PROLINE CATALYZED ALDOL, MANNICH,

AND MICHAEL REACTIONS:

APPLICATION OF ASYMMETRIC ORGANOCATALYSIS

JANUARY 19, 2005

SANJIT SANYAL
DEPARTMENT OF CHEMISTRY
MICHIGAN STATE UNIVERSITY
 What is Organocatalysis?

 “ A field of chemistry that pays my mortgage and

has gotten me many free dinners.”
- David W. C. Macmillan
 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
Me
N
Ph t-BuO Me
N O i-Pr O O O R12N
H H H H
N N N N
BOCHN N N N OMe
H H H N
O O O i-Pr O
Me Ot-Bu Me R Fe R
N Trt Me
N R R
R
Peptide-Based Catalyst (Scott J. Miller) Chiral DMAP (Gregory C. Fu)
Br

H N O
O O
H N N
AcO O
O O
OMe O
N CO2H

N H
chiral quaternary fructose-derived
acetylquinine L-proline ammonium salt chiral-ketone

H N
HO
S
OMe
O N
N H
H N
H2N OH 5,5-dimethyl thiazoli-
(S)-2-methoxy-methyl dinium-4-carboxylate (-)-cinchonidine
-pyrrolidin (SMP) (S)-phenylalanine (DTMC) a cinchona alkaloid
 Classification of Organocatalysts
 Type-I : Activation of the reaction based on the nucleophilic/electrophilic properties
of the catalyst.
O O
O 3 mol % L-proline
O
DMF, 20 ºC, 20 h O
100% OH
1 2
93% ee

Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.

 Type-II : Organic molecules that form reactive intermediates. The chiral catalyst is
consumed in the reaction and requires regeneration in parallel catalytic cycle.

O
O O

O O
O
R2 30 mol % R2 O

R1 R3 30% H2O2 (3 equiv.) R1 R3

CH3CN-K2CO3
3 4

Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807–8810.

 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.
Catalytic Enantioselective Enolate Alkylation : Br

O Catalyst (10 mol %) O H

Ph Ph N
CsOH•H2O
N EtI N N
OtBu CH2Cl2, -60 ºC, 30 h OtBu
Ph Ph Et O
H
5 6

Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–12415. 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.
O

O OH O
O O
H
Nu OH N
BOCHN NO2 BOCHN HN
1. Polymer

2. Nu HO
O
H
NO2 O
7 8
Polymer
Sellergren, B.; Karmalkar, R. N.; Shea, K. J. J. Org. Chem. 2000, 65, 4009–4027.
 Type-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 Information

OH
1. HCN, Catalyst, H
CHO N
CHCl3, rt, 24 h COOH HO
2. 4N H2SO4, 8.7%
9 (-)-10
8.9% ee N
(-)-Cinchonidine
A cinchona alkaloid

Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7–23.

Catalyst

O
Ph 1 mol % Catalyst, toluene Me
C O MeOH MeO H
110 ºC, 90% N
Me Ph AcO
11 12
OMe
74% ee (R)

N
Acetylquinine

Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-29.

 Background Information
Hajos-Parrish-Eder-Sauer-Wiechert Reaction

Catalyst
O O
Me 47 mol % catalyst, 1N HClO4 CO2H
N
CH3CN, 80 ºC, 25 h O H
O O
13 83% 15
14 L-proline
71% ee

Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 496–497.

Catalyst
O O O
O 3 mol % catalyst p -TsOH
N CO2H
O PhH, 15 min
DMF, 20 ºC, 20 h O O
100% OH 99% H

1 2 16 L-proline
93% ee 95% ee

Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.

 Why Proline?

 Proline is an optically active pyrrolidine derivative.

O N O
O H
O
DMF, rt O
OH
1 (±)-2

 Asymmetric carbon is in the same molecule next to the functional groups.

O
H2N O N
O3S O H
H
pyrrolidinium camphorsulphonic acid L–proline

Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.

 Why Proline?
 The optically active reagent should attach itself at more than one point to a
symmetrical compound. (Ogstone’s hypothesis†)
O ‡
OH
O
N
N O
O H
H
L–proline O

 The isoelectric point of proline is at pH 6.30.

Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.

† Ogstone, A. G. Nature. 1958, 181, 1462–1465.
 Why Proline?
O O
O
pyrrolidine derivatives
O
Solvent, rt O
OH
1 2

H HO
N O
CO2Et
O HN N CO2H
N
OH H
Me
(S)-azetidine-2-carboxylic acid (±)-2-piperidinecarboxylic acid (S)-proline ethyl ester N-methylproline
51% 48% trace
64% ee No Reaction Racemic Racemic

O
HO O
OH N CO2H
HO N
N
H H H2N OH H

2-(S)-trans-4-hydroxyproline (S)-(+)-prolinol (S)–phenylalanine L-proline

12.1% 59% 37% 100%
73% ee 14% ee 19% ee 93% ee

Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.

 How Proline Works

 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.
 How Proline Works
OH
O O ‡
H H O
O
O N H
HO
H N O

O O

A
Carbinolamine Intermediate
Nucleophilic substitution
mechanism
‡

HO2C N NH
O O
O O
O
O
Enamine Intermediate B

Enaminium-catalyzed
mechanism

O N CO2H O
H2O18 O
N CO2H CO2
O O (exs.)
H
O O N 18O
-H2O16 OH
CO2H OH
Enamine Intermediate N
H
-H2O16

18O
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
 How Proline Works
Nonlinear Effect Study in the Hajos-Parrish Reaction by Agami & et. al.
O NR2 NR2
H , R2NH H , R2NH
R R R
% ee of
R1Ketol–A
-R2NH, H3O -R2NH, H3O
R1 R1

-R2CHO R2CHO
O

NR2 OH NR2 O
O H , R2NH
OH
R R2 R R2
Ketol-A -R2NH, H3O
R1 R1

% ee of proline

‡
O OH
H
HO2C N N
H
O O N O
O O

Enamine Intermediate C O
Dual proline enaminium-catalyzed
mechanism
Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353–2357.
 How Proline Works

‡
O
OH
HO2C N
N
O
O
O

D O
Enamine Intermediate
Carboxylic acid-catalyzed
enamine mechanism

0 Kcal/mol

‡ ‡
O OH O ‡
H H H O
O O
N N H
O NH H
O
O N
O O
O O
O
B C O A

Enaminium-catalyzed Dual proline enaminium-catalyzed Nucleophilic substitution

mechanism mechanism mechanism

30.5 Kcal/mol 30.5 Kcal/mol 37.9 Kcal/mol

Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558–569
& references cited therein.
 How Proline Works
Absence of Nonlinear Effect in Hajos-Parrish-Eder-Sauer-Wiechert Reaction:
(Observed by K. N. Houk and coworkers)
O O O
O -H2O
(S)-Proline
O
a (n = 1) O n O n
n
b (n = 2) OH
1 2 3

% ee of 3

% ee of proline
Linh, H.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16–17.
 How Proline Works
% ee of 16
% ee of Ketol–A

% ee of proline
% ee of proline
Nonlinear Effect Study Nonlinear Effect Study
by Agami & et. al. by K. N. Houk & et. al.
‡ ‡
O O
OH
H OH
N
H N
O
O N
O
O
D O
C O
Dual proline enaminium-catalyzed Carboxylic acid-catalyzed
mechanism enamine mechanism

Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353–2357.
Linh, H.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16–17.
 How Proline Works
O O O O
O (S)-proline
(25 mol %) CO2H
O
3 vol % H2O18 18O 18O N
in DMSO, Ar, 4 d OH
A (0.1 M) B, 40% C, 50% D, 10%

‡
O
OH
N
O

D O

Carboxylic acid-catalyzed
enamine mechanism

O ‡
H H O
O O N H

A
B C D
Nucleophilic substitution
mechanism O18–incorporation study by Benzamin List and et. al.

List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. 2004, 101, 5839–5842.
 Type-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

 Aldol Reaction
O O

O
O Ab 38C2 : 94% O
L-proline : 83% 15
Ab38C2: 96% ee
L-proline: 71% ee

List, B.; Lerner, R. A.; Barbas III, C. F. Org. Lett. 1999, 1, 59–61.

O O OH
O
H
20 vol % Ab 38C2, 90%
NO2 NO2
17
>90% ee

N CO2H
O H O OH
O
H 30 mol %

20 vol % NO2 DMSO, rt, 4 h

NO2
68% 18
76% ee

List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
 Aldol Reaction
O O OH
O
Catalyst (30 mol %)
H
20 vol % DMSO, rt,
NO2 NO2
18

Entry Catalyst Yield% %ee Entry Catalyst Yield% %ee

1 (L)-His, (L)-Val < 10 n. d.a 6 S

67 73
(L)-Tyr, (L)-Phe N CO2H
H

2 N CO2H < 10 n. d. 7 68 76
H N CO2H
H
3 CO2H 55 40
N NH
H
8 85 78
HO CO2H
4 CO2H < 10 n. d.
NH NH
9 HO CO2H >50 62b
5 < 10 n. d. NH
N CONH2 10 70 74
AcO CO2H
H

aNot determined
bOpposite enantiomer
List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
 Aldol Reaction
O O O OH
Catalyst (30 mol %)
H Ar Ar
20 vol % DMSO, rt,

Product Yield% %ee

O OH
68 76
NO2
O OH

62 60

O OH

74 65
Br

O OH Cl

94 69
O OH

54 77

List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
 Aldol Reaction
Proposed Enamine Mechanism

HN - HO
N N
H HO O
O HO HO H H
O O HO

R N N N
O H O
R O RCHO H
H H O
OH O HO
O H
re-facial attack

N H
H
H O H
R O O
R N HN
O R
HO H OH O
OH OH H si-facial attack
O O

List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
 Aldol Reaction
O O (L)-proline O OH
30 mol %
H R R
DMSO, rt, 2-96 h
20 vol% 19

Entry R Yield% %ee

1 CH2R1 <2 –

2 i-Pr 97 96

3 t-Bu 81 >99

4 p-O2NPh 68 76

O NR2 NR2
H , R2NH H , R2NH
H H H
R1 -R2NH, H3O -R2NH, H3O
R1 R1

-R1CH2CHO R1CH2CHO

NR2 OH NR2 O
H , R2NH
H H
-R2NH, H3O
R1 R1 R1 R1

List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–574.

 Aldol Reaction
Aldol Reactions of α-Unsubstituted Aldehydes

O O (L)-proline O OH O
10-20 mol %
H R R R
rt, 3-7 d
20 vol% 21 22

Entry R= Yield% of 21 (22) %ee solvent

31 (38) 67 Acetone
1 29 70 CHCl3

2 35 (40) 73 Acetone

3 34 (35) 72 CHCl3

34 (42) 73 Acetone
4 23 (46) 61 CHCl3

5 22 (50) 36 CHCl3

List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–574.

 Aldol Reaction
Enone 29 is Formed Via Mannich Reaction-Elimination Sequence
O CO2
N
+ Acetone + Proline
H R R H
Proline -H2O

O OH + Acetone
R
21

CO2H
O O N
- Proline
R R
22

TBS
O O O OH 1. TBSCl, Imidazole OTf O
L-proline (20 mol %) 2. KHMDS
H rt, 3 d
20 vol% Tf Tf 23
21d N
Kg scale
SnBu3
N LiCl, THF
Pd(PPh3)4
Cl (2mol%)
57% 95%

OH OTBS

TBAF, THF
25 90% 24
(S)-Ispenol
List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–574.
 Aldol Reaction
OH
O O OH O OH OH
DERA DERA O
H
O O OH
26
H H 2,4,6-trideoxyhexose
[DERA = 2-deoxyribose-5-phosphate aldolase]

Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem. Soc. 1994, 116, 8422–8423.
‡
N H
O L-proline, THF OH O Me
O H O O
Me H 0 ºC, 5 h H H
(S) H
3 equiv. 10% 27 re-facial attack
90% ee

Cordova, A.; Notz, W.; Barbas III, C. F. J. Org. Chem. 2002, 67, 301–303.

O O OH
Me 10 mol % (L)-proline Me
H H
DMF, 4 ºC
Me 28
80%
2 equiv. 4:1 anti:syn, 99% ee

Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799.

 Aldol Reaction
O O O OH
10 mol % L-Proilne
R1
H H R2 DMF, 4 ºC, 11-26 h H R2
R1
29
‡ ‡
H H
H
R1 N H R1 N H
R2 O
O H O O O HH O
H R2
H
anti syn
Entry R1 R2 Product Yielda% anti:syn %ee
O OH
1 Me i-Bu 88 3:1 97
H
Me
O OH
2 Me c-C6H11 87 14:1 99
H
Me
O OH
3 Me Ph 81 3:1 99
H
Me
O OH
4 Bn i-Pr 75 19:1 91
H
Bn

a combined yields of diastereomers

Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799.
 Aldol Reaction
Lactonization Aldehyde-aldehyde
crossed-aldol
O
O OH OTBS O O
O TBSO
EtO H H
HO OEt

33
(-)-Prelactone B Mukaiyama aldol

O O L-proline (10 mol%) O OTBS

DMF, 40 h, 5 ºC
H H H TBSO
with crude
TBSOTf, 2,6-lutidine
30 OEt
Et2O/CH2Cl2 (1:1) 31
10 ºC, 2.5 h
61% (two steps) BF3•Et2O, CH2Cl2
-78 ºC, 65%

O
48% HF, H2O, MeCN O OH OTBS
O
( 1:2:17)
EtO
HO 4.5 h, rt, 55%
32
33
(-)-Prelactone B

 3 steps, 22% overall yield

Pihko, P. M.; Erikkila, A. Tetrahedron Lett. 2003, 44, 7607–7609.
 Aldol Reaction
A recent synthesis involves 8 steps, 33% overall yield

O O
OH O OH O
O 1. MgCl2, NaSbF6 H2, Pd/C
H Me N Me
Xc Xc
Me Bn O Et3N, TMSCl, rt EtOAc, 99%
2. MeOH, CF3CO2H Me Me Me Me
34
77% dr 15:1
TBSO OH TBSO
1. TBSOTf, THF O
2,6-Lutidine, 0 ºC Me Swern Me
H
2. LiBH4, H2O Me Me -78 ºC, 95%
Me Me
Et2O, 79% (2 steps)

OTMS O
TBSO OH O
OtBu Me HCl/THF/H2O O
OtBu Me
BF3.OEt2 rt, 48 h, 77% OH
Me Me
CH2Cl2 Me Me
-78 ºC, 75% 95:5
aldehyde re-face attack 33
Felkin/1,3-anti (+)–Prelactone B

O
Xc = N
Bn O

Dias, C. L.; Steil, L. J.; Vasconcelos, V. A. Tetrahedron: Asymmetry. 2004, 15, 147–150.
 Aldol Reaction
O O
O O OH O OH
OX OY XO
H H
H H XO OY
Aldol 1 Aldol 2
OX OX OX OH
35 36 37

 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.

O L-proline O OH
O
(20 mol %)
H
DMSO, rt OH
OH
62%
38 39 40
anti:syn = >20:1, 99% ee

Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C. F. J. Am. Chem. Soc. 2001, 123, 5260–5267.
 Aldol Reaction
Step 1: Organocatalytic Enantioselective Aldehyde Dimerization

O O OH
10 mol % L-proline
OR OR
H solvent, rt, 24-48 h H
OR

R Solvent Yield% anti:syn ee (%)

Ac DMF 0 - -
Bn DMF 73 4:1 98

PMB DMF 64 4:1 97

MOM DMF 42 4:1 96

TBDPS DMF/Dioxane 61 9:1 96a

TIPS DMSO 92 4:1 95

TBS Dioxane 62 3:1 88a

aUsing 20 mol% catalyst

Northrup, A. B.; Mangion, F. H.; Macmillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152–2154.
 Aldol Reaction
Step 2: Lewis Acid (LA) Mediated Mukaiyama Aldol–Carbohydrate Cyclization
TMS O OH
O OH OTMS O OH OH XO
LA
OY
H H H XO OY
OX OX OY OX OX OH
36 41 37
oxocarbenium 4 possible carbohydrates

O OH O OH
OTMS TIPSO
MgBr2•Et2O 79% yield
H OAc 10:1 dr, 95% ee
H Et2O, -20 to 4 ºC TIPSO OAc
TIPSO OTIPS
OH
42 43 Glucose 44

O OH O OH
OTMS TIPSO 87% yield
MgBr2•Et2O
H OAc > 19:1 dr, 95% ee
H CH2Cl2, -20 to 4 ºC TIPSO OAc
TIPSO OTIPS
OH
42 43 Mannose 45

O OH O OH
OTMS TIPSO
TiCl4 97% yield
H OAc
H CH2Cl2, -78 to -40 ºC TIPSO OAc > 19:1 dr, 95% ee
TIPSO OTIPS
OH
42 43 Allose 46
Northrup, A. B.; Macmillan, D. W. C. Science 2004, 305, 1752–1755.
 Type-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 Reaction
O O
Direct
R1 H R2 R3NH2
O NR3

R1 R2
O NR3
Indirect
R1 H R2

Preformed Preformed
enol equivalent imine

O OH O keq NR1 O NR1

kaldol R1NH2 kMannich
R H R H R R1 R
O -H2O O

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.

List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337.

 Mannich Reaction

(R)-ALB (30 mol %)

O O NEt2 O
La(OTf)3.nH2O (30 mo l%) O
Al
Ph Et2N OCH3 Ph OCH3 O O
toluene, 50 ºC, 18 h, MS 3Å Li
65% 47
40% ee 48
(R)-AlLibis(binapthoxide)
((R)-ALB)
Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 307–310.

OMe
CHO NH2
O O HN
L-proline (35 mol %)

DMSO, rt, 12 h
50% 48
NO2 OMe NO2
94% ee
OMe
NH2
O O O HN
L-proline (35 mol %)
H DMSO, rt, 12 h
OH 57% OH
OMe
49
syn:anti = 17:1, 65% ee

List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337.

 Mannich Reaction
H H
H
X N H R
N H N
N H O Ar
HO
R O
Ar H
O
H
O CO2H
N

X
H H
MeO
O O
N N
N H O H O
O

(E)-Imine H R R H
X Small (planar) R Large R X
gives high ee gives high ee
Enamine si Enamine si
Imine si Aldehyde re

O NHAr O OH

R R

syn anti

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827–833.
 Mannich Reaction
OMe
NH2
O O O HN
L-proline (20 mol %)
H R DMSO, rt, 3-24 h R
OH OH
OMe
10 vol%

R= Yield % dr %ee

p-NO2C6H4 92 20:1 >99

C6H5 83 9:1 93

P-MeOC6H4 88 3:1 61

O O
(S)-Proline
H R RNH2
OH NHR O

R
O OH
50
R Sharpless AA

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
 Mannich Reaction
O O O Ph
Ph
O NHPMP 1. CAN
Cl3CO OCCl3 2. BOC2O
NPMP NBOC
Ph O O
76% 80%
OH O O
(PMP = paramethoxyphenyl) 51 52

CF3CO3H
87%

Ph
O O
Ph NaBH4, EtOH
HO NBOC
98% O
NHBOC
54 53 O

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.

PMP
O HN NH2
Oxidation
R HO2C R
OH

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
 Mannich Reaction
PMP L-proline O NHPMP
O N (20 mol %)
H CO2Et (S) CO2Et
DMSO, 2 h, rt
55 82% 56
95% ee

Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 1842–1843.

O PMP O NHPMP
N
L-proline (5 mol %)
CO2Et
H CO2Et
[bmim]BF4, rt, 30 min
55 99%
57
>99% ee
O O OH
O L-proline (5 mol %)
H
[bmim]BF4, rt, 48 h OH
OH 30% 58
>99% ee

[bmim]BF4 = N N BF4- For an excellent review on room temperature

ionic liquids in organic synthesis, see
[bmim = 1-butyl-3-methylimidazolium]
Welton, T. Chem. Rev. 1999, 99, 2071–2084.

Chowdari, N. S.; Ramachary, D. B.; Barbas III, C. F. Synlett 2003, 1906–1909.

 Mannich Reaction
PMP L-proline O NHPMP
O N (20 mol %)
H H CO2Et
H CO2Et DMSO, 8 h, rt
iPr 80% iPr
55
2 equiv. 59
syn: anti = 10:1, 87% ee
Synthesis of Novel β-lactams :
1. NaClO2, KH2PO4, H H
O NHPMP 2-methyl-2-butene, O NHPMP iPr
LHMDS,
THF, -20 ºC CO2Et
t-BuOH/H2O
H CO2Et MeO CO2Et N
iPr
2. CH2N2, Et2O 96% O PMP
iPr
89%, two steps
59 60 61

PMP Catalyst O NHPMP

O (20 mol %)
N (S)
H H (S) CO2Et
H CO2Et DMSO, rt
nPent nPent
55
62

%ee
Catalyst Time(h) Yield% syn:anti
syn (anti) OMe
N CO2H N
H 32:1 H
(L)-Proline 3 88 >99 (31)
(S)-2-methoxy-methyl
L-proline
-pyrrolidin(SMP)
SMP 22 40 <1:10 - - (76)

Corodova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 1866–1867.
 Mannich Reaction

O
PMP
PMP N N
N H O N OMe
H H
H CO2Et H CO2Et
R R

transition state for transition state for

Proline-catalyzed Mannich reaction SMP-catalyzed Mannich reaction

Corodova,A.; Barbas, C. F. Tetrahedron Lett. 2002, 7749–7752.

PMP
NaClO2 O HN
PMP NaH2PO4 CO2Et
HO
O HN
PMP rt, 2 h
O N L-proline CO2Et
(30 mol %) H 90%
64
H H CO2Et 1. NaClO2 PMP
DMSO, rt, 6 h
55 94% 63 NaH2PO4 N
2 h, rt O
98% ee CO2Et
2. NaOH
3. HCl
5 min, 80%
65

Chowdari, N.S.; Suri. J. T.; Barbas III, C. F. Org. Lett. 2004, 2507–2510.
 Type-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

 Michael Reaction
O O
Michael addition
Nu

Nu

Nu = active methylene center, e.g., malonic acid ester

β-keto esters, nitroalkanes, etc.

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)

O HNR3 : NR2
NR2

R'

EWG EWG
Nu R' R'

I II III

Betancort, J. M.; Sakthivel, R. T.; Barbas, C. F. Tetrahedron Lett. 2001, 42, 4441–4444.
 Michael Reaction

N CO2Rb
O H O
NO2 5 mol %
NO2
24 h, CHCl3, rt
81% ( R)
65
59 % ee

Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M. Tetrahedron. 1997, 32, 11223-11236.

N CO2H
O H O
NO2 5 mol %
NO2
additive, CHCl3, rt
88% (R)
66
93 % ee
NH

additive = HN

trans-2,5-dimethylpiperazine

Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975–2978.

 Michael Reaction
O O R2
R3 NO2 L-proline (15 mol %)
NO2
R2 DMSO, rt, 2-24 h
R R1 R R1 R3
20 vol% 67 68

Entry Product Yield dr (syn: anti) eea

O Ph
1 NO2 97% 7%
–
O Ph
2 NO2 85% 3:1 10%

O Ph
NO2
3 95% 20:1 23%

O iPr
4 NO2 87% n. d. n. d.b

O Ph
NO2
5 92% 20:1 10%
S
NO2
O
6 85% n. d. n. d.

aee of syn diastereomer

List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–2425. bnot determined
 Michael Reaction
O O Ph
(L)-proline
NO2 NO2
Ph

69

Proline
Entry (equiv.) Solvent Conditions Yield%a %ee
1 0.5 DMSO rt, 1.5 d 60 54
2 0.5 MeCN rt, 4 d 6 60
3 0.5 DMF rt, 7 d 46 47

4 0.5 DMSO 15 ºC, 2 d 62 54

5 0.2 DMSO rt, 3 d 57 58

6 0.5 MeOH rt, 3 d 70 71

7 0.5 EtOH rt, 3 d 32 73

8 0.5 i-PrOH rt, 3 d 39 66

9 1.5 MeOH rt, 3 d 77 73
a 0.5 mL of
10 0.5 MeOH rt, 3 d 68 75
Solvent/mmol
of nitrostyerene
11 0.5 MeOHa rt, 3 d 70 76
Enders, D.; Seki, A. Synlett 2001, 26–29.
 Michael Reaction
O L-proline O Ph
NO2 (0.2–1.5 equiv.) NO2
R1 Ph R1
R2 MeOH, rt R2
70 71 72

Proline
Entry R1 R2 72 (equiv.) Time (d) Yield%a de (%) %ee

1 Et Me syn 0.2b 4 74 88 76

2 Et Me syn 1.5c 3 81 90 73

3 Ph(CH2)2 Me (S,R) 0.2b 8 44 80 76

4 Ph(CH2)2 Me (S,R) 1.5c 3 83 80 72

5 –(CH2)4– (S,R) 0.2b 4 79 94 57

6 –(CH2)4– (S,R) 1.5c 2 99 97 47

acombined yield of both diastereomers, b5mL solvent/mmol of 2, c0.5mL solvent/mmol of 2

Enders, D.; Seki, A. Synlett 2001, 26–29.

 Michael Reaction
O
O
N
O N
O
R1 H
R2

Proposed transition state

Enders, D.; Seki, A. Synlett 2001, 26–29.

R'
R' Catalyst 20 mol % OHC NO2
R CHO NO2
THF, rt R
73

dr %ee
R R' time yield% (syn/anti) (syn)
N
H Ph 3h 85 90/10 56 H N

iPr 77 98/2 78 O
3d
CF3
Catalyst

Betancort, J. M.; Barbas III, C. F. Org. Lett., 2001, 3, 3737–3740.

 Michael Reaction
O Catalyst (15 mol %) O Ph
Ph HCl (15 mol %) NO2
H NO2 H
CHCl3, –25 ºC, 2 d N N
71% H
74
83% ee (R,R)
(syn: anti) = 95:5 Catalyst

Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611–3614.

O Catalyst (0.3 equiv) O Ph

Ph TFA (0.3 equiv) NO2
H NO2 H
2-PrOH, 4 ºC, 48 h
87% 75
80% ee

O
Catalyst (0.3 equiv) O Ph N
Ph TFA (0.3 equiv) NO2
H N
NO2 H H
2-PrOH, 4 ºC, 24 h
93% Catalyst
76
91% ee

Betancort, J. M.; Barbas III, C. F. Org. Lett. 2004, 6, 2527–2530.

 Conclusion
 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