Retrosynthesis by Professor Beubenz

Retro Synthesis by #PROFESSSOR_BEUBENZ
RSCP, BULDHANA Page 1
Organic Synthesis by Retro Synthesis
Sant Gadge Baba Amravati University, Amravati
B PHARM 3RD
YEAR
By:
Mr. S. L. KHAN M PHARM (PhD),
ASSISTANT PROFESSOR,
PHARMACEUTICAL CHEMISTRY DEPARTMENT,
RAJARASHI SHAHU COLLEGE OF PHARMACY, BULDHANA
Subscribe to the YouTube Channel #PROFESSOR_BEUBENZ
https://www.youtube.com/channel/UC84jGf2iRN5VjwnQqi6qmXg?view_as=subscriber

ORGANIC SYNTHESIS
The preparation of a desired organic compound from a readily available starting material is known
as organic synthesis.
[Synthesis---- singular]
[Syntheses--- plural]
DESIRED ORGANIC COMPOUND
The compound which we wish to prepare is called Desired Organic Compound OR Target Molecule.
Desired Organic Compound is denoted by TM.
BOND POLARITY (Polar covalent bond)
Most heteroatoms are more electronegative than carbon i.e. O, Br, Cl, I etc…
Partial positive charge appears on carbon (δ+).
BOND POLARITY (Polar covalent bond)
Si, Mg, Li are electropositive compared with the carbon.
The polarity in this case is reversed partial negative charge appears on carbon (δ-).

RETROSYNTHETIC ANALYSIS or RETROSYNTHESIS
“The process of WORKING BACKWARD from the TM in order to devise suitable synthetic route”
OR
“The process of mentally breaking down a molecule into a starting material”
OR
“It is a problem solving technique for transforming the structure of a synthetic target molecule (TM) to a
sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially
available starting materials for a chemical synthesis”

ARROW NOTATION
Simple reaction arrow “reacts to give”
Delocalisation arrow “two different ways to draw the same
delocalised structures”
Equilibrium arrow “two structures are interconverting”
Curved arrow “motion of two electrons”
Fish-hook arrow “motion of one electron”
Retrosynthesis arrow

INTRODUCTION TO SOME BASIC TERMS
Target molecule (TM): the molecule to be synthesized
Retrosynthetic analysis or retrosynthesis: the process of mentally breaking down a molecule
into a starting material
Disconnection: an imaginary bond cleavage corresponding to a reverse of a real reaction
Functional Group Interconversion (FGI): the process of converting one functional group into
another by substitution, addition, elimination, reduction, or oxidation
Transform: the exact reverse of a synthetic reaction
Retron: structural subunit on the target that enables a transform to operate
Synthon: idealized fragment resulting from a disconnection, which is related to possible
synthetic operations
Umpolung: reversal of normal polarization of a molecule or synthon
Reagent: a real chemical compound used as the equivalent of a synthon
Synthesis tree: set of all the possible disconnections and synthons leading from the target to the
starting materials of a synthesis
Total synthesis: the chemical synthesis of a TM from relatively simple starting materials
Formal total synthesis: the chemical synthesis of an intermediate that has already been
transformed into the desired target
Linear synthesis: a synthesis of consecutive steps
Convergent synthesis: a synthesis involving the assembly of fragments

RETROSYNTHETIC ANALYSIS CAN BE DONE BY TWO METHODS:
a) Disconnection
b) Functional Group Interconversion (FGI)
a) Disconnection
It is a paper operation involving an imagined cleavage of a bond.
As a result of disconnection usually negative ion and positive ion are formed which are called ‘SYNTHONS’
Disconnection is shown by a wavy line like ~ or VVVVVVVV
PUZZLE (Target Puzzle) PUZZLE (Disconnection)

•Functional group interconversion (FGI)
•Functional group combination (FGC)
•Functional group addition (FGA)
DISCONNECTION OF C-C
b) Functional Group Interconversion (FGI)
The process of writing one functional group for another to help synthetic planning is known as FGI.
FGI can be done by,
SYNTHONS
These are idealized fragments
Synthons are shown by a + or – sign like anion or cation (Not real anion or cation)
May or may not be intermediate in the corresponding reactions.

SYNTHETIC EQUIVALENT
The actual compound used to function as synthon
Denoted by a triple line
Known as REAGENT
SYNTHONS & SYNTHETIC EQUIVALENTS
Eg:
RULES FOR DISCONNECTIONS (RETROSYNTHETIC ANALYSIS)
The hardest task in designing a retrosynthetic analysis is spotting where to make the disconnections. We shall
offer some guidelines to help you, but the best way to learn is through experience and practice.
•Guideline 1
Disconnections must correspond to known, reliable reactions
The disconnections must correspond to known reliable reactions and it’s the most important thing to bear in
mind when working out a retrosynthesis.

Eg:
•Guideline 2
For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom
In all the retrosynthetic analyses if there is a heteroatom (N, O or S) joining the rest of the molecule together, so
in each case have to make the disconnection next to that N, O or S. This guideline works for esters, amides,
ethers, amines, acetals, sulfides, and so on, because these compounds are often made by a substitution reaction.
Using Guideline 2 we can suggest a disconnection next to the sulfur atom; using Guideline 1 we know that we
must disconnect on the alkyl and not on the aryl side.

We can now suggest reagent corresponding to the synthons & propose a synthetic scheme:
Note: You shouldn’t have expected to predict that sodium ethoxide would be the base used for this
reaction, but you should have been aware that a base is needed, and have had some idea of the base
strength required to deprotonate a thiol.
The next example is the ethyl ester of, and precursor to, cetaben, a drug that can be used to lower blood lipid
levels. It is an amine, so we disconnect next to the nitrogen atom.
The alkyl bromide is available but we shall need to make the aromatic amino-ester and the best disconnection
for an ester is the C–O bond between the carbonyl group and the esterifying group.

We have now designed a two-step synthesis of our target molecule, and this is how it was carried out.
•Guideline 3
Consider alternative disconnections and choose routes that avoid chemoselectivity problems—often this
means disconnecting reactive groups first
Disconnection (e) requires alkylation of a compound that is itself an alkylating agent. Disconnection (f) is much
more satisfactory, and leads to a compound that is easily disconnected to 4-hydroxyphenol (para-cresol) and
1,2-dibromethane. Using Guideline 3, we can say that it’s best to disconnect the bromoethyl group (f) before the
benzyl group because the bromoethyl group is more reactive and more likely to cause problems of
chemoselectivity.

FUNCTIONAL GROUP INTERCONVERSION
The antihypertensive drug ofornine contains an amide and an amine functional group, and we need to decide
which to disconnect first. If we disconnect the secondary amine first (b), we will have chemoselectivity
problems constructing the amide in the presence of the resulting NH2 group.
Yet disconnection (a), on the face of it, seems to pose an even greater problem because we now have to
construct an amine in the presence of an acyl chloride! However, we shall want to make the acyl chloride from
the carboxylic acid, which can then easily be disconnected to 2-aminobenzoic acid (anthranilic acid) and 4-
chloropyridine.
The retrosynthetic transformation of an acyl chloride to a carboxylic acid is not really a disconnection because
nothing is being disconnected. We call it instead a functional group interconversion, or FGI, as written above
the retrosynthetic arrow. Functional group interconversions often aid disconnections because the sort of reactive
functional groups (acyl chlorides, alkyl halides) we want in starting materials are not desirable in compounds to
be disconnected because they pose chemoselectivity problems. They are also useful if the target molecule
contains functional groups that are not easily disconnected.

TWO-GROUP DISCONNECTIONS:
Retrosynthetic Analysis of Propranolol:
The drug propranolol is a beta-blocker that reduces blood pressure and is one of the top drugs worldwide. It has
two 1,2-relationships in its structure but it is best to disconnect the more reactive amine group first.
The second disconnection can’t make use of an epoxide, but a simple ether disconnection takes us back to 1-
naphthol and epichlorohydrin, a common starting material for this type of compound.

•GUIDELINES FOR GOOD DISCONNECTIONS
1. Disconnections must correspond to known, reliable reactions
2. For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom
3. Consider alternative disconnections and choose routes that avoid chemoselectivity problems—often
this means disconnecting reactive groups first
4. Use two-group disconnections wherever possible
SUMMARY
1. Use disconnections corresponding to known reliable reactions with the highest yields.
2. Disconnect C-C bond according to the FGs present in the molecule, take into account and exploit the
relationship between the FGs. Correlate synthons with appropriate synthetic equivalents.
3. Employ Functional Group Interconversions (FGI), including Functional Group Removal (FGR), as necessary
to get useful FGs, use Functional Group Addition (FGA) to install a required FG.
4. Aim for simplification:
 Disconnect C-X bonds,
 Disconnect rings from chains,
 Use symmetry,
 Disconnect at a branch point,
 Separate into equal sized pieces,
 Use rearrangements.
5. Try to find a key disconnection that would bring a considerable simplification to the structure or reveal
simple starting materials.
6. Whenever possible, plan a convergent synthesis.

RETRO SYNTHESIS OF IBUPROFEN:
Using retrosynthetic principles we need to remove the acid functionality. A guiding principle in retrosynthetic
anaysis is removing reactive functionality as soon as possible (to avoid side reactions) and this has the added
benefit of changing the oxidation state of the carbon to that of an epoxide (one of our starting materials).
In the forward direction this could be oxidation with Jones reagent.
The next disconnection removes the 3-carbon fragment. The forward reaction is Frieden-Crafts alkylation using
an acid to activate the epoxide (secondary carbocation more stable than a primary carbocation).
Again we remove this fragment (right hand side) so that we remove the reactive functionality (the alcohol).
Additionally, the left hand subunit is ortho/para directing.
Why don’t we add the ketone back into the molecule?
A ketone is meta directing and we would have the problem of attempting a chemoselective
reduction.

Another functional group interconversion prepares the molecule for the Friedel-Crafts acylation disconnection.
We cannot directly add the alkyl unit via a Friedel-Crafts alkylation (see right) as it is liable to rearrange to the
more stable cation.
We cannot add the epoxide unit to the ketone (bottom right) as this would give the wrong regiochemistry.

A potential synthesis of ibuprofen is shown here. Friedel-Crafts acylation is followed by ketone reduction
(hydrogenation would probably work as well as the Wolff-Kishner reaction or the silanemediated reduction).
Friedel-Crafts alkylation with the epoxide followed by oxidation gives the desired compound.
RETRO SYNTHESIS OF CIPROFLOXACIN:
Ciprofloxacin(TM)

TOTAL SYNTHESIS OF CIPROFLOXACIN:

RETRO SYNTHESIS OF SULFAMETHOXAZOLE:
DISCONNECTION SCHEME:

TOTAL SYNTHESIS FROM RETRO SYNTHETIC SYNTHONS:
Question Bank from University Exam
1) Derive Retrosynthetic pathway for Ciprofloxacin along with synthetic equivalents.
2) Write Retrosynthetic pathway for Losartan.
3) Discuss disconnections involving two functional groups with suitable examples. Write rules for
Disconnection.
4) Derive Retrosynthetic pathway for Propranolol.
5) Explain Disconnection methods.
6) Write retrosynthetic pathway for Sulfamethoxazole.
7) Write a short note on rules of disconnection.
8) What is retrosynthesis? Synthesis the Propranolol & Ciprofloxacin by retrosynthetic route.

Retrosynthesis by Professor Beubenz

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Retrosynthesis by Professor Beubenz

Similar to Retrosynthesis by Professor Beubenz (20)

Recently uploaded

Recently uploaded (20)

Retrosynthesis by Professor Beubenz