SUSMI RETROSYNTHESIS PPT

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Retro synthesis. B.Susmitha(M.pharm) pharmaceutical chemistry k.V.S.R SCOPS , vijayawada Dr.B.Anupama.M.Pharm,Ph.D Assistant professor, Pharmaceutical chemistry, k.V.S.R SCOPS vijayawada

Contents::

Contents: Definition Basic terms used in retro synthesis Examples Disconnection rules Chemo selectivity Regio selectivity Strategic rules.

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DEFINATION: “retro synthetic analysis (or antithetic analysis) is a problem-solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis Time taken for the synthesis and yield of synthesis is very high in convergent synthesis

Basic terms used in retro synthesis::

Basic terms used in retro synthesis: Retrosynthesis : the exact reverse synthesis starting from target molecule(tm). In this imaginary process bond disconnection is done in the target molecule to give synthons (charged ions), and then a new but simple structure (synthetic equivalent) from which the target can be made is involved. Disconnection ( dix ): an analytical operation which breaks a bond and converts a molecule into a possible readily available starting materials by dissconection of a target molecule(tm), imaginary bond cleavage coresponding to the reverse of a reaction. Symbol used is double halo arrow . Ph OH DIX ph CH2 CH2OH - + TM SYNTHONS RMGX Ph-MG-X O SE’S +

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Synthon (SN): a generalized fragment usually an ion produced by disconnection. Synthon arises after imaginary bond cleavage may or may not be an intermediate in the real synthesis. Synthetic equivalent(SE) : an actual compound carrying out the function of a synthon , as it cannot itself be used because of instability. This is a logical precursor of a target molecule . CH3 . Reagent : a reagent is a compound which may act in the planned synthesis as per.. Condensing agent, cyclization, in ring opening, in ring contraction, in ring expansion, redox reagent, dehydrating agent, hydrating agent CH2CH2OH DIX CH3 - CH2OH + SYNTHONS - CH3MgBr CH2OH CH2O + +

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H - Reagent used is LIAlH4 Br CH2 - CH3 + N-bromo succimide is used Ph3p CH2 + - alkylidine triphenyl phosphorane CH3MgBr

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Target molecule(TM): the molecule whose synthesis is being planned . Functional group interconvertion (FGI): writing of one functional group for another so that disconnection becomes possible to get a starting material available in the market. FGI is necessary for functional group protection. -CH2OH FGI -COOet -COOH -CN FGI C6H5COOH FGI C6H5CN

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Functional group addition (FGA): acyclic or alicyclic saturated hydrocarbons are usually unreactive. Disconnection of such hydrocarbons are difficult because the hydrocarbon is a compound having no functional group which is guiding signal for disconnection. H OH FGA CH3-CH2 - + + OH CH3CH2MgBr CH3CHO FGA NH2 NO2 FGA FGI

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this FGA is two types: Type1 : FGA to the TM first and DIX done which gives recognizable SE Type2 : DIX is done to target molecule first and then FGA to the SN so that recognizable SE is possible. O H O COOet FGA O - COOet + CH3 + TM DIX SN CH3i o COOet o DIX CH3 + CH3I FGA FGA O COOet O - SE + TM

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Terms for Synthetic Retrosynthetic Starting structure Starting material Target Steps Reactions Transforms or disconnections Steps indicated by Structural features required Functional group Retron Product after the step Intermediate Precurssor or synthon Ending structure Desired product Probable starting material or synthetic equivalent

Examples::

Examples : O TRANSFORM TM O O PRECURSSORS O RETRON On examining the target molecule carefully we find that it contains a structural feature the c=c-c=o group based on knowledge of synthesis reaction tells us that a structural feature( retron ) is produced by an aldol condensation between the carbonyl compounds . So during disconnection this functionality is disconnected. 1)Aldol retron :

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CH3 CH3 O + CH3 H O O H H O PROPANONE ETHANOL C=C-C=O that is enone functionality is synthesized The target molecule is splitted into the simpler units and they may be joined together by aldol reaction in synthetic step. The structural feature is the aldol retron.

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COOH COOH COOH COOH Transform Synthons 2)Diels alder retron : 3)Michael retron: * O O O O SYNTHONS *The addition of alfa hydrogen atom adjacent to a carbonyl group to an alkene thus forming a new c-c bond known as michael addition Keeping the michael addition in mind we see that we can disconnect the molecule at the bond indicated by star to get the synthons . Thus c-c bond α , β to carbonyl group is identified as michael retron .

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*When a suitable retron cannot be identified in a molecule , then also suitable modification of the molecule through a synthetic step may be attempted to generate a retron O Br2 Alc.KOH -HBr O Enone form o o (A)Partial retron (B) (A) has no enone form so it is called as the partial retron after several transformations it is converted into full retron (enone form)called as the aldol retron that is c=c-c=0(B)

Disconnection rules::

Disconnection rules: 1) Dix is done mainly adjacent to the functional group i:e especially –OH and C=O. CH3CH2-OH- CH2CHO CH3CHOH + CH2CHO( Synthons ). 2 ) a c-c double bond may be converted to c(OH)-CH before dix if c=c is a part of a conjugated system involving hetero atom. . + - CH2OH + + - FGI

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3 ) In a conjugated or non conjugated system the dix of = carbons of c=c may also be done without adding H2O to c=c part. (CH3)2 C=CH CH3 (CH3)2 COH + CH2CH3 4) The branch point is to be disconnected to get unbranched C- synthons which are more likely to be available. . . + CH2CH2CH3 5) It is better to DIX towords middle of the target molecule rather than cutting off one or 2 carbon atoms from the end. CH3CH2CH2CH2CH2CH3 CH3CH2CH2 +CH2CH2CH3 + - - + _ +

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6) Branches may be disconnected from rings. + + 7) Symmetric target molecules may be DIX symmetrically: + - + 8) It is worth to disconnnect a c-c bond between two functional groups separated by not more than 3 other carbons. + + -

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C-C bond DIX should be according to fragmentations in target molecule The DIX should be done in such a way that the synthetic route will be as short as possible. ONE GROUP DISCONNECTIONS : disconnection of target molecule aiming one particular functional group i:e DIX in which involve only one functional group is called one group disconnection. + + Cl- ALCL3

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TWO GROUP DISCONNECTIONS: when a target molecule contain two functional groups and if DIX is done using the two together i:e using of one functional group to help disconnection of another is called two group disconnection. CH3CH2-OH- CH2CHO CH3CHOH + CH2CHO(Synthons) + - CH3CHO CH3CHO

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Example of retrosynthetic analysis:

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CHEMOSELECTIVITY: Chemo selectivity of a reagent is its ability to react with one functional group amongst two or more and the reagent is said to be a chemo selective reagent. Chemo selectivity is a means by which one functional group is made to react keeping others intact. Selectivity in functional group regions may be utilized successfully in synthesis by understanding the following guidelines. 1) stearic effect make an functional group to react but not others. et et COOH COOH MeOH et COOH et cooMe Sterically hindred

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2) when an functional has the ability to react more than once with the reagent the first product and the starting molecule compete with each other. If the starting molecule is more reactive than first formed product the reaction can be used successfully. When acetone is brominated under basic condition the reaction can be stopped at the monobromination since mono bromo derivative is more reactive than acetone. In acidic medium the reaction stops at the monobromo derivative & this is less reactive than acetone in the acidic medium. 3) If the compound contains two identical functional groups having unequal reactivity the more reactive ones will react preferentially.allylic bromo group is more reactive Br-CH2-CH2-CH=CH-CH2-Br Br-CH2CH2-CH=CH-CH2OAC AcONR4

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4) one of the two functional groups may be made to react if one equivalent of the reagent is used. 5) the more reactive functional group between two functional groups of unequal reactivity can be made to react alone eg ) amino group is more reactive for acetylation compared to OH group this is used for preparation of paracetamol an analgesic from para amino phenol OH O- OH 1.OH- 2.Me2so4 OMe O- OH OMe OMe 1. OH- 2.Me2SO4 2equivqlents AC2O NH2 NHAC OH OH

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6) it is better to convert a compound with an identical functional groups to a derivative which will react only once with the reagent . C C O O OH OH C C O O OET OET C C O O O but etOH/H+ C C O O O C C O O ETOH/H+ OH OET -H2O EtOH/H+

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7) the choice of solvents plays the vital role to obtain the desired selectivity of a reaction. For illustration sodium borohydride in diglyme reducesvan aldehyde carbonyl group but it fails to reduce a ketonic carbonyl group while in aqueous methanolic medium NaBH4 reduces both the functional groups.

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Regioselectivity: when in a reaction one constitutional isomer is formed predominantly amongst two or more constitutional isomers the reaction is said to be regioselective. markownikoffs addition , saytzeffs and Hoffmann's elimination are regioselective reactions. Saytzeffs rule : the more substituted alkenes are more stable Hoffmann's rule : less substituted alkenes are more stable. Markownikovs rule : in an addition of an acid to the c=c bond of an alkenes the hydrogen of the acid attaches itself to the carbon that already holds the greater number of the hydrogen's.

Strategic rules::

Strategic rules: Functional-group based strategies Topological strategies Transform-based strategies Structure-goal strategies Stereo chemical strategies

Strategic rules::

Strategic rules: Functional-group based strategies Functional groups in the target structure may direct the transform search in several ways: 1)Removal of reactive and masked functionality 2)Disconnection based on the location of functional groups 3)Reconnection of functional groups to form rings retrosynthetically The reconnective strategy is constrained by strategic rules. Clearly, it is not practical to attempt every possible reconnection. aldol michael

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Topological strategies The disconnection of specific, so-called `strategic' bonds can lead to major molecular simplification. There are several types of strategic bonds: Bonds in (poly)cyclic ring systems Bonds in (poly)fused ring systems Pairs of bonds in ring systems (disconnection by intermolecular cycloaddition transforms) Bonds connecting chains to rings Bonds connecting chains to other chains Bonds connecting chains to functional groups Heuristics (empirical rules) have been devised to select these types of bonds from any target structure. It is also possible to identify rings which should be disassembled early in the retro synthetic process, or rings which should be kept intact during these stages.

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Transform-based strategies A very useful guidance for retrosynthetic analysis can be provided by the application of a powerfully simplifying transform -- corresponding to a reaction effecting a considerable increase in complexity. Very often such an application is suggested by the presence of (functionalized) rings of specific sizes in the target molecule. Some powerfully simplifying transforms are: Diels-Alder Hetero Diels-Alder Robinson annulation Birch reduction Internal ene reaction Halolactonization

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Structure-goal strategies The analysis can also be directed towards a particular (sub)structure. Such a (sub)structure can be a: Starting material Chiral building block Retron -containing structure An analysis directed towards such a structure-goal does not need to be purely retrosynthetic . It can even be synthetic, but probably the most efficient search would be a bidirectional one.

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Stereochemical strategies Here the focus is on removal of stereocenters under stereocontrol . Stereocontrol can be achieved through either mecanistic control or substrate control. Reconnections that move stereocenters from chains (where they are difficult to introduce) into rings (where introduction is usually much easier) can also be considered stereochemically strategic. Suitable stereoselective reactions must be available to reverse-engineer the stereochemistry at that particular site centre.

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Disparlure: the sex pheromone of the gypsy moth, is synthesized by a stepwise sequence that uses an epoxidation reaction as the final step. •Retrosynthetic analysis of disparlure illustrates three key operations:

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Retronecine:

References::

References: Noble lecture of prof E.Jcorey(1990). Material from web site of centre for molecular and biomolecular informatics,university of Nijmegen,Toernooivelds,p.o.box 9010,6500GLNijmegen. Retrosynthetic analysis –lecture delivered by Dr.s.chandrashekharan(chairman, dept of organic chemistry,IISC.Bangalore)at U.Ccollege,aluva on 7-11-2001