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Retrosynthesis
1. Synthon approach
Dr. Taj Khan
Dept. of Pharmaceutical Chemistry,
Oriental college of pharmacy
Sanpada, New Mumbai.
Ref: Stuart Warren , Iyer R P
2.
3. Retrosynthesis is the process of “deconstructing” a target molecule into readily
available starting materials by means of
imaginary breaking of bonds (disconnections) and
by the conversion of one functional group into another (functional group
interconversions).
Its useful for finding out new route for synthesis of new drugs or existing drugs and
comparing them in logical & straightforward way
An operation that involves breaking of a bond between 2 atoms to produce
oppositely charged synthons.
Indicates disconnection
Functional group interconversion (FGI): process of converting 1 fun grp into
another by substitution, addition, elimination, oxidn or redn. Reverse operation is
used in analysis
4. Terms for Synthesis Retro analysis
Starting structure SM Target
Steps Rx Transformation/dis
connection
Steps shown by
Stru features
needed
Fun grp Retron
Prdt after the step intermediate Precursor/ Synthon
Ending stru Desired prdt Possible SM
5. Disconnection: An analytical operation, which breaks a bond and converts a
molecule into a possible starting material. The reverse of a chemical reaction. Symbol
and a curved line drawn through the bond being broken.⇒
FGI: Functional Group Inter-conversion: The operation of writing one functional
group for another so that disconnection becomes possible. The reverse of a chemical
reaction. Symbol with FGI written over it. –COOH -CN, -NH⇒ ⇒ 2 NO⇒ 2 -H⇒
Target Molecule: The molecule whose synthesis is being planned
Functional grp addition: process in which functional grp is addedin the retro scheme
in order to make stable fragment e.g. addition of COOEt grp
Functional grp removal: removal of fun grp in order to make stable fragment
6. Transform: reverse of synthetic rx
Retrosynthetic analysis: Logical process of analysing stru of TM to transform the target to a
sequence of progressively simpler stru along a pathway which finally give simple & comm
viable SM.
“process of breaking down TM into available SM by FGI & disconnection”
7. Synthon: A generalized fragment, usually an ion
(cation/anion/radical), produced by a disconnection. (some people also
use synthon for a synthetic equivalent).
2 types
dn Synthon (d= donor n= distance bet FG & reactive centre)
functionalized Nu
an Synthon ( a= acceptor ) functionalized E+
8. Reagent: A compound which reacts to give an intermediate in the planned synthesis or to
give the target molecule itself. The synthetic equivalent of a synthon. e.g. MeI is reagent for
Me+
Synthetic equivalent (SE ) A reagent carrying out the function of a synthon which cannot
itself be used, often because it is too unstable. Every synthon has its SE
H2SO4 and HNO3 mixture is SE of NO2
+
Retron: Minimal stru in mole in TM which causes transformation e.g. in Deil’s Alder rx 6
memb ring with pie electrons
B: SM and A TM
Arrow: it could be made from
Synthetic tree: Set of all possible disconnections and synthons leading from
TM to SM
9. Strategies for disconnection approach:
1) Simple route: good for industrial purpose. Avoid radical and photochemistry.
2) Disconnection shd be done such that it gives stable ion fragments. Break down
molecule 1 bond at a time. For heterocyclic compd disconnection is done such that 2
fragments in which 1 is +ve and other is -ve fragments generated e.g disconnection of
C-C bond
10. Strategies for disconnection approach:
contd
Stability of ion generated governs the mode to be followed
Carbanion (C-) fragment is stabilized by EWG like CN, NO2, COOEt
Carbonuim ion (C+) fragment stabilized by EDG or e releasing grp like R or OR
In this case route 1 is preferred because it gives Stabilized ion fragment , whereas route 2
gives both unstabilized fragments
3) No of fragments generated shd be small in number as possible i.e. few steps strategy is
preferred.
11. Examine
1) mole as whole
2) watch various fun grps and
3) positional relationship between fun grps
12. 4) C-C db can be considered to result from dehydration, dehydrohalogenation or
Elimination of NH3, NH2OH....etc.
Addition of mole of water or NH3 to db can set up the target for further disconnection
5) A bond joining a C atom to hetero atom (O, N, S) is always broken with electron pair
remaining on hetero atom i.e. hetero atom shd have –ve charge
In this case disconnection follows principle of electronegativity i.e O, N, S > C
13. 6) Sometimes disconnection does not generate stable fragments in such cases FGI concept
can be used to generate stabilized ion fragments
e.g. synthesis of alkylamine
14. 7) Fun grp addition: Sometimes disconnection does not generate sufficiently stable
fragments in such cases stability could be achieved by introducing additional EWG &
removing after use.
15. 8) In some cases reconnection of acyclic fragments can help to generate cyclic fragments that
could result in simpler starting material & Rxn sequences. Of course, strategy must be in place
for conversion of acyclic to cyclic fragments during synthetic sequence.
16.
17. Retro analysis followed by synthesis:
One grp disconnection (C-X disconnection)
Disconnection of simple alcohols, alkyl halide, ethers
Alkyl halide:
C-X disconnection in aliphatic compds gives a Nu (XH) &
E+
carbon species usually represented by alkyl halide, tosylate and mesylate
26. Rings (5 & 6 membered), fused heterocyclic rings –more
common in drugs
3 & 4 memb less common tranyl cypromine (3 C) Beta
lactum ring (4C)
Retrosynthesis:
1) Follow similar rules with additional possibilities.
2) Rich in functional grps so handle only readily predictable
fragments like NH3, NH2NH2, NH2OH, guanidine, thiourea,
(NH2)2(CH2)2, HO(CH2)2NH2
3)Break C-Het
4) Addition of H2O to db ( NH3, NH2OH etc)
5) 3-component cyclization, DA rxn, 1,3 dipolar rxn
C+
+ -
Hetero atom
48. Strategies:
Guiding principles for selection of transform so as to keep size of retero-synthetic tree in control
Types of strategies in disconnection:
1)Transform based strategies depend on application of powerfully simplifying transformation
like DA, Robbinsons annulation, Birch rx
2)Structure based strategies depend on recognition of possible SM /key intermediate for synthesis
3) Functional grp based strategies identify functional grp as key structural subunit
OH, C=O , = etc can be useful for identifying suitable pts for disconnection
4) Topological based strategies depends on identification of 1/more individual bond disconnection
Or correlated bond-pair disconnection.
There are several types of strategic bonds e.g. bonds in polycyclic syst, poly fused ring syst, bond
connecting chai to ring, chain to fun grp
5) Stereochemical based strategies remove stereocenters stereorelationships under control.
Stereocontrol can be achieved by mechanistic or by substrate. Reconnection that moves
stereocenters from chain (where they r difficult to introduce) or into rings (where introduction
is much easier)
49. Basic rules of disconnection:
Rule 1: Bond shd be disconnected such that stable fragment(ion) obtd
Route A ok as carbcation stabilized by EDG like OR
Carbanions are stabilized by EWG like NO2, Cl
50. Rule 2: Total no of fragments shd be as min as possible i.e. synthesis shd be short. Disconnection
shd be made in middle of mole/ at branch pt
51. Rule 3: compds with 2 parts joined with hetero atom, disconnection shd be next to hetero atom,
e pair remain with het atom (het atom more negative than C & so accommodate -ve charge easily)
52. Rule 3: If disconnection doesn’t give stable fragment then FGI done/ simple grps introduced so
as to give stable fragments
53. Rule 5: Use disconnections corresponding to known reliable rx with high yields. +ve & -ve
fragments generated by disconnection r replaced by known available chemicals.
56. Rule 6: Disconnection route that avoid chemoselectivity (Rx of 1 fun grp in presence of other)
shd be selected. For this reactive grps r disconnected first & 2 grp disconnection is done.
Route a involve 2 OH selectivity problem so route b is better
59. Guidelines for disconnection:
G3: If FGI I needed it shd be done at proper stage to get right orientation. Other subs
added either before or after FGI
CCl3 is meta director (it is introduced by FGI)
CH3 is para director so FGI shd be done before C-Cl disconnection
60. Guidelines for disconnection:
G4: Avoid sequences that lead to unwanted rx at other site of mole
Route b is preferred as nitration e.g. benzaldehyde may lead to oxidation CHO oxidise to COOH
61. Guidelines for disconnection:
G5: when fun grp of unequal reactivity present in mole, more reactive grp to be considered for
Rx
e.g. In Phenyl ring containing both OH and COOH grps in basic soln (pH> 10) phenolate ion is
more reactive than carboxylate ion.
62. Guidelines for disconnection:
G6: For adding 2 O/ a P directing grp M to each other, dummy NH2 grp is added, which could
be removed by diazotization and reduction
64. Guidelines for disconnection:
G8: If 1 fun grp can react twice then SM & final prdt compete for same reagent. Rx will be
successful only when first prdt is less reactive than SM. Both contain COCl
Above Rx works as half ester TM is less reactive than phosgene b’se of conjugation
67. Disconnection involving 1 functional grp:
C-X Disconnection:
1) C-X means C joining to hetero atom X. It gives cationic Carbon syst
The reagent for R+ is good leaving grp attached to R
72. Disconnection involving 1 functional grp:
C-C Disconnection:
a) Disconnection should be of C-C bond adjacent to fun grp specially next to -OH, -C=O
73. Disconnection involving 1 functional grp: (Contd)
C-C Disconnection:
b) If C=C is a part of conjugated system involving hetero atom then C=C may be
converted to C(OH)-CH before disconnection
c) If there is a branching branch pt shd be disconnected to get unbranched C synthon
74. Disconnection involving 1 functional grp: (Contd)
C-C Disconnection:
d) In a conjugated/ non conjugate system, of double bond the disconnection of C=C can be
done without adding H2O to C=C part
e) It is better to cut TM in middle rather than making uneven parts
75. Disconnection involving 1 functional grp: (Contd)
C-C Disconnection:
f) Branches must be disconnected from rings
g) Disconnect C-C bond bet 2 fung grp separated by NMT 3 other C atoms
76. Disconnection involving 2 functional grps:
1,1-dix: Synthons are obtd by 2 grp disconnection on single C atom. Acetal, cyanohydrin,
α hydroxy acid, α Amino acid, halohydrin r prepared from ald & ketone these TM need 1,1,dix
77. Disconnection involving 2 functional grps: Contd
1,2-dix: When 2 heteroatom r present on 2 adjacent C compound called 1,2 difunctionalised e.g.
78. Disconnection involving 2 functional grps: Contd
Disconnect C-C bond which has 1 hetero atom on each C
79. Disconnection involving 2 functional grps: Contd
1,3-dix (1,3 difunctionalized compounds)
In 3 carbon compound 2 het atom on 2 C at 1,3 position it is 1,3 difunctional compd
80. Disconnection involving 2 functional grps: Contd
1,4-dix (1,4 difunctionalized compounds)
In 4 carbon compound 2 het atom on 2 C at 1,4 position it is 1,4 difunctional compd
81. Disconnection involving 2 functional grps: Contd
1,5-dix (1,5 difunctionalized compounds)
1,5 Dicarbonyl compound can be disconnected at either α, β bond in reverse Michael Rx to give
Michael acceptor (a3 synthon)
82. Disconnection involving 2 functional grps: Contd
1,6-dix (1,6 difunctionalized compounds)
Such compound can be synthesised from Diels Alder Rx. Difficult synthon as C=O is
Electrophilic. Instead of disconnection Fun grp reconnection can be used.
