Enantioselective Reductions

Question 1

What did Wilkinson discover

Answer 1

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

Question 2

What were enantioselective variants of Wilkinson’s

Answer 2

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

Question 3

How does enantioselective hydrogenation: Curtin Hammett control work

Answer 3

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

Question 4

What do most modern enantioselective hydrogenations use

Answer 4

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

Question 5

Describe variety of bisphosphine ligands used for hydrogenation catalyst

Answer 5

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

Question 6

What does enantioselective hydrogenation rely on

Answer 6

1. Low energy diastereomeric transition state which delivers H2 to one side

Question 7

What are two examples of enantioselective hydrogenation use

Answer 7

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

Question 8

What was the first transition metal-catalysed highly enantioselective hydrogenation of a functionalised ketone

Answer 8

1. Used beta-keto ester as substrate
2. Produced enantiopure secondary alcohol
3. RuCl2[(R)-BINAP]
4. Noyori asymmetric hydrogenation

Question 9

What happens if a chiral substrate undergos rapid epimerisation

Answer 9

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

Question 10

What is the mechanism of the Noyori asymmetric hydrogenation of functionalised ketones

Answer 10

1. 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
2. The keto group is pi-bound whereas the ester group is sigma-bound to the metal

Question 11

Describe what determines the enantioselectivity in the Noyori asymmetric hydrogenation of functionalised ketones

Answer 11

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

Question 12

What is an example of Noyori asymmetric hydrogenation in synthesis

Answer 12

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

Question 13

What is a CBS reduction

Answer 13

1. Enantioselective ketone reduction
2. CBS catalyst is commercially available as either enantiomer

Question 14

How do you prepare the CBS catalyst

Answer 14

1. 3 Steps from proline
2. COCl2, Et3N
3. PhMgBr
4. (MeBO)3
5. L- proline –> S-CBS
6. D-proline –> R-CBS

Question 15

Describe process of CBS catalyst reduction of ketone

Answer 15

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

Question 16

What can CBS reduction be used for

Answer 16

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

Question 17

What is example of CBS use in synthesis

Answer 17

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

Question 18

What is the prefered method for aromatic ketones

Answer 18

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

Question 19

Describe Noyori asymmetric transfer hydrogenation catalytic cycle

Answer 19

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

Question 20

How is there enantiomeric control in the Noyori asymmetric transfer hydrogenation of ketones

Answer 20

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

Question 21

What can be used for electron-poor alkenes

Answer 21

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

Question 22

Describe how Enantioselective conjugate reaction of electron poor alkenes works

Answer 22

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