what is retrosynthetic analysis?
Why stereochemistry is important in organic reactions?
Review of stereospecific and stereoselective reactions
Stereoselectivity in retrosynthesis
Types of selectivity
Stereoselectivity with examples
Enantioselectivity with examples
Diastereoselective with examples
Stereospecificity with examples
Chemistry of stereospecificity
Practice problem
2. CONTENT o what is retrosynthetic analysis?
o Why stereochemistry is important in organic reactions?
o Review of stereospecific and stereoselective reactions
o Stereoselectivity in retrosynthesis
o Types of selectivity
o Stereoselectivity with examples
o Enantioselectivity with examples
o Diastereoselective with examples
o Stereospecificity with examples
o Chemistry of stereospecificity
o Practice problem
o References
3. WHAT IS RETEROSYNTHETIC ANALYSIS?
Imaginary process by
which bonds are broken to
get simple possible starting
materials. Also called
retrosynthetic analysis or
disconnection approach.
A wiggly line is used at
point of disconnection of
bond & double line arrow
is used to represent the
disconnection.
5. In previous both examples we simply disconnected the bonds and write down the
starting materials which was possible.
In first example we knew that an ester can be made from alcohol and acyl chloride,
so we draw a wiggly arrow and write the reactants.
6. WHY
STEREOCHEMISTRY
IS IMPORTANT IN
ORGANIC
REACTIONS?
The biological properties of organic molecules depends on
there stereochemistry. This is true for drugs, insecticides,
plant growth regulator, perfumery and flavoring
compounds and all compounds with biological activity.
Like cis hydroxy aldehyde (1) has a strong and pleasant
smell and is used in lily of valley perfumes while the trans
isomer (2) is odorless.
7. STEREOSELECTIVE
AND
STEREOSPECIFIC
REACTIONS
Stereospecific reactions: reactions in which
the stereochemistry of starting material
determines the stereochemistry of the
products and no choice involved.
Stereoselective reactions: reaction in
which one stereoisomer is formed
predominantly over the other because the
reaction has choice of pathways and one
pathway is more favorable than the other.
This is got clear to us now we can move to
our topic which is stereoselectivity in
retrosynthesis of organic molecules.
retrosynthesis Of organic molecules
8. STEREOSELECTIVITY IN RETROSYNTHESIS
So selectivity is very important in retrosynthesis in this.
In some reactions we have to get specific products as in above discussed aldehyde we knew
that cis isomer has the desired properties of perfumery, so we want that isomer in excess or
selectively cis isomer not the trans one as it is odorless.
As in retro analysis we discuss the disconnection to understand how the product is formed. At
first, we disconnect the bonds, synthons are formed then we select the equivalent starting
material and we disconnect until we get the easily available starting material.
10. STEREOSELECTIVE
stereoselectivity is the property of a chemical reaction in which a single reactant forms an
unequal mixture of stereoisomers during a non-stereospecific creation of a new
stereocenter or during a non-stereospecific transformation of a pre-existing one.
The selectivity arises from differences in steric effects and electronic effects in the
mechanistic pathways leading to the different products. Stereoselectivity can vary in
degree but it can never be total since the activation energy difference between the two
pathways is finite. Both products are at least possible and merely differ in amount.
However, in favorable cases, the minor stereoisomer may not be detectable by the analytic
methods used.
11. CONTINUE..
E1 and SN1 are examples of this type of
reactions. In these after the formation of
carbocation in first step, there is possibility
of attack from both sides so two products
with inversion and retention of
configuration is formed.
12. FOR EXAMPLE
Like cis hydroxy aldehyde (1) has a strong
and pleasant smell and is used in lily of
valley perfumes while the trans isomer (2)
is odorless. So we must synthesize (1)
selectively rather than (2). because (1) has
desired properties.
13. ENANTIOSELECTIVE
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical
synthesis. It is defined as a chemical reaction in which one or more new elements of
chirality are formed in a substrate molecule and which produces the stereoisomeric
(enantiomeric or diastereoisomeric) products in unequal amounts.
An enantioselective reaction is one in which one enantiomer is formed in preference to
the other, in a reaction that creates an optically active product from an achiral starting
material, using either a chiral catalyst, an enzyme or a chiral reagent. The degree of
selectivity is measured by the enantiomeric excess. An important variant is kinetic
resolution, in which a pre-existing chiral center undergoes reaction with a chiral
catalyst, an enzyme or a chiral reagent such that one enantiomer reacts faster than the
other and leaves behind the less reactive enantiomer, or in which a pre-existing chiral
center influences the reactivity of a reaction center elsewhere in the same molecule.
14. CONTINUE..
So we have two enantiomers in unequal amounts in this selection and they are mirror images. Look at given
example down, two isomers of diol are formed from same alkene only by changing catalyst.
15. DIASTEREOSELECTIVE A diastereoselective reaction is one in
which one diastereomer is formed in
preference to another (or in which a subset
of all possible diastereomers dominates
the product mixture), establishing a
preferred relative stereochemistry.
In this case, either two or more chiral
centers are formed at once such that one
relative stereochemistry is favored, or a
pre-existing chiral center (which needs not
be optically pure) biases the
stereochemical outcome during the
creation of another. The degree of relative
selectivity is measured by the
diastereomeric excess.
17. STEREOSPECIFICITY
As we have defined in definition, stereospecificity is the formation of one specific product.
SN2 and E2 are examples of this type because specifically inversion product is formed.
18. CHEMISTRY OF
STEREOSPECIFICITY
If we want to make a single diastereomer we can
reverse the type of reaction. So instead of making
single geometry from a single alkene
diastereomer, we can make a single alkene
diastereomer from a single geometry.
Here is example, the electrophilic addition of
bromine to an alkene is stereospecific and anti
product is formed across double bond.
So if we want anti dibromide, we choose to start
with trans double bond and if we want syn
dibromide we choose cis double bond to start
with.
20. STEREOSPECIFIC REACTIONS
Know we shall use stereospecific to describe the reaction whose mechanism demands a specific
stereochemical outcome. This must result whether it leads to stable product or not and that each stereoisomer
of a starting material gives different stereoisomer of product. These may be
23. LET’S DISCUSS A PROBLEM
20 is pheromone of elm bark beetle.
It has four chiral centers. One of
them (a) is turned out to be
unimportant as disconnection of
acetal reveals 21, as true target. 21
cyclizes to form 20 no other
stereochemistry is possible.
27. CONTINUE..Now we need to remove
acetal from (27) and replace it
with a protecting group as
two OH groups are not
needed for next reaction. This
can be done
thermodynamically, treatment
of (27) with acid rearranges it
to (28) as five membered ring
is more stable than seven
membered ring. The free OH
group can be converted to
iodide (29) with known chiral
Now moving to next half of
synthesis to final product.
28.
29. CONTINUE..
This synthesis give 85%
of natural isomer with
only 15% of wrong
stereochemistry at
center b. the natural
isomer predominates
because it has an
equatorial methyl
group.
