Year 3 CH3E9 Notes: Asymmetric Catalysis 2023-2024 PDF

Year 3 CH3E9 notes: Asymmetric Catalysis, Prof Martin Wills 2023-2024 This course will cover the following types of reaction: 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 c...

Year 3 CH3E9 notes: Asymmetric Catalysis, Prof Martin Wills 2023-2024 This course will cover the following types of reaction: 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. Key features, mechanisms, applications. 3) Asymmetric organocatalysis. Including C=N reduction, aldol reaction, C-N and C-Cl bond formation. 4) Asymmetric Pd-catalysed allylic substitution. Mechanism and applications. 1 Year 3 CH3E9 notes: Asymmetric Catalysis, Prof Martin Wills 2023-2024 You will be aware of the importance of chirality (e.g. amino acids, carbohydrates, DNA, RNA etc., living things, us, are of a single handedness. New pharmaceuticals need to be created in single enantiomer form. Hence, new pharmaceuticals need to be prepared and tested in a single enantiomeric form, since each enantiomer can have significantly different effects (you will have seen examples). Methods to achieve this include: i) Starting from an available single-enantiomer reactant – difficult to obtain sufficient amounts. ii) Resolution – inefficient and wasteful. iii) Asymmetric synthesis using auxiliaries – not very efficient on a large scale. iv) Asymmetric catalysis – multiplies the chirality, efficient, atom-economic etc. Often the best way. Enzymes are a type of asymmetric catalyst, but this section will focus on chemical methods. How are transformations like these achieved?: You will find out in this section. Examples for illustration. No need to memorise (they will be revisited later). 2 Asymmetric catalysis can be achieved through a variety of methods, however this section of CH3E9 will focus on the most common method, i.e. the conversion of double bonds (containing sp2 atoms and hence ‘flat’) to single bonds (containing sp3 atoms and hence three-dimensional). Illustrated for the case of asymmetric hydrogenation: To achieve an asymmetric synthesis, the face of the double bond to which the hydrogen adds, has to be controlled, i.e.: But how is this controlled??? Understand how the absolute stereochemistry is related to the face to which a new group (e.g. hydrogen in the case above) is added. 3 Example: L-Phenylalanine is naturally available (but not unlimited) but what if we want to make a non-natural version, or a novel derivative? MeO OMe Ph Ph R S HO2C H NH2 HO2C H S NH2 L-phenylalanine (amino acid) (natural) D-phenylalanine (amino acid) (non-natural) Naturally-available (in limited amounts) Need to make it by synthesis (or engineering an enzyme) HO2C H NH2 L-phenylalanine derivative (amino acid) (non-natural) Need to make it by synthesis (or engineering an enzyme) A conceptual approach is to reduce an alkene, in an enantioselective manner (hydrogen adds to the upper face in this theoretical example): But a few issues: i) The alkene starting material will not be very stable. ii) Which catalyst do we use? Understand that asymmetric catalysis opens a route to new compounds. 4 A better reactant is the protected version below (with an acetyl group on the N atom) as this is stable: How would you prepare the substrate shown – revise alkene formation methods, particularly condensation but also other methods. Note that, if a heterogeneous catalyst such as Pd/C Is used,* then a racemic product will be formed, because there is not control over the face to which the hydrogens are added: So I need a homogeneous catalyst - but which one? Understand that a homogeneous asymmetric catalyst is required for asymmetric synthesis. * Some heterogeneous catalysts have been modified to make them asymmetric but are not 5 widely used. Catalyst design - The general mechanism (simplified) for hydrogenation with a homogeneous catalyst – Rh(PPh3)3Cl: Throughout the cycle, two ligands (L) remain on the metal and could be used to direct the enantioselectivity of the reaction! This allows a ligand to be designed which can create a chiral environment to control the enantioselectivity of the reaction. 6 Reduction reactions of C=C double bonds provides a means for the synthesis of amino acids: Addition of hydrogen to an acylamino acrylate results in formation of an amino acid precursor. Using an enantiomerically-pure diphosphine in place of the two remaining ligands (‘L’ on previous page) results in formation of an asymmetric catalyst: The combination of an enantiomericallypure (homochiral) ligand with rhodium(I) results in formation of a catalyst for asymmetric reactions. Understand how a chiral environment is created around Rh(I) by the chiral diphosphine and how the enamine substrate co-ordinates (next slide). 7 Rh-diphosphine complexes control asymmetric induction by controlling the face of the alkene which attaches to the Rh. Two diastereoisomeric complexes of different energy can be formed. Hydrogen is transferred preferentially from one of these, in a stepwise manner, from the metal to the alkene. Co-ordination of the amide (N-C=O) group to the metal is important to the control. Ph Ph O HO2C O N H OMe Ph P HO2C Rh CO2H N H P O N H OMe Rh/DiPAMP There are two hydrides on the Rh however these have been omitted for clarity OMe Ph P O Rh OMe Less stable, but more reactive leads to product CO2H N H More stable, but less reactive complex Rapid Ph Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high enantioselectivity. P O H H S N H H CO2H Understand how a chiral environment is created around Rh(I) by a chiral phosphine and how the enamine substrate co-ordinates to the metal and helps direct the reaction. 8 Other chiral diphosphines are not chiral at P, but contain a chiral backbone which ‘relays’ chirality to conformation of the arene rings. Understand how a chiral environment is created around Rh(I), no need to memorise 9 the ligands, but understand that a variety can be used. Reduction reactions of C=C Double bonds using Rh(I) complexes– the nearest (proximal) alkene is reduced: Understand that the sense of reduction is relative to the directing group X. For a series of similar substrates, and a particular catalyst system (metal+ligand), the sense of reduction (i.e. which enantiomer product you get) relative to the directing group is generally predictable. However a different catalyst may have a different selectivity. 10 Reduction reactions of Double bonds using catalysts derived from Ru(II) (C=C): Similar to Rh(I) but more versatile. Learn that Ru(II) complexes of diphosphine ligands can also direct hydrogenations and are very versatile in their applications, although a directing group is still required. No need 11 to memorise the examples – they are there to illustrate the scope. Reduction reactions of Double bonds using catalysts derived from Ru(II) (C=C). Allyliic alcohols provide a good example of how the directing group works. alcohol is directing group OH R 0.2 mol% Ru(S-BINAP) OH H2 H3C H H OH 0.2 mol% Ru(S-BINAP) Hydrogen on front face relative to OH OH H3C Hydrogen on front face relative to OH H2 S OH H CH3 Learn that Ru(II) complexes of diphosphine ligands can also direct hydrogenations of allylic alcohols. No need to memorise examples, but understand how the position of the alcohol relative to the alkene controls the sense of reduction. 12 Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtree’s catalyst, which is Iridium-based. Crabtree's catalyst works well on isolated (i.e. no nearby co-ordinating group) C=C, bonds: + N R1 2 R PCy3 N Ir R4 R3 The catalyst is prepared with a cycloactadiene (COD) ligand but this is hydrogenated at the start of the catalytic cycle. The 'parent' Crabtree catalyst is nonchiral. + PCy3 Ir R1 PF6- H R4 H 2 H2 R3 R No directing group required Asymmetric versions of the Crabtree catalyst (prepared as COD complexes, but with the COD left off for clarity): CH3 0.1 mol% catalyst A 50 atm H2 + H CH3 PPh2 97% ee O N rt, CH2Cl2 Ir(COD) tBu B((3,5-C6H3(CF3)2)4(BARF-) A + CH3 1 mol% catalyst B H CH3 O 92% ee CH3 50 atm H2 rt, CH2Cl2 CH3 N Ph P(oTol)2 Ir(COD) B B((3,5-C6H3(CF3)2)4- No need to memorise examples – just understand the concepts, and remember that with 13 this Ir catalyst, there is no requirement for a directing group in the substrate. Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtree’s catalyst. + O N Ph Particularly challenging application: P(oTol)2 Ir(COD) B B((3,5-C6H3(CF3)2)41 mol% catalyst B AcO R O 50 atm H2 rt, CH2Cl2 Vitamin E precursor AcO R R R O >98% RRR enantiomer. Each reduction is controlled by the catalyst i.e. it is not diastereocontrol. Remember that Ir(I) complexes with P and N donors can reduce double bonds without a directing group in the substrate, i.e. sterically-driven. No need to memorise the specific examples. 14 Reduction reactions of C=O Double bonds using organometallic complexes. The same principle regarding directing groups also applies to C=O reduction, Ru and Rh are most commonly used: O O H3C 0.1 mol% [(R-BINAP)Ru(OAc)2] OMe 86 atm H2 51h, 20oC, EtOH,100% H OH O H3C OMe 99% ee directing group directing group O O 0.1 mol% [(R-BINAP)Ru(OAc)2] P 4 atm H2 OMe 72h, 25oC, MeOH,99% OMe H3C H OH O P H3C OMe >95% ee OMe bromine is directing group O H3C Br 0.1 mol% [(R-BINAP)Ru(OAc)2] 86 atm H2 62h, 20oC, EtOH,97% H OH Br H3C >92% ee Understand that a C=O group can be reduced by a chiral Ru or Rh complex as well as a C=C bond, and that a directing group is also needed. No need to memorise 15 specific examples. Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: O Racemic! O R2 OMe 1 R H2 catalyst O Overall O O R2 OMe 1 H R2 O O OMe 1 R reduced very slowly R enol O R2 1 R O Me fast H OH 2 R O OMe H R1 Principle: The substrate is rapidly racemising and one enantiomer is selectively reduced: Enantiomerically Pure Learn that a beta-keto ester can epimerise rapidly and that one enantiomer is more quickly reduced, therefore leading to an enantiomerically-enriched product. Be able to draw the mechanism of this. No need to memorise the specific examples. 16 Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: No need to memorise examples – these illustrate the diversity of the process – but understand the concept. 17 Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. Ph2 P H Ru P Ph2 O H Ph O Me Ph2 P P Ph2 H Ru H N H2 N H2 Ph HO H Ph OH Me H H N Ph Very high e.e. from very low catalyst loadings H2 , solvent Mechanism H2 N H Ph Ph2 P P Ph2 Ph Ru H N N H2 H Ph Ph H2 Understand that the mechanism changes when a diamine is added to a Ru(II)/diphosphine complex, and this allows C=O bonds to be reduced without a nearby directing group present. Be able to draw the mechanism of this. 18 Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. O 0.2 mol% catalyst 2.5 mol% KOH 5 atm H2, EtOH, 5h, 100% H OH 97% e.e. OH O 0.2 mol% catalyst 0.24 mol% KOH 5 atm H2, iPrOH, 3.5h, 100% No need to memorise the examples – just designed to show the scope of the process. cis:trans 100:1 19 Oxidation reactions of alkenes. R1 R1 R2 2 R1 O This represents a good way to create chiral centres. OH R R3 Dihydroxylation 2 R3 epoxidation R R3 R1 OH 2 R OH NH2 3 R1 OH NH2 2 R R aminohydroxylation The Sharpless dihydroxylation reaction employs ligand-acceleration to turn the known dihydroxyation reaction into an asymmetric version. This process depends on the use of an amine to accelerate a reaction: Dihydroxylation OH OsO4 OH Dihydroxylation OsO4 slow fast OH OH N use of the amine below speeds the reaction up: OsO4 N O Os O N O Os O O O O N can be converted back to OsO4 O A complex directs the reaction to one face in the cycloaddition: N O H2O O Os OH HO O OH HO Os O O O Understand the amine speeds up the reaction via a complex. 20 R3 Oxidation reactions of alkenes. The Sharpless dihydroxylation reaction employs ligand-acceleration to turn the known dihydroxyation reaction into an asymmetric version. The mechanism is as on the previous slide, but the amine creates a chiral environment for the reaction (like an active site in an enzyme): Understand how each enantiomer of ligand gives a different product enantiomer. 21 For trans-alkenes, medium/large groups are interchangeable. For trisubstituted alkenes, focus on the position of the H atom. Understand how each enantiomer of ligand gives a different product enantiomer. Be aware and learn which enantiomer is formed relative to the substituents using each form of 22 ‘ADmix’. Oxidation reactions of alkenes - Some extra examples for interest. RM CO2Et R OH 1 eq. MeSO 2NH2 AD-mix- , 0oC tBuOH/H2O L CO2Et CO2Et OH OH (DHQD)2PHAL CO2Et (AD-mix- ) OH 92% ee 97% ee Follow rules for trans alkenes OH Cl OH 1 eq. MeSO 2NH2 Cl AD-mix- , rt tBuOH/H2O OH 98% ee nC6H13 SPh SPh AD-mix- , 0oC tBuOH/H2O OH nC6H13 (AD-mix- ) Me3Si OH 97% ee Me3Si OH 1 eq. MeSO 2NH2 (DHQD)2PHAL AD-mix- , 0oC tBuOH/H2O RL OH OH 88% ee up to 96% ee with alternative ligand. 98% ee OH OH 1 eq. MeSO 2NH2 o AD-mix- , 0 C tBuOH/H2O OH 1 eq. MeSO 2NH2 Ph OH 93% ee H AD-mix- , 0oC tBuOH/H2O Ph HO HO H 97% ee relate configuration to position of H atom No need to memorise the examples – these are just intended to illustrate the scope, but understand what the dihydroxylation achieves, and how versatile it can be. 23 Asymmetric transfer hydrogenation by organocatalysis – an alternative to hydrogen gas. Understand that Hantzsch esters are used as reagents for reduction of C=N bond in organocatalysis reactions. Be able to draw the mechanism of the hydride transfer step and 24 the imine formation. No need to memorise examples. Asymmetric transfer hydrogenation by organocatalysis. No need to memorise examples, which are here to illustrate the scope of the methodology, but understand the concepts and learn the mechanism of hydrogen transfer. 25 More applications of organocatalysis – C-C bond formation (aldol reaction). Examples of common organocatalysts: L-proline CO2H N H or pyrrolidines: Ph N H Ph Ph N H or other N-heterocycles: O NMe Ph Understand that the combination of a chiral amine and a ketone or aldehyde forms an enamine which directs a subsequent aldol reaction. Be able to draw the mechanism of the enamine formation, the reaction with a ketone or aldehyde and the subsequent hydrolysis step. No need to memorise examples. N H CO2H 26 More applications of organocatalysis which proceed via formation of an enamine – bonds to C atoms. This is an example to provide an appreciation of the scope, no need to memorise, but sure you know the mechanism of enamine formation and the subsequent reaction. The addition reactions are achieved by the reaction of the enamine with an electrophile. In the example above the electrophile is the azadicarboxylate with the N=N bond shown above. 27 Allylic substitution reactions are powerful methods for forming C-C bonds. But how does the Nu: add to one end? Understand that a flat allyl complex is formed and that the ligand directs a nucleophile to one end by a combination of steric and electronic factors. No need to memorise 28 examples. Allylic substitution reactions are powerful methods for forming C-C bonds. Example ligand: 0 O O Ph2P + Ph Ph2P N Pd N Pd R O -AcO Ph2P H N Pd OAc R Ph OAc Favoured conformation: the allyl group is in front of the Pd complex. 0 Ph2P R Pd N O Ph Ph R Ph Ph Ph Nu Ph Alternative conformation: Ph Ph2P Pd N H O Ph disfavoured by steric clash with equatorial H or slower to react. Trans effect favours addition to end opposite the P atom. and from the front of the allylic group (because the Pd is blocking the back group). Ph2P Pd N Ph Ph R H Nu Ph Ph (enantiomerically enriched) and catalyst is released to re-enter cycle. Understand that a flat allyl complex is formed and that the ligand directs a nucleophile to one end by a combination of steric and electronic factors. No need to memorise examples. 29 Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples. Understand that a Pd/chiral ligand combination is required. 30