OXIDATION
Oxidation is one of the major chemical transformations.
There is an increasing demand
for selective and mild oxidation
methods, in particular catalytic
reactions using molecular
oxygen as an end oxidant are in
focus.
Enantioselective epoxidation of alkenes is an appealing strategy for the synthesis of
optically active compounds.
OXIDATION Nobel Prize in Chemistry for 2001 for the development of catalytic
asymmetric synthesis William S. Knowles, Ryoji Noyori and Barry Sharpless.
Sharpless’s chirally catalyzed oxidations
Parallel to the progress in catalytic asymmetric hydrogenations Barry Sharpless
developed chiral catalysts for very important oxidation reactions. The epoxidation
reaction discovered in 1980 by Sharpless and Kazuki is a very fine example of a strategy
of using a reagent to achieve stereochemical control.
Using titanium(IV)tetraisopropoxide, tert-butyl hydroperoxide, and an enantiomerically
pure dialkyltartrate, the Sharpless reaction accomplishes the epoxidation of allylic
alcohols with excellent stereoselectivity.
This powerful reaction is very predictable. When the D-(-)-tartrate ligand (D-(-)-DET) is
used in epoxidation, the oxygen atom is delivered to the top face of the olefin when
the allylic alcohol is depicted as in Figure 1 (i.e. OH group in lower right hand corner).
OXIDATION Nobel Prize in Chemistry for 2001 for the development of catalytic
asymmetric synthesis William S. Knowles, Ryoji Noyori and Barry Sharpless.
Sharpless’s chirally catalyzed oxidations
Parallel to the progress in catalytic asymmetric hydrogenations Barry Sharpless
developed chiral catalysts for very important oxidation reactions. The epoxidation
reaction discovered in 1980 by Sharpless and Kazuki is a very fine example of a strategy
of using a reagent to achieve stereochemical control.
Using titanium(IV)tetraisopropoxide, tert-butyl hydroperoxide, and an enantiomerically
pure dialkyltartrate, the Sharpless reaction accomplishes the epoxidation of allylic
alcohols with excellent stereoselectivity.
This powerful reaction is very predictable. When the D-(-)-tartrate ligand (D-(-)-DET) is
used in epoxidation, the oxygen atom is delivered to the top face of the olefin when
the allylic alcohol is depicted as in Figure 1 (i.e. OH group in lower right hand corner).
OXIDATION
CATALYTIC OXIDATION
The asymmetric complex formed from
titanium alkoxide and a chiral tartrate ester
delivers the peroxy oxygen to one face or the
other of the allylic alcohol depending on the
absolute configuration of the tartrate used.
Figure 1: The predictive stereoselectivity of the Sharpless epoxidation is shown together
with an example of its regioselectivity.
CATALYTIC OXIDATION
If allylic alcohol has substituents, the order of the enantioselectivity might change.
For example, a substituent is placed in C1 as shown in the figure. Oxygen is now
delivered at different rates to the two enantiomers depending on the orientation of
the R group.
Often the difference in rates is of sufficient magnitude that one enantiomer is
completely oxidized while other remains largely unoxidized. The slow reacting
enantiomer has the R group to the direction of “oxygen” delivery.
Opposite enantiomer will be obtained, if D(+) diethyltartrate complex is used instead.
CATALYTIC OXIDATION
The success in the use of titanium tartrate catalyzed asymmetric epoxidation depends on
the presence of the hydroxyl group of the allylic alcohol; the hydroxyl group enhances
the rate of the reaction, thereby providing selective epoxidation of the allylic olefin in
the presence of other olefins, it is also essential for the achievement of asymmetric
induction.
The need for a hydroxyl group necessarily limits the scope of the epoxidation to a fraction
of olefins. On the other hand allylic alcohols are easily introduced to synthetic
intermediates and are very versatile in organic synthesis.
CATALYTIC OXIDATION
The ligands on titanium are in rapid exchange. When equimolar solutions of a titanium
alkoxide and dialkyl tartrate are mixed, equilibrium is quickly reached.
The equilibrium is far right because a chelating diol has a much higher binding constant (also higher acidity
enhanced by ester groups) for titanium than do monodentate alcohols.
Rapid ligand exchange continues as hydroperoxide (oxidant) and allylic alcohol are added.
Rate law clearly illustrates that the ligand exchange process is essential for catalytic
epoxidation.
Because achiral Ti(OR)4 complexes are also active in epoxidation, it is important to
suppress their concentration (Ti(tartrate)2 is inactive; 10-20%mol excess of tartrate is
optimal for high yields and selectivity).
CATALYTIC OXIDATION
After forming the tartrate complex, the two remaining alkoxide ligands are replaced by
hydroperoxide and allylic alcohol.
r.d.s
Epoxy alcohols are replaced by more allylic alcohol and TBHP to regenerate the
“loaded” (active) complex and complete the catalytic cycle.
CATALYTIC OXIDATION
The olefin works as a nucleophile toward the activated peroxide oxygen in the epoxidation:
unsubstituted cinnamyl alcohol ; the relative rate =1.0
Electron withdrawing p-nitro group; the relative rate = 0.4
Electron donating p-MeO group; the relative rate 4.4
If two double bonds are available,
the epoxidation takes place rather
on a propenyl than a vinyl group.
This is consistent with the
nucleophilic role of olefin.
Rapid exchange reactions make the characterization of the catalyst structure
extremely difficult. The major molecular species in solution is dimeric composite
Ti2(tartrate)2(OR)4.
This structure has C2 axis of symmetry (with two titanium atoms in identical
stereochemical environments). Fluxional equilibrium proposed is shown in the figure.
CATALYTIC OXIDATION
In active form the orientation of the hydroperoxide and substrate is a crucial issue. Three
coordination sites, two axial and one equatorial become available by exchange of two
isopropoxides and dissociation of the coordinated ester carbonyl group.
The reactions cause only minimal disturbance to the rest of the molecule.
Coordination of the hydroperoxide is considered to bidentate. It must occupy the
equatorial and one of the available axial coordination sites, with allylic in the
remaining axial site.
To achieve the oxygen transfer, the distal oxygen is placed to equatorial site. The
axial site is at lower face of the complex is chosen for the peroxide because of the
large steric demand of the t-Bu group in comparison to allylic alcohol.
CATALYTIC OXIDATION
The L-(+)-tartrate ligand (L-(+)-DET), on the other hand, allows the bottom face of the
olefin to be epoxidised. When achiral allylic alcohols are employed, the Sharpless
reaction exhibits exceptional enantiofacial selectivity (ca. 100:1) and provides
convenient access to synthetically versatile epoxy alcohols.
The emergence of the powerful Sharpless asymmetric epoxidation in the 1980s has
stimulated major advances in both academic and industrial organic synthesis. Through
the action of an enantiomerically pure titanium-tartrate complex, a myriad of achiral
and chiral allylic alcohols can be epoxidised with exceptional stereoselectivity. Interest
in the Sharpless epoxidation as a tool for industrial organic synthesis increased
substantially after Sharpless et al. had discovered that the asymmetric epoxidation
process can be conducted with catalytic amounts of the enantiomerically pure
titanium-tartrate complex simply by adding molecular sieves to the epoxidation
reaction mixture.
Using this practical and reproducible catalytic variant, an industrial process for ton-
scale productions of (S)- and (R)-glycidol and (S)- and (R)-methylglycidol has been
developed. These low molecular weight epoxy alcohols are versatile building blocks for
the synthesis of a number of chiral molecules. As an example glycidol is used in the
pharmaceutical industry to produce β-blockers, used as heart medicines.
Another successful industrial application of the Sharpless epoxidation, is the synthesis
of (7R,8S)-disparlure, the pheromone of the gypsy moth.
CATALYTIC OXIDATION
The cis dihydroxylation of olefins first reported early last century is another most
useful oxidation reaction. It converts an olefin to a vicinal diol present in many natural
products and unnatural molecules. The original dihydroxylation reaction used
stoichiometric amounts of osmium tetroxide (OsO4), which is expensive, volatile and
toxic, with the result that even small-scale reactions were inconvenient.
CATALYTIC OXIDATION
The cis dihydroxylation of olefins first reported early last century is another most
useful oxidation reaction. It converts an olefin to a vicinal diol present in many natural
products and unnatural molecules. The original dihydroxylation reaction used
stoichiometric amounts of osmium tetroxide (OsO4), which is expensive, volatile and
toxic, with the result that even small-scale reactions were inconvenient.
However, the dihydroxylation shows specificity for double bonds and has no particular
substrate requirements, which were advantages. Over the years, the original
dihydroxylation procedure has been modified to operate catalytically, more rapidly,
and in better yield.
Methods for the conversion of olefins to diols with only catalytic amounts of osmium
tetroxide and a stoichiometric co-oxidant have been known almost as long as the
reaction itself. Criegee first observed that the addition of amines, such as pyridine, to
the dihydroxylation reaction increases its rate. Presumably this is due to the formation
of an electron-rich coordination complex with the osmium atom. A useful
stoichiometric co-oxidant is N-methylmorpholine N-oxide (NMO).
CATALYTIC OXIDATION
The first attempt at non-enzymatic asymmetric dihydroxylation utilized a
chiral, enantiomerically pure pyridine to determine if this induced asymmetry
in the diol.
A modest ee was obtained. However, the cinchona alkaloid ligands proved to
have more balanced properties and gave more pronounced ”ligand
accelerated catalysis”.
This concept was introduced by Sharpless in the same paper where he
reported the first catalytic asymmetric dihydroxylation. The seemingly trivial
marriage of the Sharpless cinchona alkaloid stoichiometric dihydroxylation
process (now optimized with the ligand) with the practical qualities of NMO
resulted in good yields and moderate to good enatiomeric excesses.
CATALYTIC OXIDATION
A [3+2]-cycloaddition with the alkene (3) gives the cyclic intermediate 4. Basic
hydrolysis liberates the diol (5) and the reduced osmate (6). Finally, the
stoichiometric oxidant regenerates the osmium tetroxide – ligand complex (2).
CATALYTIC OXIDATION
The first attempt at non-enzymatic asymmetric dihydroxylation utilized a
chiral, enantiomerically pure pyridine to determine if this induced asymmetry
in the diol.
A modest ee was obtained. However, the cinchona alkaloid ligands proved to
have more balanced properties and gave more pronounced ”ligand
accelerated catalysis”.
This concept was introduced by Sharpless in the same paper where he
reported the first catalytic asymmetric dihydroxylation. The seemingly trivial
marriage of the Sharpless cinchona alkaloid stoichiometric dihydroxylation
process (now optimized with the ligand) with the practical qualities of NMO
resulted in good yields and moderate to good enatiomeric excesses.
CATALYTIC OXIDATION
Since Sharpless’s discovery of the chirally catalyzed dihydroxylations, there has
been considerable progress with respect to the understanding of the reaction
mechanism.
Better ligands have been designed and procedures have been improved making
Sharpless’s catalytic asymmetric dihydroxylation an extremely useful reaction.
CATALYTIC OXIDATION
In general, Sharpless asymmetric dihydroxylation favors oxidation of the more
electron-rich alkene
CATALYTIC OXIDATION
EPOXIDATION OF UNFUCTIONALIZED OLEFINS
Enantioselective epoxidation of unsubstituted alkenes is an appealing strategy for the
synthesis of optically active compounds.
Iodosylmesitylene as a
stoichiometric oxidant
After Sharpless results, the methods for epoxidation of unsubstituted alkenes were
looked for. Fe(III) porphyrin complexes are model for cytochrome P450 and received a
lot attention for the reaction.
CATALYTIC OXIDATION
Cis olefins are more reactive than trans olefins. This suggests a side-on approach of the
olefin towards iron-oxo intermediate.
The porphyrine ligand is symbolized by the heavy line.
The side-on approach is supported by the X-ray structure below.
CATALYTIC OXIDATION
Vaulted binaphthyl derivatives were developed:
79 ee for p-Cl- styrene
72% ee for β-methyl styrene (-15 ˚C)
The wedgelike pocket (sterics) was rationalized as a reason for ee.
CATALYTIC OXIDATION
The lack of selectivity with tert-butyl ethylene suggests that epoxidation by oxo-
transfer reaction might proceed with an different mechanism.
CATALYTIC OXIDATION
An impressive series of other chiral porphyrin derivatives bearing conformationally
restricted bridged ligands.
CATALYTIC OXIDATION
The catalysts tend to be unstable in the oxidation conditions
ees were low
Conversions were low
(extremely) low yields in complex synthesis
CATALYTIC OXIDATION
To avoid sensitivity in oxidation a “chiral wall” catalyst was designed.
Unfortunately, ees were below 40%
Even for cis-β-methyl styrene.
TON= 3000
CATALYTIC OXIDATION
Oxidation is one of the major chemical transformations.
An example of the D4 symmetric
systems.
It is robust (TON = 2000) and ees are up
to 76% for β-methyl styrene.
CATALYTIC OXIDATION
Chiral salen complexes bear tetravalent and thus potentially
stereogenic carbon atoms in the vicinity of the metal centre.
They are easy to synthesize.
CATALYTIC OXIDATION
CATALYTIC OXIDATION
CATALYTIC OXIDATION
CATALYTIC OXIDATION
Diphenylethylenediamine derivative 13 was one of the first chiral epoxidation catalysts
based on Mn salen. Trans-stilbene afforded promising (33% ee) results.
Introduction of tert-butyl
groups to 3,3’ positions
increased the selectivity.
(salen)Mn(V) oxo-
intermediate
To improve selectivity,
bulky substituents like
in 41-43 were
introduced. No success,
even the activity went
down.
How about unhindered
catalysts (49-53)? No
success.
CATALYTIC OXIDATION
CATALYTIC OXIDATION
CATALYTIC OXIDATION
65 was designed to prevent all side on approaches except D. In deed this is the most
selective catalyst so far.
CATALYTIC OXIDATION
Because the ees are so high, epoxidation seems to go via a single pathway.
Because of high ee, last two mechanisms seem unlike. High ee needs a highly ordered
stereo-determining transition state (with covalent bonding?)
CATALYTIC OXIDATION
Because alkyl substituted cis
olefins are reacted
stereospecifically, but cis aryl
substituted olefins give varying
amounts of trans epoxides, the
results discriminate the (a)
mechanism.
CATALYTIC OXIDATION
Formation of trans epoxides from cis olefins.
CATALYTIC OXIDATION
CATALYTIC OXIDATION
Oxidation is one of the major chemical transformations.
CATALYTIC OXIDATION