The fascinating story of how total synthesis revealed the true structures of α- and β-diversonolic esters
In the world of chemistry, natural products have long been treasure troves of complex molecular structures with potential medical applications. Among these treasures were α- and β-diversonolic esters, compounds first isolated from fungi that represented a growing family of natural products with striking antibiotic activities. For years, chemists accepted their proposed structures as fact—until one research team discovered that nature had been hiding the truth through an elaborate molecular disguise.
The revelation came through the meticulous work of chemists K.C. Nicolaou and A. Li, who embarked on a program to synthesize these molecules in the laboratory. What began as a straightforward synthetic challenge evolved into a chemical detective story that would ultimately rewrite the structures of these natural products and demonstrate the power of total synthesis to validate—and sometimes correct—nature's blueprints 2 .
The diversonol family represents a fascinating class of natural products, with some members exhibiting promising antibiotic properties that captured scientific interest. Among them, diversonol was the first identified member of the monomeric series within this structural class, while other relatives like rugulotrosins and secalonic acids form more complex dimeric structures 2 .
Several members of the diversonol family show significant antibiotic activity against various pathogens.
These compounds feature tetrahydroxanthone and chromone lactone frameworks with multiple interconnected rings.
These compounds share common structural motifs centered around tetrahydroxanthone and chromone lactone frameworks—complex arrangements of carbon, hydrogen, and oxygen atoms organized into multiple interconnected rings that create significant three-dimensional complexity. It was this very complexity that initially led to the misidentification of the diversonolic esters' structures, a problem that would remain hidden until chemists attempted to recreate these molecules from scratch 6 .
Total synthesis—the complete chemical synthesis of complex organic molecules from simpler, commercially available materials—represents one of chemistry's most demanding disciplines. When Nicolaou and Li set out to synthesize the diversonolic esters, they employed a multi-step strategy that involved carefully constructing the molecular framework piece by piece 2 .
Using diethylaluminum cyanide to add cyanide groups to the molecular framework.
Employing IBX•MPO as a key reagent to transform intermediate structures.
Using DIBAL-H to selectively reduce functional groups.
Building complexity through carefully controlled chemical transformations.
When the team successfully created what should have been the α- and β-diversonolic esters according to the originally proposed structures, they encountered a puzzling discrepancy: the spectroscopic data (NMR) of their synthetic compounds didn't match what had been reported for the natural products 2 . This critical finding suggested that something was fundamentally wrong with the accepted structural assignments.
| Intermediate | Structure Features | Key Transformation |
|---|---|---|
| Enone 6 | Starting material with racemic center | Cyanation with Etâ‚‚AlCN |
| Nitrile enone 7 | Cyano group, enone system | IBX•MPO oxidation |
| Ester enone 8 | Ester functionality, enone system | Multi-step conversion from nitrile |
| Bromo hydroxy ester 9 | Bromine atom, hydroxy group | Bromination followed by reduction |
The plot thickened when the researchers modified their synthetic approach, using MOM protecting groups on the aromatic segment of the molecule. When they subjected intermediate 21 to acidic deprotection conditions, instead of obtaining the expected products, they observed two new compounds isomeric to their target structures 2 .
One of the unexpected compounds crystallized, allowing X-ray crystallography to reveal its true structure.
Under acidic conditions, the molecules underwent a surprising transformation into different shapes.
The crystal structure revealed a surprising skeletal rearrangement had occurred under the acidic conditions—the molecules had morphed into different shapes entirely. Even more remarkably, the NMR data of these rearranged compounds matched perfectly with those reported for the naturally occurring diversonolic esters 2 .
This serendipitous discovery led to the proposal of revised structures for α- and β-diversonolic esters, correcting the scientific record and highlighting how synthetic chemistry can reveal nature's secrets.
| Compound | Originally Proposed Structure | Revised Structure | Key Evidence |
|---|---|---|---|
| α-Diversonolic ester | 1 | 4 | NMR matching, X-ray crystallography |
| β-Diversonolic ester | 2 | 5 | NMR matching, X-ray crystallography |
| Blennolide C | Not originally known | Same as original structure 2 | Isolated after Nicolaou's work |
Chemical synthesis relies on specialized reagents that enable precise molecular transformations. The diversonol synthesis utilized several key reagents, each serving specific functions in building the complex architecture of these natural products.
| Reagent | Function in Synthesis | Specific Application |
|---|---|---|
| Etâ‚‚AlCN | Cyanation reagent | Adds cyanide group to enone system |
| IBX•MPO | Oxidation agent | Converts nitrile TMS enol ether to nitrile enone |
| DIBAL-H | Reducing agent | Reduces nitrile to aldehyde intermediate |
| NaBH₄-CeCl₃ | Selective reduction | Reduces keto group to hydroxy group |
| HF•pyridine | Desilylation agent | Removes silicon-protecting groups |
| nBu₃SnH/Pd(PPh₃)₄ | Deallylation system | Removes allyl protecting groups |
The structural revision of the diversonolic esters represents more than just an academic exercise—it demonstrates the critical importance of total synthesis in validating natural product structures. When scientists isolate compounds from nature, they typically have limited material and must infer structures through indirect methods. Total synthesis provides unambiguous proof of structure when the synthetic and natural materials match spectroscopically 2 .
Provides definitive proof of molecular structure
Strategies to reconfigure molecular frameworks
Opens doors to therapeutic property exploration
This work also highlights the growing importance of skeletal editing—strategies that allow chemists to reconfigure molecular frameworks through atom insertion, deletion, or exchange. The accidental skeletal rearrangement that led to the revised structures exemplifies how such processes can occur both in nature and in the laboratory 8 .
Furthermore, making these natural products readily available through synthesis opens doors to biological investigations that may reveal valuable therapeutic properties. With reliable synthetic routes established, scientists can explore analogs and derivatives that might possess enhanced antibiotic activity or other medically useful properties 2 .
The resolution of the diversonolic ester structures continues to influence natural product synthesis years later. Subsequent research has developed more efficient, enantioselective routes to these molecules and related compounds like blennolide C and gonytolide C 7 .
These advances demonstrate how chemical synthesis continues to evolve, with researchers developing increasingly elegant strategies to construct complex natural architectures. The first enantioselective total syntheses of blennolide C and gonytolide C, for instance, employed sophisticated catalytic methods including a domino-Wacker/carbonylation/methoxylation reaction to precisely control stereochemistry .
Such methodological improvements not only make these compounds more accessible but also expand the synthetic chemist's toolkit for tackling even more challenging molecular targets in the future.
The story of the diversonolic esters reminds us that scientific understanding is always provisional, subject to revision as new evidence emerges. What began as a straightforward synthetic project transformed into a journey of discovery that corrected the structural record and demonstrated the power of chemical synthesis to reveal nature's hidden truths.
The diversonol family's structural revision stands as a testament to human curiosity and ingenuity—a reminder that even nature's most carefully guarded secrets cannot forever withstand the determined investigation of the scientific mind.
As synthetic methodologies continue to advance—through skeletal editing, catalytic asymmetric reactions, and other innovative strategies—chemists are better equipped than ever to unravel nature's complexity. Each corrected structure and improved synthesis represents both an end and a beginning: the resolution of one mystery and the starting point for new investigations into the molecular world that surrounds us.