How Synthesis and Computation Reveal Nature's Hidden Structures
The mysterious medium-sized lactones, long elusive to scientists, are finally yielding their structural secrets to a powerful combination of chemical synthesis and computational chemistry.
Explore the DiscoveryImagine a molecular detective story where the suspects constantly change their shape, and traditional identification methods often lead to false accusations. This is the challenge faced by chemists studying medium-sized lactones, a class of natural products with remarkable biological activities but notoriously tricky structures to decipher.
For decades, these molecules have baffled scientists with their conformational flexibility, sometimes leading to incorrect structural assignments that take years to correct. Today, thanks to advances in synthetic chemistry and theoretical calculations, researchers are developing innovative methods to finally solve these molecular mysteries and unlock their potential for medicine and technology.
Lactones form the chemical backbone of numerous natural products with diverse biological activities, ranging from antibiotics to anticancer agents.
Medium-sized lactones (typically 8-11 membered rings) exhibit elevated levels of conformational flexibility, complicating their characterization .
Unlike their smaller counterparts, medium-sized lactones exhibit elevated levels of conformational flexibility. This inherent structural feature complicates determining their three-dimensional arrangement, often posing challenges in deciphering their stereochemistry and in some instances has led to proposing incorrect structures entirely 1 .
Provides information about atom connectivity and spatial relationships through chemical shifts and coupling constants.
NMR signals can be broadened or averaged, obscuring crucial structural details for flexible molecules.
Can provide a precise three-dimensional molecular snapshot of compounds.
Requires high-quality crystals, difficult to obtain for flexible compounds. Shows only solid-state structure, which may differ from solution-phase conformation.
These limitations created what became known as "structural misassignments"—cases where initially proposed structures were later found to be incorrect, sometimes years after their initial publication 1 . Such errors have significant implications, particularly when these natural products show promising biological activity.
The emerging powerful approach combines chemical synthesis with theoretical calculations to tackle these structural challenges 1 . This dual methodology creates a virtuous cycle of hypothesis and verification:
Allows researchers to build proposed structures atom by atom, confirming or refuting structural assignments through comparison with natural samples.
Particularly density functional theory (DFT), predict NMR parameters and stable conformations for candidate structures.
This synergy enables what Professor Ryo Katsuta describes as "DFT-NMR-guided structure revision"—using computational chemistry to recalculate expected NMR spectra for different possible structures and comparing them with observed data to identify the correct arrangement 7 .
A perfect example of this methodology in action is the structure revision of cremenolide, a plant-growth promoting and antifungal compound isolated from Trichoderma cremeum 7 .
The structure was initially proposed based on traditional spectroscopic methods.
Katsuta and colleagues combined NMR reanalysis with quantum chemical calculations and synthesis.
They discovered the originally proposed structure was incorrect.
Through total synthesis and DFT-NMR calculations, they successfully determined the true structure of cremenolide 7 .
This case exemplifies how the synthetic-computational approach can correct misassigned structures, ensuring researchers work with the correct molecular architecture for future studies and applications.
To appreciate how researchers are overcoming the challenges of medium-sized lactone synthesis, it's helpful to examine a specific innovative method recently reported in Nature Communications 2 .
A team of chemists developed what they describe as an "easy access to medium-sized lactones through metal carbene migratory insertion enabled 1,4-palladium shift" 2 . This mouthful describes an elegant solution to the entropic and transannular challenges of forming these rings.
Instead of trying to force linear molecules to cyclize (the traditional approach), the researchers used a palladium-catalyzed process that builds the lactone skeleton through a series of carefully orchestrated steps:
N-tosylhydrazone compounds generate reactive diazo intermediates
A palladium catalyst moves along the molecular framework through a "1,4-palladium shift"
The rearranged structure naturally forms the medium-sized lactone
This method overcomes the traditional requirement for high-dilution conditions or slow addition of reagents typically needed for medium-sized ring formation. It represents a more efficient and controllable approach to these challenging structures 2 .
| Lactone Product | Substituents | Yield (%) |
|---|---|---|
| 3 | None | 76 |
| 5 | 4-Fluorophenyl | 84 |
| 9 | 4-Chlorophenyl | 79 |
| 14 | 2-Naphthyl | 55 |
| 28 | Trimethylsilyl | 67 |
| 29 | Phenylethynyl | 81 |
Data adapted from 2
| Lactone Product | Biological Precursor | Yield (%) |
|---|---|---|
| 31 | Methylparaben | 72 |
| 32 | Paracetamol | 68 |
| 33 | Carvacrol | 65 |
| 34 | Thymol | 71 |
| 35 | Eugenol | 63 |
| 36 | Estrone | 58 |
Data adapted from 2
The method showed remarkable versatility, successfully producing lactones with various functional groups. Importantly, potentially reactive sites such as carbon-carbon triple bonds and labile silyl groups remained intact during the process—a testament to the selectivity of this approach 2 .
| Tool | Function | Application in Lactone Research |
|---|---|---|
| Palladium Catalysts (e.g., Pd(OAc)₂, Pd₂(dba)₃) | Facilitate key bond-forming steps | Enables carbon-carbon and carbon-oxygen bond formation under mild conditions 2 |
| Phosphine Ligands (e.g., Xantphos, dppb) | Modify reactivity and selectivity of metal catalysts | Controls stereochemistry and prevents side reactions during lactone formation 2 |
| DFT Calculations | Predict molecular properties, stability, and NMR parameters | Verifies proposed structures and guides synthesis 1 7 |
| N-Tosylhydrazones | Serve as diazo compound precursors | Provides carbene intermediates for palladium-catalyzed lactonization 2 |
| Ring Expansion Strategies | "Grow" smaller rings into medium-sized ones | Avoids entropic penalties of direct cyclization 6 |
The implications of these methodological advances extend far beyond academic interest. Correctly determining lactone structures opens doors to:
Many medium-sized lactones show promising biological activities. Knowing their true structures enables rational drug design and optimization.
Tricyclic ring systems containing a dibenzo-fused seven-membered lactone show potential for preventing or treating malignant diseases 2 .
Lactones with plant growth-promoting or antifungal activities, like cremenolide, could lead to new crop protection agents 7 .
Lactones contribute significantly to aroma and flavor profiles; understanding their structures aids in creating new or improved versions .
As research continues, the synergy of synthesis and computation continues to solve longstanding structural puzzles while enabling the discovery of new biologically active compounds.
The field of natural products chemistry has entered an exciting era where theoretical calculations and chemical synthesis work in concert to solve structural mysteries that once seemed intractable.
For medium-sized lactones, this partnership has been particularly fruitful, correcting past misassignments and establishing robust methods for future discoveries.
As Professor Katsuta notes in his recent review, these advancements have been pivotal in unveiling the structures of lactones that had previously "eluded definitive elucidation" 1 . The ongoing refinement of these approaches promises to accelerate the identification and application of these fascinating natural products.
The journey to decipher nature's molecular puzzles continues, but with powerful synthetic and computational tools at their disposal, researchers are better equipped than ever to meet the challenge.