Synthon or Disconnection or Retrosynthesis Approach in Organic Synthesis Presented by: Ms. Sarika Mohite B.Pharm , M.Pharm IIIrd Semester Guided by: Dr . Amit G. Nerkar, Associate Professor in Medicinal Chemistry, Sinhgad Technical Education Society’sSmt. Kashibai Navale College of Pharmacy, Kondhwa(Bk), Pune-48, Maharashtra, India
An analytical approach in organic synthesis in which the target molecule is brokeninto fragments through a series of logical disconnection to get the best possible &likely starting materials ( Synthon) An analytical operation that breaks a bond & converts a molecule into possible starting materials It is exactly the reverse of chemical synthesis .Therefore also called Reterosynthesis TerminologiesDisconnection – An operation involving breaking of bonds between atomsSynthon – An idealized fragment usually an ion or radical obtained by disconnectionReagent – Actual comp (chemicals) used in practice for a synthesis e.g.- Synthon-Me⁺ Reagent-Me2SO4
FGI or FGE – Functional group interconversion or functional group equivalence usually written on double arrow This means substitution of functional group by another one equivalent to it. e.g.- -COOH FGI -CN -NH2 -NO2 -Cl -OH Basic rule Disconnection of a bond should be such that stable fragment ion are obtained e.g. two mode of disconnection A&B A - + O 2N C C R O 2N C C R B + - O 2N C C RA will be preferred as carbocations are stabilized by electron donor gr. R,OR ,etc,While carbinions are stabilized by electron withdrawing gr. NO2,CN,COOR etc.
Number of fragments generated through a disconnection should be as minimum aspossible O O O O + - C H 2C R R R R + O R O 2 O halo R OC 2 H 5 R 1 3 OH O O 5 4 O R R O O O O + C R R R - H2C R O O 2 1 R R
Always a C-hetero atom (O,S,N) bond is broken ,with the electron pair beingtransferred to the heteroatom (as heteroatom are more electro negative than Cthey can accommodate the electron pair ) + - C N C N .. .. C Cl HN ..
Some time a disconnection doesn’t generate sufficient stabilised fragments butsuch fragment can be obtained using FGI or introducing additional electronwithdrawing & removing them . a CH2 + NH3 R NH2 R b R X + - R CH2 NH2 (not sufficiently stabilised) Cl - CH2NO2 ( introduction of electrowithdrawing groups R
The –ve & + ve fragments generated by disconnection are replaced by recognizable &Meaningful chemical entities. + R-CH2-X(alkyl halide) R-CH2 R-CH2-OH(alcohol) ( vely charged alkyl) R-CH2OC2H5(ether) + R-C=O ( vely charged acyl) R-CO-X(acylhalid) R-CO-OH(acid) R-CO-OC2H5(ester) R-CO-O-CO-R(anhydride) - O2N-CH-R O2N-CH2-R - R-O R-O-H - R-NH RNH2 - vely charged fragments are considered equivalent to their protonated species .
Oe.g O + H3C CH2 - + H2C OH H3C OH O Cl H3C CH3 OH HO O OH + H3C - C + C CH3 HO OH O Cl CH3 H3C O O O O Base - H3C CH 3 H 3C CH 3 H 3C CH 2 Cl O O H 3C OH
Examine relationship between gr. i.e, which gr. is the proper directing gr.( disconnect it last ) to get the target molecule here thus order is important.e.g.
The most electron withdrawing gr. to be disconnected first ( i.e. to be added last inthe analysis ) e.g.Analysis Synthesis
If FGI is needed do it at an appropriate stage to get the desired effect on orientationAnalysisHere CCl3 is meta director , but it FGI ,CH3 is P- directional. Therefore, do FGIprior to C-Cl disconnection.synthesis
Avoid sequences that may lead to unwanted reaction at other sites of the molecule b CH3 Toluene Therefore b to be adopted as nitration of benzaldehyde may lead to side reaction i.e., Oxidation CHO COOH
For compound consisting of two parte by heteroatom ,disconnect next to theheteroatom e.g.- ChlorbenisideAnalysis Synthesis
Multiple step synthesis –avoid chemo selectivityproblem In this structure with two ether & an amine? functional gr. itrequires several disconnection totake it back to simple comp.The question is which do we dofirst? Here there are four reasonabledisconnection one at each of theether gr. ( a, b) or on either sideof the amine.( c, d) Both a & b posses problem ofchemo selectivity as it would behard to alkylate the phenol in thepresence of basic nitrogen atom. In between c & d , c appears to be the better choicebecause the next disconnection after d will have to be an alkylation of O in thepresence an NH2 gr. To avoid chemo selectivity problem like this , we want to try & introduce reactive gr. late in the synthesis.
Protecting group Protection allows us to over come simpleproblem of chemo selectivity . 2 It easy to reduce the keto - ester 1 to alcohol 2 1with nucleophilic reagent such as NaBH4 thatattack only the more electrophilic ketone. 3 4 1 To making alcohol 3 by reducing the less electrophilic ester is not so easy but protection of ketone as an acetal 4 a functional gr. that does not 3 react with nucleophiles allows 5 reduction of the ester with more nucleophilic LiAlH4. H OH O
Protecting groupQualities needed in the protecting groupIt must be easy to put in.It must be resistant to reagents that would attack the unprotectedfunctional group.It must be easily removed
Protecting group Ethers and amides as protecting group Protection of alcohol and amides look simple. Methyl ether & simple amides are easy to make & are very resistant to a wide variety of reagent. These protecting gr. used when the molecule is robust enough to take the deprotection condition. If aniline is brominated the 2,4,6-tribromo derivative is formed. The yield is quantitative but we are more likely to want mono- brominationprotection is needed against over reaction . The amide is easily made ,bromination goes only in the para position & the hydrolysisDoes not destroy the benzene ring.
Protecting group Achilles heel strategy Achilles heel for an ether is commonly the DHP gr. that make the ether intoan acetal . Dihydropyran (DHP ) 1 , is protonated an carbon 2 to give the cation 3 thatcaptures the alcohol to give the mixed 4 acetal. After the reaction the hydrolysis needs only the weak aq. acid used for acetal. The secret is that the weak acetal bond (b in 5) is cleaved rather than the strongether bond ( a in 5) 1 2 3 4 5
ChemoselectivityIf a molecule has two reactive group & we want to react one of them & not the other we need chemoselectivity. If 2 group have unequal reactivity , the more reactive can be made to react alone. NH2 ? NH CH3 OH O O + HO HO H3C O The amide 2 is paracetamol the popular analgesic. Amine are more Nucleophilic than phenol so reaction with acetic anhydride gives the amide we want without any of ester 3. The aminophenol 1 can be made by Omethods. + NH2 N - NH CH3 O C-N FGI O amide HO HO HO nitration C-N HO
The synthesis is straight forward. Nitration of phenol needs only dilute nitricacid & the reduction is best carried out catalytically. dilute NO 2 HNO 3 NH2 H2/ Pd/C HO H3C HO Ac2O NH CH3 O HO
If one functional group can react twice the product of the first reaction willcompete with reagent .The reaction will stop cleanly after one reaction only if theStarting material is more reactive than the product. Reaction of alkyl halide with NaSH or Na2S can not usually be made to stop afterone alkylation as the anione of the first product is at least as nucleophilic asHS- or S2- .this is obivous in reaction with Na2S.Less obviously with NaSH the first reaction gives 1 gives the thiol 2 but this is inequilibrium with RS- & a second displacement 3 give the sulfide 4. + - Br R - HS R SH + H S R S R Br 3 1 2 R S R 4
Problem from gidelines 1& 2 may be solved by protecting group If we want to react the less reactive of two functional group we protect themore reactive . If we want a reagent to react once when it could react twice we protect reagent. a protection group is something added to a functional group that reduces oreliminate unwanted reactivity . e.g amino acid chemistry . The amine is more nucleophilic than carboxylic acid , soif we want to use the carboxylic group as a nucleophile , we must protect the aminogroup to Benzyl chloroformate 1 is often used in this way . It cleanly acylate theamino group to give the carbamate 3 if compare 1& 2 the carbonyl group be comingless electrophilic . Ph O R Ph O O + H2N COOH O Cl 2 1 NH R COOH O OR 3 NH R COOH
One –Group C-X disconnectionWe disconnect a bond joining the heteroatom (X) to the rest of the molecule : aC-O ,C-N,C-S disconnection . The corresponding reaction are mostly ionic involving nucleophilic displacement by SN1 ,SN2 or carbonyl substitution with amine, alcohol, and thiols on carbon electrophiles. The normal polarity of disconnection 1 will be a cationic carbon synthon 2 & anionicheteroatom synthon 3 represented by acyl or alkyl halides 4 as electrophiles andamine , alcohol or thiols 5 as nucleophiles. + - R X R + X RHal + HX 2 3 4 5 1 synthons reagents
One –Group C-X disconnection Synthesis of Ethers The question of which bond to disconnect can be much more significant in thesynthesis of ether .with many ether , like the gardenia perfume compound 1 , it doesn’tmatter much . The starting material will be an alcohol 3 or 4 and alkyl halide 2& or 5 CH3 CH3 a Ph Cl + HO CH3 a 2 3 b Ph O CH3 CH3 1 b Ph OH + Cl CH3 4 5 The reaction will be carried out by treating the alcohol with a base strong to formthe anion – sodium hydride is favourite as the hydride ion ( H- ) is extremely hard & act only as a base , never as a nucleophile . Either chloride is available , both react inSN2 reaction . We prefer route ‘a’ as benzyl chloride 2 is more reactive & can not undergo elimination whlile 5 just might . CH3 CH3 CH3 Ph Cl - - O CH3 HO CH3 6 CH3 Ph O CH3 3 1 HO CH3 2
One –Group C-X disconnection Synthesis of sulfides Unsymmetrical sulfide 1 need the same disconnection we have just used for ether.The anion 3 of a thiol 4 will combine with an alkyl halide 2 to make a new C-S bond . The reaction is much easier with sulfur . Thiols are more nucleophilic towardssaturated carbon than are alkoxides and the risk of elimination is much less. 1 R 2 1 - 2 2 C-S HS R S R R halogen + S R 1 2 3 4 The acaricide (kill mice & ticks) chlorobenside 5 is disconnected to give an acidic thiophenol 6 & reactive alkyl halide 7. the synthesis merely combine these two in ethanol with NaOEt as base. S Cl SH + Cl Cl 5 6 7
One gr. C-C disconnection I -Alcohol 1,1 dix disconnection For compound with two heteroatoms joined to the same carbon , we used a 1,1 diXdisconnection 1 removing one heteroatom to reveal a carbonyl compound , here analdehyde & a heteroatom nucleophile 2 replacing the heteroatom by R2 , disconnectin the same way to reveal the same aldehyde & same nucleophilic carbon reagent 4probably R2MgBr. OH O OH O 1,1 dix - - + - P(OR) 2 2 1 + R2 1 R R R C- X R C - C R P (OR) 2 O 4 3 1 O 2 For compound with 1,2 relationship we used an epoxide 6 at the alcohol oxidation levelin combination with a heteroatom nucleophile disconnecting the corresponding C-C bond 7 ,we use the same epoxide & carbon nucleophile such as RLi or RMgBr. O 1,2 dis - 2 OH X + X C- X 1 6 5 - O 2 C- C R OH R + 1 6 7
One gr. C-C disconnection I -Alcohol The same 1,2 dix relationship at the carbonyl level was 8 disconnected to give carbon electrophile 9 ,probably an α –bromoketone & heteroatom nucleophile.we generally Preferred nucleophilic heteroatoms but we can use nucleophile or electrophile carbon atoms whichever better . Here we can should much rather use the nucleophilic carbon synthon 11 as it is an enolate. - + 2 R 1,2 diX - H2C R R C - C - X 1 Br R1 H2C R2 X- C R X + + O O O O 10 8 11 9The 1,3 diX relationship 12 was quickly recognized as conjugate addition to the enone .The corresponding C-C disconnection 14 uses the same enone 13 but the nucleophiliccarbon species should be a copper derivative ; RCu, R2CuLi or RMgBr with Cu(I)Br. O O 1 - 3 diX - H2C X CH3 C- X X + CH3 12 13 O O - R H2C CH3 C - C + CH3 R 13 14
One gr. C-C disconnection I -Alcohol 1,1 C-C disconnections- The synthesis of alcohol Disconnection 3 shows that any alcohol may be disconnected at a bond to the OH group .Isomeric alcohol 15 &17 can both be made from acetone using perhaps a Grignard reagent 16 in the first case & available BuLi in the second. H3C OH O C-C CH3 H3C CH3 C - C H3C CH3 MgBr + + H3C H3C Li OH CH3 H3C CH3 H3C 15 17 16 Aldehyde & ketoneThe simplest route to aldehyde & ketone using the same strategy is oxidation of anAlcohol. So the analysis involve FGI back to the alcohol & then a C-C disconnectionof one of the bond next to the OH group. O OH CHO FGI Br C-C C-C OH FGI R R
One gr. C-C disconnection I -Alcohol Carboxylic acid Same disconnection 3 can be used for carboxylic acids with CO2 as the electrophile for aGrignard reagent 2 .Switching polarity by FGI to the nitrile 4 ,the same disconnection nowuses cyanide ion as the nucleophile but the same alkyl halide 1 was used to make theGrignard reagent. FGI C-C - R COOH R CN R Br + CN 3 4 1 C-C FGI R MgBr R Br 2 + CO2 1 1,2 C-C disconnection the synthesis of alcohol Alcohol 1 is used in perfumery & can be disconnected at the next butone bond to the alcohol group with the idea of using the epoxide 2 made from the but-1-ene 3 Ph CH3 1,2 C - C O 2C-O CH3 PhMgX + CH3 H2C OH 1 3 2
General strategy – Choosing a disconnectionOnly one of the five bonds 1a is good choice & for two reasons .To achieve thegreatest simplification in our disconnection so that get back simple startingmaterial . This make the synthesis as short as possible. CH3 c d H3C e a ? b CH3 HOSo disconnect bonds that are- Towards the middle of the molecule. This breaks the molecule into two reasonablyequal parts & is much better than simply lopping one atom of the end. At a branch point in the molecule : this is more likely to give simple straight chain material. Here we get the aldehyde 2 & grignard reagent 3 coming from thestraight chain halide 4. both 2 & 4 are commercially available. CH3 H C-C + MgBr CH3 H3C 3H3C CH3 OH 2 O FGI 1a H3C CH3 4 Br
General strategy – Choosing a disconnection The series of drug based on bicyclic structure 5 has an excellent disconnection between the two ring. OCH3 1,1 OH O OCH3 C-C + N N H3C MgBr H3C 5 6 7Symmetry The symmetrical tertiary alcohol 1 can be made from two molecule of the Grignardreagent 2 & one of ethyl acetate. Then back to the alcohol 3 by FGI & a connection atthe branch point give starting material . H3C CH3 H3C CH3 CH3 MgBr CH3 OH 1,1- FGI OH C-C 3 CH3 H3C 1 H3C 2 + C-C MeCOOEt 1,2- CH3 + O H3C MgBr 5 4
General strategy – Choosing a disconnectionSummary of guideline for the good disconnections Make the synthesis as short as possible Use only disconnection corresponding to the known reliable reaction . Disconnect structural C-X bonds first & try to use two gr. disconnections Disconnect C-C bonds using FGI in the molecule.a) aim for the greatest simplification , if possible disconnect near the middle of the mol. Disconnect at a branch point Disconnect ring from chainb) Use symmetry (if any) Use FGI to make disconnection easier Disconnection back to available stating materials or ones that can easily be made.
One group C-C disconnection II- carbonyl compoundDisconnection deals with carbonyl compound chiefly aldehyde & ketone by tworelated disconnection . Started by comparing the acylation of heteroatoms by acidderivatives such as ester . O O - 1,1 dix1,1-dix disconnection + X C- X R R X OCH3 1 O O - + R2 C-C R1 OCH3 1 2 R R 2 R + 1,2 dix - H2C R 1,2 – dix disconnection X X + 4 3 O O - R2 C-C H2C R2 R1 Br R1 + 6 O O 5
One group C-C disconnection II- carbonyl compound Synthesis of aldehyde & ketone by acylation at carbonThe disconnection 2 is not useful because as MeO is the best leaving group from the tetrahedral intermidiate 7, the ketone 2 is formed during the reactionThe ketone is more electrophilic than the ester so it reacts again & the productis tertiary alcohol 8. - O O O R2 HO R2 R2MgBr RLi R1 R3MgBr R1 or RLi R1 R2 R1 OMe OMe R3 2 8 7
One group C-C disconnection II- carbonyl compound Carbonyl compound by alkylation of enols Disconnection 1 again uses the natural polarity of the carbonyl group but atthe next bond 1. So we use some enolate derivative 2 in an alkylation reaction. The problem is that ketone is it self electrophilic & the self condensationby the aldol reaction is generally preferred to alkylation. synthesis (no good) R2 H3C R2 R2 H2C 1 1,2 C - C R Br TM 1 R1 R1 Br + O - O base O 2 1 3 First of all to convert the ketone 3 completely into some enolate derivative so that there is no ketone left for self condensation . Lithium enolate 4 & anians 6 of 1,3 dicarbonyl compound 5 act as the enolate anion of acetone. H3C CH3 H C CH i-Pr2NLi 3 3 O 4 O 3 Li H3C H3C OEt COOEt EtO- - CH2 O O 5 6
One group C-C disconnection II- carbonyl compound Carbonyl compound by conjugate addition Conjugate addition of a heteroatom to the enone 2b give the 1,3 relationship in 1 & the same process with a carbon nucleophile gives 3. O CH2 1,3 dix - X + H2C R X R C-X 2 1 Corresponding c-c disconnection O R1 O - R1 + H2C R2 R2 2 3we can use either organo-lithiums or Grignard reagent as the carbon nucleophiles but we need copper (I) to ensure conjugate addition without Cu (I) bothnucleophiles are inclined to add directly to the carbonyl group. Disconnection of the ketone with conjugate addition in mind could remove thevinyl group or the methyl group. There are two reasons why we prefer ‘a’ . The addition is likely to occur from the opposite face of the molecule to he COOEtgroup & that is why we want the vinyl group .
One group C-C disconnection II- carbonyl compound Conjugate addition to 3 might occurs at the β position but it could equally welloccurs at the very exposed δ position .The starting material is also available hagemann’s ester EtOOC EtOOC EtOOC C-C C-C a a H2C b H2C O O H2C MgBr O CH3 b δ β
RegioselectivityHow to react one specific part of a single functional group & no other .This is Regioselectivity. We have seen that anions of phenol 2 are alkylate at oxygen togive ether 3. while enolate anions 5 are alkylated at carbon to form a new C-C bond 6. o- alkylation - OH O OCH3 Base CH3 1 2 3 c-alkylation - O O O CH3 Base CH3 H3C H3C H3C COOEt COOEt COOEt 6 4 5
Regioselectivity Carbon nucleophiles in conjugate additionThe very basic & aggressive nucleophilic organo-lithiums tend to do direct additionto all α ,β unsaturated carbonyl compound If we react 1 with grignard reagent with Cu (I) catalysis we get 2 as product the lithium enolate 3 giving us the opportunity to add an electrophile to make 4If the electrophile is proton , the product still 2. R1 R2 RMgBr R1 R2 R2 CuLi R1 R2 cat CuBr R O R OLi O 3 2 1 + E E R1 R2 R OLi 4
Regioselectivity Regioselective alkylation of ketone Lithium enolates & 1,3 dicarbonyl compound both will help us to solve the Regioselectivity problem in the alkylation of unsymmetrical ketone. Suppose we want make 1 at first sight it appears that we must alkylate anunsymmetrical ketone on the more substituted side but if we remove thebenzyl group & add our activating COOEt group to give 2 it is clear that we canmake this by another alkylation & the activating group ill promote both. O O O CH3H3C CH3 H3C H3C Ph COOEt COOEt 1 + + 3 2 PrBr Br Ph
Regioselectivity Benzyl is the more reactive bromide so it makes sense to add it last since making the quaternary carbon will be difficult. O O O COOEt NaOEt NaOEt CH3 PrBr CH3 BnBrH3C H3C H3C COOEt COOEt 2 Ph 3 heat NaOH + H H2O O CH3 H3C Ph 1
Regioselectivity Regioselectivity in nucleophilic addition to enonesThe problem of getting direct (1,2) or conjugate( 1,4 or michael ) addition toα ,β unsaturated compounds such as enones 1 can be solved without finding abstrusstrategies by choice of reagent. 1,4-or Michael or R1 R2 R2 conjugate addition R1 1,2- or direct addition R1 R2 Nu O Nu- Nu- O Nu OH 2 3 1
Two gr. C-C disconnection I –Diels Alder Reaction Disconnection is often best found by reverse reaction mechanism . you may drawthe arrow either clockwise or anticlockwise but one start from the alkene. It makessense to draw this arrow first. The disconnection is 1 for the general case & 2 for specific case, revealing a diene 3 &dienophile 4. These reagent 3 & 4 need. Only to be heated together in a sealed tube togive 2 . 1 2 3 4 This is two group disconnection because it can be carried out only when two featuresare present in the target molecule . The cyclohexene ring & electron withdrawinggroup outside the ring & on the opposite side to the alkene. The relationship betweenthese features must be recognized.
Two gr. C-C disconnection I –Diels Alder Reaction Stereospecificity The reaction occurs in one step so there is no chance for either diene or the dienophile to rotate & the stereochemistry of each must be faithfullyreproduced in the product .The two Hs in 1 are cis because they were cis in thestarting anhydride .The two Hs in 3 are trans in the diester 2. 1 2 3
Two gr. C-C disconnection I –Diels Alder Reaction FGI on Diels – Alder ProductThe cyclic ether comes from the diol that can be made by reduction of variousDiels –Alder adducts such as the anhydride. H O H H CH3 CH3 CH3 C-O FGI HO O ether O HO H H H O DA O H2C CH3 O + H2C O
Two gr. C-C disconnection I –Diels Alder Reaction Synthesis O HH2C CH3 CH3 H heat LiAlH4 CH3 O HO OH2C HO H O H O TsCl O NaOH H CH3 O H
Two gr. C-C disconnection II: 1,3 –Difunctionalised compound Target molecule of two main type 1 Hydroxyketone & 1,3 or β – diketones 4 both have a 1-3 relationship between the two functionalised carbons both can be disconnected at one of the C-C bonds between functional group to reveal the enolate 2 of one carbonyl compound reacting with either an aldehyde 3 or acid derivative 5 such as an ester. 1 2 3 4 2 35Most electrophilic Most stablecarbonyl comp carbonyl compMost stable enols Most nucleophilic enols oror enolates enolates
Two gr. C-C disconnection II: 1,3 –Difunctionalised compound β - Hydroxy carbonyl compound : The Aldol reaction With the compound 1 only one of the two C-C bonds in worth disconnecting , the one next to the hydroxyl carbon . A simple example without any selectivity is ketone 6 which disconnects to theenolate 7 & the ketone 8. It is easy to see that 7 is enolate of 8 so this is a selfcondensation .We simply need to reduce a small amount of enolate 7 in the presenceof much unenolised ketone 8 & the reaction will occur . 6 7 8
Two gr. C-C disconnection III – 1,5 difunctionalised compound conjugate addition &Rabinson annelation O O + O O 1,5 -diCO H2C - R2 C-C CH2 R1 R2 R1 3 2 2 a d enolate 1 O H2C 3 R2 The odd number relationship means are we still use Synthon of natural polarity . The 1,5 –diketone 1 disconnect to a d2 synthon, an enolate & an a3 synthon 2 it represented by the reagent 3. The conjugation in the enone makes the terminal carbon atom electroplilic.
Two gr. C-C disconnection III – 1,5 difunctionalised compound conjugate addition &Rabinson annelation Specific enol equivalence good at michael addition 1,3 –Dicorbonyl compound If we want to make 1 we have a choice between adding an enolate equivalent of aldehyde 5 to an unsaturated ester 4 or an enolate equivalent of ester 3 to an unsaturated aldehyde 2. We prefer the first 1a as unsaturated ester 4 is more likely to do conjugate addition .an enamine would be good choice for 5 5 4 1 2 3 O O O O 1,5 -diCO + H2C O b O + - 1,5 -diCO H2C H CH2 OEt C-C EtO - CH2 H H a OEt C-C
Two gr. C-C disconnection III – 1,5 difunctionalised compound conjugate addition &Rabinson annelation Robinson annelation Combining aldol & michael reaction in one sequence is very powerful, particularly if one of the reaction is cyclisation .The Robinson annelation makes new ring in the compound like 1 that were needed to synthesize steroids. Disconnection of the reversal tri -ketone 2 having 1,3 & 1,5 dicarbonyl relationship 1,3 disconnection would not remove any carbon atom but the 1,5 at the branch point gives a symmetrical β -diketone that should be good at conjugate addition. analysis O O O O CH3 CH3 3 1,5 diCO CH2 5 1 H3C 2 H3C 6 4 3 3 O O + 2 1 O H3C - C O 4
Two gr. C-C disconnection III – 1,5 difunctionalised compound conjugate addition &Rabinson annelation synthesis O CH2 O O CH3 O CH3 3 R2NH H3C R 1 H3C H3C 2 5 4 O H2 O OH O O O CH3 O
Two gr. C-C disconnection III – 1,5 difunctionalised compound conjugate addition &Rabinson annelation Heterocycles made from 1,5 dicarbonyl comp A family of calcium channel antagonist based on the general structure 1 is widely used to combat high blood pressure. Disconnecting the structure C-N bonds we discover symmetrical 1,5 diketone 2 So disconnection of either appropriate bond give the same starting material & enone 3 an acetoacetate ester 4 Ar Ar Ar COOR COOR COOR COOR COOR COOR 2C-N enamines + O H3C N CH3 H3C O O CH3 H H3C O CH3 2 4 1 3
Two gr. disconnection IV -1,2 difunctionalised compoundIn simple case of 1,2 diketone ,or an a- hydroxy –ketone 4. there is one C-C bondbetween the functionalized carbon. so, while we can use an acid derivative 3 orAn aldehyde 5 for one half of the mol, we are forced to use a synthon ofunnatural polarity, the acyl anion 2 for other half. O O R2 1,2-diCO R1 - C R1 + X R2 3 O O 1 2 O O R2 1,2-diCO R1 - 3 C R1 + H R2 4 HO 2 O CH3 O CH3 HO HO H3C 1,2-diCO - CH3 FGI CH3 HC C + H3C CH3 Hydration 1 HC 2 O The hydroxy – ketone that could come from the acetylenic alcohol by hydration &hence from acetone with the anion of acetylene acting as the acyl anion equivalent.
Two gr. disconnection IV -1,2 difunctionalised compound Method from alkenes. OH R2 FGI witting +R1 electrophilic addition R2 R1- CHO + Ph3P R1 R2 HO FGI Br R2Epoxide give rise to many 1,2 difunctionalised comp such as 6 with control overstereochemistry . Reaction of the epoxide give the anti stereochemistry in 6 in contrastTo the syn stereochemistry in 1. OH O electrophilic addition R2 C-N CH3 R1 R1 R2 FGI H3C 1,2 dix H2N Many possible starting material
Two gr. disconnection IV -1,2 difunctionalised compound α Functionalisation of carbonyl compoundMetaproterenol 1 is an adrenaline analogue used as bronchodilater .the might be inserted by reductive amination on the aldehyde 2 & this might aΑ –functionalisation of the available ketone .HO HO 2 OH reductive amination OH C-N NH CHOHO CH3 HO 1 H3C 1,2 diCO Functionalisation HO OH 3 CH3 HO
Two gr. disconnection V: 1,4 difunctionalised comp. The problem of unnatural polarity also arise in making C-C disconnection for thesynthesis of 1,4 difunctionalised compound. If we start with 1,4 diketone 1, disconnection in the middle of the molecule givesa synthon with natural polarity 2 represented in real life by an enolate 4 & one ofunnatural polarity, the synthon 3 represented by same reagent of the kind suchas α - haloketone 5. + O H2C R2 O R2 1,4 diCO + - O R1 R1 CH2 3 O 2 1 - O O X R1 CH2 R2 5 4 enolate
Two gr. disconnection V: 1,4 difunctionalised comp. Reaction of enol (ate)s with reagents for a2 synthonsA simple example would be the keto-ester 1 disconnect the bond at thebranch point & that suggest the synthon 2&3 . The reagent for 3 can bebromoester 5 but we shall need to choose our enolate equivalent carefully .If should not too basic as the marked proton in 5 between Br & COO2Et are ratheracidic. O O + - H2C COOEt COOEt 1,4 diCO CH + 3 2 1 H - Br O 5 4 H COOEt
Two gr. disconnection V: 1,4 difunctionalised comp. Conjugate addition of acyl anion equivalentsThe anticonvulsant phensuximide 1 being an imide , comes from adicarboxylic acid 2 with 1,4 relationship between the two carbonyl gr.changing one to cyanide we get back to cinnamic acid as the availableStarting material. H N 2C-N Ph Ph Ph O O FGI HOOC COOH NC COOH COOH Ph + - 1 2 CN
Two gr. disconnection V: 1,4 difunctionalised comp. Direct addition of homoenolatesThe same disconnection but of the opposite polarity requires someacylating agent for synthon this no problemas we have various derivative at our disposal but the nucleophilic synthon 3 or homoenolate, isanother matter.There is no stabilisation of the anione as drawn but if wereto cyclise to oxyanion 4, it would be rather more stable & there isevidence trapping with silicon to give 5 . O O + C R2 R2 - R1 + H2C R1 O 3 O 2 1 R2 R2 - OSiMe3 O 5 4
Reconnection synthesis of 1,2 & 1,4diCO comp by oxidative cleavage.If we wanted to add bromketones 4 to enolate 3 to make the 1,4 dicarbonyl compound 5 .We could not use a lithium enolate because it would be too basic no such difficulties exist in the reaction of enolate with allylic halides such as 2 Any enol equivalent will do as there are no acidic hydrogen & allylic halidesare good electrophilic for the SN2 reaction. CH3 O CH3 - O H3C O H3C CH3 CH3 H3C CH2 O H3C H3C 2 CH3 CH2 CH3 4 CH3 O 3 1 5 Reconnection ; joining the target molecule back up to something to reveal the precursor ,so consider the synthesis of the cis- enone 1 a structure found in insect pheromones, perfumes , flavourings . A witting reaction would ake the cis –alkene from phosphonium salt 2 but the ketoaldehyde 3 would need protection , perhaps as the acetal 4.
Reconnection O O Ph3P+ CH3 witting CH3 R + OHC R 3 1 2 FGI OHC CH3 O OH 4 CH3The problem is how to protect the ketone rather than the aldehyde & the answer isProtect it when the aldehyde is not there .Reconnection to the alkene achievesthis & the ketone can be made by reaction of some enolate with allyl bromide. OHC CH3 reconnect CH3 CH3 H2C FGI O O 4 O O H2C O C-C O Br - + H3C CH2 CH2
Reconnection The extraordinary polycyclic tetraketone 1staurone was made from 2 The 1,2 diCO relationship in 2 is an ideal candidate for reconnection in this style . O O O COOEt O COOEt reconnect OHC COOEt COOEt O 3 2 Ph 1 O aldol O O COOEt Br COOEt - + H2C CH3 COOEt H3C Br COOEt 5 6 4The aldol disconnection 3 reveals methyl ketone with 1,4 diCO relationshipThat could be made by double alkylation of some enolate of acetone with ethylbromoacetate 6. the synthesis used benzyl acetoacetate for the double alkylationSo that the benzyl ester 8 could be specifically cleaved by hydrogenation to give 4 .Condensation with unenolisable benzaldehyde is unambiguous & ozone does the rest.
Reconnection O BnO2C O COOEt CO2Bn 2(NaH) H3C 2( Br COOEt) 7 Me 8 COOEt Pd/C H2 O COOEt O COOEt PhCHO base COOEt 3 Me COOEtPh 4 Me2S O3 O COOEt OHC COOEt 2
Two gr. C-C disconnection VI- 1,6 dicarbonyl compound 1,6 dicarbonyl compound disconnect in the middle we might be relived to seean a3 synthon 2 easily recognised as an enone in real life , but the d3 synthon 3 withunatural polarity, can cause problem ,so use reagent for 3 that does conjugate addition . O O 5 R2 R2 + - R1 1 3 4 6 CH2 H2C 2 O R1 + O 2 3 1 ? Disconnecting else where is no help as the true difficulty is that the two carbonyl group are too far apart for this approach. Strategy of reconnection is needed the main strategy for the synthesis of 1,6 diCO compound
Two gr. C-C disconnection VI- 1,6 dicarbonyl compoundReconnect intramolecularly the marked atom C-1 & C-6 form a ring 4 &the bond between these atom must be made weaker than any other bond inthe molecule Ironically we can do this by making it a double bond 5 O 5 R1 R1 R2 R1 1 3 weaken ? 2 4 6 1 O R2 R2 4 5 Bicyclic ketone made from the simple enone that had to be made. Aldol disconnection reveals the keto- aldehyde. O O O CH3 CH3 CH3 CH3 4 CH3 aldol 6H3C H3C 5 H3C 3 CH3 CH3 CH3 2 6 7 OHC1 8
Two gr. C-C disconnection VI- 1,6 dicarbonyl compound This is 1,6 dicarbonyl compound so reconnection to the cyclohexene 9 is needed FGI & removal of the methyl group reveals a simple cyclohexanone 11 . O CH3 4 CH3 6 OHH3C 5 CH3 CH3 O 3 CH3 2 H3C H3C H3C OHC1 H3C H3C H3C CH3 CH3 CH3 8 11 9 10 synthesis CH3 O O 4 CH3 CH3 H3C O3 6 H3C MeLi 5 H3C 3 H+H+ H3C Me2S CH3 2 H3C CH3 CH3 OHC1 11 9 MeOH KOH O CH3 CH3 H3C CH3
Two gr. C-C disconnection VI- 1,6 dicarbonyl compound The Diels –Alder Route to 1,6 dicarbonyl compound Normally we have to make the cyclohexene , need for oxidative cleavage & one ofthe best route to such is Diels – Alder reaction .Generalized example would be ozonolysis of alkene .The product has a 1,6 relationship between two carboxylic acids. Since Diels –Alder adduct have a carbonyl group outside the ring ,the cleavage product also have 1,5 & 1-4 diCO relationship & would be a matter for personal judgment which of those should be disconnected instead if you choose that alternative strategy. O O O H2C R R HOOC R + O3 H2C CH2 H2O 2 HOOC 2 4 1 3
Two gr. C-C disconnection VI- 1,6 dicarbonyl compound diester required for synthesis of the antibiotic pentalenolactonereconnecting the ester gives the cyclohexene . We must change the two ethergroup into carbonyl group & one starting material is , diels alder adduct ofbutadiene & maleic anhydride . O H H H reconnection MeOOC OMe OMe FGI O OMe 1,6 diCO OMe MeOOC H H 7 H O 6 5 D-A H2C O O O + H2C 1 8
Two gr. C-C disconnection VI- 1,6 dicarbonyl compound The synthesis followed this pattern with the ether 6 being madeimmediately after the reduction of 7 & the ester made with diazomethaneCH2N2 after oxidative cleavage. O H H H LiAlH4 OMe O MeOH,H O MeOOC OMe O 3 2 2 NaH,Mel OMe CH2N2 MeOOC OMe H 7 H H O 6 5The bicyclic double lactone used as precursor for all four heterocyclic ring in synthesis of Vit. B12 .disconnection of both lactones reveals a ketone . COOH CH3 COOH CH3 CH3 COOH HOOC O COOH 1,1 dix HOOC 2(C - O ) COOH O ester HO OH O CH3 O H3C CH3 O 9 10 11
Two gr. C-C disconnection VI- 1,6 dicarbonyl compound The ketone 11 in fact has 1-4,1-5 & 1-6 relationship & if we redraw in 11a tosee 1,6 relationship clearly Being careful to get the sterochemistry right,wecan reconnect to the cyclohexene 12 & hence , byDiels- Aldrdisconection ,find the reactive dienophil disconnection 13 .The methyl & czrboxylicgroup are cis in 12 & must be cis in 13 6 5 COOH 2 CH3 6 HOOC 3 4 1 COOH 1 5 H3C reconnect diels H2C COOH 4 CH3 1,6 diCO 2 COOH alder + 3 H3C CH2 O H3C H2C 11 H3C O 1 13 12
Introduction to ring synthesis: Saturated Heterocycles Cyclisation reactionSynthesis of butanone by reaction of the primary alkyl chloride with MeNH2 waslikely to give a poor yield . The problem is that the product 2 is also a nucleophile &will react at similar rate with alkyl chloride as does MeNH2. The reaction isintermolecular & so bimolecular. MeHN OEt Cl OEt MeNH2 OEt OEt 2 1 Cl OEt OEt OEt OEt EtO N OEt 3 CH3
Introduction to ring synthesis: Saturated HeterocyclesThe very similar reaction of 4 gives exclusively the pyrrolidine 5.The reaction 6 isnow intramolecular a unimolecular cyclisation in fact & is greatly preferred to anybimolecular processes. Cl MeHN Cl .. + MeHN N H CH3 base N H3C
Introduction to ring synthesis: Saturated Heterocycles Three membered ringThe simple formation of epoxide 3 by the action of peroxyacids such asmCPBA on alkenes 4.They can equally well be made by cyclisation of chloro- alcohols 2 as in theCornforth addition of a Grignard reagent to an α-chloroketone & cyclisation in base. H3C CH3 CH3 Mg.OEt H3C CH3 NaOH CH3 3 H3C Br Cl H3C Cl H3C OH O O 1 2 CH3 CH2 H3C CH3 4
Introduction to ring synthesis: Saturated Heterocycles Four membered ringUpjohn’s analgesic & antidepressant tazadoline 1 contain a foue member cyclicamine , an azetidine , simple disconnection of C-N bonds give 2 & then enone 3,the aldol product from cyclohexanone 4 & benzaldehyde. Ph Ph Ph X C-N C-N Reductive amination NH O N 3 2 aldol 1 PhCHO + O 4
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