Enantioselective Oxidation of Alkenes Flashcards
Describe what is used in Sharpless Asymmetric Epoxidation
- Titanium-tartrate complexes e.g. Ti(Oi-Pr)4
2.t-butyl hydroperoxide (t-BuOOH) in excess - Used with chiral ligand L-(+)-DET or L-(+)-DIPT which are from the chiral pool
- effect the catalytic, enantioselective epoxidation of allylic alcohols
What is the mode of catalysis in Sharpless Asymmetric Epoxidation
- Electrophilic activation of the peroxide oxidant (t-BuOOH) by the Lewis acidic titanium centre
- Lewis acid accepts electrons from O
- Forms a highly strained intermediate which creates a chiral environment if there is a chiral ligand attached to Ti
Describe catalytic cycle of Sharpless asymmetric epoxidation - First step
- 2Ti(Oi-Pr)4 molecules added to 2 (+)-DET to produce a dimeric titanium species and 4-iPrOhH
- can be represented as monomeric for simplification
- One Titanium chelated by one DET
- One Ester groups point up and on down
Describe catalytic cycle of Sharpless asymmetric epoxidation second step
- t-BuOOH (epoxidising agent) is added
- The OH displaces an Oi-Pr group and donates electron density to titanium
Describe catalytic cycle of Sharpless asymmetric epoxidation third step
- The allylic alcohol substrate is added through displacement of the top apical i-Pr to create a chiral intermediate
- Aligns allylic alcohol fragment in correct place for O of peroxy fragment to undergo transfer generating desired epoxide ring system
- Results in high enantioselective facial selectivity
Describe catalytic cycle of Sharpless asymmetric epoxidation once the epoxide has been formed
- Once epoxidation occured
- Chiral epoxide fragment and t-BuOH are displaced by 2 i-PrOH to regenerate.
Describe scope of Sharpless Asymmetric Epoxidation
- Gives excellent enantioselectivities for a wide range of allylic alcohols
- Z-configured allylic alcohols tend to give lower ers
What chiral ligand do you use if you want the oxidation on top face
- D-(-)-DET
What chiral ligand do you use if you want the epoxidation on bottom face
- L-(+)-DET
What happens if you take a chiral sharpless catalyst and conduct it on a chiral enantiopure substrate
- Double diastereocontrol
- Gives very strong reagent control - catalyst control
- Get matched or mismatched
What has stronger directing effect the catalyst or substrate if mismatched
- Directing effect of chiral catalyst overrules seelctivity of inherent diastereo substrate- opposite product
What can be used instead of t-BuOOH
- CHP
- It is less explosive
Give example of where Sharpless asymmetric epoxidation is used in industry
- Used in production of glycidol
- Valuable enantiopure C3 building bloc,
Give example of where Sharpless asymmetric epoxidation is used in pharma
- Combination of SAE followed by a regioselective epoxide reduction to prepare 1,3-diols
- En route to antifungal agent amphotericin B
Describe use of SAE in kinetic resolutions or racemic allylic alcohols
- Both enantiomers of allylic alcohol should be epoxidized from the same face but the rates of epoxidation are different
- THe rate ratio kfast/kslow (selectivity factor, S) is typically high for SAE
- So %ee of the unreacted alcohol is essentially 100% at 60% conversion
- The conversion of the reaction is controlled by the limiting oxidant available and how much t-BuOOH is used is dictated by whether or not you want the enantiopure allylic alcohol or the enantiopure epoxy alcohol product
Which allylic alcohol enantiomer is slower
- Where R group is pointing towards the epoxidizing agent - steric hindrance
How much t-buOOH do you use if you wan the fast epoxide
- 0.45 eq
- Past 50% less reactive enantiomer starts to be produced - reduces selectivity
- low conversion levels ideal- so low [t-BuOOH]
How much t-BuOOH do you use if you want enantiopure less reactive alcohol
- 0.6 eq
- Ensures all the more reactive alcohol has reacted so only left with less
What is the max yield of kinetic resolution
- 50%
What is desymmetrization and max yield
- Enantiotopic group discrimination
- 100%
- Effectively the same as two kinetic resolutions
- The first deyymmetrises the compound
- The second removes any trace of unwanted enantiomer
- er of product increases with time
Describe how symmetrisation works for an alcohol with two symmetrical allyl units either side
- One is pro-R group and one is a pro-S group
- One of the groups is favoured for oxidation by DIPT so is fast reaction and produces the desired product
- The other is slow and produces the undesired product
- The undesired product then undergoes fast epoxidation favoured group is being epoxidized-
- Therefore you get the desired single epoxide as undesired epoxide is epoxidized fast to produce a diepoxide
What are limitations of the Sharpless assymetric epoxidation reaction
- Limited to allylic alcohols
- Z-configured alkenes are poor substrates
What is a reaction that can be used for the enantioselective epoxidation of unfunctionalised (z)-alkenes
- Jacobsen-Katsuki epoxidation
- Chiral (salen) manganese (III) complexes typically using NaOCl as the oxidant
How is the ligand for the manganese complex formed
- Condensation of chiral diamine with 2 eq of substituted salicylaldehyde
What are the different pathways that have been proposed for the mechanism of oxygen transfer to alkene in the Jacobsen-Katsuki epoxidation
- A Mn(V) oxo complex is most likely the active oxygen-transfer agent
- Concerted pathway
- Radical pathway - would explain formation of trans-epoxide minor products
- Manganaoxetane pathway
What is the most famous application of the Jacobsen-Katsuki epoxidation in synthesis
- Used in synthesis of HIV protease inhibitor indinavir
- Prepares enantiopure amino alcohol from indene
Describe the transition state of the Jacobsen-Katsuki epoxidation
- Substituents on the diamine backbone adopt equatorial positions (chair-like transition state) , causing the salen moiety to lean
- All approach vectors other than right-hand side approach are blocked
- Alkene substituents directed upwards, away from salen ligand
- Small alkene substituent Rs positioned near t-Bu group on salen ligand.
What is the Sharpless asymmetric dihydroxylation
- Catalytic and enantioselective version of the syn-dihydroxylation of alkenes using OsO4 to produce a syn diol
- Basis that tertiary amines as ligands accelerate the reaction of OsO4 with alkenes (ligand accelerated catalysis)
What are the two ligands used in Sharpless asymmetric dihydroxylation
- (DHQ)2PHAL
- (DHQD)2PHAL
- Coordinate the Os via nitrogen
- Diastereomers but behave as pseudo-enantiomers
What is needed in a Sharpless Asymmetric Dihydroxylation
- K2OSO2(OH)4- water-soluble, non-volatile Os(VI) precursor to OSO4
- DHQ ligand
- K3Fe(CN)6- water-soluble re-oxidant for osmium (OS(VI)–> OS(VIII))
- MeSO2NH2 - accelerates turnover by catalysing hydrolysis of the Os(VI) ester - optional
- K2CO3 - promotes Os(VI) ester hydrolysis by maintain high pH and promotes phase splitting
- t-BuOH - organic solvent
Describe scope of Sharpless Asymmetric dihydroxylation
- Works for both normal and electron-poor alkenes
- Different ligand classes better for different alkene types
What alkenes are best to use with PHAL ligands
- Either trans-disubstituted or trisubstituted
Describe transition state in Sharpless asymmetric dihydroxylation
- The ligand adopts a u-shaped binding pocket with OsO4 coordinating to a quinuclidine nitrogen of the C2-symmetric ligand
- Stabilising dispersion interactions exist between the ligand’s aromatic groups and the alkene substrate
What happens when NMO is used as the re-oxidant in Sharpless Asymmetric Dihydroxylation instead of K3Fe(CN)6
- Reoxidation competes with osmate(VI) ester hydrolysis giving a competing (ligand-free) catalytic cycle that is less enantioselective
- Problem solved by running the reactions as aqueous-organic biphasic mixtures and using K3Fe(CN)6 as a water-soluble oxidant
- Now oxidant resides entirely in the aqueous phase and so reoxidation of the osmate(VI) ester in the organic phase is prevented
What is the point of K2CO3 in SAD
- The K2CO3 not only acts as a stoichiometric base (absorbs H+ ions generated) but also promotes necessary phase-splitting of t-buOH/H2O mixture
Why is the second catalytic cycle which is generated when NMO is used in a SAD reaction less enantioselective
- Osmate (VI) ester is produced
- But in presence of NMO the chiral ligand can dissociate and Os oxidise to (VIII) without chiral ligand
- This can then compete with the Os(VI)L species in dihydroxylation - low enantioselectivity as no ligand
How could you use NMO in SAD
- If add alkene very slowly- suppresses the second cycle oxidation
What is a useful thing Sharpless developed
- Covert 1,2-diols into epoxides seterospecifically- not converting other alkenes present e.g. monosubstituted
