CH402 Asymmetric catalytic reactions Prof M. Wills

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CH402 Asymmetric catalytic reactionsProf M.
Wills
Think about chiral centres. How would you make
these products?
Think about how you would make them in racemic
form first, then worry about the asymmetric
versions! What does a catalyst need to be able to
provide in a catalytic version?
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Examples of reactions which form chiral centres
Hydrogenation of CC, CO, CN bonds
Epoxidation of CC bonds
Hydroboration of CC bonds
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Examples of reactions which form chiral centres,
cont
Hydrocyanation of CO bonds
Dihydroxylation of CC bonds
Addition of Grignard reagent to CO bonds
Hydrovinylation of CC bonds
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Examples of reactions which form chiral centres,
cont. 2
Enolate alkylation
Aldol reaction
Hydroformylation of CC bonds
Diels-Alder (cycloaddition)
And many, many more.
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What properties are required of an asymmetric
catalyst? Turnover, rate enhancement,
selectivity
The catalyst must recognise the reagents,
accelerate the reaction, direct the reaction to
one face of a substrate and release the product
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Asymmetric epoxidation of alkenes (1980s)
Mechanism? Could you modify this in an asymmetric
manner?
Sharpless discovered that a combination of
diethyl tartrate, titanium isopropoxide and a
peroxide. But it requires an allylic alcohol as
substrate. The oxidant is used stoichiometrically
(i.e. you need one equivalent), but the titanium
and tartrate are used in catalytic amounts (ca. 5
mol).
The (-)-diethyl tartrate gives the opposite
enantiomer.
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How the Sharpless epoxidation (of allylic
alcohols) works (catalytic cycle)
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Asymmetric epoxidation of alkenes using Mn/Salen
complexes (Jacobsen epoxidation)
The iodine reagent transfers its oxygen atom to
Mn, then the Mn tranfers in to the alkene in a
second step. The chirality of the catalyst
controls the absolute configuration. Advantage?
You are not limited to allylic alcohols.
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Asymmetric hydrogenation for the synthesis of
amino acids
Addition of hydrogen to an acylamino acrylate
results in formation of an amine acid precursor.
The combination of an enantiomerically-pure
(homochiral) ligand with rhodium(I) results in
formation of a catalyst for asymmetric reactions.
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Asymmetric catalysis - hydrogenation
Rh-diphosphine complexes control asymmetric
induction by controlling the face of the alkene
which attaches to the Rh. Hydrogen is
transferred, in a stepwise manner, from the metal
to the alkene. The intermediate complexes are
diastereoisomers of different energy.
Using Rh(DIPAMP) complexes, asymmetric reductions
may be achieved in very high enantioselectivity.
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Asymmetric catalysis - hydrogenation
Other chiral diphosphines are not chiral at P,
but contain a chiral backbone which relays
chirality to conformation of the arene rings.
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Asymmetric catalysis Ketone reduction
The reduction of a ketone to a secondary alcohol
is a perfect reaction for asymmetric catalysis
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Asymmetric catalysis Ketone reduction by
pressure hydrogenation (I.e. hydrogen gas)
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Asymmetric catalysis Isomerisation
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Asymmetric catalysis Organocatalysis (no
metals)
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Asymmetric catalysis Organocatalysis (no
metals)
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Asymmetric catalysis Organocatalysis Other
applications
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Asymmetric catalysis Enolate alkylation
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Asymmetric catalysis Enolate alkylation for
synthesis of amino acids.
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Asymmetric catalysis Addition to an aldehyde
(C-C bond forming reaction) for interest only.