Biosynthesis — cationic polyene cyclization
Terpene cyclization (squalene → lanosterol-type)
How the Terpene cyclization (squalene → lanosterol-type) works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Squalene 2,3-oxide (model polyene shown), oxidosqualene cyclase (acid residue, Asp). Conditions: Aqueous, 37 °C, enzyme active site holding a pre-folded chair–chair conformation. Bonds formed: Several C–C σ bonds; rings A/B; new C=C; C–H; bonds broken: Epoxide C–O; C=C π (each alkene); migrating C–H and C–C. Stereochemistry: Pre-organised folding sets all ring-fusion stereocentres. Rate and selectivity: Enzyme-controlled; epoxide protonation triggers the whole cascade.
At a glance
Step 1: Acid opens the epoxide
An enzyme-bound Lewis or Brønsted acid activates one end of a polyene chain (commonly an epoxide, as in squalene oxide), generating a carbocation that the rest of the pre-organized, folded polyene chain is perfectly positioned to attack.
Step 2: Alkene additions build rings A and B
A cascade of intramolecular alkene additions follows: each alkene's π electrons attack the adjacent cation in turn, exactly like the acid-catalyzed alkene addition covered early in this library, just repeated four or five times in a single concerted-feeling enzymatic cascade, building multiple rings at once.
Step 3: 1,2-H and CH₃ shifts, then −H⁺
A final 1,2-hydride and methyl shift (the same migration logic as the pinacol rearrangement) followed by loss of a proton terminates the cascade — this single mechanism, built entirely from reactions already covered in this library, is how nature constructs the complex polycyclic skeletons of steroids and terpenes from one simple linear precursor.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- Markovnikov
- Markovnikov’s rule. In HX addition, H goes to the carbon with more H’s so the more stable cation forms.
- Asp
- Aspartate. Acidic amino acid.
How it compares with related reactions
| Terpene cyclization (squalene → lanosterol-type) | Cytochrome P450 | DNA glycosylase | |
|---|---|---|---|
| Reagents | Squalene 2,3-oxide (model polyene shown), oxidosqualene cyclase (acid residue, Asp) | Cytochrome P450 (heme-thiolate), O₂, NADPH (2 e⁻ via reductase), 2 H⁺, substrate R–H | DNA glycosylase (e.g. uracil-DNA glycosylase), H₂O |
| Conditions | Aqueous, 37 °C, enzyme active site holding a pre-folded chair–chair conformation | Aqueous, pH ~7.4, 37 °C, membrane-bound or soluble enzyme | Physiological pH, 37 °C |
| Stereochemistry | Pre-organised folding sets all ring-fusion stereocentres | Rebound is fast, so configuration is often largely retained | Inversion or retention at C1′ depending on enzyme |
| Rate / selectivity | Enzyme-controlled; epoxide protonation triggers the whole cascade | Compound I formation fast; C–H abstraction is rate-limiting | Base flipping and oxocarbenium-like TS control rate |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Terpene cyclization (squalene → lanosterol-type)?
Squalene 2,3-oxide (model polyene shown), oxidosqualene cyclase (acid residue, Asp). Conditions: Aqueous, 37 °C, enzyme active site holding a pre-folded chair–chair conformation.
Which bonds are formed and which are broken?
Formed: Several C–C σ bonds; rings A/B; new C=C; C–H. Broken: Epoxide C–O; C=C π (each alkene); migrating C–H and C–C.
What is the stereochemical outcome?
Pre-organised folding sets all ring-fusion stereocentres
What controls the rate or the selectivity?
Enzyme-controlled; epoxide protonation triggers the whole cascade
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- Curved-arrow notation: rules and the mistakes students make