Enantioselective Reductions

• RhCl(PPh3)3 catalyses homogenous hydrogenation of alkenes with H2(g)

• Using rhodium catalysts bearing chiral diphosphine ligands • Enantioselective • E.g. (R,R)-DiPAMP used to synthesise anti-Parkinson’s drug L-DOPA

• Two diastereoisomeric substrate-catalyst complexes are formed, but the more stable one is actually the least reactive towards H2 gas- slow • Thus, reaction proceeds almost exclusively via the minor substrate-catalyst diastereomer

• Rhodium Rh Catalysts • Ruthenium Ru catalysts • Iridium Ir catalysts • Typically require alkenes bearing a suitable coordinating functional group for high enantioselectivity e.g. C=O group

• Wide array of chiral (mainly C2 symmetric) bisphosphine ligands have been optimised

• Low energy diastereomeric transition state which delivers H2 to one side

• Alkene hydrogenation in production of candoxatril using (R)-MeO-BIPHEP • Imine hydrogenation in production of (S)-Metolachlor using xyliphos catalyst

• Used beta-keto ester as substrate • Produced enantiopure secondary alcohol • RuCl2[(R)-BINAP] • Noyori asymmetric hydrogenation

• kinv>ks,s/kR,R • Can give rise to dynamic kinetic resolution DKRs • Where max theoretical yield is 100% compared to 50%

• Insertion of a Ru-bound hydride ligand into the C=O bond of the ketone that is initiated by protonation of the carbonyl group of the beta-keto ester • The keto group is pi-bound whereas the ester group is sigma-bound to the metal

• As the keto group is pi-bound it is more sensitive to steric interactions with equatorial Ph ligands • Therefore favoured product is that which goes via binding that avoids clash of R groups in ester with Ph ligands

• Noyori hydrogenation DKR strategy was used to prepare a beta-hydroxy ester en route to the complex alkaloid -codaphniphylline

• Enantioselective ketone reduction • CBS catalyst is commercially available as either enantiomer

• 3 Steps from proline • COCl2, Et3N • PhMgBr • (MeBO)3 • L- proline –> S-CBS • D-proline –> R-CBS

• Add BH3.L - BH3 is activated by N • Ketone coordinates to B of catalyst • Both reagents coordinate on convex face of system as more accessible • Envelope transition state forms • Avoid Me <–> RL interaction • Ph group prevents ketone rotating underneath the catalyst • Forms product and catalyst recycled

• Wide range of ketones • Ketones with phenyl and methyl group • alpha, beta unsaturated ketones • Ketones which contain two similar phenyl group with different substituents e.g. NO2, MeO

• S-CBS catalyst with BH3.THF used in synthesis of Ginkolide B • R-CBS catalyst with BH3.SMe2 used in synthesis of ezetimibe

• The Noyori asymmetric transfer hydrogenation which uses isopropanol as a source of hydrogen and solvent • [Ts-DPEN RuCl(p-cymene)] Catalyst • Can use HCO2H, Base instead of i-PrOH as solvent and hydrogen source

• First addition of isopropanol where hydrogen is transferred Ru and N on catalyst producing acetone by product • Two hydrogens are then transferred to the ketone to produce a secondary alcohol • Chiral secondary alcohol is eliminated to recycle catalyst

• C-H bond of aromatic ligand of Ru forms Pi interaction with aromatic of ketone • This enables carbonyl to be brought into close proximity to two hydrogens of chiral Ru complex • Two phenyl groups adopt equatorial groups • Ar group points up towards Ph of catalyst and R group points down.

• Small organic molecules as catalysts • Based on generation of highly electrophilic alpha,beta-unsaturated iminium ions as intermediates (‘iminium catalysts’) • Hantzsch esters as reducing agents

• High load of organic catalyst (contains t-bu) and amine is added to the alkene (which contains aldehyde) to form an iminium ion • s-trans geometry minimises A1,3 strain of t-bu to alkene • Add a non-aromatic ester (Hantzsch) which wants to become aromatic so donates H to system • Attacks on bottom face to avoid t-bu • Water is added to separate - produces aldehyde and recycles catalyst