Subtopic Deep Dive
Atropisomerism in Biaryl Natural Products
Research Guide
What is Atropisomerism in Biaryl Natural Products?
Atropisomerism in biaryl natural products refers to axial chirality arising from restricted rotation around the biaryl bond in natural products like vancomycin aglycon and korupensamine due to steric hindrance from ortho substituents.
Researchers focus on total synthesis of these axially chiral biaryls using diastereoselective methods and configurational stability tests. Key strategies include lactone-bridged biaryls and dynamic kinetic resolution. Over 20 papers from 1999-2022 address synthesis, with Bringmann et al. (1999) cited 221 times and Gustafson et al. (2010) cited 437 times.
Why It Matters
Syntheses of biaryl atropisomers like mastigodiene enable analog development for antibiotics and anticancer drugs. Bringmann et al. (1999) lactone concept synthesizes natural products with >95% ee, aiding drug discovery. Gustafson et al. (2010) peptide-catalyzed bromination achieves dynamic kinetic resolution, producing enantioenriched biaryls for vancomycin derivatives. Carmona et al. (2021) reviews desymmetrization strategies applied to pharmaceuticals.
Key Research Challenges
Configurational Stability Assessment
Determining rotational barriers in biaryl natural products requires variable-temperature NMR and DFT calculations to predict racemization. Leroux (2004) compares fluorine effects on twist angles and barriers. Accurate prediction prevents synthesis of unstable atropisomers.
Diastereoselective Biaryl Coupling
Achieving high diastereoselectivity in total synthesis of vancomycin aglycon demands chiral auxiliaries or catalysts. Bringmann et al. (1999) uses lactone bridges for atroposelective ring cleavage. Wallace (2006) highlights challenges in controlling axial chirality during coupling.
Scalable Dynamic Kinetic Resolution
Dynamic kinetic resolution via peptide catalysis, as in Gustafson et al. (2010), needs optimization for gram-scale natural product synthesis. Carmona et al. (2021) classifies methods but notes scalability limits in complex biaryls.
Essential Papers
Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-Catalyzed Asymmetric Bromination
Jeffrey L. Gustafson, Daniel Lim, Scott J. Miller · 2010 · Science · 437 citations
Selectively Spun Biaryl compounds, in which two phenyl rings are linked by a single bond, exhibit an interesting sort of chirality, termed atropisomerism. If bulky substituents block the mutual rot...
Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications
Hong‐Hao Zhang, Feng Shi · 2022 · Accounts of Chemical Research · 388 citations
Catalytic atroposelective syntheses of axially chiral compounds have stimulated extensive interest in multiple communities, such as synthetic chemistry, biochemistry, and materials science, because...
Atroposelective transformation of axially chiral (hetero)biaryls. From desymmetrization to modern resolution strategies
José A. Carmona, Carlos Rodríguez-Franco, Rosario Fernández et al. · 2021 · Chemical Society Reviews · 379 citations
Atroposelective transformations of (hetero)biaryls are classified into desymmetrization, kinetic resolution, dynamic kinetic resolution, and dynamic kinetic asymmetric transformation depending on t...
The Lactone Concept: An Efficient Pathway to Axially Chiral Natural Products and Useful Reagents
Gerhard Bringmann, Matthias Breuning, Stefan Tasler · 1999 · Synthesis · 221 citations
A highly efficient concept for the stereoselective synthesis of axially chiral biaryl target molecules is presented: the atroposelective ring cleavage of configurationally unstable lactone-bridged ...
Chiral Pd-Catalyzed Enantioselective Syntheses of Various N–C Axially Chiral Compounds and Their Synthetic Applications
Osamu Kitagawa · 2021 · Accounts of Chemical Research · 197 citations
Biaryl atropisomers are key structural components in chiral ligands, chiral functional materials, natural products, and bioactive compounds, and their asymmetric syntheses have been reported by man...
Pd‐Catalyzed Atroposelective C−H Allylation through β‐O Elimination: Diverse Synthesis of Axially Chiral Biaryls
Gang Liao, Bing Li, Hao Ming Chen et al. · 2018 · Angewandte Chemie International Edition · 190 citations
Abstract Biaryl atropisomers are of great importance in natural products, pharmaceuticals, and asymmteric synthesis. The efficient synthesis of these chiral scaffolds with full enantiocontrol and h...
Asymmetric Synthesis of Axially Chiral C−N Atropisomers
Patricia Rodríguez‐Salamanca, Rosario Fernández, Valentı́n Hornillos et al. · 2022 · Chemistry - A European Journal · 187 citations
Abstract Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric c...
Reading Guide
Foundational Papers
Start with Bringmann et al. (1999) for lactone concept applied to natural products; Gustafson et al. (2010) for DKR benchmarks; Wallace (2006) for biaryl coupling overview.
Recent Advances
Carmona et al. (2021) reviews atroposelective transformations; Kitagawa (2021) on Pd-catalyzed C-N atropisomers; Zhang et al. (2022) on torsional strain ring-opening.
Core Methods
Lactone-bridged cleavage (Bringmann 1999); peptide-catalyzed bromination DKR (Gustafson 2010); Pd-catalyzed C-H allylation (Liao et al. 2018); organocatalytic desymmetrization (Zhang 2022).
How PapersFlow Helps You Research Atropisomerism in Biaryl Natural Products
Discover & Search
Research Agent uses citationGraph on Gustafson et al. (2010, 437 citations) to map DKR methods across 50+ biaryl papers, then exaSearch for 'lactone concept biaryl natural products' to find Bringmann et al. (1999) descendants.
Analyze & Verify
Analysis Agent runs readPaperContent on Bringmann et al. (1999) to extract lactone cleavage yields, verifies stereoselectivity claims with verifyResponse (CoVe), and uses runPythonAnalysis to plot rotational barriers from Leroux (2004) DFT data via NumPy, graded by GRADE for evidence strength.
Synthesize & Write
Synthesis Agent detects gaps in scalable DKR for korupensamine via contradiction flagging across Carmona et al. (2021) reviews; Writing Agent applies latexEditText to draft schemes, latexSyncCitations for 20+ refs, and latexCompile for publication-ready synthesis routes with exportMermaid for biaryl coupling diagrams.
Use Cases
"Extract Python code from papers on DFT modeling of biaryl rotational barriers"
Research Agent → searchPapers('DFT biaryl atropisomerism') → Code Discovery (paperExtractUrls → paperFindGithubRepo → githubRepoInspect) → runPythonAnalysis sandbox outputs barrier plots and stability predictions.
"Draft LaTeX scheme for lactone-bridged vancomycin synthesis"
Synthesis Agent → gap detection in Bringmann et al. (1999) → Writing Agent → latexEditText('insert biaryl lactone scheme') → latexSyncCitations(Gustafson 2010) → latexCompile → PDF with stereo-controlled route.
"Find similar papers to Gustafson 2010 DKR for mastigodiene analogs"
Research Agent → findSimilarPapers(Gustafson 2010) → citationGraph → Analysis Agent → readPaperContent(5 top matches) → verifyResponse(CoVe) → enantioenrichment yields table.
Automated Workflows
Deep Research workflow scans 50+ papers via searchPapers on 'biaryl atropisomer natural products', structures DKR/lactone reports with GRADE grading. DeepScan applies 7-step analysis to Carmona et al. (2021), checkpoint-verifying desymmetrization yields. Theorizer generates hypotheses for Pd-catalyzed routes from Kitagawa (2021) and Liao et al. (2018).
Frequently Asked Questions
What defines atropisomerism in biaryl natural products?
Restricted rotation around the biaryl axis due to ortho steric bulk creates stable enantiomers, as in korupensamine (Leroux 2004).
What are key synthesis methods?
Lactone concept (Bringmann et al. 1999) via atroposelective ring cleavage; peptide-catalyzed DKR bromination (Gustafson et al. 2010).
What are top cited papers?
Gustafson et al. (2010, 437 citations, Science); Bringmann et al. (1999, 221 citations, Synthesis); Carmona et al. (2021, 379 citations, Chem Soc Rev).
What are open problems?
Scalable enantioselective synthesis of multi-axis atropisomers (Bao et al. 2020); predicting barriers in complex natural products without DFT (Leroux 2004).
Research Axial and Atropisomeric Chirality Synthesis with AI
PapersFlow provides specialized AI tools for Chemistry researchers. Here are the most relevant for this topic:
AI Literature Review
Automate paper discovery and synthesis across 474M+ papers
Paper Summarizer
Get structured summaries of any paper in seconds
Deep Research Reports
Multi-source evidence synthesis with counter-evidence
Code & Data Discovery
Find datasets, code repositories, and computational tools
See how researchers in Chemistry use PapersFlow
Field-specific workflows, example queries, and use cases.
Start Researching Atropisomerism in Biaryl Natural Products with AI
Search 474M+ papers, run AI-powered literature reviews, and write with integrated citations — all in one workspace.
See how PapersFlow works for Chemistry researchers