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Síntese Avançada · Modern methods

Estratégias para ligações carbono–carbono

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O que você vai aprender

  • Use silyl enol ethers, silyl ketene acetals and allylsilanes with Lewis acids (Mukaiyama aldol and Michael, Hosomi–Sakurai) and predict where the new C–C bond forms.
  • Choose and push arrows through Peterson, Julia–Kocienski and sulfur-ylide (Corey–Chaykovsky) reactions, including how the conditions decide alkene geometry and ring stereochemistry.
  • Follow π-allylpalladium (Tsuji–Trost) and organochromium (Nozaki–Hiyama–Kishi) chemistry through the metal's oxidation states, and predict their regio-, stereo- and chemoselectivity.
  • Plan Johnson, Eschenmoser and Ireland–Claisen rearrangements from allylic alcohols and predict the γ,δ-unsaturated ester, amide or acid they give.
  • Explain and quantify the diastereoselectivity of enolate alkylations controlled by an oxazolidinone auxiliary, a chelated dianion or an existing ring stereocentre.

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Silicon nucleophiles need an activated electrophile

Silyl enol ethers, silyl ketene acetals and allylsilanes are neutral, weak π nucleophiles: they do not react with an aldehyde or enone until a Lewis acid (TiCl₄, BF₃·OEt₂) or a silyl triflate binds the carbonyl oxygen or creates an oxocarbenium ion. Because neither partner is a free enolate, crossed reactions give one product. In the Mukaiyama aldol the enol carbon bonds to the activated carbonyl carbon and the silicon is passed on (to chloride with TiCl₄), so TiCl₄ is used in a full equivalent; the open transition state, with no metal linking the two oxygens, means the syn/anti ratio does not follow the enol ether geometry the way lithium enolate aldols do. The same nucleophiles add 1,4 to Lewis-acid-bound enones (Mukaiyama–Michael), building crowded quaternary carbons. Allylsilanes (Hosomi–Sakurai) attack through the carbon remote from silicon, because the cation formed is β to silicon and is stabilised by overlap with the C–Si σ bond. Loss of the silyl group then re-forms the alkene one position over, so a crotylsilane transfers its allyl unit with transposition. Here too the Lewis acid, not silicon, holds the carbonyl oxygen, so the transition state is open and (E)- and (Z)-crotylsilanes both give mainly the syn alcohol. Nucleophilicity rises from allylsilanes (Mayr N ≈ 2) to silyl enol ethers (≈ 5) to silyl ketene acetals (≈ 9); enamines (≈ 11 for the morpholine enamine of cyclohexanone) are stronger still. In the Mayr equation, log k = s(N + E), s is close to 1, so each unit of N is roughly a factor of ten in rate constant.

Alkenes and three-membered rings from heteroatom-stabilised carbanions

A Peterson olefination adds an α-silyl carbanion to a carbonyl group. The β-hydroxysilane eliminates in two stereochemically opposite ways: with base (KH) the alkoxide attacks silicon and a syn elimination runs through a four-membered oxasiletanide, while acid protonates the hydroxyl and the C–Si bond pushes water out anti-periplanar. One diastereomer therefore gives the (E)-alkene with base and the (Z)-alkene with acid. The Julia–Kocienski olefination uses a 1-phenyl-1H-tetrazol-5-yl (PT) or benzothiazol-2-yl sulfone: after the sulfonyl carbanion adds to an aldehyde, the alkoxide attacks the heteroaryl carbon (a Smiles rearrangement) and the sulfinate then loses SO₂ and the aryloxide in one anti-periplanar step, giving mainly the (E)-alkene. A phenyl sulfone cannot undergo this rearrangement, so in the classical Julia–Lythgoe olefination the β-hydroxy sulfone is acylated and then reduced with sodium amalgam. Sulfur ylides (Corey–Chaykovsky) add to C=O or C=N and the oxygen or nitrogen anion displaces a neutral sulfide: aldehydes and ketones give epoxides, N-sulfonyl imines give aziridines, and a benzylide gives mainly trans-2,3-diaryloxiranes because only the anti betaine closes quickly. Phosphorus and silicon reagents, by contrast, remove the oxygen and give alkenes.

π-Allylpalladium and organochromium reagents

In the Tsuji–Trost reaction Pd(0) displaces an allylic acetate from the face opposite the leaving group, giving a cationic η³-allylpalladium(II) complex. Soft, stabilised nucleophiles (conjugate acid pKa below about 25: malonates, amines) attack the allyl terminus from the face opposite palladium, so two inversions give overall retention of configuration; hard nucleophiles (organozinc, aryl metal reagents) transfer first to palladium and are delivered from the metal's face by reductive elimination, giving overall inversion. Attack occurs mainly at the less hindered allyl terminus. In the Nozaki–Hiyama–Kishi reaction, CrCl₂ with a trace of NiCl₂ converts a vinyl or aryl iodide into an organochromium(III) reagent: Ni(0) inserts into the C–I bond and transfers the organic group to chromium. Two Cr(II) are oxidised to Cr(III) per halide. The organochromium adds to aldehydes in the presence of ketones, esters and nitriles, and keeps the vinyl geometry. Manganese powder and Me₃SiCl make the chromium catalytic by reducing Cr(III) back to Cr(II) and silylating the chromium alkoxide.

Claisen variants from allylic alcohols

All three variants build an allyl vinyl ether in the flask and let a chair-like [3,3] shift form the C–C bond at the far end of the allyl unit, with the C=C moving one position. In the Johnson orthoester Claisen an allylic alcohol, triethyl orthoacetate and catalytic propanoic acid at about 140 °C exchange ethanol for the allylic alcohol, lose a second ethanol to a ketene acetal, and give a γ,δ-unsaturated ethyl ester. The Eschenmoser–Claisen uses N,N-dimethylacetamide dimethyl acetal to make an N,O-ketene acetal and gives a γ,δ-unsaturated N,N-dimethylamide. The Ireland–Claisen deprotonates an allylic ester with LDA and traps the enolate on oxygen with a silyl chloride; the silyl ketene acetal rearranges at or near room temperature to a silyl ester that hydrolyses to the γ,δ-unsaturated acid. Because the chair transition state is well defined, the relative configuration of the two new stereocentres follows the alkene geometry and the ketene acetal geometry, which the solvent sets (THF versus THF with HMPA).

Stereocontrolled enolate alkylation

An N-acyloxazolidinone (Evans auxiliary) gives the Z-enolate with NaHMDS; the metal chelates the enolate oxygen and the ring carbonyl, fixing the enolate in one plane, and the C4 substituent (benzyl) shields one face so the alkyl halide enters from the other. The new stereocentre's configuration therefore depends on which group is already on the acyl chain and which comes from the alkyl halide. Lithium hydroperoxide removes the auxiliary by attacking the exocyclic carbonyl. Without an auxiliary, an existing stereocentre can control alkylation: the dianion of a β-hydroxy ester (two equivalents of LDA) is chelated and alkylates anti to the hydroxyl-bearing carbon's substituent (Fráter–Seebach), and the enolate of a β-substituted γ-lactone is alkylated on the face opposite that substituent, giving the trans lactone. A diastereomer ratio converts to a free-energy difference of the competing transition states by ΔΔG‡ = RT ln(major/minor); 95:5 at −78 °C corresponds to only about 4.8 kJ/mol.

What to carry forward

For every C–C bond ask three questions: which carbon is the nucleophile and how it was made (silyl enol ether, allylsilane, ylide, sulfonyl or silyl carbanion, π-allyl partner, organochromium, enolate), what activates the electrophile (Lewis acid, palladium, a [3,3] array), and what controls the stereochemistry (open or chair transition state, syn or anti elimination, double inversion, a shielding or chelating group). The answers predict the product and tell you which reagent to change when you need the other isomer.

Problemas de prática (40)

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Desenhe o mecanismo 18

Olefination and three-membered rings

  • Corey–Chaykovsky aziridination of an N-tosyl imineDraw the addition of dimethylsulfonium methylide to an N-tosyl imine and the intramolecular displacement of dimethyl sulfide by nitrogen that closes 2-phenyl-1-tosylaziridine.
  • Corey–Chaykovsky epoxidation of benzaldehyde with a benzyl sulfonium ylideDraw the formation of a benzylic sulfonium ylide, its addition to benzaldehyde and the intramolecular displacement of dimethyl sulfide that closes 2,3-diphenyloxirane, and explain why the trans epoxide dominates.
  • Julia–Kocienski olefination of 3-phenylpropanal with a phenyltetrazolyl sulfoneDraw the one-pot Julia–Kocienski olefination with a PT sulfone: deprotonation, addition to the aldehyde, the Smiles rearrangement that moves the tetrazolyl group from sulfur to oxygen, and the elimination of SO₂ and the tetrazolate that forms the alkene.
  • Acid-promoted Peterson elimination of (4R*,5R*)-5-(trimethylsilyl)octan-4-olDraw the acid-promoted Peterson elimination: protonation of the hydroxyl, then the anti-periplanar loss of water and the silyl group, and use the anti geometry to predict the alkene geometry.
  • Peterson methylenation of benzophenoneDraw the addition of (trimethylsilyl)methyllithium to benzophenone and the base-mediated syn elimination, through a four-membered oxasiletanide, that gives 1,1-diphenylethene.

Claisen variants

  • Eschenmoser–Claisen rearrangement of (E)-cinnamyl alcoholDraw the Eschenmoser–Claisen rearrangement: exchange of methanol for the allylic alcohol on N,N-dimethylacetamide dimethyl acetal, formation of the N,O-ketene acetal, and the [3,3] shift that gives a γ,δ-unsaturated N,N-dimethylamide.
  • Ireland–Claisen rearrangement of (E)-hex-2-en-1-yl propanoateDraw the Ireland–Claisen rearrangement: ester enolate formation with LDA, O-silylation to the silyl ketene acetal, the [3,3] shift near room temperature, and hydrolysis of the silyl ester to the γ,δ-unsaturated acid.
  • Johnson–Claisen rearrangement of cyclohex-2-en-1-olDraw the Johnson orthoester Claisen: acid-catalysed exchange of ethanol for the allylic alcohol, formation of the ketene acetal, and the [3,3] shift that gives ethyl 2-(cyclohex-2-en-1-yl)acetate.

Stereocontrolled enolate alkylation

  • Removing an Evans auxiliary with lithium hydroperoxideDraw the cleavage of an N-acyloxazolidinone by lithium hydroperoxide: formation of HOO⁻, attack at the exocyclic carbonyl, expulsion of the oxazolidinone anion and proton transfer, recovering the auxiliary and the peroxy acid.
  • Diastereoselective allylation of an Evans N-propanoyloxazolidinoneDraw the Z-enolate formation from an Evans N-propanoyloxazolidinone and its SN2 alkylation by allyl iodide on the face opposite the benzyl group, giving the (R)-2-methylpent-4-enoyl imide.
  • Fráter–Seebach allylation of ethyl (S)-3-hydroxybutanoateDraw the double deprotonation of a β-hydroxy ester to its chelated dianion, the diastereoselective alkylation anti to the carbinol methyl group, and the workup that gives ethyl (2S,3S)-3-hydroxy-2-(prop-2-en-1-yl)butanoate.
  • Trans-selective methylation of (R)-4-benzyloxolan-2-oneDraw the lithium enolate formation of a β-benzyl γ-lactone and its methylation on the face opposite the benzyl group, giving the trans-3-methyl-4-benzyl lactone.

Silicon nucleophiles and Lewis acids

  • TiCl₄-promoted Mukaiyama aldol of 1-(trimethylsilyloxy)cyclohexene with benzaldehydeDraw the TiCl₄-promoted Mukaiyama aldol: Lewis-acid activation of benzaldehyde, C–C bond formation by the silyl enol ether, chloride-to-silicon transfer that leaves a titanium aldolate, and the aqueous workup that releases the β-hydroxy ketone.
  • Mukaiyama–Michael addition of a silyl ketene acetal to cyclohex-2-en-1-oneDraw the TiCl₄-promoted conjugate addition of a silyl ketene acetal to cyclohex-2-en-1-one, the chloride-to-silicon transfer that releases the ester, and the workup that protonates the titanium enolate on carbon.
  • TMSOTf-catalysed allylation of benzaldehyde dimethyl acetal with allyltrimethylsilaneDraw how catalytic trimethylsilyl triflate ionises a dimethyl acetal to an oxocarbenium ion, how allyltrimethylsilane attacks it through the β-silyl cation, and how triflate takes the silyl group back so the catalyst is regenerated.
  • Hosomi–Sakurai methallylation of 3-phenylpropanalDraw the TiCl₄-promoted Hosomi–Sakurai reaction of a methallylsilane with an aldehyde: attack through the alkene carbon remote from silicon, the β-silyl carbocation, and loss of the silyl group that re-forms the alkene.

π-Allylpalladium and organochromium chemistry

  • Palladium-catalysed amination of (E)-cinnamyl acetate with morpholineDraw the Tsuji–Trost amination of (E)-cinnamyl acetate: ionisation by Pd(0) to the π-allylpalladium cation, attack of morpholine at the less hindered CH₂ terminus, and deprotonation that gives the linear (E)-allylic amine.
  • Tsuji–Trost allylation of dimethyl malonate with cyclohex-2-en-1-yl acetateDraw the Tsuji–Trost allylation: malonate enolisation by NaH, oxidative addition of Pd(0) to the allylic acetate to give a π-allylpalladium(II) cation, and attack of the malonate carbanion on the allyl terminus that returns Pd(0).

Preveja o produto 5

Claisen variants

  • Johnson–Claisen of a secondary allylic alcoholPredict the constitution and alkene geometry of the Johnson–Claisen product of a secondary allylic alcohol.

π-Allylpalladium and organochromium chemistry

  • Which carbonyl does the vinylchromium attack?Predict the chemoselectivity and alkene geometry of a Nozaki–Hiyama–Kishi coupling with a substrate carrying both an aldehyde and a ketone.
  • Retention by double inversionPredict the relative configuration of a Tsuji–Trost product from the double inversion of a soft nucleophile pathway.

Olefination and three-membered rings

  • Base-promoted Peterson eliminationPredict the alkene geometry from the syn-periplanar Peterson elimination of a given β-hydroxysilane diastereomer.

Silicon nucleophiles and Lewis acids

  • Allylsilane and an enonePredict the conjugate (1,4) allylation of a Lewis-acid-activated cyclic enone by allyltrimethylsilane.

Classificar 2

Stereocontrolled enolate alkylation

  • Major and minor alkylation productsClassify the two products of an Evans auxiliary alkylation as diastereomers and state the practical consequence.

Claisen variants

  • Match the variant to its productClassify the Johnson, Eschenmoser and Ireland–Claisen rearrangements by the carbonyl group they produce.

Comparar 2

Stereocontrolled enolate alkylation

  • Rank the selectivities by energyRank diastereoselective alkylations by the transition-state energy difference implied by their ratio and temperature.

Silicon nucleophiles and Lewis acids

  • Rank the π nucleophilesRank an allylsilane, a silyl enol ether, a silyl ketene acetal and an enamine by nucleophilicity from the cation each forms on attack.

Calcular 4

π-Allylpalladium and organochromium chemistry

  • d-Electron count of the π-allyl complexCount the d electrons of palladium in the cationic η³-allylpalladium intermediate of the Tsuji–Trost reaction.
  • How much CrCl₂ for an NHK reaction?Calculate the minimum mass of chromium(II) chloride needed to convert a vinyl iodide into its organochromium(III) reagent.

Silicon nucleophiles and Lewis acids

  • How much faster is a silyl ketene acetal?Use the Mayr equation to compare the rate constants of two silicon nucleophiles toward the same electrophile.

Stereocontrolled enolate alkylation

  • From ΔΔG‡ to diastereomeric excessConvert a transition-state free-energy difference into the diastereomeric excess expected at −78 °C.

Encontre o erro 1

  • Catalytic chromium stallsDiagnose why a chromium-catalytic NHK reaction stops at low conversion when chlorotrimethylsilane is omitted.

Trabalhe de trás para frente 1

  • Which allylic alcohol?Work back from a γ,δ-unsaturated ester to the allylic alcohol needed for a Johnson orthoester Claisen rearrangement.

Planeje uma síntese 3

Stereocontrolled enolate alkylation

  • The other enantiomer from the same auxiliaryPlan an Evans alkylation that gives the opposite α-stereocentre by exchanging the roles of acyl chain and alkyl halide.

Silicon nucleophiles and Lewis acids

  • A clean crossed aldolChoose silyl enol ether and Lewis acid conditions that give one crossed aldol product from a ketone and an enolisable aldehyde.

Olefination and three-membered rings

  • From a ketone to a spiro epoxideChoose the sulfur ylide that converts a ketone into a terminal epoxide rather than an alkene or a lactone.

Explique por quê 4

Silicon nucleophiles and Lewis acids

  • Why crotylsilane geometry hardly mattersExplain why Lewis-acid-promoted crotylsilane additions give the same major diastereomer from either alkene isomer.

Claisen variants

  • HMPA flips the Ireland–ClaisenExplain how changing the enolization solvent switches the relative configuration of an Ireland–Claisen product.

Olefination and three-membered rings

  • Why the phenyl sulfone needs a second stepExplain why a heteroaryl (PT) sulfone gives an alkene in one pot while a phenyl sulfone adduct needs acylation and reduction.

π-Allylpalladium and organochromium chemistry

  • Why a trace of NiCl₂?Explain the role of the nickel co-catalyst in the Nozaki–Hiyama–Kishi coupling of vinyl iodides.

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