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Síntese Avançada · Stereoselective synthesis

Catálise assimétrica e auxiliares quirais

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O que você vai aprender

  • Convert between enantiomeric excess, enantiomeric ratio and the free-energy gap between competing diastereomeric transition states, and measure ee with chiral derivatising agents.
  • Predict the configuration of alcohols from CBS and Noyori ketone reductions and explain how each catalyst delivers hydride to one face of the carbonyl.
  • Predict the products of Sharpless epoxidation, Sharpless dihydroxylation and Jacobsen epoxidation from their face-selection models, and recognise the substrates each method suits.
  • Use an Evans oxazolidinone to set α-stereocentres by enolate alkylation and boron aldol reactions, and remove the auxiliary without touching the new stereocentre.
  • Relate enolate and crotyl geometry to syn or anti products through the chair-shaped Zimmerman–Traxler transition state.

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Measuring selectivity: ee, er and ΔΔG‡

Enantiomers have identical energies, so a chiral catalyst or auxiliary can only favour one of them by making the two competing transition states diastereomeric. The outcome is reported as the enantiomeric ratio (er, for example 95:5) or the enantiomeric excess, ee = (major − minor)/(major + minor) × 100%, so 95:5 is 90% ee. Under kinetic control the ratio of the two products equals the ratio of the two rate constants, and er = exp(ΔΔG‡/RT). At 25 °C a 95:5 ratio needs ΔΔG‡ = RT ln 19 ≈ 7.3 kJ/mol, comparable to the energy of one weak hydrogen bond, which is why lowering the temperature usually raises ee. Enantiomers have identical NMR spectra in an achiral solvent, so ee is measured by chiral HPLC or GC, or by converting the sample into diastereomers with an enantiopure reagent such as Mosher's acid chloride (MTPA-Cl) and integrating the separate NMR signals. Optical rotation gives the optical purity, which equals ee only when rotation is linear in composition.

Asymmetric ketone reduction: CBS and Noyori

The Corey–Bakshi–Shibata (CBS) catalyst is an oxazaborolidine made from (S)-diphenylprolinol, itself made from (S)-proline. Borane binds the ring nitrogen, which makes the ring boron a stronger Lewis acid and the borane a better hydride donor. The ketone binds the ring boron through the oxygen lone pair on the side of its smaller group, so the larger group points away from the B-methyl, and hydride passes from the N-bound borane to the carbonyl carbon through a six-membered ring. (S)-Me-CBS (shown) reduces acetophenone to (R)-1-phenylethanol in about 97% ee. Noyori–Ikariya transfer hydrogenation uses RuCl[(S,S)-TsDPEN](p-cymene) with isopropanol or formic acid as the hydrogen source. The 18-electron Ru–H complex carries an N–H on the diamine; the hydride on ruthenium and the proton on nitrogen move together to the carbonyl carbon and oxygen through a six-membered ring, without the ketone ever binding the metal. The (S,S) catalyst gives (S)-1-phenylethanol. The related Ru–BINAP catalysts hydrogenate β-keto esters with H₂, where the ester carbonyl helps bind the substrate to the metal.

Asymmetric oxidation: Sharpless and Jacobsen

The Sharpless asymmetric epoxidation needs an allylic alcohol: Ti(OiPr)₄, diethyl or diisopropyl tartrate and tert-butyl hydroperoxide assemble a titanium complex that binds the substrate's alkoxide, so only the alkene next to the OH is epoxidised. Draw the allylic alcohol in the plane of the page with the CH₂OH at the lower right: L-(+)-DET delivers oxygen from below the plane and D-(−)-DET from above. (E)-Cinnamyl alcohol with (+)-DET gives (2S,3S)-3-phenylglycidol (shown). Secondary allylic alcohols react at very different rates for the two enantiomers, so a racemate undergoes kinetic resolution, with at most 50% recovery of the slow enantiomer. The Sharpless asymmetric dihydroxylation uses catalytic osmium, a cinchona-alkaloid ligand and K₃Fe(CN)₆ as the stoichiometric oxidant; AD-mix-β contains (DHQD)₂PHAL and AD-mix-α contains (DHQ)₂PHAL. With the largest alkene substituent in the lower-left quadrant, AD-mix-β adds both oxygens from the top face: trans-stilbene gives (R,R)-hydrobenzoin. Jacobsen–Katsuki epoxidation uses a chiral (salen)Mn(III) complex and bleach and works best for cis-disubstituted alkenes conjugated with an aryl or alkenyl group. The related (salen)Co(III) catalysts resolve racemic terminal epoxides by hydrolytic kinetic resolution.

Chiral auxiliaries: Evans oxazolidinones

A chiral auxiliary is attached to the substrate, directs one reaction, and is then removed and recovered. Unlike a catalyst it is used in stoichiometric amounts, but its products are diastereomers, which can be separated by chromatography to give enantiopure material. (S)-4-Benzyloxazolidin-2-one is made from (S)-phenylalanine and is N-acylated with n-BuLi and an acid chloride (the propionyl imide is shown). NaHMDS or LDA at −78 °C gives the Z-enolate, held flat by chelation of the metal between the enolate oxygen and the ring carbonyl. The benzyl group then shields one face, and an alkyl halide adds to the other: allyl iodide gives the (R)-2-methylpent-4-enoyl imide. Lithium hydroperoxide (LiOH with H₂O₂) attacks the exocyclic imide carbonyl and releases the carboxylic acid and the intact auxiliary without epimerising the new stereocentre.

Chair transition states: aldol and crotylation

Boron and other metal enolates add to aldehydes through a chair-shaped six-membered transition state (the Zimmerman–Traxler model). The metal, enolate oxygen, enolate carbons, aldehyde carbon and aldehyde oxygen make up the ring, and the aldehyde substituent sits equatorial. In this chair a Z-enolate gives the syn aldol and an E-enolate the anti aldol. Short B–O bonds make the boron chair compact, which magnifies every steric difference. Evans aldol reactions use Bu₂BOTf and a hindered amine to make the Z boron enolate of an oxazolidinone imide. Boron has no free site for chelation, so the imide turns its ring carbonyl away from the enolate oxygen, and the benzyl group then picks the aldehyde face: (S)-4-benzyl-3-propionyloxazolidin-2-one and benzaldehyde give the (2'S,3'S) syn aldol (shown). Allyl- and crotylboranes and boronates react through the same chair: an (E)-crotyl reagent gives the anti homoallylic alcohol and a (Z)-crotyl reagent the syn one. Brown's diisopinocampheyl (Ipc) reagents, made from either enantiomer of α-pinene, choose the aldehyde face as well.

What to carry forward

Every enantioselective reaction works by making two transition states diastereomeric, and a few kJ/mol between them decides the ee. Learn each method's face-selection model (the CBS lone-pair rule, the Sharpless epoxidation and dihydroxylation mnemonics, the Evans auxiliary's shielding group, the Zimmerman–Traxler chair), apply it to the drawn substrate, and then assign R or S from scratch: the same face can carry a different CIP label when the priorities change.

Problemas de prática (40)

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Desenhe o mecanismo 12

Asymmetric ketone reduction

  • CBS reduction of acetophenone with (S)-Me-CBSDraw how borane and the ketone bind the CBS oxazaborolidine, the intramolecular hydride transfer that sets the (R) alcohol centre, and the release that regenerates the catalyst.
  • Noyori transfer hydrogenation of acetophenone with Ru–(S,S)-TsDPENDraw the concerted outer-sphere transfer of a ruthenium hydride and an amine proton to acetophenone, and the reverse transfer from isopropanol that regenerates the Ru–H catalyst.

Chair transition states: aldol and crotylation

  • Crotylboration of benzaldehyde with (E)-crotylboronic acid pinacol esterDraw the chair-shaped, six-membered transition state of an allylboration and use it to predict that an (E)-crotyl reagent gives the anti homoallylic alcohol.
  • Evans syn aldol: Z boron enolate + benzaldehyde through a Zimmerman–Traxler chairDraw aldehyde coordination to boron and the six-membered pericyclic C–C bond formation of the Evans aldol, and assign the (2'S,3'S) syn product.
  • Forming the Z boron enolate of an Evans imide with Bu₂BOTfDraw Lewis-acid activation of the imide by dibutylboron triflate and the amine deprotonation that gives the Z boron enolate used in the Evans aldol reaction.

Evans oxazolidinone auxiliaries

  • Making (S)-4-benzyloxazolidin-2-one from (S)-phenylalaninolDraw the two acyl substitutions that join an amino alcohol to diethyl carbonate and close the oxazolidinone ring, and show that the stereocentre from the amino acid passes into the auxiliary unchanged.
  • Evans alkylation: allylation of the (S)-4-benzyl propionyl imideDraw formation of the Z sodium enolate of an Evans imide and its SN2 reaction with allyl iodide on the face away from the benzyl group, creating the (R) stereocentre.
  • Removing the Evans auxiliary with lithium hydroperoxideDraw hydroperoxide formation, its addition to the exocyclic imide carbonyl and the release of the intact oxazolidinone, leaving the α-stereocentre untouched.
  • N-Propionylation of (S)-4-benzyloxazolidin-2-oneDraw the deprotonation of the oxazolidinone N–H by n-butyllithium and the acyl substitution on propionyl chloride that attaches the propionyl group to nitrogen.

Measuring enantioselectivity

  • Mosher ester formation from (R)-MTPA-Cl and (R)-1-phenylethanolDraw the acyl substitution that turns an enantioenriched alcohol into its Mosher ester, and show that neither stereocentre is touched, so the diastereomer ratio of the esters equals the enantiomer ratio of the alcohol.

Asymmetric alkene oxidation

  • Payne rearrangement and thiolate opening of (2S,3S)-3-propyloxiranemethanolDraw the base-induced Payne rearrangement of a 2,3-epoxy alcohol to the terminal 1,2-epoxide with inversion at C2, and its regioselective opening by thiophenoxide at C1, to give a 1-thio-2,3-diol.
  • Sharpless asymmetric dihydroxylation of trans-stilbene with AD-mix-βDraw the face-selective cycloaddition of ligand-bound OsO₄ to trans-stilbene and the hydrolysis of the osmate(VI) ester that releases (R,R)-hydrobenzoin.

Preveja o produto 6

Chair transition states: aldol and crotylation

  • Enolate geometry decides syn or antiPredict the relative configuration of an aldol product from the geometry of a boron enolate.
  • Brown (Z)-crotylborationPredict the relative configuration and connectivity of a homoallylic alcohol from a chiral crotylborane of known geometry.
  • Evans aldol with isobutyraldehydePredict the full stereostructure of an Evans boron aldol product and assign its CIP descriptors when the aldehyde substituent changes.

Asymmetric ketone reduction

  • CBS reduction of 2-chloroacetophenonePredict the configuration of a CBS product when a heteroatom substituent changes the CIP priorities but not the face of attack.

Asymmetric alkene oxidation

  • Sharpless epoxidation of cinnamyl alcohol with (−)-DETPredict the configuration of a Sharpless epoxidation product from the tartrate enantiomer and the alkene geometry.
  • Which alkene of geraniol is epoxidised?Predict which alkene of a polyene alcohol a Sharpless epoxidation attacks.

Classificar 3

Asymmetric alkene oxidation

  • What is consumed in AD-mix-β?Classify the components of AD-mix as catalyst, ligand, base or stoichiometric oxidant.
  • Choosing a substrate for Jacobsen epoxidationClassify alkenes by how well they suit Jacobsen–Katsuki asymmetric epoxidation.

Asymmetric ketone reduction

  • Which ketone suits Ru–BINAP hydrogenation?Classify ketones by whether they carry the second donor group that Ru–BINAP hydrogenation needs.

Comparar 4

Evans oxazolidinone auxiliaries

  • What an auxiliary offers that a catalyst does notCompare chiral auxiliaries with asymmetric catalysts in terms of the stereoisomers they produce and how those can be purified.

Measuring enantioselectivity

  • Rank ee from transition-state energy gapsPredict how the transition-state energy gap and the reaction temperature together set the enantiomeric excess.
  • Rank four reports of selectivityPut selectivities reported as ratios and as ee on one scale and rank them.

Asymmetric ketone reduction

  • Isopropanol or formic acid as the hydrogen sourceCompare isopropanol and formic acid–triethylamine as hydrogen donors in Noyori transfer hydrogenation.

Calcular 3

Measuring enantioselectivity

  • Free-energy gap behind 90% eeCalculate the free-energy difference between two diastereomeric transition states from the ee of a kinetically controlled reaction.
  • Enantiomeric excess from a chiral HPLC traceConvert an enantiomeric ratio from chiral HPLC into an enantiomeric excess.
  • Combine two batches of different eeCalculate the enantiomeric excess of a blend of two batches with different masses and opposite major enantiomers.

Encontre o erro 1

  • Why did the CBS reduction lose its ee?Diagnose the loss of enantioselectivity in a CBS reduction run under wet conditions with fast ketone addition.

Interprete as evidências 1

  • Enantiomeric excess from optical rotationRead an enantiomeric excess from a measured specific rotation and the rotation of the pure enantiomer.

Planeje uma síntese 3

Asymmetric ketone reduction

  • Switching the enantiomer in a CBS reductionChoose the change that gives the opposite enantiomer of a CBS reduction product.

Evans oxazolidinone auxiliaries

  • Reaching the other epimer with the same auxiliaryPlan which acyl group and which alkyl halide to combine with one auxiliary enantiomer to make a chosen α-stereocentre.
  • Order the steps of an Evans alkylationSequence the operations of an Evans auxiliary alkylation, including when the diastereomers must be separated.

Explique por quê 7

Chair transition states: aldol and crotylation

  • Why boron enolates are more selectiveExplain why boron enolates give higher aldol diastereoselectivity than lithium enolates.

Asymmetric ketone reduction

  • Why borane binds the CBS nitrogenExplain how coordination of borane to the oxazaborolidine nitrogen activates both the ketone and the hydride source.
  • More than 50% from a racemateExplain how dynamic kinetic resolution converts a racemic α-substituted β-keto ester into one stereoisomer in more than 50% yield.

Evans oxazolidinone auxiliaries

  • Why the imide enolate is ZExplain the Z selectivity of N-acyl oxazolidinone enolization in terms of A(1,3) strain.

Asymmetric alkene oxidation

  • Where does the trans epoxide come from?Explain why a conjugated cis alkene gives some trans epoxide in a Jacobsen epoxidation.
  • Kinetic resolution of a secondary allylic alcoholExplain why a Sharpless epoxidation of a racemic secondary allylic alcohol leaves one enantiomer behind, and why its yield is capped.

Measuring enantioselectivity

  • Why (R)-MTPA-Cl gives an (S)-MTPA esterExplain why acylation with Mosher's acid chloride changes the CIP label of the reagent's stereocentre without changing its configuration.

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