proline catalyzed aldol, mannich, and michael reactions

52 Pages·2005·3.29 MB·English

PPRROOLLIINNEE CCAATTAALLYYZZEEDD AALLDDOOLL,, MMAANNNNIICCHH,,
AANNDD MMIICCHHAAEELL RREEAACCTTIIOONNSS::
AAPPPPLLIICCAATTIIOONN OOFF AASSYYMMMMEETTRRIICC OORRGGAANNOOCCAATTAALLYYSSIISS
JANUARY 19, 2005
SANJIT SANYAL
DEPARTMENT OF CHEMISTRY
MICHIGAN STATE UNIVERSITY
WWhhaatt iiss Organocatalysis?
 “ A field of chemistry that pays my mortgage and
has gotten me many free dinners.”
- David W. C. Macmillan
WWhhaatt iiss 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 H O i-Pr H O H O H O R12N
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
N Me 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
CO H O
N 2
H
N chiral quaternary fructose-derived
acetylquinine L-proline ammonium salt chiral-ketone
H
N
HO
S
OMe
N
O
N H
H N
5,5-dimethyl thiazoli-
H N OH
2
(S)-2-methoxy-methyl dinium-4-carboxylate (-)-cinchonidine
-pyrrolidin (SMP) (S)-phenylalanine (DTMC) a cinchona alkaloid
CCllaassssiiffiiccaattiioonn ooff 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
O
R R
2 30 mol % 2
R1 R3 30% H2O2 (3 equiv.) R1 R3
CH CN-K CO
3 2 3
3 4
Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807–8810.
CCllaassssiiffiiccaattiioonn ooff 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
Catalyst (10 mol %)
Ph O Ph O H N
CsOH•H O
2
N EtI N N
OtBu OtBu
Ph CH2Cl2, -60 ºC, 30 h Ph H Et O
5 6
Chiral quaternary
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–12415.
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 O O OH O
H
Nu OH N
BOCHN NO2 1. Polymer BOCHN HN
HO
2. Nu
O
H
NO2 O
7 8
Polymer
Sellergren, B.; Karmalkar, R. N.; Shea, K. J. J. Org. Chem. 2000, 65, 4009–4027.
TTyyppee--II
 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
BBaacckkggrroouunndd IInnffoorrmmaattiioonn
OH
1. HCN, Catalyst, H
N
CHO CHCl , rt, 24 h
3 COOH HO
2. 4N H SO , 8.7%
2 4
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
N
Me 110 ºC, 90% Ph AcO
11 12
OMe
74% ee (R)
N
Acetylquinine
Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-29.
BBaacckkggrroouunndd IInnffoorrmmaattiioonn
Hajos-Parrish-Eder-Sauer-Wiechert Reaction
Catalyst
O
O
Me 47 mol % catalyst, 1N HClO CO H
4 N 2
O O CH3CN, 80 ºC, 25 h O H
83%
13 14 15 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
CO H
N 2
O
DMF, 20 ºC, 20 h PhH, 15 min
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.
WWhhyy PPrroolliinnee??
 Proline is an optically active pyrrolidine derivative.
O O
N
O H
O
DMF, rt
O
OH
1 (±)-2
 Asymmetric carbon is in the same molecule next to the functional groups.
O
H N N
2 O S O
3 O
H H
pyrrolidinium camphorsulphonic acid L–proline

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