Catalyst
H
O
NO2Ph
Catalyst (0.3 equiv) TFA (0.3 equiv)
2-PrOH, 4 ºC, 48 h 87%
NO2
O
H
Ph
80% ee
NO2Ph
Catalyst (0.3 equiv) TFA (0.3 equiv)
2-PrOH, 4 ºC, 24 h 93%
NO2
O
H
Ph
91% ee
O
H
75
76
ConclusionConclusion
Proline is nontoxic, inexpensive (1gm/$5), and readily available in both enantiomeric forms.
Eliminating the protection-deprotection and oxidation state adjustment steps, proline-catalyzed aldol reactions can shorten the path of total synthesis.
Products from proline-catalyzed Mannich reactions are useful in terms of both biological and chemical aspects and are complements of Sharpless-AA.
The reactions do not require inert conditions and are run at room temperature or at lower temperatures.
Organocatalysis is emerging as a complement to metal catalysis.
“It constitutes the tip of the iceberg of a novel catalytic principle, of which the entire scope still remains to be fully uncovered. ” – Benjamin List