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aa Topics in organic chemistry 1 > Enantioselective Oxidation of Alkenes > Flashcards

Enantioselective Oxidation of Alkenes Flashcards

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1
Q

Describe what is used in Sharpless Asymmetric Epoxidation

A
  1. Titanium-tartrate complexes e.g. Ti(Oi-Pr)4
    2.t-butyl hydroperoxide (t-BuOOH) in excess
  2. Used with chiral ligand L-(+)-DET or L-(+)-DIPT which are from the chiral pool
  3. effect the catalytic, enantioselective epoxidation of allylic alcohols
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2
Q

What is the mode of catalysis in Sharpless Asymmetric Epoxidation

A
  1. Electrophilic activation of the peroxide oxidant (t-BuOOH) by the Lewis acidic titanium centre
  2. Lewis acid accepts electrons from O
  3. Forms a highly strained intermediate which creates a chiral environment if there is a chiral ligand attached to Ti
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3
Q

Describe catalytic cycle of Sharpless asymmetric epoxidation - First step

A
  1. 2Ti(Oi-Pr)4 molecules added to 2 (+)-DET to produce a dimeric titanium species and 4-iPrOhH
  2. can be represented as monomeric for simplification
  3. One Titanium chelated by one DET
  4. One Ester groups point up and on down
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4
Q

Describe catalytic cycle of Sharpless asymmetric epoxidation second step

A
  1. t-BuOOH (epoxidising agent) is added
  2. The OH displaces an Oi-Pr group and donates electron density to titanium
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5
Q

Describe catalytic cycle of Sharpless asymmetric epoxidation third step

A
  1. The allylic alcohol substrate is added through displacement of the top apical i-Pr to create a chiral intermediate
  2. Aligns allylic alcohol fragment in correct place for O of peroxy fragment to undergo transfer generating desired epoxide ring system
  3. Results in high enantioselective facial selectivity
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6
Q

Describe catalytic cycle of Sharpless asymmetric epoxidation once the epoxide has been formed

A
  1. Once epoxidation occured
  2. Chiral epoxide fragment and t-BuOH are displaced by 2 i-PrOH to regenerate.
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7
Q

Describe scope of Sharpless Asymmetric Epoxidation

A
  1. Gives excellent enantioselectivities for a wide range of allylic alcohols
  2. Z-configured allylic alcohols tend to give lower ers
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8
Q

What chiral ligand do you use if you want the oxidation on top face

A
  1. D-(-)-DET
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9
Q

What chiral ligand do you use if you want the epoxidation on bottom face

A
  1. L-(+)-DET
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10
Q

What happens if you take a chiral sharpless catalyst and conduct it on a chiral enantiopure substrate

A
  1. Double diastereocontrol
  2. Gives very strong reagent control - catalyst control
  3. Get matched or mismatched
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11
Q

What has stronger directing effect the catalyst or substrate if mismatched

A
  1. Directing effect of chiral catalyst overrules seelctivity of inherent diastereo substrate- opposite product
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12
Q

What can be used instead of t-BuOOH

A
  1. CHP
  2. It is less explosive
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13
Q

Give example of where Sharpless asymmetric epoxidation is used in industry

A
  1. Used in production of glycidol
  2. Valuable enantiopure C3 building bloc,
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14
Q

Give example of where Sharpless asymmetric epoxidation is used in pharma

A
  1. Combination of SAE followed by a regioselective epoxide reduction to prepare 1,3-diols
  2. En route to antifungal agent amphotericin B
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15
Q

Describe use of SAE in kinetic resolutions or racemic allylic alcohols

A
  1. Both enantiomers of allylic alcohol should be epoxidized from the same face but the rates of epoxidation are different
  2. THe rate ratio kfast/kslow (selectivity factor, S) is typically high for SAE
  3. So %ee of the unreacted alcohol is essentially 100% at 60% conversion
  4. 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
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16
Q

Which allylic alcohol enantiomer is slower

A
  1. Where R group is pointing towards the epoxidizing agent - steric hindrance
17
Q

How much t-buOOH do you use if you wan the fast epoxide

A
  1. 0.45 eq
  2. Past 50% less reactive enantiomer starts to be produced - reduces selectivity
  3. low conversion levels ideal- so low [t-BuOOH]
18
Q

How much t-BuOOH do you use if you want enantiopure less reactive alcohol

A
  1. 0.6 eq
  2. Ensures all the more reactive alcohol has reacted so only left with less
19
Q

What is the max yield of kinetic resolution

A
  1. 50%
20
Q

What is desymmetrization and max yield

A
  1. Enantiotopic group discrimination
  2. 100%
  3. Effectively the same as two kinetic resolutions
  4. The first deyymmetrises the compound
  5. The second removes any trace of unwanted enantiomer
  6. er of product increases with time
21
Q

Describe how symmetrisation works for an alcohol with two symmetrical allyl units either side

A
  1. One is pro-R group and one is a pro-S group
  2. One of the groups is favoured for oxidation by DIPT so is fast reaction and produces the desired product
  3. The other is slow and produces the undesired product
  4. The undesired product then undergoes fast epoxidation favoured group is being epoxidized-
  5. Therefore you get the desired single epoxide as undesired epoxide is epoxidized fast to produce a diepoxide
22
Q

What are limitations of the Sharpless assymetric epoxidation reaction

A
  1. Limited to allylic alcohols
  2. Z-configured alkenes are poor substrates
23
Q

What is a reaction that can be used for the enantioselective epoxidation of unfunctionalised (z)-alkenes

A
  1. Jacobsen-Katsuki epoxidation
  2. Chiral (salen) manganese (III) complexes typically using NaOCl as the oxidant
24
Q

How is the ligand for the manganese complex formed

A
  1. Condensation of chiral diamine with 2 eq of substituted salicylaldehyde
25
Q

What are the different pathways that have been proposed for the mechanism of oxygen transfer to alkene in the Jacobsen-Katsuki epoxidation

A
  1. A Mn(V) oxo complex is most likely the active oxygen-transfer agent
  2. Concerted pathway
  3. Radical pathway - would explain formation of trans-epoxide minor products
  4. Manganaoxetane pathway
26
Q

What is the most famous application of the Jacobsen-Katsuki epoxidation in synthesis

A
  1. Used in synthesis of HIV protease inhibitor indinavir
  2. Prepares enantiopure amino alcohol from indene
27
Q

Describe the transition state of the Jacobsen-Katsuki epoxidation

A
  1. Substituents on the diamine backbone adopt equatorial positions (chair-like transition state) , causing the salen moiety to lean
  2. All approach vectors other than right-hand side approach are blocked
  3. Alkene substituents directed upwards, away from salen ligand
  4. Small alkene substituent Rs positioned near t-Bu group on salen ligand.
28
Q

What is the Sharpless asymmetric dihydroxylation

A
  1. Catalytic and enantioselective version of the syn-dihydroxylation of alkenes using OsO4 to produce a syn diol
  2. Basis that tertiary amines as ligands accelerate the reaction of OsO4 with alkenes (ligand accelerated catalysis)
29
Q

What are the two ligands used in Sharpless asymmetric dihydroxylation

A
  1. (DHQ)2PHAL
  2. (DHQD)2PHAL
  3. Coordinate the Os via nitrogen
  4. Diastereomers but behave as pseudo-enantiomers
30
Q

What is needed in a Sharpless Asymmetric Dihydroxylation

A
  1. K2OSO2(OH)4- water-soluble, non-volatile Os(VI) precursor to OSO4
  2. DHQ ligand
  3. K3Fe(CN)6- water-soluble re-oxidant for osmium (OS(VI)–> OS(VIII))
  4. MeSO2NH2 - accelerates turnover by catalysing hydrolysis of the Os(VI) ester - optional
  5. K2CO3 - promotes Os(VI) ester hydrolysis by maintain high pH and promotes phase splitting
  6. t-BuOH - organic solvent
31
Q

Describe scope of Sharpless Asymmetric dihydroxylation

A
  1. Works for both normal and electron-poor alkenes
  2. Different ligand classes better for different alkene types
32
Q

What alkenes are best to use with PHAL ligands

A
  1. Either trans-disubstituted or trisubstituted
33
Q

Describe transition state in Sharpless asymmetric dihydroxylation

A
  1. The ligand adopts a u-shaped binding pocket with OsO4 coordinating to a quinuclidine nitrogen of the C2-symmetric ligand
  2. Stabilising dispersion interactions exist between the ligand’s aromatic groups and the alkene substrate
34
Q

What happens when NMO is used as the re-oxidant in Sharpless Asymmetric Dihydroxylation instead of K3Fe(CN)6

A
  1. Reoxidation competes with osmate(VI) ester hydrolysis giving a competing (ligand-free) catalytic cycle that is less enantioselective
  2. Problem solved by running the reactions as aqueous-organic biphasic mixtures and using K3Fe(CN)6 as a water-soluble oxidant
  3. Now oxidant resides entirely in the aqueous phase and so reoxidation of the osmate(VI) ester in the organic phase is prevented
35
Q

What is the point of K2CO3 in SAD

A
  1. The K2CO3 not only acts as a stoichiometric base (absorbs H+ ions generated) but also promotes necessary phase-splitting of t-buOH/H2O mixture
36
Q

Why is the second catalytic cycle which is generated when NMO is used in a SAD reaction less enantioselective

A
  1. Osmate (VI) ester is produced
  2. But in presence of NMO the chiral ligand can dissociate and Os oxidise to (VIII) without chiral ligand
  3. This can then compete with the Os(VI)L species in dihydroxylation - low enantioselectivity as no ligand
37
Q

How could you use NMO in SAD

A
  1. If add alkene very slowly- suppresses the second cycle oxidation
38
Q

What is a useful thing Sharpless developed

A
  1. Covert 1,2-diols into epoxides seterospecifically- not converting other alkenes present e.g. monosubstituted

aa Topics in organic chemistry 1 (11 decks)

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