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Análise retrossintética e estratégia de síntese

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O que você vai aprender

  • Disconnect targets by their heteroatom relationships: 1,3- and 1,5-dioxygenated patterns from natural-polarity synthons, 1,2-, 1,4- and 1,6-patterns by umpolung, unnatural electrophiles or reconnection.
  • Translate synthons into real reagents, including dithiane and O-silyl cyanohydrin acyl anion equivalents, and draw how they are made and alkylated.
  • Choose orthogonal protecting groups and the conditions that remove one while leaving the others intact.
  • Compare linear and convergent routes by overall yield and longest linear sequence, and calculate the material a route consumes.
  • Explain the key steps of classic syntheses: the Robinson annulation to the Wieland–Miescher ketone for steroids and Corey's iodolactonization route to the prostaglandin lactone.

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Disconnect at the heteroatom relationships

Retrosynthesis works backwards from the target. Each disconnection (⇒) breaks a bond into two idealised fragments called synthons, and each synthon is then matched to a real reagent, its synthetic equivalent. Good disconnections are guided by the functional groups. Number the carbons that carry oxygen and count between them. In a 1,3-dioxygenated target, such as the β-hydroxy ketone drawn here (4-hydroxy-4-phenylbutan-2-one), the bond between the α- and β-carbons disconnects to an enolate (a nucleophilic synthon at the α-carbon, d²) and an aldehyde (an electrophilic carbonyl carbon, a¹): the aldol reaction, here acetone plus benzaldehyde. A 1,5-dicarbonyl compound disconnects to an enolate and an α,β-unsaturated carbonyl compound whose β-carbon is the electrophile (a³): the Michael addition. Joining a d² synthon to an a¹ or a³ synthon always gives an odd relationship, so 1,3- and 1,5-patterns are called consonant: the natural polarity of carbonyl chemistry builds them directly.

Even relationships need umpolung

A 1,2-, 1,4- or 1,6-dioxygenated target is dissonant: no pair of natural-polarity synthons gives it. There are three ways out. First, reverse the polarity of one partner (umpolung). A 1,3-dithiane, made from an aldehyde and propane-1,3-dithiol with an acid catalyst, has a weakly acidic C2–H (pKa about 31 when C2 carries a phenyl group, about 39 for the parent dithiane in DMSO); n-butyllithium removes it, and the sulfur-stabilised carbanion is an acyl anion equivalent (d¹). It alkylates with primary halides, opens epoxides at the less hindered carbon and adds to ketones. Hydrolysis with HgCl₂ and CaCO₃ in aqueous acetonitrile then releases the aldehyde or ketone; the soft Hg²⁺ ion binds the soft sulfur atoms, which ordinary aqueous acid barely protonates. The drawn adduct of 2-methyl-1,3-dithiane and 2-methyloxirane hydrolyses to 4-hydroxypentan-2-one, so an umpolung reagent can also reach a 1,3-pattern. An O-trimethylsilyl cyanohydrin of an aromatic aldehyde does the same job: LDA removes the benzylic C–H next to the nitrile, the anion is alkylated, and removing the silyl group lets the alkoxide expel cyanide to reveal a ketone. The free cyanohydrin cannot be used, because base removes its O–H first and the alkoxide simply expels cyanide. Second, use an electrophile with unnatural polarity: an α-halo ketone is an a² synthon, so an enolate plus chloroacetone gives a 1,4-diketone. Third, reconnect: ozonolysis of a cyclohexene cleaves one C=C bond into a 1,6-dicarbonyl compound.

Functional group interconversion

Some functional groups cannot be disconnected directly, so they are first converted on paper into one that can (FGI). An amine is traced back to an imine, which disconnects to a ketone and an amine: reductive amination with NaBH₃CN avoids the over-alkylation and E2 elimination that plague SN2 reactions of amines with secondary alkyl halides. An alcohol is traced to a carbonyl compound, an alkene to an alcohol (dehydration) or to a carbonyl compound (Wittig), and a 1,6-dicarbonyl compound to a cyclohexene. Write the FGI as a separate retrosynthetic arrow so that every step has a real forward reaction.

Protecting groups and orthogonality

A protecting group masks a functional group that would not survive a later step, at the cost of two extra steps. Two groups are orthogonal when each can be removed under conditions that leave the other intact. Common orthogonal sets: TBS ethers fall to fluoride (TBAF) but survive base, hydrogenolysis and DDQ; benzyl ethers, benzyl esters and Cbz carbamates fall to H₂ over Pd/C; a p-methoxybenzyl (PMB) ether is also removed by the oxidant DDQ, which leaves a plain benzyl ether untouched; Boc carbamates and tert-butyl esters fall to trifluoroacetic acid; Fmoc falls to piperidine; acetates fall to K₂CO₃ in methanol. Silyl ethers become more stable to acid as the silicon becomes more hindered, in the order TMS < TES < TBS < TIPS < TBDPS. Bulk also slows silylation of hindered alcohols, so TBSCl protects a primary alcohol in preference to a secondary one. A trimethylsilyl group on a terminal alkyne carbon hides the acidic C–H from organolithium reagents and is removed by K₂CO₃ in methanol. Ketals and acetals are stable to base, hydride and organometallic reagents but fall to aqueous acid, so remove a nearby TBS group with fluoride rather than aqueous acid.

Linear and convergent routes

In a linear route every step is carried out on the growing main chain, so the overall yield is the product of all step yields: ten steps at 90% give 0.9¹⁰ ≈ 35%. In a convergent route fragments are made separately and joined late. The overall yield and the time to the target are set by the longest linear sequence (LLS): the largest number of steps from any starting material to the target, counting the coupling steps along that path. Steps in a side branch do not multiply into the overall yield, and less material has to be carried through each step. To find the starting material needed, divide the moles of target by the overall yield and convert to mass.

Two classic routes

Steroid syntheses often start from the Wieland–Miescher ketone (drawn). 2-Methylcyclohexane-1,3-dione is doubly activated, so catalytic KOH in methanol forms its enolate, which adds to methyl vinyl ketone in a Michael reaction and creates the quaternary carbon that becomes the angular methyl group. The resulting triketone, 2-methyl-2-(3-oxobutyl)cyclohexane-1,3-dione, closes in an intramolecular aldol reaction: the enolate of its methyl ketone attacks a ring carbonyl to form a new six-membered ring, and dehydration gives the conjugated enone. Bridged aldol adducts can also form, but they cannot dehydrate without putting a double bond at a bridgehead, so under reversible conditions material drains to the fused enone. With catalytic L-proline the cyclization is enantioselective (the Hajos–Parrish–Eder–Sauer–Wiechert reaction). Corey's prostaglandin route used 2-chloroacrylonitrile as a ketene equivalent in a Diels–Alder reaction with 5-(methoxymethyl)cyclopentadiene; hydrolysis of the α-chloronitrile gave a bicyclo[2.2.1]heptenone, whose rigid framework fixes the relative configuration of the ring substituents. A Baeyer–Villiger oxidation, in which the more substituted bridgehead carbon migrates, gave a bicyclic lactone, and saponification gave a cyclopentene hydroxy acid. Iodolactonization (KI₃, NaHCO₃, water) then closed a cis-fused five-membered lactone with iodine on the neighbouring carbon, and Bu₃SnH later removed the iodine.

What to carry forward

Read the target's heteroatom pattern first: odd relationships (1,3 and 1,5) come from enolates with carbonyl or Michael electrophiles; even ones need an acyl anion equivalent such as a dithiane or a silylated cyanohydrin, an unnatural electrophile such as an α-halo ketone, or a reconnection such as ozonolysis. Back every synthon with a real reagent, protect only what a later step would destroy and choose orthogonal groups, and judge routes by their longest linear sequence.

Problemas de prática (40)

Praticar é grátis com uma conta.

Desenhe o mecanismo 6

Classic total synthesis steps

  • Iodolactonization in Corey's prostaglandin synthesisDraw the iodolactonization that converts Corey's cyclopentene hydroxy acid into the cis-fused iodolactone, and explain why the five-membered lactone forms.
  • Michael addition of 2-methylcyclohexane-1,3-dione to methyl vinyl ketoneDraw the base-catalysed Michael addition that builds the quaternary carbon of the Wieland–Miescher ketone precursor, and identify the 1,5-dicarbonyl relationship it creates.

Umpolung: dithianes and cyanohydrins

  • Benzylation of 2-lithio-2-phenyl-1,3-dithianeDraw the deprotonation of 2-phenyl-1,3-dithiane by n-butyllithium and the SN2 benzylation of the resulting acyl anion equivalent.
  • 2-Lithio-2-methyl-1,3-dithiane opens 2-methyloxiraneDraw the deprotonation of 2-methyl-1,3-dithiane, the SN2 opening of 2-methyloxirane by the dithiane anion and the workup, and relate the product to a 1,3-dioxygenated target.
  • 2-Phenyl-1,3-dithiane from benzaldehyde and propane-1,3-dithiolDraw the acid-catalysed conversion of benzaldehyde into 2-phenyl-1,3-dithiane, the first step in using the aldehyde carbon as an acyl anion equivalent.
  • Allylation of a silylated cyanohydrin anionDraw the deprotonation of benzaldehyde's O-trimethylsilyl cyanohydrin by LDA and the SN2 allylation of the anion, and explain how the product is unmasked to a ketone.

Preveja o produto 3

Classic total synthesis steps

  • Baeyer–Villiger on Corey's bicyclic ketonePredict the regiochemistry of the Baeyer–Villiger oxidation of Corey's bicyclo[2.2.1]heptenone.

Umpolung: dithianes and cyanohydrins

  • Two alkylations of one dithianePredict the ring formed when a dithiane anion is alkylated twice by a 1,3-dihalide.

Protecting groups and orthogonality

  • Protect one of two alcoholsPredict which hydroxyl of a primary/secondary diol a bulky silyl chloride protects.

Classificar 8

Disconnections and synthons

  • Which pattern has natural polarity?Classify dioxygenation patterns as consonant or dissonant from the natural polarity of carbonyl synthons.
  • Which reaction makes a 1,5-diketone?Recognise a 1,5-dicarbonyl relationship and assign it to the Michael disconnection.
  • Label the Michael acceptor synthonAssign donor/acceptor synthon labels (aⁿ/dⁿ) to the reactive carbon of a Michael acceptor.
  • Match a synthon to its reagentIdentify the practical reagent that serves as the synthetic equivalent of a nucleophilic acetic acid synthon.

Linear and convergent routes

  • Spot the convergent planClassify route descriptions as convergent, linear or divergent.

Protecting groups and orthogonality

  • Which pair is not orthogonal?Recognise a pair of protecting groups that cannot be removed independently because they share a cleavage mechanism.
  • Remove PMB, keep benzylSelect the reagent that removes a p-methoxybenzyl ether orthogonally to a benzyl ether.
  • Protect a terminal alkyne C–HChoose the protecting group that masks an acidic terminal alkyne C–H during an organolithium step.

Comparar 2

Linear and convergent routes

  • Rank four routes by overall yieldRank linear and convergent routes by overall yield calculated along each longest linear sequence.

Protecting groups and orthogonality

  • Rank silyl ethers by acid stabilityOrder common silyl protecting groups by their resistance to acidic hydrolysis.

Calcular 6

Linear and convergent routes

  • Yield of a convergent routeCalculate the overall yield of a convergent route along its longest linear sequence.
  • Find the longest linear sequenceDetermine the longest linear sequence of a three-fragment convergent synthesis from its step counts.
  • How much starting material is needed?Calculate the mass of starting material a multistep linear route consumes to deliver a target mass.
  • Yield of a ten-step linear routeCalculate the overall yield of a linear route as the product of its step yields.

Classic total synthesis steps

  • Count stereocentres in Corey's iodolactoneCount the stereocentres of Corey's iodolactone to appreciate how many relative configurations the route must control.

Protecting groups and orthogonality

  • The yield cost of a protecting groupCalculate how a protection–deprotection pair lowers the overall yield of a linear route.

Encontre o erro 2

Umpolung: dithianes and cyanohydrins

  • Find the flaw in a dithiane planDiagnose why a dithiane alkylation fails when the electrophile is a tertiary alkyl halide.

Protecting groups and orthogonality

  • Why was the ketal lost?Diagnose a deprotection that destroys a second, acid-labile protecting group and choose the orthogonal alternative.

Trabalhe de trás para frente 5

Disconnections and synthons

  • Disconnect a β-hydroxy ketoneApply the aldol disconnection to a 1,3-dioxygenated target and choose the correct enolate and carbonyl partners.
  • Build a 1,4-diketoneChoose reagents for a dissonant 1,4-dicarbonyl target by using an α-halo ketone as the electrophile.
  • Reconnect a 1,6-diketoneTrace a 1,6-dicarbonyl target back to the cycloalkene whose ozonolysis gives it.

Umpolung: dithianes and cyanohydrins

  • Plan an α-hydroxy ketone by umpolungChoose the dithiane and carbonyl partners that give a 1,2-dioxygenated target after hydrolysis.

Classic total synthesis steps

  • Disconnect the Wieland–Miescher ketoneApply the Robinson annulation disconnection to the Wieland–Miescher ketone and identify its two starting materials.

Planeje uma síntese 2

Disconnections and synthons

  • Disconnect a secondary amineUse the amine ⇒ imine functional group interconversion to choose a reductive amination for a specified C–N disconnection.

Protecting groups and orthogonality

  • Free only the carboxylic acidChoose a deprotection that removes one of three protecting groups in a serine derivative while leaving the other two intact.

Explique por quê 6

Classic total synthesis steps

  • Why 2-chloroacrylonitrile?Explain the role of 2-chloroacrylonitrile as a ketene equivalent in Corey's prostaglandin synthesis.
  • What did the iodolactonization achieve?Explain the net transformation of an iodolactonization followed by radical deiodination in Corey's route.
  • Fused enone, not bridged ketolExplain why the triketone's aldol cyclization gives the fused Wieland–Miescher enone rather than a bridged aldol product.

Linear and convergent routes

  • Why go convergent?Explain why a convergent route usually gives more product than a linear route of the same total length.

Umpolung: dithianes and cyanohydrins

  • Why mercury(II) unmasks a dithianeExplain, using hard–soft acid–base reasoning, why dithiane hydrolysis needs a thiophilic metal ion rather than aqueous acid.
  • What is reversed in umpolung?Explain what polarity reversal means for the carbon of an aldehyde converted into a 1,3-dithiane.

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