Chapter 37 — Case Study 2: Olefin Metathesis in Natural Product Synthesis
"Before metathesis, making a 16-membered ring took 10 steps and a lot of luck. After metathesis, it takes 1 step and a Grubbs catalyst. The chemistry is so general that whenever a synthesis is published with a macrocyclic ring, the chances are 50:50 that RCM was used to close it." — paraphrase of an organic synthesis review
Olefin metathesis (Grubbs, Schrock, Chauvin — 2005 Nobel Prize in Chemistry) is one of the most important reactions developed in the past 50 years. The Ru-based Grubbs catalyst, in particular, has become a workhorse of natural product synthesis. This case study explores how metathesis transformed the synthesis of complex natural products, with focus on macrocycles and ring-closing metathesis.
The big picture: making large rings
Many natural products contain macrocyclic rings (rings of 12+ atoms). Examples: - Erythromycin (macrolide antibiotic): 14-member ring. - Ivermectin (antiparasitic): 16-member ring. - Rapamycin (immunosuppressant): 31-member ring. - Epothilones (anticancer): 16-member ring. - Boceprevir, simeprevir (HCV antivirals): macrocyclic peptidomimetics.
Macrocycles are pharmaceutically important because: - The constrained ring geometry can mimic protein-protein interfaces. - Macrocycles often have improved drug-like properties (better cell permeability, target binding). - They are a "middle ground" between small molecules and biologics.
But making macrocycles is hard. Traditional methods (macrolactonization, macrolactamization) require: - High dilution (to favor intramolecular ring closure over intermolecular oligomerization). - Specific starting materials with appropriate functional groups. - Often low yield (10-30% typical).
Then came Grubbs.
Ring-closing metathesis (RCM): the new standard
The Grubbs catalyst (a Ru-based carbene complex) catalyzes the cyclization of a diene to a cyclic alkene + ethylene:
$$\text{H}_2\text{C=CH-(CH}_2\text{)n-CH=CH}_2 \xrightarrow{\text{Grubbs cat.}} \text{cyclic alkene} + \text{H}_2\text{C=CH}_2$$
The reaction: - Works on a wide range of dienes. - Tolerates many functional groups (ester, amide, ketone, alcohol, etc.). - Releases ethylene as a volatile byproduct (drives equilibrium forward). - Requires only catalytic Grubbs (1-5 mol%). - Works in dichloromethane, toluene, or other solvents. - Often runs at room temperature to mild heat.
For macrocycle synthesis: convert the linear precursor into a diene with terminal alkenes at both ends; RCM closes the ring.
How the Grubbs catalyst works
The Ru carbene complex (Ru=CHR) reacts with an alkene in a [2+2] cycloaddition to form a metallacyclobutane (4-member ring with Ru and 3 C). The metallacyclobutane breaks open in the productive direction, giving a new Ru carbene and a new alkene.
For RCM, this happens twice: 1. Grubbs catalyst (Ru=CHR) reacts with one terminal alkene of the substrate. New Ru=CHR' (attached to substrate) + ethylene released. 2. The new Ru=CHR' encounters the second terminal alkene (the other end of the substrate, now in proximity since they're tethered). [2+2] cycloaddition forms a metallacyclobutane. 3. The metallacyclobutane breaks open productively, releasing ethylene and giving the cyclic alkene + regenerated Ru=CHR (initial catalyst).
The driving force: ethylene release (entropy + volatility removes it from the system, shifting equilibrium toward the cyclic product).
Generations of Grubbs catalysts
The Grubbs catalysts evolved over years: - Grubbs 1st generation (1995): Ru=CHPh + PCy₃ + Cl. Functional group tolerant but sometimes slow. - Grubbs 2nd generation (1999): Ru with NHC (N-heterocyclic carbene) ligand. More active; tolerates more functional groups. - Hoveyda-Grubbs 2nd generation: same NHC + a chelating styrenyl ether. More stable; recyclable. - Grubbs 3rd generation: a fast-initiating variant; very active.
For most natural product RCM, Grubbs 2nd generation or Hoveyda-Grubbs 2nd is used.
Examples in natural product synthesis
Epothilones (anticancer)
Epothilones are 16-member macrolide-like natural products with potent anticancer activity. Their tubulin-binding mechanism resembles paclitaxel's, but they are simpler structurally.
Multiple total syntheses of epothilones have been published; many use RCM to close the macrocyclic ring. For example, Schinzer's 1997 synthesis used RCM at a key step. Nicolaou's synthesis also used RCM.
Ixabepilone (a clinically used epothilone analog) is made on industrial scale, with RCM as a critical step.
Boceprevir (HCV antiviral)
Boceprevir was approved by the FDA in 2011 for hepatitis C. It is a 16-member macrocyclic peptidomimetic that inhibits the HCV NS3/4A protease.
Its synthesis includes an RCM step that closes the macrocyclic ring. The Pd-catalyzed coupling and RCM steps together build the molecule efficiently.
Simeprevir (HCV antiviral)
Simeprevir (FDA 2013) is another HCV protease inhibitor with a 14-member macrocycle. Like boceprevir, it uses RCM in its synthesis.
Eribulin (anticancer)
Eribulin is a synthetic analog of halichondrin B (a marine natural product). It is one of the most complex synthetic drugs ever marketed (62 stereocenters total). The synthesis (developed by Eisai) includes multiple metathesis steps.
Many natural product total syntheses
Total syntheses of: amphidinolide, latrunculin, peloruside A, salicylihalamides, leucascandrolide, taxol (paclitaxel), and dozens of other natural products use metathesis at key ring-forming steps.
Cross-metathesis for diverse alkene products
Beyond RCM, cross-metathesis (combining two different terminal alkenes) is widely used to make E-alkenes:
$$R_1-CH=CH_2 + R_2-CH=CH_2 \to R_1-CH=CH-R_2 + H_2C=CH_2 \text{ (E selective)}$$
The Hoveyda-Grubbs 2nd-generation catalyst is particularly effective for cross-metathesis.
Applications: - Making E-alkenes that traditional methods (Wittig, etc.) would give as Z. - Late-stage diversification of complex molecules. - Elongation of carbon chains.
ROMP for specialty polymers
Ring-opening metathesis polymerization (ROMP) opens strained cyclic alkenes (norbornene, cyclooctene, etc.) and polymerizes them.
Industrial uses: - Vestenamer (DSM): ROMP of cyclooctene; used as a rubber additive. - NORDEL EPDM (Dow): a co-polymer of ethylene + propylene + diene; some grades use ROMP. - Specialty polymers for medical devices, electronics, etc.
ROMP gives living polymerization with control over molecular weight, allowing block copolymers and graft architectures.
Asymmetric metathesis
Modern Mo and Ru catalysts enable enantioselective metathesis. The chiral catalyst directs the C=C exchange to give one enantiomer preferentially.
Applications: - Asymmetric RCM of dienes with prochiral substrates. - Asymmetric synthesis of cyclic chiral natural products.
This is an active area of research; new chiral catalysts are continuously developed.
Why metathesis was hard to discover
The mechanism of olefin metathesis was elusive until the 1970s. The "Chauvin mechanism" (proposed 1971) involves a metallacyclobutane intermediate — initially controversial because no metallacyclobutane had been isolated. Schrock's work (1980s) on Mo and W carbene complexes proved the mechanism. Grubbs's Ru catalysts (1990s+) made metathesis practical for organic chemists.
The 2005 Nobel Prize was awarded to all three (Chauvin for the mechanism; Schrock for the Mo catalysts; Grubbs for the Ru catalysts).
Take-home
- Olefin metathesis (Grubbs catalyst) revolutionized macrocyclic natural product synthesis.
- Ring-closing metathesis (RCM) closes diene precursors into cyclic alkenes + ethylene. Used to make 12+ membered rings efficiently.
- Cross-metathesis (CM) swaps alkene substituents; gives E-alkenes preferentially.
- Ring-opening metathesis polymerization (ROMP) opens strained cyclic alkenes for polymers.
- Examples: epothilones, boceprevir, simeprevir, eribulin, taxol — all use metathesis in their syntheses.
- The Grubbs catalyst (Ru-based) is widely used; modern variants (2nd gen, Hoveyda) tolerate many functional groups.
- The 2005 Nobel Prize (Chauvin, Schrock, Grubbs) recognized this transformative chemistry.
- Metathesis is now a standard tool — alongside Pd cross-coupling — for modern natural product and pharmaceutical synthesis.
- Mastery of Chapter 37 organometallic chemistry is the foundation for understanding modern synthesis at industrial and research scale.