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Asymmetric Organocatalytic TransformationsLewis Base Organocatalysis
Stoltz / Reisman Group MeetingJanuary 09, 2015
Seojung Han
H
O
R1
+N
NHPh
O
cat.
R2R2
H
O
R1
+
O O
O
(S)-Proline(3 mol%)
O
O
OH
p-TsOH
C6H6
O
O
Ph
O
H
CN
Ph
O
OH
Ph
Organocatalysis
Catalysis
Biocatalysis Metal catalysis Organocatalysis
Organocatalysis
Lewis bases
Lewis acids
Brønsted bases
Brønsted acids
· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.
iminium catalyst, enamine catalyst, NHC catalystchiral dialkylaminopyridine
phase transfer catalyst, ketone catalyzed epoxidations
small molecule H-bond catalyst
cinchona alkaloid catalyzed alcoholyses of anhydride
Organocatalysis
Catalysis
Biocatalysis Metal catalysis Organocatalysis
Organocatalysis
Lewis bases
Lewis acids
Brønsted bases
Brønsted acids
· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.
iminium catalyst, enamine catalyst, NHC catalystchiral dialkylaminopyridine
phase transfer catalyst, ketone catalyzed epoxidations
small molecule H-bond catalyst
cinchona alkaloid catalyzed alcoholyses of anhydride
Organocatalysis
Catalysis
Biocatalysis Metal catalysis Organocatalysis
Organocatalysis
Lewis bases
Lewis acids
Brønsted bases
Brønsted acids
· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.
iminium catalyst, enamine catalyst, NHC catalyst
chiral dialkylaminopyridine
phase transfer catalyst, ketone catalyzed epoxidations
small molecule H-bond catalyst
cinchona alkaloid catalyzed alcoholyses of anhydride
N
Lewis Base Catalysis: Iminium Catalysis
N
N
cycloaddition nucleophilic1,4-addition
N
Nu
O O
Nu
LUMO: empty p* orbital
N
LUMO: empty p* orbital
Nu
R1
N
R2
Nu
N
R2
H
NHR
R2
R1
N
R2
R1
N
R2
nucleophilic1,2-addition
(R1 = H)
trans-amination
enamineformation
(R1 = H)
s-bondcleavage
X
O
R2
N
LUMO: empty
p* orbital
Nu
N
LUMO: empty
s* orbital
Iminium Catalyzed cycloadditions
Diels–Alder Reactions Catalyzed by Primary Amines
· The limitation of secondary amine catalysts: The catalytically active nitrogen atom is located in a sterically hindered environment, imposing strict demands on the structure of the substrate aldehyde or ketone. (e.g., a-substituted a,b-unsaturated aldehydes and an isopropyl-substituted ketone as dienophiles)· Novel primary amine organocatalyst has overcome this problem
H
O
O O
R
+
NH2
NH
N
R3
R4R6
R5
R1
R2
R3
R4
R2R1
R6 R5
CHO
O2CRCatalyst 1 (2.5-20 mol%)
C6F5SO3H (6.9-55 mol%)THF or EtNO2, 0 or 23 °C
Catalyst 181-99% yield
79-92% eeexo:endo 6.7:1-99:1
Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457.Ishihara, K. J. Am. Chem. Soc. 2005, 127 , 10504.
H
N
O O
R
H
N
Bn
R
N
H
R'
R''X
X
H
NH
N
Bn
R
N
H
R'
R''X
X vs
OO
R
favored disfavored
NH2
NH2
Iminium Catalyzed cycloadditions
R O
O
CHO
+
Catalyst 2 (5 mol%)Tf2NH (9.5 mol%)
EtCN, –75 °C
CHO
O
R
O
Catalyst 2
48-95% yieldexo/endo 91:9-94:6
86-94% ee
Ishihara, K. Org. Lett. 2006, 8, 2229.Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457.
Organocatalysis
Catalysis
Biocatalysis Metal catalysis Organocatalysis
Organocatalysis
Lewis bases
Lewis acids
Brønsted bases
Brønsted acids
· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.
iminium catalyst, enamine catalyst, NHC catalyst
chiral dialkylaminopyridine
phase transfer catalyst, ketone catalyzed epoxidations
small molecule H-bond catalyst
cinchona alkaloid catalyzed alcoholyses of anhydride
Enolendo AldolizationsHajos-Parrish-Eder-Sauer-Wiechert Reactions
O O
O
(S)-Proline(3 mol%)
DMF, rt20 h
(100% yield)
O
O
OH
93% ee
p-TsOH
C6H6
O
O
O
O
O(S)-Proline(3 mol%)
DMF, rt72 h
(52% yield)
O
OOH
p-TsOH
C6H6
O
O
O O
O
(S)-Proline(47 mol%)1N HClO4
MeCN, 80 °C, 20 h(87% yield) O
O
O
O
O O
O
(S)-Proline(47 mol%)1N HClO4
MeCN, 80 °C, 25 h(83% yield)
Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, 1971.Eder, U.; Sauer, G. R.; Wiechert, R. German Patent DE 2014757, 1971.Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.Houk, K. N. J. Am. Chem. Soc. 2001, 123 , 12911.
NH
CO2H
(S)-Proline
84% ee
74% eeO
ON O
O
H
TS
74% ee
N O O
O
(S)-Proline1N HClO4
MeCN, 80 °C, 10 d(67% yield)
O
O
N
27% ee
86% ee
(S)-Phenylalanine1N HClO4
MeCN, 80 °C, 40 h(82% yield)
O
O
O
(S)-Proline
DMSO, 65 °C, 5 d
(S)-Phenylalanine1N HClO4
MeCN, 80 °C, 40 h
O
O32% ee
95% ee
H2N CO2H
Ph
(S)-Phenylalanine
Danishefsky, S. J. J. Am. Chem. Soc. 1976, 98, 4975Agami, C. Tetrahedron 1984, 40, 1031.
Phenylalanine Catalyzed Intramolecular Aldolizations
O
CHO
1a(25 mol%)
CH3CN, rt, 23 h(68% yield) O OH
>99% de, 94% ee
HO O
98% de, 94% ee
1b(5 mol%)
CH3CN, rt, 3 h(77% yield)
NH
TBDPSO
CO2H
NH
TBDPSO
CO2
1a
1b
R2
O
OO
R1
R'
R
(S)-Proline(30 mol%)
DMF, rt or 5 °C20 h - 5 d
O
OHR2
O
R1
R'
R
74-96% yield73-99 % de, 76-87% ee
Iwabuchi, Y. Org. Lett. 2005, 7, 4185.Enders, D. Synlett 2006, 3399.
NBu4
Intramolecular Aldol Reactions
Direct Catalytic Asymmetric syn-Aldol Reactions
O
OHR'+
H Ar
Ocat. A or B(20 mol%)
NMP4 °C, 16-48 h
O
R'Ar
OH
OHORH3C
H2N CO2H
H
A: R = HB: R = t-Bu
O
OH
OH
NO2
O
OH
OH O
OH
OH
NO2
With cat. AWith cat. B
75%, 15:1 dr, 90% ee>95%, 18:1 dr, 98% ee
70%, 8:1 dr, 86% ee87%, 10:1 dr, 80% ee 78%, 12:1 dr, 94% ee
O
HR
N
HO
H
H
R'
O
OH
Barbas, C. F., III, J. Am. Chem. Soc. 2007, 129 , 288
Organocatalysis
Catalysis
Biocatalysis Metal catalysis Organocatalysis
Organocatalysis
Lewis bases
Lewis acids
Brønsted bases
Brønsted acids
· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.
iminium catalyst, enamine catalyst, NHC catalystchiral dialkylaminopyridine
phase transfer catalyst, ketone catalyzed epoxidations
small molecule H-bond catalyst
cinchona alkaloid catalyzed alcoholyses of anhydride
Isolable NHCs
N
N
R
R
R1
R1
p-electrondonation
s-electronwithdrawal
*Electronic factors operating in both the p and s frameworks resultin a "push-pull" synergistic effect to stabilize the carbene.
*p donation into the carbene from the out-of-plane p orbital of heteroatoms stabilizes electrophilic reactivity of carbenes.
*The electronegative heteroatoms adjacent to C-2 provide additional stability through the framework of s bonds.
* The combined effect is to increase the singlet-triplet gap and stablize the singlet-state carbene over the more reactive triplet-state carbene.
Scheidt, K. A. Aldrichimica Act. 2009, 42, 55.Bertrand, G. Chem. Rev. 2000, 100 , 39.
Additive Effect
O+
H
O
R
(S)-Proline (30 mol%)(S)-BINOL (1 mol%)
acetone/DMSO (3:1)0 °C, 48 h
O OH
R
OH
OH
(S)-BINOL
O OH
Br
O OHO OH
Without BINOLWith BINOL
82%, 75% ee76%, 97% ee 43%, 72% ee
56%, 98% ee
10%, 92% ee23%, 87% ee
Shan, Z. J. Org. Chem. 2006, 71, 9510.