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OrganicChemistry IIUNIT 4.RetrosynthesisMain guidelines

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isClClOOOH2-(2,4-dichlorophenoxy)acetic acidTarget moleculeChoosing a disconnectionSynthons Equivalent reagentsReliable reactions

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isClClOOOH2-(2,4-dichlorophenoxy)acetic acidTarget moleculeChoosing a disconnectionSynthons

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isWhich reagent should weuse?? Only experimentscan tell us which is thebetter optionSynthonsSynthon Equivalent reagentsSynthonEquivalent reagentsReliable reactions

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isChoosing a disconnectionWhich reagent should we use?? Onlyexperiments can tell us which is thebetter option

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isChoosing a disconnectionSynthonsEquivalent reagents

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isChoosing a disconnectionSynthons Equivalent reagents

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isChoosing a disconnectionReliable reactions

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isChoosing a disconnectionPROBLEM 1. HOW WOULD YOU MAKE THESE TWO COMPOUNDS? GIVE YOUR DISCONNECTIONS.BRIEFLY , EXPLAIN WHY YOU CHOSE THEM AND THEN GIVE REAGENTS FOR THE SYNTHESIS.MOODLE PLATFORM

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isMultiple step synthesisChemoselectivity problemAlkylation of phenol in presence of basic nitrogenAlkylation of phenol in presence of basic nitrogenNot a good option: next disconectionshould be next to the oxigen and thenthe same problem like in red or greenWe want to introducereactive group late in thesynthesis in order to avoidchemoselectivity problemsICI-D7114 potentialantiobesity drug

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isICI-D7114 potentialantiobesity drugRequires alkylation of a compoundthat is itself an alkylation agentMultiple step synthesis

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isICI-D7114 potentialantiobesity drugMultiple step synthesisOHOPhBrBr

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isFuncional group interconversionWhich disconection choose firstNext disconection:We need to prepareamide in the presence ofNH2Next disconection:We need to prepareamine in presence of acylchlorideNHOHONantihipertensivo / vasodilatador

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isRetrosynthetic transformation of acyl chloride to carboxylic acid is not really a disconnection.We call it instead functional group interconversion FGIFGI often aid disconnection because the sort of reactive functional groups (acyl chlorides, alkyl halides) we want instarting materials are not desirable in compounds to be disconnected – chemoselectivity problemsFuncional group interconversion

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isAmine synthesis FGIReminder - when alkylation of primary amine can produce multiple alkylated productThere are 2 better approximations1. By amide reduction

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isReminder when alkylation of primary amine can produce multiple alkylated productThere are 2 better approximations2. By imine reductionAmine synthesis FGI1. By amide reduction

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isReminder when alkylation of primary amine can produce multiple alkylated productThere are 2 better approximations2. By imine reductionAmine synthesis FGI

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isAmine synthesis FGIPROBLEM 2. HOW WOULD YOU MAKE THESE TWO AMINE DERIVATIVES USING AMINE FGI? GIVEYOUR DISCONNECTIONS. BRIEFLY , EXPLAIN WHY YOU CHOSE THEM AND THEN GIVE REAGENTSFOR THE SYNTHESIS.

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s is

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isDisconnections with carbonyl group1,2-disconnection 1,3-disconnection

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s is1,2-disconnection with carbonyl groupAlpha-halocarbonylSynthesis:α-halocarbonyl compound are easly made by halogenation of a keton, ester or carboxylic acid and they are goodequivalent for synthon B

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s is1,3-disconnection with carbonyl groupReminder:Disconnection:Example:

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C disconectionDisconnection:Reaction:Alkynes are valuable assynthetic intermediatesCan be reduce either to cisor trans double bonds

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C DisconnectionsC-C 1,2-disconnectionC-C 1,1-disconection on alcoholsC-C 1,3-difunctionalized compoundsC-C 1,5-related functional groups

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isExample:C-C disconnection

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C 1,2-disconnection1,2 C-C disconnection, 2carbons away of thecarbonyl groupCarotene precursor If you think of enolate ofacetone stop right hereRemember that beta-ketoester can beeasily decarboxylateEnolates once again

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isCarotene precursor If you think of enolate ofacetone stop right hereEnolates once againC-C 1,2-disconnection

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C 1,1-disconection on alcohols Grignard to carbonyl

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C 1,1-disconection on alcohols Grignard to carbonylTo synthesis this compound rout “c”has been chosen because is thecheapest way to obtain the perfumeWhich rout would youchoose?

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isGrignard to carbonylDo you know why is thatpossible ?C-C 1,1-disconection on alcohols

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C 1,3-difunctionalized compoundsAldol reactionTwo group disconnectionDo you remember?Part that attacks is enolate and where is hydroxyl is aplace that have been attackedNow it would be easier: close to oxygen is + and otherpart need to be -

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isAldol reactionAldol product can be dehydratedTo simplify we can say alpha, betaC-C 1,3-difunctionalized compounds

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isAldol reactionA good equivalent for the ester enolate d2 synthon is beta-dicarbonyl compoundbecause it can easily be disconnected to diethyl malonate and an alkylation agentHydrolysis and decarboxylationC-C 1,3-difunctionalized compounds

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isAldol style with N and ONitriles can be reduce toaminesCN – is electrowithdrawing group soit’s alpha proton isenolizable1,3 and 1,2 relationsAldol like reactionAddition to the carbonylC-C 1,3-difunctionalized compounds

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isAldol style with N and OC-C 1,3-difunctionalized compounds

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isC-C 1,5-related functional groups

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isRetrosynthesis Problems 3MOODLE PLATFORM

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting groups – an necessary evilIf only exists somethingthat allowed us to blockthis very reactiveketone….

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting groups – an necessary evilProtecting groupBut why is evil?• We need to add two reactions protecting/deprotecting – we will lost somematerial – lower global yield• Atom economy

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting aldehydes and ketonesPG - ACETAL

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting AlcoholsPG – silyl etherWhat can we do then?PG - TBDMS

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isPG – silyl etherPG - TBDMSSilicon has a strong affinity for electronegative elements – FLUOR ion. TBAF (Tetra-n-ButylAmmonium Fluoride –soluble in organic solvents is normally used to remove TBDMS (TertButylDiMethylSylil) groupProtecting Alcohols

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isPG – silyl etherOther silyl ether protecting groupsWhen the group is bigger more stable protecting group – can beadvantage and disadvantageNot stable under acidic conditions!Protecting Alcohols

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isPG – acetalProtecting Alcohols

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isPG – acetalTHP-acetal protecting groupNot stable under acidic conditions!Protecting Alcohols

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isPG – etherBn-benzyl ether protecting groupHow we remove it?• Pd/C + H2 typical conditions• Do not confuse with Pt – hydrogenation of aromatic ringProtecting Alcohols

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting amines and carboxylic acidsPeptide synthesisBecause of effectiveness of theprotecting groups peptides can besynthetize by machine!!!!!!!!!Amines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl esterWould be a mess!!

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting amines and carboxylic acidsPeptide synthesisAmines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl ester

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting amines and carboxylic acidsPeptide synthesisAmines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl esterThis is preferable way to make tert-butyl ester• If we use alcohol – this is very hindered so reaction is very slow even with acid chloride or anhydrideisobutene

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting amines and carboxylic acidsPeptide synthesisAmines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl esterBut why is stable in presence of hydroxyl group??• Bulky tert butyl group makes it very hindered for nucleophilic attackRemoval of t-butyl ester

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting aminesPeptide synthesisAmines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl esterRemoval of Cbz (carboxybenzyl)Carbamic acid not stable – suffer decarboxylation to give amine

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting aminesPeptide synthesisAmines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl esterRemoval of Boc (tert-butoxycarbonyl)For Boc removal we can use diluted aqueous acid like 3M HCl for Cbz we need to use stronger conditions

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting aminesPeptide synthesisAmines:• Cbz• Boc• FmocCarboxylic acids:• t-butyl esterRemoval of Fmoc (fluorenylmethyloxycarbonyl)Nonnucleophilic base is usedThis protecting group cannot be lost bysubstitution in the manner of Cbz or t-Bocbecause neither SN1 nor SN2 mechanisms canoperate at the ringed carbon atom: it is bothprimary and hindered.

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isProtecting groups

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isFmoc/t-Bu Boc/Bn

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isOOHPh PhProblems 4OEtOHow would you make the following compound starting from ethyl benzoate?

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isOOHPh PhProblems 4How would you make the following compound starting from ethyl benzoate?

Re t ro synt he t i c a n a ly s isRe t ro synt he t i c a n a ly s isOOHPh PhProblems 4OEtOHow would you make the following compound starting from ethyl benzoate?OOEtOPh MgBr2I need to protect ketoneOEtOClO

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