Download evans enolate alkylation

Enantioselective Synthesis
Preparation of Enantiomerically enriched Compounds
This is critically important because the two enantiomers of the same compounds often/usually
have very different properties when in come to biological activity.
There are a number of different types of approaches to enantioselective synthesis. They include:
1) Substrate Control
-A situation where a chiral auxiliary is temporarily attached to the desired substrate, and a
diastereoselective reaction is performed. The auxiliary is then removed to give the pure
enantiomer.
2)
Reagent Control – this approach has several variations, including:
i)
Stoichiometric reagent
ii)
Chiral Catalysis
iii)
Enzyme Based processes
These are considered more elegant than substrate control, but what if you only get 80% ee
(90:10 er)…what do you do?
3) Both are chiral – Double stereodifferentiation
-Note: There will be cases where the substrate and reagent’s chiralities reinforce each
other (matched pair)
-There will also be cases where they work against each other (mismatched pair)
We will look at a few of the major cases, but will hardly be comprehensive.
Enolate Alkylation
(Evans’ oxazolidinone enolates)
The basis for the most commonly employed chiral enolates involves an N-acyl oxzolidinone that
enantiomerically pure in the heterocycle. This is an important example of substrate control by formation
of a chiral auxiliary.
O
O
O
O
N
R1
enantiomerically
R pure
O
N-
O
+
Cl
R1
R
The source of chirality in the oxazolidinone is an amino alcohol, which are usually commericially
available and cheap, or come from reduction of the amino acid. Recall that it’s the (S)- enantiomers
1
which are the natural and therefore cheap ones. The most common ones come from valine (valinol) and
phenylalanine (phenylalaninol).
O
NH2
HO
For
O
NH
NH2
HO
(S)-valinol
≡
HO
Ph
NH2
(S)-phenylalaninol
Bn
R
And the (R)- enantiomer? There are usually two choices: i), the (R)- enantiomer of valinol (or valine) is
more expensive, but not crazily so; ii), (1S, 2R)-norephedrin has (R)- chirality at the methyl (proper) site.
O
NH2
HO
NH2
HO
(1S, 2R)-norephedrin
(R)-valinol
For
O
NH
Ph
R
The N-acyl oxazolidinones are similar to esters in terms of ability to form enolates, most
commonly with LDA or the base that functions as its sodium analogues, NaHMDS. Since these are
essentially amides, the enolates are entirely the Z- isomer (using the particular definition for enolates).
The metal counterion in chelated to the oxazolidinone oxygen atom, making one face of the enolate (the
re face), away from the R of the oxazolidinone, much more available for attach on the electrophile. The
selectivity obtained ranges from pretty good (smaller electrophiles, like CH3I, EtBr) to excellent (for less
small electrophiles). Some examples follow:
M
O
O
O
O
LDA, THF
N
R
O
N
R
or NaHMDS
O
O
N
O
2)
E+ = CH3-I (NaHMDS, -78 o )
E+ = PhCH2Br (LDA, 0 o )
2
N
O
N
E+
Pr-i
O
O
Pr-i
91
99
R
R
E
O
1) base, THF
R
O
OK
blocked
O
O
E+
0 o with Li
-78 o with Na
O
+
O
O
N
R
E
Pr-i
9
1
E
H
O
O
N
O
1) base THF
O
O
R
2)
N
E+
Ph
Me
Ph
E+ = CH 3-I (NaHMDS, -78 o )
O
O
Me
R
O
+
O
N
R
E
Ph
Me
E
93
7
2
98
E+ = PhCH2Br (LDA, 0 o )
Note: Other electrophiles can also be put into the Li, Na, B, Sn, or Ti enolates, such as halogenation or
amination. See the reviews for detail on this.
Aldol Condensations
The Evans’ N-acyloxazolidinones are wonderful at doing selective aldol condensations using
their boron enolates. The stereoselection is even more outstanding than for alkylation, but there is
(superficially) a surprise here. Firstly, because the oxazolidone is essentially an amide and of significant
size, it is once again impossible to get anything other than the Z- enolate. The key is that even though
there is a chelate in the boron enolate, when the aldol occur the chelate must fall apart (or else there is
no Zimmerman-Traxler transition state). With this chelate gone, there is a repulsive dipole-dipole
interaction between the oxygen atoms, so the dominant conformation flips 180 o. The result is still the
syn- aldol product, but relative to the oxazolidine the face of attack is opposite from alkylations!! This is
easy to miss if simply skimming the results.
O
O
O
N
O
1) Bu2BOTf, CH2Cl 2
i-Pr2NEt, -78
o
O
syn:anti > 99.1 : 0.9
syn1:syn2 ≥ 141 : 1
O
O
O
Bu2
B
O
2) RCHO, -78 o
N
OH
dipole-dipole repulsion
Bu2
O
O B
O
N
O
H
Bu2
O B
3) H2O 2
N
R
O
N
R
O
H
R
O
note that the aldehyde is
attacked from the TOP face
3
O
O
N
O
1) Bu2BOTf, CH2Cl2,
O
i-Pr2NEt, -78 o
Bu2
B
O
O
OH
N
O
N
O
O
2) RCHO, -78 o
R
3) H2O 2
Ph
Ph
Ph
Other electrophiles can also be reacted with Li, Na, B, Sn, or Ti enolates, such as in amination or
halogenation reactions. You should consult the reviews if interested.
Cleavage of the Oxazolidinone
For this chemistry to be a useful enantioselective synthesis, it has to be possible to get rid of the
oxazolidinone auxiliary. There are several protocols for this, but just a couple will be given.
Carbonyl Hydrolysis: The amide like carbonyl should be more susceptible to nucleophilic attack, than the
carbamate carbonyl, so HO- should be able to hydrolyze this to a carboxylic acid. When it’s done, LiOH is
used, because it is least likely to cause base induced side reactions, like epimerization or retro- aldol
reactions.
O
O
O
O
LiOH, THF-H2O
N
20
O
O
NH
+
HO
o
Pr-i
recoverable
Pr-i
after acidification
This usually works, but if the R groups on the ‘amide’ get too large, hydrolysis of the carbamate can start
to compete.
O
O
O
N
HO HN
20
Pr-i
O
O
LiOH, THF-H2O
O
O
N
o
Pr-i
Pr-i
Ph
also an example
LiOOH also works for the intended transformation (H2O2 + LiOH). As a reagent, it is sterically less
hindered, and is also less basic (pKa H2O2 = 10). Therefore, it’s more likely to attack the ‘amide’ carbonyl
in hindered cases, and less likely to cause undesired base initiated processes.
4
also an example
O
O
O
OH
N
1) LiOOH, THF-H2O,
0o
O
O
OH
+
HO
O
NH
2) Na2SO3
Ph
Ph
88%
T etrahedr on Let t . 1987, 28, 6142.
An alternative to hydrolysis of the N-acyl oxazolidinone is reduction, which can be accomplished by
LiAlH4 or LiBH4 (more reactive that NaBH4). Since the N-acyl oxazolidinone is ester-like in its reactivity,
the reduction occurs twice, to give the alcohol.
O
O
O
OH
N
Ph
1) LiAlH4, THF,
0o
OH
O
OH
+
O
NH
2) H2O
Ph
We will come back to the Evans’ oxazolidinones for the purposes of aldol chemistry, but the first
matter to address is the question of how to do analogous enolate alkylations on ketones instead of acid
derivatives.
Ketone Enolate Alkylation
For the analogous asymmetric alkylation of ketones, the most common method involves
hydrazones, which can also be derived from amino acids. In particular 1-amino-2-(methoxymethyl)pyrrolidine is available either as its (S)- enantiomer (SAMP) or its (R)- enantiomer (RAMP); both are
commercially available but rather expensive. Since the (S)- enantiomer can be prepared from (S)proline, it is the cheaper of the two. The (R)- enantiomer may be made from either (R)- proline or (R)glutamic acid.
5
OMe
CO2H
N
H
N
NH2
(S)- proline
(S)- 1-amino-2-(methoxymethyl)prrolidine
SAMP
OMe
HO 2C
CO2H
CO2H
N
H
O
NH2
N
NH2
(R)- 1-amino-2-(methoxymethyl)prrolidine
(R)-glutamic acid
RAMP
When these hydrazines are subjected to exposure to ketones, the expected imine formation
chemistry occurs, save that these are called hydrazones. Ultimately the C=N double bond is formed as a
mixture of (E)- and (Z)- isomers, but these interconvert pretty easily and turns out to not matter.
RT for R = H
O
+
R1
H2N
OMe
R2
N
N
N
60 oC for
R = alkyl, aryl
OMe
R1
SAMP
(or RAMP)
R2
Under kinetic conditions, this hydrazine deprotonates at the less substituted side (except for those
derived from aldehydes, where only one site is possible). At 0 oC, in THF or Et2O, only one of the 4
possible isomers is obtained.
LDA, 0
N
N
oC
HN
N
THF or Et2O R1
OMe
R1
_
Li +
≡
OMe
R
R
_
2
Me
O
R1
E+
E CC, Z CN generated
almost exclusively
N
R2
N
Li
N
OMe
H
N
H
R2
R2
Li+
1
E+
original
proposal
updated
proposal
The temperature is then dropped very low (to -78 oC or even lower), and an electrophile such as an alkyl
halide is added. With the auxiliary blocking the top face, electrophile attack on the bottom face is almost
exclusive to generate a new chiral centre.
MeO
2
R
R1
N
H
E
6
N
bottom face attack
on E+
N
≡
N
E
R1
H
R2
OMe
Hydrolysis – Hydrazones are types of imines and therefore can be hydrolyzed in strong acid at reflux.
Unfortunately, these vigourous conditions cause racemization at the careful crafted chiral centre due to
acid catalyzed keto-enol tautomerism (also called epimerization). There are two solutions to this
problem:
i)
Quaternize then hydrolyze – Subjecting the hydrazine to MeI alkylates mostly the nitrogens.
This ionic species is more readily hydrolyzed, and acidic but less aggressive conditions can be
found for the hydrolysis without racemizations.
Me
MeI
N
+
N
Me
N
E
R1
OMe
60 o C
N
OMe
R1
R2
1-6 M HCl,
pentane
E
two phase 1
R
OMe
N
+
E
N+
R1
R2
O
E
R2
R2
can also recomp SAMP indirectly
Oxidation/ozonolysis – Instead, one can pretend that the imine is more like an alkene and
cleave the double bond similarly, with ozone (or other oxidants). The advantage here is that
the recovered hydrazine derivative is an intermediate in the (S)-proline to SAMP
preparation.
ii)
N
E
R1
O
O3, -78 o C
N
OMe
E
+
R1
CH2Cl 2
ON
intermediate in (S)-proline
to SAMP preparation
N
2
OMe
R
R2
A couple of specific examples of asymmetric alkylation of ketones by way of Enders SAMP hydrazones
follow.
1) LiTMP, 0 o,
THF
N
N
OMe
2) n-PrI, -78
N
1) MeI, ∆
N
o
OMe
H
H
O
H
2) 4 N HCl,
pentane
97:3 er, 94% ee
'good yields'
97:3 dr, 94% de
T et rahedron Lett. 1998, 39, 7823
N
N
1) LDA, 0 o,
THF
N
N
OMe
OMe
2) EtI, THF,
-95 o
O 3, -78 o ,
CH2Cl 2
O
68%
87%
~100% ee
Enders has also done aldol chemistry with these, but this area will not be covered. For reviews, see:
7
Enders, D. Asymmetric Synthesis 1984, 3, 275; Comprehensive Organic Synthesis, Vol 3, 38.
There are other very important chiral enolate sources. I will show some of them below, without further
discussion.
N
N
R
O
OH
O
MeO
Ph
O
N
OMe
Whitesell
Schollkopf
CR, 1992, 92, 953
Evans
8-phenylmenthol
R
O
O
SO 2NR2O
Oppolzer
T et rahedron 1987, 43, 1969
8
E
N
S
O2
Oppolzer
camphor sultams
O
Ph
OH
N
H
Myers
pseudoephedrine
amides
R