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Síntese Avançada · Stereoselective methods

Organocatálise assimétrica

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O que você vai aprender

  • Draw enamine catalysis by proline and its relatives (aldol, Mannich, α-amination, Hajos–Parrish cyclisation) and explain how the carboxylic acid directs the electrophile in the Houk–List transition state.
  • Draw iminium catalysis by imidazolidinones and diarylprolinol silyl ethers, and decide whether a given aldehyde reacts through an iminium ion (β-carbon electrophile) or an enamine (α-carbon nucleophile).
  • Use N-heterocyclic carbenes to reverse carbonyl polarity, and trace the Breslow intermediate through benzoin and Stetter reactions.
  • Explain catalysis by hydrogen-bond donors, chiral phosphoric acids, chiral ammonium ions and cinchona bases, including the role of each part of a bifunctional catalyst.
  • Convert between enantiomeric ratio, enantiomeric excess and the free-energy difference between competing transition states.

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Enamine catalysis: proline as a small aldolase

A secondary amine condenses with a ketone or aldehyde to give an iminium ion, and loss of an α-proton gives an enamine. The enamine is a neutral enolate equivalent: the nitrogen lone pair raises the HOMO, so the terminal carbon attacks electrophiles. L-Proline adds two things. Its carboxylic acid acts as an internal acid and base for every proton transfer, and in the carbon–carbon bond-forming step it hydrogen-bonds to (and protonates) the developing alkoxide of the aldehyde. In this Houk–List transition state the anti enamine attacks one face of the aldehyde, the Re face for aromatic and branched aldehydes, so acetone and 4-nitrobenzaldehyde give the (R)-aldol. Water then hydrolyses the product iminium ion and releases proline. The same enamine attacks protonated imines (Mannich reaction) and azodicarboxylates (α-amination). Proline also condenses with aldehydes to oxazolidinones, cyclic N,O-acetals that sit off the cycle and hold some of the catalyst.

Choosing between enantiotopic carbonyl groups

In the Hajos–Parrish–Eder–Sauer–Wiechert reaction, 2-methyl-2-(3-oxobutyl)cyclopentane-1,3-dione forms an enamine at the methyl ketone of its side chain. That enamine can reach either ring carbonyl group; the two are enantiotopic, and proline makes the enamine attack only one of them, closing a six-membered ring. With about 3 mol% L-proline in DMF the bicyclic ketol forms with over 90% ee, and acid dehydration gives the (S)-Hajos–Parrish ketone. The cyclohexane-1,3-dione analogue gives the Wieland–Miescher ketone, a common steroid building block, in lower ee.

Iminium catalysis: lowering the LUMO

An α,β-unsaturated aldehyde condenses with a chiral secondary amine salt to give an α,β-unsaturated iminium ion. The positive nitrogen lowers the LUMO just as a Lewis acid on oxygen does, so dienes, electron-rich arenes and other nucleophiles add at the β-carbon. In MacMillan's imidazolidinones, made from phenylalanine, the iminium ion adopts the (E) geometry and the benzyl group covers one face of the alkene, so the nucleophile approaches the other face. The cycloadduct or conjugate adduct is an enamine or iminium ion that water hydrolyses to the aldehyde product and the free catalyst. Diarylprolinol silyl ethers (Jørgensen–Hayashi catalysts) work in both modes: with enals they form iminium ions, and with saturated aldehydes they form enamines that add to nitroalkenes and give syn γ-nitroaldehydes. They direct by steric shielding with the bulky CAr₂OSiR₃ group rather than by a hydrogen bond, and the silyl ether stops the catalyst from tying itself up as an N,O-acetal.

N-heterocyclic carbenes and umpolung

A base removes the C–H between the two heteroatoms of a thiazolium or triazolium salt, giving an N-heterocyclic carbene. The carbene adds to an aldehyde, and a proton transfer gives the Breslow intermediate, an enaminol whose former carbonyl carbon is now nucleophilic: an acyl anion equivalent. Adding to a second aldehyde gives a benzoin (an α-hydroxy ketone), a reversible reaction; adding 1,4 to a Michael acceptor gives a 1,4-dicarbonyl compound (the Stetter reaction), which is effectively irreversible. Loss of the carbene from an alkoxide regenerates the catalyst at the end of each cycle. Chiral triazolium salts give enantioenriched benzoins and Stetter products.

Hydrogen-bond donors and chiral Brønsted acids

A thiourea donates two parallel N–H hydrogen bonds to a nitro group, a carbonyl oxygen or an anion. Electron-poor aryl groups such as 3,5-bis(trifluoromethyl)phenyl make the N–H bonds more acidic and stronger donors. Takemoto's bifunctional catalyst adds a tertiary amine on a chiral cyclohexane: the amine deprotonates a malonate while the thiourea holds the nitroalkene, so both partners are organised in one chiral complex. In Jacobsen's Strecker reaction the thiourea binds cyanide after HCN protonates the imine. Chiral phosphoric acids derived from BINOL, such as TRIP with 2,4,6-triisopropylphenyl groups at the 3- and 3′-positions, protonate an imine and stay bound to it as a chiral phosphate ion pair; a Hantzsch ester, a 1,4-dihydropyridine that becomes an aromatic pyridine, then delivers a hydride to one face of the iminium ion. The chirality of the binaphthyl reaches the reacting centre only through bulky 3,3′-substituents, which wall in the ion pair; the parent acid with hydrogen at C3 and C3′ gives low ee.

Chiral ion pairs and chiral bases

In asymmetric phase-transfer catalysis hydroxide deprotonates the substrate at the interface with aqueous KOH, and a lipophilic quaternary ammonium ion derived from a cinchona alkaloid carries the enolate into the organic phase as a tight chiral ion pair. The ammonium ion has no lone pair, so it is not the base; its tetrahedral nitrogen is shielded on most faces by the quinuclidine cage and a large N-substituent such as 9-anthracenylmethyl, so the enolate pairs with it in one orientation. The benzophenone imine of glycine tert-butyl ester (O'Donnell's substrate) is benzylated this way; the product is much less acidic than the starting imine, so it is not deprotonated again and does not racemise or dialkylate. Cinchona alkaloids themselves are chiral tertiary amines. Their quinuclidine nitrogen acts as a general base that helps methanol open a meso cyclic anhydride at one of two enantiotopic carbonyl groups, giving one enantiomer of a hemiester. Because every meso molecule carries both enantiotopic groups, such a desymmetrisation can turn all of the substrate into one enantiomer, whereas a kinetic resolution of a racemate gives at most 50% of one product enantiomer. Shi's fructose-derived ketone is also an organocatalyst: Oxone converts it into a chiral dioxirane that transfers an oxygen atom to a trans alkene, and running at about pH 10.5 makes dioxirane formation faster than the Baeyer–Villiger decomposition of the ketone.

Measuring selectivity

Enantiomeric excess is ee = (major − minor)/(major + minor) × 100%, so a 95:5 enantiomeric ratio is 90% ee. When both enantiomers form irreversibly from the same intermediate, the ratio reflects the difference in activation free energy of the two diastereomeric transition states: ΔΔG‡ = RT ln(er). At 25 °C, RT ≈ 2.48 kJ/mol, so 90% ee (er 19) corresponds to about 7.3 kJ/mol. The same ΔΔG‡ gives a higher ee at lower temperature, which is why many organocatalytic reactions are run cold.

What to carry forward

For every organocatalytic reaction ask what the catalyst does to the substrate (raises its HOMO as an enamine or Breslow intermediate, lowers its LUMO as an iminium ion or by protonation, or pairs with it as a chiral ion), which group on the catalyst blocks or directs one face, and which step returns the catalyst. Those three answers give the product, its configuration and the side reactions to watch for.

Problemas de prática (40)

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Desenhe o mecanismo 15

Brønsted acids, ion pairs and selectivity

  • Cinchona-base desymmetrisation of a meso anhydride with methanolDraw general-base catalysis by a quinuclidine nitrogen in the methanolysis of a meso cyclic anhydride, through the tetrahedral intermediate to the hemiester, and explain why a chiral amine gives one enantiomer.
  • Phosphoric acid-catalysed transfer hydrogenation of a ketimine with a Hantzsch esterDraw protonation of a ketimine by a phosphoric acid, hydride transfer from a Hantzsch ester to the iminium ion and proton return that regenerates the acid.
  • Phase-transfer benzylation of the benzophenone imine of glycine tert-butyl esterDraw the deprotonation of O'Donnell's glycine imine at the interface and the SN2 benzylation of its enolate, and say what the chiral quaternary ammonium ion contributes.

Enamine catalysis with proline

  • Hajos–Parrish cyclisation: proline picks one of two enantiotopic ketonesDraw the intramolecular aldol in which the proline enamine of the side-chain methyl ketone attacks one enantiotopic ring carbonyl to close a six-membered ring, then the hydrolysis that releases the cis-fused bicyclic ketol and proline.
  • Proline-catalysed aldol reaction of acetone with 4-nitrobenzaldehydeDraw the carbon–carbon bond-forming step of the proline aldol with the carboxylic acid protonating the developing alkoxide, then the hydrolysis of the iminium ion that releases the (R)-aldol and regenerates proline.
  • Proline-catalysed α-amination of propanal with diethyl azodicarboxylateDraw the attack of the proline enamine of propanal on diethyl azodicarboxylate with the carboxylic acid protonating the distal nitrogen, then the hydrolysis that releases the (R)-α-hydrazino aldehyde and proline.
  • L-Proline and acetone form the nucleophilic enamineDraw the condensation of L-proline with acetone through the hemiaminal and the iminium carboxylate to the enamine, using the carboxyl group of proline for every proton transfer.
  • Proline-catalysed Mannich reaction of acetone with an N-PMP imineDraw the attack of the proline enamine of acetone on the acid-activated (E)-N-PMP imine, then the hydrolysis that releases the (S)-β-amino ketone and proline.

Iminium and diarylprolinol catalysis

  • Diarylprolinol silyl ether catalysed Michael addition of propanal to nitrostyreneDraw the attack of the diarylprolinol silyl ether enamine of propanal on β-nitrostyrene, protonation of the nitronate and hydrolysis of the iminium ion to the syn γ-nitroaldehyde.
  • Iminium-catalysed Diels–Alder reaction of cinnamaldehyde with cyclopentadieneDraw the concerted cycloaddition of cyclopentadiene to the MacMillan iminium ion of cinnamaldehyde and the hydrolysis that releases the bicyclic aldehyde and the catalyst.
  • MacMillan imidazolidinone and cinnamaldehyde form the iminium ionDraw the acid-catalysed condensation of the first-generation MacMillan imidazolidinone with cinnamaldehyde to the (E)-α,β-unsaturated iminium ion.
  • Iminium-catalysed Friedel–Crafts alkylation of N-methylindole with crotonaldehydeDraw the conjugate addition of indole C3 to the MacMillan iminium ion, rearomatisation, α-protonation of the enamine and hydrolysis to the 3-(indol-3-yl)butanal.

Carbenes and hydrogen-bond donors

  • Triazolylidene-catalysed benzoin condensationDraw carbene formation from a triazolium salt, its addition to benzaldehyde, formation of the Breslow intermediate, attack on a second benzaldehyde and release of benzoin with regeneration of the carbene.
  • Bifunctional thiourea-catalysed Michael addition of diethyl malonate to nitrostyreneDraw the deprotonation of diethyl malonate by the tertiary amine of a bifunctional thiourea catalyst, the conjugate addition of the enolate to the hydrogen-bonded nitroalkene and the proton return to the nitronate.
  • Thiourea-catalysed Strecker reaction: HCN and an N-benzhydryl imineDraw protonation of an N-benzhydryl imine by HCN to an iminium cyanide ion pair and the addition of cyanide to the iminium carbon, and explain how a thiourea controls the ion pair.

Preveja o produto 3

Iminium and diarylprolinol catalysis

  • Which atoms join in the nitro-Michael reaction?Predict the constitution of the γ-nitroaldehyde from an aldehyde enamine and a nitroalkene.

Enamine catalysis with proline

  • Predict the proline aldol productTranslate attack on the Re face of an aldehyde into the CIP configuration of the aldol product.

Carbenes and hydrogen-bond donors

  • Carbene catalysis with an aldehyde and acrylonitrilePredict the Stetter product of an aldehyde and a Michael acceptor under azolium/base catalysis.

Classificar 4

Enamine catalysis with proline

  • Which atom of the enamine attacks?Identify the nucleophilic carbon of a proline enamine from its resonance form.

Iminium and diarylprolinol catalysis

  • Enamine or iminium?Classify a secondary-amine-catalysed aldehyde reaction as enamine or iminium catalysis from the bond being formed.
  • Which catalyst can form an iminium ion?Recognise which organocatalyst can condense with an enal to an iminium ion.

Brønsted acids, ion pairs and selectivity

  • Which reagent delivers the hydride?Identify the hydride donor in a phosphoric acid-catalysed transfer hydrogenation.

Comparar 3

Brønsted acids, ion pairs and selectivity

  • Desymmetrisation or kinetic resolution?Compare the maximum yield of one enantiomer from desymmetrising a meso substrate with that from kinetically resolving a racemate.
  • Rank selectivities reported in different formatsPut enantioselectivities given as ratios, ee values and transition-state energy gaps on one scale.

Carbenes and hydrogen-bond donors

  • Rank hydrogen-bond donors by N–H acidityRank ureas and thioureas by N–H acidity, the property that tracks their strength as hydrogen-bond-donor catalysts.

Calcular 3

Brønsted acids, ion pairs and selectivity

  • Transition-state energy gap from eeConvert an enantiomeric excess measured at low temperature into the free-energy difference between the two diastereomeric transition states.
  • Why run it cold? Predict the ee at −78 °CPredict how the enantiomeric excess of a catalytic reaction changes when the temperature is lowered at constant ΔΔG‡.
  • Enantiomeric excess from a chiral HPLC traceCalculate the enantiomeric excess of a product from the peak areas of its two enantiomers.

Encontre o erro 1

  • Find the error in a bifunctional mechanismDiagnose a mechanism that swaps the acid and base roles of a bifunctional thiourea catalyst.

Interprete as evidências 1

  • What does proline turn into with an aldehyde?Identify the oxazolidinone formed from proline and an aldehyde from NMR evidence and explain its effect on catalysis.

Trabalhe de trás para frente 2

Carbenes and hydrogen-bond donors

  • Which target needs an acyl anion equivalent?Recognise the 1,4-dicarbonyl disconnection that requires carbonyl umpolung by an N-heterocyclic carbene.

Enamine catalysis with proline

  • Which triketone gives the Wieland–Miescher ketone?Work back from the Wieland–Miescher ketone to the achiral triketone that proline cyclises.

Planeje uma síntese 2

Carbenes and hydrogen-bond donors

  • Generating the carbene catalystChoose the reagent combination that generates an N-heterocyclic carbene catalyst in situ.

Enamine catalysis with proline

  • Replacing proline's carboxylic acidChoose a proline analogue that keeps the acidic group needed for the directed enamine transition state.

Explique por quê 6

Brønsted acids, ion pairs and selectivity

  • Why put large groups at C3 and C3′?Explain how the 3,3′-substituents of a BINOL phosphoric acid create the chiral environment around the bound iminium ion.
  • Why an anthracenylmethyl group on the catalyst?Explain how a large N-arylmethyl group on a cinchona-derived ammonium ion improves enantioselectivity in a phase-transfer alkylation.
  • What does the ammonium salt do?Explain why a quaternary ammonium salt is needed to alkylate an enolate in a toluene/aqueous KOH two-phase system.

Iminium and diarylprolinol catalysis

  • Why silylate diphenylprolinol?Explain why diarylprolinol silyl ethers outperform the free diarylprolinol as enamine catalysts.
  • Why does the iminium ion react faster?Explain iminium activation of an enal toward a diene in frontier-orbital terms.

Carbenes and hydrogen-bond donors

  • Why 3,5-bis(trifluoromethyl)phenyl?Explain why electron-poor aryl groups improve thiourea hydrogen-bond-donor catalysts.

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