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Biosíntesis y productos naturales · Biosynthetic pathways

Terpenos y esteroides

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Lo que aprenderás

  • Count isoprene units and classify terpenes as hemi-, mono-, sesqui-, di-, tri- or tetraterpenes from their carbon count.
  • Explain why DMAPP is the electrophile and IPP the nucleophile, and draw the isomerase and the ionization–condensation–elimination steps that build GPP and FPP.
  • Draw monoterpene and sesquiterpene cyclizations: the linalyl and nerolidyl diphosphate detours, the α-terpinyl cation and its fates (limonene, α-terpineol, pinene, bornyl diphosphate, terpinen-4-ol, sabinene, 1,8-cineole) and the bisabolyl cation, and explain why FPP can close a ten-membered ring directly.
  • Follow squalene to lanosterol: tail-to-tail coupling, epoxidation, protonation-initiated cyclization, 1,2-shifts and the final deprotonation, and relate lanosterol to the steroid skeleton of cholesterol.
  • Read steroid stereochemistry (5α/5β ring fusion, axial or equatorial 3-OH, stereocentre counts) and apply bench reactions of terpenes and steroids: bromination and protection of cholesterol, ozonolysis, borohydride reduction of camphor, and NMR and polarimetry of monoterpenes.

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The isoprene rule and the two C₅ building blocks

Terpenes are built from C₅ units with the branched isoprene skeleton, so their carbon counts are multiples of five: hemiterpenes C₅ (isoprene), monoterpenes C₁₀, sesquiterpenes C₁₅, diterpenes C₂₀, triterpenes C₃₀ (squalene, the sterols) and tetraterpenes C₄₀ (the carotenoids). The units are isopentenyl diphosphate (IPP, left) and dimethylallyl diphosphate (DMAPP, right), isomers that differ only in where the C=C bond sits. Animals, fungi and the plant cytosol make IPP by the mevalonate pathway, whose last step phosphorylates the tertiary 3-OH of mevalonate 5-diphosphate so that it can leave as phosphate; the tertiary cation then loses CO₂ from the neighbouring CH₂–CO₂⁻ group, and the C–C electrons become the C=C of IPP. Most bacteria and plant plastids use the methylerythritol phosphate (MEP) pathway instead. From IPP onward the chemistry is the same carbocation chemistry in every organism. Regular terpene chains are joined head to tail; squalene (C₃₀) and the carotenoids (C₄₀) have one tail-to-tail link at their centre.

Allylic diphosphates are the electrophiles

Diphosphate (OPP) is a good leaving group once Mg²⁺ ions in the active site neutralize its charges, and an allylic C–OPP bond ionizes to a resonance-stabilized allylic cation. IPP has no allylic C–O bond, so it cannot ionize this way; its terminal C=C is the nucleophile instead. IPP isomerase protonates that C=C at the CH₂ end (Markovnikov, giving a tertiary cation) and removes a proton from the neighbouring CH₂, which moves the double bond one position along so that the C–OPP bond becomes allylic: DMAPP. Prenyltransferases then run ionization–condensation–elimination: DMAPP ionizes, the CH₂= end of IPP attacks C1 of the allylic cation (a 1′-4 or head-to-tail link), giving a tertiary cation, and loss of one specific C2 proton creates a new (E) double bond. DMAPP + IPP gives geranyl diphosphate (GPP, C₁₀), one more IPP gives farnesyl diphosphate (FPP, C₁₅) and another gives geranylgeranyl diphosphate (GGPP, C₂₀). The same allylic cations also alkylate electron-rich aromatic rings, for example a phenol ortho to its OH group, in a Friedel–Crafts-type substitution.

Monoterpene cyclases: one cation, many products

GPP cannot close a six-membered ring directly: its C2=C3 bond is (E), which holds C1 away from the distal C6=C7 bond. Monoterpene cyclases first ionize GPP and let the diphosphate return at C3, giving linalyl diphosphate (LPP). Rotation about the new C2–C3 single bond brings C1 near C6; reionization and attack of the C6=C7 π bond on C1 closes the cyclohexene ring and leaves the tertiary α-terpinyl cation (shown). The enzyme then decides its fate: loss of a methyl proton gives limonene, capture of water gives α-terpineol, attack of the ring C=C on the cation gives the bicyclic pinyl cation (then α- or β-pinene) or the bornyl cation (captured by diphosphate as bornyl diphosphate, the precursor of borneol and camphor), a 1,2-hydride shift gives the terpinen-4-yl cation (then terpinen-4-ol or, by cyclopropane closure, sabinene), and protonation of α-terpineol followed by attack of its OH gives the bridged ether 1,8-cineole. Acyclic products come straight from the geranyl or linalyl cation: myrcene by loss of a methyl proton, linalool by capture of water at C3.

Sesquiterpenes: larger rings from FPP

FPP has the same (E) C2=C3 bond, but its chain is long enough for C1 to reach the third double bond (C10=C11) without any isomerization. Germacrene A synthase (product shown) ionizes FPP and lets that π bond attack C1, closing a ten-membered ring and leaving a cation on the exocyclic isopropyl carbon; loss of a methyl proton gives germacrene A. Six-membered ring closure needs the nerolidyl diphosphate (NPP) detour, exactly as monoterpenes need linalyl diphosphate: NPP reionizes in the cisoid form, the C6=C7 bond closes the ring onto C1 to give the bisabolyl cation, and loss of a methyl proton gives β-bisabolene (capture by water gives α-bisabolol).

From squalene to lanosterol

Squalene synthase joins two FPP tail to tail (C1 to C1′, through a cyclopropane intermediate, presqualene diphosphate) and uses NADPH, giving the symmetrical C₃₀ hydrocarbon squalene with six C=C bonds. Squalene epoxidase (O₂, NADPH, FAD) makes (3S)-2,3-oxidosqualene. Lanosterol synthase folds this chain chair–boat–chair and starts the cascade with a proton, not by ionizing a diphosphate: an aspartic acid protonates the epoxide, the nearest C=C opens it at the tertiary carbon and closes ring A, and the next alkenes close rings B, C (first as a five-membered ring that expands) and D. The resulting protosteryl cation then undergoes two 1,2-hydride shifts and two 1,2-methyl shifts, each moving the charge one carbon, before an active-site base removes the C9 proton to give the C8=C9 double bond of lanosterol. Plants make cycloartenol instead: in the same C8 cation, H9 shifts to C8, and loss of a proton from the C19 methyl closes a cyclopropane onto the new C9 cation. Squalene–hopene cyclase in bacteria protonates a C=C of squalene directly and folds it all-chair.

Steroid skeleton and stereochemistry

Every steroid has the same 6-6-6-5 tetracyclic nucleus, rings A, B and C six-membered and ring D five-membered, numbered from C1 in ring A; C18 and C19 are the angular methyls on C13 and C10, and C17 carries the side chain. Lanosterol (C₃₀H₅₀O) has four rings and two C=C bonds. Cholesterol (C₂₇H₄₆O, shown) is reached by removing three methyl groups (the two on C4 and the one on C14), moving the ring double bond to C5=C6 and reducing the side-chain C24=C25 bond; it keeps the 3β-OH. Saturated steroids with H5 on the α face (5α) have a trans A/B ring fusion; 5β steroids such as the bile acids have a cis A/B fusion. In the flat 5α skeleton the axial bond at C3 points α, so a 3β-OH is equatorial; in the bent 5β skeleton the 3β-OH is axial and the 3α-OH of the bile acids is equatorial. Cholesterol has eight stereocentres (C3, C8, C9, C10, C13, C14, C17 and C20), so 2⁸ = 256 stereoisomers share its constitution; its biosynthesis makes only one.

Terpenes and steroids at the bench

The C=C bonds of terpenes undergo the familiar alkene reactions. Bromine adds to the C5=C6 bond of cholesterol through a bromonium ion on the α face, away from the axial C19 methyl; bromide opens it at C6 from the β face, giving the trans-diaxial 5α,6β-dibromide (shown). Zinc dust removes the two anti bromines again, so bromination protects the alkene while dichromate oxidizes the 3-OH, the classic route to cholest-5-en-3-one; acid, base or an Oppenauer oxidation instead give the conjugated cholest-4-en-3-one. Ozonolysis cuts every C=C bond: squalene gives two acetone, four 4-oxopentanal and one succinaldehyde, which reads out its isoprene units and its central tail-to-tail link. Sodium borohydride reduces camphor from the endo face, because the gem-dimethyl bridge blocks the exo face, so isoborneol (CH–OH near δ 3.6) outweighs borneol (near δ 4.0), and the ratio is read from the ¹H NMR integrals. Alkene ¹H signals tell monoterpene isomers apart: limonene shows one ring =CH near δ 5.4 and a 2H =CH₂ signal near δ 4.7. Polarimetry gives enantiomeric purity: ee = observed [α] ÷ [α] of the pure enantiomer, and the major enantiomer makes up (100 + ee)/2 per cent of the sample.

What to carry forward

Terpene biosynthesis is carbocation chemistry under enzyme control. An allylic diphosphate ionizes (or an alkene or epoxide is protonated), a nearby C=C attacks the cation, and the new cation either rearranges by 1,2-shifts, attacks another alkene, is captured by water or diphosphate, or loses a proton. Count carbons in fives, look for the allylic cation, follow Markovnikov unless the fold dictates otherwise, and remember that the final step is almost always a deprotonation or a capture. Lanosterol (shown) is the product of the longest such cascade.

Problemas de práctica (40)

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Dibuja el mecanismo 18

Terpene cyclases and cation fates

  • Pinene synthase: α-terpinyl cation to α-pineneDraw the attack of the ring double bond of the α-terpinyl cation on its exocyclic cationic carbon that closes the four-membered ring of the pinyl cation, and the deprotonation that gives α-pinene.
  • α-Terpineol synthase: water captures the α-terpinyl cationDraw the capture of the α-terpinyl cation by water and the deprotonation of the oxonium ion that gives α-terpineol.
  • β-Bisabolene synthase: nerolidyl diphosphate to β-bisaboleneDraw the ionization of nerolidyl diphosphate, the six-membered ring closure of its cisoid allylic cation that gives the bisabolyl cation, and the deprotonation that gives β-bisabolene.
  • Bornyl diphosphate synthase: α-terpinyl cation to bornyl diphosphateDraw the second ring closure of the α-terpinyl cation that forms the bornyl cation, and its capture by the diphosphate that gives bornyl diphosphate.
  • 1,8-Cineole synthase: α-terpineol closes a bridged etherDraw the Markovnikov protonation of the ring double bond of α-terpineol, the attack of its hydroxyl oxygen across the ring on the new cation, and the deprotonation that gives 1,8-cineole.
  • Limonene synthase: linalyl diphosphate to limoneneDraw the reionization of linalyl diphosphate, the ring closure of the cisoid allylic cation onto the C6=C7 double bond that gives the α-terpinyl cation, and the deprotonation that gives limonene.
  • Linalool synthase: water captures the geranyl cation at C3Draw the ionization of GPP, the attack of water at the tertiary end of the allylic cation, and the deprotonation that gives linalool.
  • Monoterpene cyclases first isomerize GPP to linalyl diphosphateDraw the ionization of GPP and the return of the diphosphate to C3 of the allylic cation that gives linalyl diphosphate, and explain why cyclization needs this detour.
  • Myrcene synthase: an acyclic monoterpene from GPPDraw the ionization of GPP, the allylic resonance that places charge on C3, and the loss of a methyl proton that gives myrcene.
  • Sabinene synthase: a cyclopropane from the terpinen-4-yl cationDraw the attack of the ring double bond on the terpinen-4-yl cation that closes the three-membered ring of the sabinyl cation, and the deprotonation that gives sabinene.
  • A 1,2-hydride shift on the way to terpinen-4-olDraw the 1,2-hydride shift that moves the charge of the α-terpinyl cation into the ring, then water capture and deprotonation giving terpinen-4-ol.

Isoprene units and prenyl transfer

  • Aromatic prenylation: geranylation of 4-hydroxybenzoateDraw the ionization of GPP, the attack of the aromatic ring of 4-hydroxybenzoate ortho to its OH group on the geranyl cation, and the loss of the ring proton that restores aromaticity.
  • FPP synthase: GPP and IPP give farnesyl diphosphateDraw the second chain-elongation round of FPP synthase: ionization of GPP, head-to-tail attack by IPP and deprotonation to (2E,6E)-farnesyl diphosphate.
  • GPP synthase: DMAPP and IPP give geranyl diphosphateDraw the ionization of DMAPP, the head-to-tail attack of the IPP double bond on the allylic cation, and the deprotonation that forms the (E) double bond of geranyl diphosphate.
  • IPP isomerase converts IPP into DMAPPDraw the protonation of the terminal C=C of isopentenyl diphosphate that gives a tertiary cation, and the deprotonation of the neighbouring CH₂ that gives dimethylallyl diphosphate.
  • Isoprene synthase: DMAPP to isopreneDraw the ionization of DMAPP to the dimethylallyl cation, its resonance form with the charge on the tertiary carbon, and the loss of a methyl proton that gives isoprene.
  • Mevalonate diphosphate decarboxylase makes IPPDraw the loss of the 3-phosphate from 3-phosphomevalonate 5-diphosphate to give a tertiary carbocation, and the decarboxylation that turns that cation into the C=C of isopentenyl diphosphate.

Terpene and steroid lab chemistry

  • Bromination of cholesterol: anti, diaxial addition to C5=C6Draw the formation of the 5α,6α-bromonium ion from the C5=C6 bond of cholesterol and its opening by bromide at C6 from the β face, and explain why the product is the trans-diaxial 5α,6β-dibromide.

Predice el producto 3

Squalene, lanosterol and steroids

  • Order the events of the lanosterol cascadePlace the protonation, ring closures, 1,2-shifts and final deprotonation of the oxidosqualene cyclization in order.

Isoprene units and prenyl transfer

  • The cation after IPP attacksPredict the structure of the carbocation formed when IPP adds head to tail to the dimethylallyl cation.

Terpene cyclases and cation fates

  • Deprotonating the α-terpinyl cation in the ringPredict which monoterpene forms when the α-terpinyl cation loses the ring proton next to the cationic carbon.

Clasificar 5

Squalene, lanosterol and steroids

  • 5α or 5β?Relate the 5α/5β descriptor of a saturated steroid to the cis or trans A/B ring fusion.
  • Axial or equatorial 3β-OH?Use the A/B ring fusion of a saturated steroid to decide whether its 3β-OH group is axial or equatorial.
  • Find the steroid ring systemIdentify the 6-6-6-5 tetracyclic steroid nucleus among related fused ring systems.

Isoprene units and prenyl transfer

  • Which one is DMAPP?Recognize dimethylallyl diphosphate as the allylic C₅ diphosphate, distinct from its isomer IPP.
  • Spot the sesquiterpeneClassify a terpenoid as a sesquiterpene by counting its carbons in units of five.

Comparar 1

  • Order terpenes by isoprene unitsRank terpenes from hemiterpene to tetraterpene by the number of isoprene units they contain.

Calcular 5

Squalene, lanosterol and steroids

  • How many stereoisomers could cholesterol have?Find every stereocentre of cholesterol, including the side chain, and calculate the number of possible stereoisomers.
  • How many C=C bonds remain in lanosterol?Use degrees of unsaturation and the ring count to find the number of C=C bonds in lanosterol.
  • From lanosterol to cholesterolUse molecular formulas to count the carbons removed between lanosterol and cholesterol.

Terpene and steroid lab chemistry

  • How much (R)-limonene is in the sample?Convert an observed specific rotation into enantiomeric excess and then into the percentage of each limonene enantiomer.
  • Ozonolysis of squalenePredict the fragments of exhaustive ozonolysis of squalene and count the 4-oxopentanal molecules formed.

Encuentra el error 1

  • Where does the 3-OH come from?Find the error in a proposal that has water supplying the hydroxyl group of lanosterol at the end of the cascade.

Interpreta la evidencia 2

Terpene and steroid lab chemistry

  • Isoborneol : borneol from the ¹H NMR spectrumUse the integrals of the CH–OH signals to find the diastereomer composition of the alcohols from the borohydride reduction of camphor.
  • Which monoterpene gives this spectrum?Identify a C₁₀H₁₆ monoterpene from the number, integration and shifts of its alkene ¹H NMR signals.

Trabaja hacia atrás 1

  • Taking squalene apartWork back from the symmetry of squalene to the tail-to-tail coupling of two farnesyl units.

Planea una síntesis 1

  • Oxidize the 3-OH but keep C5=C6 in placePlan a protection–oxidation–deprotection sequence that turns cholesterol into the non-conjugated cholest-5-en-3-one.

Explica por qué 3

Squalene, lanosterol and steroids

  • Who sets the stereocentres?Explain how one enzyme sets the configurations of the many stereocentres formed in the oxidosqualene cascade.
  • How the cascade startsContrast the ionization start of diphosphate-dependent terpene cyclases with the protonation start of lanosterol synthase.
  • Lanosterol or cycloartenol?Explain how lanosterol synthase and cycloartenol synthase reach different sterols from the same oxidosqualene.

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