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Title: Asymmetric synthesis
Description: Well comprehensive notes on Asymmetric synthesis
Description: Well comprehensive notes on Asymmetric synthesis
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Asymmetric Synthesis
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Asymmetric Synthesis
What is Asymmetric Synthesis?
Asymmetric synthesis relates to any synthetic process that
introduces one or more new elements of chirality during a
functional group transformation
...
Prior to the development of efficient methods of asymmetric
synthesis, resolution was used to access enantiopure
molecules
...
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Asymmetric Synthesis
Why is Asymmetric Synthesis Important?
The ability to synthesize single enantiomers of chiral molecules
is important since biological systems, where they are intended
for application, are also chiral
...
Example
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Asymmetric Synthesis
The Way Forward in Asymmetric Synthesis
To access enantiomerically pure molecules for biological
applications as drugs, sweeteners and moisturizers, there is
need for adoption of efficient strategies for asymmetric
synthesis
...
Common chiral starting materials derived from nature include
amino acids, chiral carboxylic acids and monosaccharides
...
The chiral centre(s) in the starting material are (but not all are
always) preserved in the target molecule (TM)
...
The new chiral centres can be generated through substitution
or addition reactions
...
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Chiral Pool Synthesis
Functional Group Interconversion
Chiral pool synthesis of the essential amino acid, L-lysine from
the natural non-essential amino acid L-serine can also be
achieved
...
Asymmetric Synthesis
SN2 Reactions: Strong Nucleophile Needed
A nucleophile is an electron rich species that has a negative
charge or at least a lone pair of electrons
...
It avoids steric hinderance if
it is smaller or linear
...
Nucleophilicity decreases across
the periodic table (C > N > O > F)
3) Polarizability- The more polarizable an atom is, the more
nucleophilic it will be
...
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Asymmetric Synthesis
Synthetically Important Nucleophiles
Nucleophile Source
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Synthetic Targets
-SH
NaSH
Thiols such as cysteine
RS-
RSNa
Thioglycosides
I-
NaI
Alkyl iodides
Br-
NaBr
Alkyl bromides
-CN
NaCN
Cyanohydrins and 1o amines
-N3
NaN3
Chiral amines and amino acids
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Asymmetric Synthesis
SN2 Reactions: Good Leaving Groups Needed
A leaving group is an atom (or a group of atoms) that is displaced as stable
species taking with it the bonding electrons
...
g
...
g
...
The better the leaving group, the more likely it is to depart: The more the
stable a Lvg- is, the more it favours its "leaving"
...
Some of the strongest organic acids are the sulphonic acids
...
These functional groups have to be converted into good leaving
groups that can be used in substitution reactions
...
Any synthetic success dictates for a judicious introduction of
protecting groups in the starting material to assist subsequent
4:06 PM functionalization to the target molecule
...
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Chiral Pool Asymmetric Synthesis
Synthesis of Natural Amino Acids
The chiral pool synthesis of L-alanine from L-lactic acid can be
achieved via double inversion through an iodide
...
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Chiral Auxiliary Approach to Asymmetric
Synthesis
What is a Chiral Auxiliary?
A chiral auxiliary is a chiral molecular unit that can be
temporarily incorporated in an achiral substrate to guide
selective formation of one of a possible pair of enantiomers
...
Examples of chiral auxiliaries used in the alkylation of enolates
...
Since the chiral auxiliary is enantiopure, the two trajectories are
not equivalent but diastereomeric
...
The stereochemistry of the new chiral centre can be
rationalized based on steric considerations
...
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Chiral Auxiliary Approach
Asymmetric Synthesis of an Antiepileptic Drug
The antiepileptic drug, levetiracetam, can be synthesized based
on the chiral auxiliary approach outlined below
...
Steric bias plays a
major role in facial differentiation
...
This is one property that many strategies in asymmetric
synthesis have in common
...
Since diastereomers have
different reactivities, there will be preferential formation of one
diastereomer
...
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Terminology of Chiral Auxiliary Approach
to Asymmetric Synthesis
Enantiomeric excess (ee)
The enantiomeric excess (ee) is defined as the excess of one
enantiomer over the other generated in an enantioselective
reaction and is usually expressed as a percentage of the whole
...
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Chiral Auxiliary Approach to Asymmetric
Synthesis
Advantages of Using Chiral Auxiliaries
(a) The levels of diastereofacial control in the reactions are
usually high leading to high ee
...
(c) Chiral auxiliaries can be recycled (re-used) thus reducing the
expenses of buying the chiral reagent routinely
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Chiral Auxiliary Approach to Asymmetric
Synthesis
Disadvantages of Using Chiral Auxiliaries
(a) Both enantiomers of a chiral auxiliary are usually not readily
available
...
(b) Chiral auxiliaries need to be synthesized
...
The chiral auxiliary has to
be introduced and then removed once it purpose has been
accomplished
...
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Title: Asymmetric synthesis
Description: Well comprehensive notes on Asymmetric synthesis
Description: Well comprehensive notes on Asymmetric synthesis