Subtopic Deep Dive
Ring-Closing Metathesis Applications
Research Guide
What is Ring-Closing Metathesis Applications?
Ring-Closing Metathesis (RCM) applications involve the olefin metathesis reaction where diene substrates cyclize to form cyclic alkenes using transition metal catalysts, enabling synthesis of rings from 5 to over 20 members.
RCM has become a cornerstone in synthetic organic chemistry for constructing carbocycles and heterocycles prevalent in natural products and pharmaceuticals. Key reviews document over 1000 citations for foundational works like Grubbs et al. (1995, 1031 citations) and Schuster & Blechert (1997, 895 citations). Applications span rigidified amino acids, peptides, and functionalized olefins as shown in Miller et al. (1996, 430 citations) and Chatterjee et al. (2000, 611 citations).
Why It Matters
RCM provides efficient access to medium and large rings critical for drug candidates, as in peptide synthesis via Grubbs catalysts (Miller et al., 1996). It streamlines total syntheses of complex molecules by forming C=C bonds under mild conditions, reducing steps compared to traditional cyclizations (Grubbs et al., 1995). Industrial applications include polymer networks with dynamic covalent bonds from metathesis (Winne et al., 2019). Handbook of Metathesis (2003, 1661 citations) details catalyst advancements enabling substrate scope expansion to electron-deficient olefins (Chatterjee et al., 2000).
Key Research Challenges
Stereocontrol in Large Rings
Achieving E/Z selectivity in macrocycles remains difficult due to thermodynamic control favoring E-alkenes in rings over 8 members (Grubbs et al., 1995). Catalyst design addresses this but substrate effects complicate outcomes (Schuster & Blechert, 1997). Recent dynamic networks highlight persistent issues in precise stereochemistry (Winne et al., 2019).
Substrate Scope Limitations
Electron-withdrawing groups on dienes lead to low yields in RCM, as initial attempts with α,β-unsaturated carbonyls failed (Chatterjee et al., 2000). Coordinating heterocycles like chelating ethers pose deactivation risks (Armstrong, 1998). Expanded catalysts mitigate but not eliminate these barriers (Handbook of Metathesis, 2003).
Catalyst Efficiency in Peptides
Ruthenium complexes enable peptide RCM but suffer from side reactions in polar media (Miller et al., 1996). Macrocycle formation requires high dilution to favor intramolecularity over oligomerization (Grubbs, 2004). Optimization persists for biologically relevant scaffolds.
Essential Papers
Handbook of Metathesis
· 2003 · 1.7K citations
Preface.CATALYST DEVELOPMENTS.Introduction.The Role of the Tebbe in Olefin Metathesis.The Discovery and Development of High Oxidation State Mo and W Imido Alkylidene Complexes for Alkene Metathesi...
Olefin metathesis
Robert H. Grubbs · 2004 · Tetrahedron · 1.2K citations
Ring-Closing Metathesis and Related Processes in Organic Synthesis
Robert H. Grubbs, Scott J. Miller, Gregory C. Fu · 1995 · Accounts of Chemical Research · 1.0K citations
Carbon-carbon bond forming reactions remain among the most important for the synthesis of organic structures. The transition metal alkylidene-catalyzed olefin metathesis reaction (eq 1) and the rel...
Olefin Metathesis in Organic Chemistry
Matthias Schuster, Siegfried Blechert · 1997 · Angewandte Chemie International Edition in English · 895 citations
Abstract Transition metal catalyzed CC bond formations belong to the most important reactions in organic synthesis. One particularly interesting reaction is olefin metathesis, a metal‐catalyzed ex...
Olefin metathesis and metathesis polymerization
K. J. Ivin, I. C Mol · 1997 · 664 citations
Dynamic covalent chemistry in polymer networks: a mechanistic perspective
Johan M. Winne, Ludwik Leibler, Filip Du Prez · 2019 · Polymer Chemistry · 637 citations
A selection of dynamic chemistries is highlighted, with a focus on the reaction mechanisms of molecular network rearrangements, and on how mechanistic profiles can be related to the mechanical and ...
Synthesis of Functionalized Olefins by Cross and Ring-Closing Metatheses
Arnab Chatterjee, John P. Morgan, Matthias Scholl et al. · 2000 · Journal of the American Chemical Society · 611 citations
The generation of olefins with electron-withdrawing functionality, such as α,β-unsaturated aldehydes, ketones, and esters, remains a difficult task in organic chemistry. A practical method to appro...
Reading Guide
Foundational Papers
Start with Grubbs, Miller, Fu (1995, 1031 citations) for RCM principles in synthesis; follow with Handbook of Metathesis (2003, 1661 citations) for catalyst history; Schuster & Blechert (1997, 895 citations) details substrate scope.
Recent Advances
Winne et al. (2019, 637 citations) covers dynamic networks; Chatterjee et al. (2000, 611 citations) advances functionalized olefins.
Core Methods
Core techniques: Grubbs 1st/2nd gen Ru catalysts for 6-14 membered rings; high dilution for macrocycles; NHC ligands for sterics (Grubbs, 2004).
How PapersFlow Helps You Research Ring-Closing Metathesis Applications
Discover & Search
Research Agent uses citationGraph on Grubbs et al. (1995, 1031 citations) to map RCM evolution from early Mo/W catalysts to Ru systems, revealing 50+ connected papers. exaSearch queries 'ring-closing metathesis medium rings stereocontrol' to find niche applications like Armstrong (1998). findSimilarPapers expands Schuster & Blechert (1997) to substrate-specific reviews.
Analyze & Verify
Analysis Agent employs readPaperContent on Chatterjee et al. (2000) to extract yield data for electron-deficient RCM, then runPythonAnalysis plots conversion vs. catalyst loading using NumPy/pandas. verifyResponse with CoVe cross-checks stereoselectivity claims against Grubbs (2004), achieving GRADE A evidence grading. Statistical verification confirms E/Z ratios via matplotlib histograms.
Synthesize & Write
Synthesis Agent detects gaps in macrocycle applications post-2000 via contradiction flagging between Miller (1996) and Winne (2019), suggesting dynamic RCM networks. Writing Agent uses latexEditText to draft schemes, latexSyncCitations for 20+ metathesis papers, and latexCompile for publication-ready reviews. exportMermaid generates RCM mechanism flowcharts.
Use Cases
"Extract RCM yield data from Chatterjee 2000 and plot vs ring size"
Research Agent → searchPapers 'Chatterjee Grubbs 2000' → Analysis Agent → readPaperContent → runPythonAnalysis (pandas data extraction, matplotlib ring size/yield scatterplot) → CSV export of 15+ functionalized olefin examples.
"Write LaTeX review section on RCM in peptide synthesis citing Miller 1996"
Synthesis Agent → gap detection in peptide RCM → Writing Agent → latexEditText (insert mechanism), latexSyncCitations (Grubbs/Miller refs), latexCompile → PDF with embedded schemes from Miller et al. (1996).
"Find GitHub repos with RCM reaction predictors from metathesis papers"
Research Agent → paperExtractUrls on Handbook of Metathesis (2003) → Code Discovery → paperFindGithubRepo → githubRepoInspect → Python scripts for catalyst screening simulations linked to Grubbs catalysts.
Automated Workflows
Deep Research workflow scans 50+ metathesis papers via searchPapers → citationGraph, generating structured reports on RCM applications with GRADE-scored sections (e.g., stereocontrol from Grubbs 2004). DeepScan applies 7-step CoVe to verify substrate scope claims in Chatterjee (2000), checkpointing against Schuster (1997). Theorizer hypothesizes new Ru catalysts for chelating dienes from Armstrong (1998) patterns.
Frequently Asked Questions
What defines ring-closing metathesis applications?
RCM applications use diene intramolecular metathesis to form cyclic alkenes with rings of 5-20+ members via Ru or Mo catalysts (Grubbs et al., 1995).
What are key methods in RCM?
First-generation Ru catalysts (Cl2(PCy3)2Ru=CHPh) enable basic RCM; second-generation with NHC ligands improve activity for hindered substrates (Handbook of Metathesis, 2003; Chatterjee et al., 2000).
What are foundational papers?
Grubbs, Miller, Fu (1995, Accounts, 1031 citations) introduced organic synthesis applications; Handbook of Metathesis (2003, 1661 citations) compiles catalyst developments.
What open problems exist in RCM?
Challenges include Z-selective macrocycle RCM, low yields with electron-poor dienes, and peptide side reactions under aqueous conditions (Winne et al., 2019; Miller et al., 1996).
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