1 CH402 Asymmetric catalytic reactions Prof M. Wills Think about chiral centres. How would you make these products? Think about how you would make them in racemic form first, then worry about the asymmetric versions! What does a catalyst need to be able to provide in a catalytic version?

2 Examples of reactions which form chiral centres Hydrogenation of C=C, C=O, C=N bonds: Hydroboration of C=C bonds: Epoxidation of C=C bonds:

3 Examples of reactions which form chiral centres, cont… Dihydroxylation of C=C bonds: Hydrocyanation of C=O bonds: Hydrovinylation of C=C bonds: Addition of Grignard reagent to C=O bonds:

4 Examples of reactions which form chiral centres, cont. 2… Enolate alkylation:Aldol reaction: Diels-Alder (cycloaddition): And many, many more…. Hydroformylation of C=C bonds:

5 What properties are required of an asymmetric catalyst? Turnover, rate enhancement, selectivity The catalyst must recognise the reagents, accelerate the reaction, direct the reaction to one face of a substrate and release the product:

6 Asymmetric epoxidation of alkenes (1980s) Sharpless discovered that a combination of diethyl tartrate, titanium isopropoxide and a peroxide. But it requires an allylic alcohol as substrate. The oxidant is used stoichiometrically (i.e. you need one equivalent), but the titanium and tartrate are used in catalytic amounts (ca. 5 mol%). Mechanism? Could you modify this in an asymmetric manner? The (-)-diethyl tartrate gives the opposite enantiomer.

7 How the Sharpless epoxidation (of allylic alcohols) works (catalytic cycle):

8 Asymmetric epoxidation of alkenes using Mn/Salen complexes (Jacobsen epoxidation): The iodine reagent transfers its oxygen atom to Mn, then the Mn tranfers in to the alkene in a second step. The chirality of the catalyst controls the absolute configuration. Advantage? You are not limited to allylic alcohols.

9 Asymmetric hydrogenation for the synthesis of amino acids: Addition of hydrogen to an acylamino acrylate results in formation of an amine acid precursor. The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I) results in formation of a catalyst for asymmetric reactions.

10 Asymmetric catalysis - hydrogenation Rh-diphosphine complexes control asymmetric induction by controlling the face of the alkene which attaches to the Rh. Hydrogen is transferred, in a stepwise manner, from the metal to the alkene. The intermediate complexes are diastereoisomers of different energy. Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high enantioselectivity.

11 Asymmetric catalysis - hydrogenation Other chiral diphosphines are not chiral at P, but contain a chiral backbone which ‘relays’ chirality to conformation of the arene rings.

12 Asymmetric catalysis – Ketone reduction The reduction of a ketone to a secondary alcohol is a perfect reaction for asymmetric catalysis:

13 Asymmetric catalysis – Ketone reduction by pressure hydrogenation (I.e. hydrogen gas)

14 Asymmetric catalysis – Isomerisation

15 Asymmetric catalysis – Organocatalysis (no metals)

16 Asymmetric catalysis – Organocatalysis (no metals)

17 Asymmetric catalysis – Organocatalysis Other applications

18 Asymmetric catalysis – Enolate alkylation

19 Asymmetric catalysis – Enolate alkylation for synthesis of amino acids.

20 Asymmetric catalysis – Addition to an aldehyde (C-C bond forming reaction) – for interest only.