Cinchona Alkaloid Derived Quaternary Ammonium Salts

18 Pages·2005·0.56 MB·English

Asymmetric Phase Transfer Catalysis:
Cinchona Alkaloid Derived Quaternary Ammonium Salts
Anita Mattson
March 9, 2004
Contents:
-Introduction
-Mechanism
-Alkylations H R
N R H
-Micheal Additions HO
H
N
-Darzens Reactions HO
-Aldol Reactions
H
-Epoxidations
N N
References:
-Dalko, P.I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726-3748.
-Jones, R. Quaternary Ammonium Salts and Their Use as Phase Transfer Catalysts;
Academic Press: New York, 2001.
The General Principle of Phase Transfer Catalysis
Consider the Following Reaction:
Cl + Na+CN- CN + Na+Cl-
The 4-chlorobutane and sodium cyanide form two separate layers and the
reaction between them is only able to take place at the interface of these layers.
Even reflux does not speed up the desired reaction significantly.
Addition of a phase transfer catalyst, such as a quaternary ammonium salt,
is able to speed up the reaction.
A General Picture for the Process:
Organic Phase Cl + Q+CN- CN + Q+Cl-
Interfactial Region
Aqueous Phase Cl- + Q+CN- CN- + Q+Cl-
Cinchona Alkaloid Derived Quaternary Ammonium Salts
X
X
R H
H N R HO
R1 N
H
R1
HO
H
N
N
a) R=OMe, X=OH [(-)-quinine] $3.15/g a) R=OMe [(+)-quinidine] $5.50/g
b) R=H, X=OH [(-)-cinchonidine] $0.72/g b) R=H [(+)-cinchonine] $1.20/g
-Chincona Alkaloids are a family of natural products that can be isolated from cinchona trees
-The following four are the most abundent and can be easily isolated from the bark of the trees:
1) Quinine
2) Cinchonidine
3) Quinidine
4) Cinchonine
Selected Catalysts for Enantioselective Phase
Transfer Reactions
Br
HO Ph
R
Ph
N Br
Me Me Me
F C
3 N
OHMe Me
N Ph
R
Cl Ephedra Alkaloid Catalysts
Me
C -Symmetric
2
Maruoka et al., J. Am. Chem. Soc. 1999, 121, 6519.
Me Ph
OH
N
Me
Br
O R O
H
H N N Bu Oligopeptides and Polymers
2
N N
H H
R O R
Roberts et. al., Chem. Commun. 1997, 739.
Phase Transfer Catalysis: Enantioselective Reactions
•Several reactions have been done using cinchona alkaloid derived quaternary ammonium salts as
asymmetric phase transfer catalysts.
•Reactions have been done in the following areas:
1) Alkylations
2) Michael Additions
3) Aldol and Related Condensations
6) Darzen Reactions
5) Epoxidations
Phase Transfer Catalysis: Enantioselective Alkylations
First Example: Enantioselective Synthesis of (+)-Indacrinone
Dolling et al, J. Am. Chem. Soc. 1984, 106, 446-447.
Cl Cl O Cl O
O
Cl Cat. (10 mol %) Cl CH3 Cl CH3
MeCl
HO
H CO NaOH (50%) H3CO O
3
PhCH /H O 95% yield
3 2 O
92% ee
20° C, 18h
Catalyst:
Conlcusions of Kinetic and Mechanistic Studies:
H
Hughes, Dolling et al, J. Org. Chem., 1987, 52, 4745-4752. Br
O
N
Step 1: Enolate Anion Formation N CF
3
Base concentration dependent, H
Rxn proceeds best in 50% NaOH
Step 2: Anion Extraction into Organic Phase
Catalyst could be working as a dimer?
Ammonium Salts more soluble with
bromide counterion.
Rationale:
Step 3: Chiral Methylation in Organic Phase
H
Higher ee's with less polar solvents Cl
O
O
Stirring has no effect on rate or ee. N
Cl
N
H δ CF3
H CO
3
Phase Transfer Catalysis: Enantioselective Alkylations
Application to the Synthesis of Amino Acids
O R-X
O
10 mol% cat.
Ph N
Ph N
OtBu
OtBu
50% aq. NaOH
Ph
Ph R
CH Cl , 25°C
2 2
1) O'Donnell's Work 3) Lygo's Work
O'Donnell et al., J. Am. Chem. Soc., 1989, 111, 2353.
Catalyst:
Catalyst:
H Cl Br
H
O N yields: 60-85% N
N
ee: 42-66%
H
OH
yields: 40-86%
N
ee: 67-91%
2) Corey's Work
Corey et al., J. Am. Chem. Soc., 1997, 119, 12414.
Catalyst: Br
H
Catalyst:
O
N
Br N
H
H
N yields: 68-91%
ee: 92-99.5%
O
N
Lygo et al., Acc. Chem. Res. ASAP
Lygo et al., Tetrahedron Lett. 1999, 40, 1389.
Lygo et al., Tetrahedraon Lett. 1999, 40, 1385.
Phase Transfer Catalysis: The Mechanism of Imine Alkylation
R X
Ph OtBu
Ph Ph
N CO tBu
2 N N CO tBu
2
Ph Ph O Ph
Q
Ph
Q X
ORGANIC PHASE
Ph
N CO2tBu Ph OtBu
Ph N
Ph O INTERFACE
K OH K
AQUEOUS PHASE
•Studies into the kinetics of phase transfer reactions indicate that the
deprotonation most likely occurs one the interface of the two phases.
•Steps: 1) Deprotonation of Substrate
K OH 2) Transfer of Substrate Anion
3) Alkylation in Organic Phase
Lygo, B.; Andrews, B. Acc. Chem. Res. ASAP
Phase Transfer Catalysis: Enantioselective Alkylations
Stereochemical Rationale
OR
N N RO N H N N
H N
O
O
O O
cinchonidine derived cinchonine derived
Lygo, B.; Andrews, B. Acc. Chem. Res. ASAP.
Phase Transfer Catalysis: Alkylations
Structural Effects of the Catalyst
Catalyst:
R1 e.e. (%) Yield (%)
Variation of R1:
CH 36 59
3
n-Butyl 50 57
R1O PhCH 48 64
N X 2
CH OCH 26 60
H
3 2
R2 PhCH OCH 30 50
R3 2 2
Variation of R2: R2 e.e. (%) Yield (%)
Cyclohexyl 23 64
O
O CH OCH 10 66
Ph N 10 mol% cat. 3 2
Ph N Ph 48 52
OtBu
OtBu
50% aq. NaOH Napthyl-1-yl 36 76
Ph
Ph R
CH Cl , 25°C Quinoin-4-yl 56 76
2 2
Variation of R3: R3 X e.e. (%) Yield (%)
H I 8 67
n-Propyl I 2 76
Cyclohexyl Br 4 56
Conclusions:
4-Nitrophenyl Br 38 66
-N-Anthracenylmethyl substituent 4-Methoxyphenyl Cl 38 69
substantially enhances enantioselectivity Napthyl-1-yl Cl 52 67
-1-Quinolyl group also is key in Napthyl-2-yl Br 40 67
Anthracen-9-yl Cl 75 57
enantioselectivity
Ph Br 2 73
Lygo et al, Tetrahedron, 2001, 57, 2391-2402.