asymmetric-catalysis.pdf

lOMoARcPSD|6077384 Asymmetric catalysis Advanced Organic Chemistry and Laboratory (The University of Warwick) Studocu is not sponsored or endorsed by any college or university Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 Martin – Organic 25/02: slide 27 1) Asymmetric hy...

lOMoARcPSD|6077384 Asymmetric catalysis Advanced Organic Chemistry and Laboratory (The University of Warwick) Studocu is not sponsored or endorsed by any college or university Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 Martin – Organic 25/02: slide 27 1) Asymmetric hydrogenation of C=C and C=O bonds using Rh, Ru and Ir complexes. a) C=C hydrogenation with Rh/diphosphine complexes. b) C=C hydrogenation with Ru/diphosphine complexes. c) C=C hydrogenation with Ir complexes. d) C=O hydrogenation including examples of dynamic kinetic resolution. 2) Asymmetric dihydroxylation of C=C bonds using Os complexes. 1. Key features, mechanisms, applications. 3) Asymmetric organocatalysis. 2. Including C=N reduction, aldol reaction, C-N and C-Cl bond formation. 4) Asymmetric Pd-catalysed allylic substitution. 3. Mechanism and applications. 5) Asymmetric isomerisation (one slide). Challenge 1    Back face addition we get backward hydrogen and visa versa  high enantioselectivity How do we make via aldol from 2x simple starting materials? H becomes more acidic due to carbonyl group  E1b would be favourable to make an alkene on the basis that it can be deprotonated Hydrogenation of C=C bonds and C-O bonds using Rh, Ru and Ir complexes     Alkene + H2 + catalyst i.e. Pd/C  alkane  hydrogenation on surface Hydrogenation is 100% atom efficient, forming 2 enantiomers (50:50, racemic mixture) Asymmetric synthesis is harder: o Need to use a homogeneous catalyst i.e. Wilkinsons catalyst: o [(Ph3P)3RhCl]  not asymmetric o Need to modify it General processes of aldehydes, amines and alkenes: General mechanism for hydrogenation with metal complex: 1. 2. 3. 4. 5. 6. Rh(1), Catalyst precursor, L= Ligand Rh(1), Active precursor Rh(3), Hydrogenated catalyst: formed by addition of hydrogen Rh(3), Formed by addition of alkene substrate Rh(3) Formed by transferring one hydrogen Product formed due to reductive elimination of catalyst (+ active precursor, Rh(1)) Challenge 2 Reduction reactions of C=C double bonds provides a means for the synthesis of amino acids:     Addition of an acylamino acrylate results in formation of an amino acid precursor Using an enantiomerically pure (homochiral) diphosphate in place of 2 ligands results in formation of an asymmetric catalyst Mechanism in the notes DiPAMP: Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384         Rh-diphosphine complex control asymmetric induction by controlling the face of the alkene that attaches to the Rh. 2x diasteroisomeric complexes of different energy can be formed. H is transferred from one of these in a stepwise fashion to the alkene. Coordination of amide group to metal is important: o Alkenes alone are not good at binding to metals  hence another group such as an amide helps hold the alkene to the metal and creates a directing affect  amide binds to the metal and promotes addition of hydrogen to the alkene I have put these in so its more clear in the exam, however they are drawn out in notes to show the reaction scheme of the second complex. Hydrogen is added that fits with the stereochemistry of the molecule  hydrogen go one at a time to the double bond and can only go to the face of the rhodium  back face as the complex is on the back face  cant flip round to the front For 2) we get the s product and for 1) we get theoretically get R product but it is too slow to occur Red part remains unchanged on both sides (back) and then the black molecule comes in at the front faces, flipped both way rounds In a square planar coordination Other chiral diphosphines are not chiral at p, but contain a chiral backbone which relays chirality to conformation of the arene rings: Reduction reactions of C=C double bonds using Rh(1) complexes – the nearest alkene is reduced.   For any particular combination of metal and ligand, reduction/addition of hydrogen is relative to coordinating group  directing group helps us predict stereochemistry, improve rates and enantioselectivity However, a catalyst might have a different selectivity 1. Reduction reactions of C=C bonds using catalysts derived from Ru(2):    1. CO2H used as a directing group Ru(2) is in higher oxidation state than Rh(1), react similarly but is more versatile In each case, directing group is the same Alkene reduced with 1atm H2, 0.5 mol%, MeOH/ DCM (5:1) and [(R-BINAP)]Ru(OAc)2]  acid group directing + front face directing 2. Amide group directing  S-BINAP  back face directing 3. Acid directing  R-BINAP  front face directing 4. Carbonyl directing  R-BINAP  front face Challenge 3   Directing groups and overall stereoechmistry Relative groups is important 2. Reduction reactions of double bonds using catalysts derived from Ru(2) C=C       Allylic alcohols provide a good example of how directin groups work Alcohol acts as the directing groups -> directs to the front face 100% atom efficient 1. Small amount of catalyst required  hydrogen on front face relative to OH 2. S product  front face relative to OH Position of alcohol relative to alkene (z or E) controls reduction Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtrees catalyst, which is Iridium-based    Crabtrees catalyst works well on isolated alkenes i.e. with no other coordinating groups  difference to Ru and Rh which require a directing group Ir binds strongly to C=C bonds and do direct hydrogenation of isolated double bonds Hetero nitrogen in a ring and phosphorus donor in catalyst Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384  COD hydrogenated at the start and drops off  vacancy for the alkene Challenge 4 1. Reduction reactions of C=O double bonds using organometallic complexes     Same principles with regard to directing groups also applies to C=O reduction  Ru and Rh are commonly used Directing group is required  bromine (pair of electrons that binds to the metal), phosphorous, OMe Enantiomerically selective Amides and esters good for hydrogenation but not asymmetric 2. Reduction reactions of C=O double bonds using organometallic complexes   Asymmetric Beta-keto ester can epimerise rapidly due to the acidic proton and one enantiomer is more quickly reduced and so there is a enantiomerically- enriched product. 3. Reduction reactions of C=O double bonds using organometallic complexes       Real life examples Dynamic kinetic resolution can result in 2x chiral centres on the same molecule MeOH good solvent  dissolves lots of things, doesn’t get involved de = diasterisomer excess – syn/anti in the bottom complex ne, there is 3x chiral centres formed  quite acidic protons 1. Ketone reduction by pressure hydrogenation  No directing groups  can be achieved by using a modified catalyst containing diamine and phosphorus group which changes the mechanisms (must be able to draw this) and Ru no longer is in direct contact with the substrate  outer-sphere Figure 1:Vitamin E  Usually X group is also coordinated to Ru, to hold carbonyl or C=C bond in place 2. Ketone reduction by pressure hydrogenation Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384  Considering the different catalysts (one with a diamine and one without) and how the directing group will control the reaction of 1 1. Oxidation reactions of alkenes     Good way of creating chiral centres Sharpless- dihydroxylation reaction employs ligand-acceleration to turn the known dihydroxylation process into an asymmetric one Requires an (enantiomerically-enriched) amine to accelerate the reaction: OsO 4 as a reactant Reaction scheme: Examples of amines used as a catalyst  natural products:      Quinine has an alkene in the backchain  hence we have to use hydroquinone DHQ and DHQD aren’t quite enantiomers, but behave like they are (pseudo enantiomers) They influence the reaction Improvement: DHQ-PHAL, Admix  bound 2 of them together ADMix contains K3Fe(CN)6 that helps reoxidisation of the osmium back to osmium 8 from 6 OsO4 mechanism OsO4 catalysed reaction  Note that it is very toxic and so is favourable to use low amounts of it (5%), with 95% of the salt      Admix- alpha gives us backface attack Admix-beta gives us the upper face addition of OH Remember that trans and trisubsituted are dependent on different things: o Trans need to consider that m and l groups are interchangeable (swapping them around would give the same product) o For tri-substituted, the hydrogen is the consideration and dominates the selectivity High degree of selectivity Can superimpose most alkenes onto this model 2. Oxidation reactions of alkenes  2x mechanisms to consider as we still are not 100% sure how it goes Figure 2: OsO4 catalyst model for directing and predicting the stereochemically active product Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384   Concerted mechanism or {2+2} cycloaddition  leads to the same product Without knowing how everything is precisely aligned in the transition state  it is hard to predict the relative positions of everything and how they interact to give the product    2X alkenes  one furthest from the electron withdrawing group favoured If we have an alkene and triple bond, double bond is favoured Tri-substituted hardest to predict so just follow the hydrogen for aid in the reaction process Challenge 7 Asymmetric transfer hydrogenation by organocatalysis – an alternative to hydrogen gas      Inspired by natures NADH, a coenzyme which transfers hydride Coenzyme is consumed in the reaction and then regenerated Transfers hydride  natures equivalent of H-  i.e. to NaBH4 Hydrogen acts like a hydride  nucleophilic attack of the ketone  achieving the reduction product (alcohol) CN reduction requires a combination of a chiral acid with a hydride source -> examples: Mechanism for reaction: Figure 3: All direct in the same direction (beta mix)  Chiral environment formed  like an enzyme does Figure 4: P acts as a catalyst (Hantzsch esters) + reducing agent = source of hydride  very easily oxidised to pyridine – phosphine     1st step: amine deprotonates acid to form an iminium salt  chiral environment like seen in an enzyme 2nd step: hydride transfer same mechanism as above with protonated imine Protonated amine  imine in 2nd step Hantsch esters are expensive and hard to make Some examples  Can form an imine in situ: Mechanism the formation of an imine Challenge 8: mechanism of formation of Imine under acidic catalysis  Everything has to be positively charged  no negative charges in acidic catalysis More applications of organocatalysis– C-C bond formation       Robinson annelation reaction  asymmetric cyclisation of a diketone Intramolecular Aldol reaction  drawn out in the notes Adding L-proline makes the reaction selective to S product (major) only 1st step: Condensation to form an enamine and push electron density and cyclise o Chiral centre on CO2H  favoured diastereomer Know the mechanism of the enamine: o Organocatalyst/ amine/ L-proline adds to the ketone to form an enimane o This goes on to react with the 2nd carbonyl/aldehyde o Hydrolysis See in the notes for more mechanistic view on this Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 Challenge 9  Full mechanism of organocatalysis with enamine formation Allylic substitution reactions are powerful methods for forming C-C bonds (and CN bonds)         Flat allyl complex is formed  ligand directs nucleophile by a combination of sterics and electronic factors Catalyst helps control selectivity 2nd step: Lose an acetate group  remaining complex has a positive charge Feta3-allyl complex  cation charge spread out over the whole structure Why does nucleophile add to the front? and give solely one enantiomeric product? o Lots of steric hindrance of the palladium  nucleophile will come underneath So, first of all the transition states A and B are shown in the notes  but think of the alkene sitting in front of the palladium and binding A is disfavoured due to the clash of hydrogen and phenyl group The nucleophile then attacks from the front face to the right-hand side this leads to the nucleophile sitting on the front face  trans effect  N attack (opposite to the phosphorus) as P withdraws electron density from the palladium, making the N side more electropositive and attracts the nucleophile more Examples: Challenge 10 Asymmetric catalysis – isomerisation     Hydrogen migrates and creates a chiral centre [BINAP(Rh)] Conjugation means a more stable product ZnBr2 drives reaction Downloaded by Anushaya Jeyabalan ([email protected])