Dr. P. Wipf
Page 1 of 7
9/21/2009
Enolate Chemistry I
Cornforth:
“Nature is an organic chemist with a preference for the aldol
reaction”
Many natural products contain polyhydroxylated carbon arrays, usually a mix of 1,2and 1,3-diols; biosynthetically, these compounds are related and are commonly referred
to as polyacetates/polypropionates.
Typical examples of polyether antibiotics isolated from Streptomyces are:
OMe
Me
Me
O
Me
Me
MeO
Me
Me
O
O
O
O
OMe
Me
Me
O
HO
OH
OH
Me
Me
Me
O
H
OMe
O
Me
O
N
Me
Calcimycin (A-23187)
HO2C
Me
Me
Me
H
Me H
O
OH
Me
O
Me
H
Me
Me
OH
O
O
HO
Me
CO2H
OH
Ionomycin
OH
Me
Me
NH
Me
Lonomycin C
O
O
O
Me
Me
HO2C
H
Me
O
Me
Me
O
O
OH
Et
Et
H
O
Me
Lasalocid A
HO
Me
MeO H
Me
Et
Me
OH
NHMe
O
Me H
O
Et H
Monensin
Me
O
H H
Me
O
CH2OH
OH
Dr. P. Wipf
Page 2 of 7
9/21/2009
Most of these compounds are metal chelators (ionophores). Monensin as a food
additive kills bacteria in poultry by the transporting Na+ outside the cell, thus increasing
the intracellular osmotic pressure and causing the coccidia to explode.
Macrolide antibiotics are characterized by the macrocyclic lactone moiety and can be
grouped into: polyoxo, polyene, ionophore, and ansamycin macrolides.
O
O
HO
Me
O
Me
HO
Me
Me
O
O
Me
Me
Me
Me
O
OR
Me
Me
Me
HO
Me
OR
O
Me
O
O
Me
Methymycin
R = desoaminyl
OR
OR'
O
Me
Pikromycin
R = desoaminyl
Erythromycin A
R = desoaminyl
R' = cladinosyl
O
O
Me
Me
Me
CHO
MeO
O
Me
OH
Me
Me
OH
Me
O
CHO
R'O
OR
O
O
OH
Me
OR
OH
Me
Tylosin
R = mycarosyl-mycaminosyl
R' = mycinosyl
Leucomycin A1
R = mycarosyl-mycaminosyl
OH
OH
OH
O
HO
O
OH OH OH
OH O
OH
O
OH
HO
O
OH OH
OH OH O
CO2H
OH
O
NH2
OH
CO2H
O
O
Nystatin A1
OH
Amphotericin B
OH
O
NH2
OH
Dr. P. Wipf
Page 3 of 7
9/21/2009
O
O
H
O
O
H
O
H
O
H
H
O
H
O
H
O
O
H
O
O
Nonactin
Ac
OH
Me
OH
H
N
Me
Cl Me O
O
O
MeO
OCH2CO2H
O
HO
Me Me
Me
O
O
O
N
Me
Me
Me
Me
O
N
OMe OAc OH
O
OH
OMe H
Me
Maytansine
Rifamycin S
O
O
Bistramide C
N
Me
O
O
Me
H
N
O
HO
HN
O
O
O
H
H
13
5
9
O
MeO
O
H
H O
O 1'
O
1
5'
O
17
7'
O
9'
HN
O
N
OMe
Leucascandrolide A
Dr. P. Wipf
Page 4 of 7
9/21/2009
1. Introduction
O
O
R2C
C
R2C
R'
C
H
R'
H
α proton is relatively
acidic (pKa≈20); it can
be removed by bases
carbonyl group is electrophilic; nucleophilic reagents
add to carbonyl group
α carbon atom of enol
is nucleophilic; it attacks
electrophilic reagents
Carbonyl compounds exist in equilibrium with their tautomers, which are enols. They can express
a variety of different kinds of chemical reactivity.
The enol tautomer is quite reactive toward electrophiles, and the above equilibrium
rapidly regenerates new enols in the presence of acid or base catalysts. However,
most reactions of electrophiles with carbonyl compounds take advantage of the higher
nucleophilicity of the deprotonated enol, the enolate anion.
When unsymmetrical carbonyl compounds are converted to their enolates under conditions that
allow equilibrium to be established (high temperatures and weak bases) the enolate anion with the
more highly substituted double bond is formed. This ion is the more stable of the two possible
enolates and is called the thermodynamic enolate. If the carbonyl compound is added to an excess
of a strong base (usually LDA) at low temperatures, the least hindered hydrogen atom is removed.
The ion with the less substituted double bond forms; it is the less stable of the two possible
enolates but is the one that forms faster. For this reason, it is called the kinetic enolate.
Dr. P. Wipf
Page 5 of 7
9/21/2009
Reactions of aldehydes and ketones that involve enol or enolate ion intermediates
include:
Enolization. Aldehydes and ketones exist in
K
equilibrium with their enol forms. The rate at
OH
O
which equilibrium is achieved is increased by
K = 1x10-8
acidic or basic catalysts. The enol content of simple
aldehydes and ketones is quite small; β-diketones, however, are extensively enolized.
α-Halogenation. Halogens react with aldehydes and ketones by substitution; An acid catalyst (or
base) increases the rate of enolization (enolate formation), which is the rate-determining step. The
reaction of a methyl ketone with a halogen in base is known as the haloform reaction. Once one of
the α-H's is replaced by a halogen atom, the remaining H's are more acidic and are more easily
substituted. C,C-bond cleavage is facilitated by the e-withdrawing effect of the halogens.
Aldol condensation. A reaction of great synthetic value for C,C-bond formation.
Nucleophilic addition of an enolate ion (or an enol in the acid-catalyzed version of this
process) to a carbonyl group leads to a β-hydroxy aldehyde or ketone (reversible!).
Subsequent dehydration (acid- or base-catalyzed) yields an α,β-unsaturated carbonyl
compound.
O
RCH2
C
HO
NaOCH2CH3
R'
HOCH2CH3
RCH2
(2 equiv)
O
O
R'
R'
R
LDA
O
R'
NaOCH2CH3
HOCH2CH3
-H2O
RCH2
O
OLi
Li
CH3CH2CHO
O
R'
R
THF, -78° C
CH2CH3
H2O
O
OH
85%
(workup)
CH2CH3
The irreversible, rapid enolization of carbonyl compounds with very strong base (LDA), followed by
addition of aldehydes or ketones, allows the direct formation of a single aldol product in crossed
aldol condensations.
Dr. P. Wipf
Page 6 of 7
9/21/2009
Claisen-Schmidt reaction. A crossed aldol condensation in which a non-enolizable
aldehyde reacts with an enolizable aldehyde or ketone.
O
Ph
C
O
H
+
(CH3)3C
C
HO
NaOH
CH3
O
Ph
HOCH2CH3
H2O
C(CH3)3
H
H
NaOH
O
90%
HOCH2CH3
-H2O
C(CH3)3
Ph
Robinson annulation. A combination of conjugate addition of an enolate anion to an α,βunsaturated ketone (Michael addition) with subsequent intramolecular aldol condensation. Michael
additions are typical for soft nucleophiles, including enols, cyanides, cuprates and thiol(ate)s. In
contrast, hard nucleophiles (hydrides, Grignard and lithium reagents) prefer 1,2-addition.
Alkylation reactions. Treatment of enolates with halides provides a means for carbon
chain extensions at the α-position. However, polyalkylation can be a problem, and the
use of a strong, nucleophilic base or the enamine is recommended.
O
O
1. pyrrolidine, benzene
2. butyl iodide
3. 10% H2SO4
O
H
pyrrolidine, benzene
H
N
+
TsOH
85 :
15
N
Dr. P. Wipf
Page 7 of 7
9/21/2009
Aldol Methodology
Synthetic problem: control of aldol regio- and stereoselectivity.
O
OH
O
OH
+
Ph
O
Ph
OH
O
Ph
O
+
O
+
OH
Ph
base
+ enantiomers
O
Ph
O
OH
O
Ph
+
Ph
+
OH
Ph
OH
O
OH
Ph
Woodwardʼs synthesis of cortisone (Woodward, R. B. et al. J. Am. Chem. Soc.
1952, 74, 4223):
O
O
OH
OH
H
H
H
O
cortisone
Target molecule: 6 chiral centers, 64 possible stereoisomers.
This synthesis illustrates, rather ingeniously, the selective manipulation of
functionalities on six-membered rings, and a vastly increased synthetic arsenal.