Forging Carbon Bonds with Biradical Flair
A remarkable base-mediated reaction that forges two carbon-carbon bonds in a single transformation, with applications ranging from anticancer therapies to advanced materials.
Imagine a chemical process so versatile that it can help in the fight against cancer and contribute to the development of advanced materials, all while solving fundamental challenges in organic synthesis. This is the reality of the Garratt-Braverman (GB) cyclization, a remarkable base-mediated reaction that forges two carbon-carbon bonds in a single transformation.
First discovered in the 1970s through the collaborative work of chemists Garratt and Braverman, this reaction has evolved from a chemical curiosity to a powerful synthetic tool capable of constructing complex aromatic systems that are prized in both medicine and materials science 1 3 .
What makes this reaction particularly fascinating to researchers is its intriguing mechanistic pathway that walks the line between diradical and ionic processes—a chemical tightrope act that continues to captivate synthetic and theoretical chemists alike 1 .
At its core, the Garratt-Braverman cyclization is a base-mediated rearrangement of bis-propargyl sulfones, sulfoxides, sulfides, ethers, amines, and sulfonamides that leads to the formation of biaryl-based aromatic systems 1 .
The reaction begins when a base abstracts protons from the starting material, triggering an isomerization to bis-allene intermediates. These intermediates then undergo cyclization through either a diradical or ionic pathway—with the specific route depending largely on the heteroatom connecting the two propargyl arms—ultimately forming a new six-membered ring fused to a five-membered heterocycle 1 6 .
Initial studies suggested a diradical-mediated pathway for the cyclization. These diradical intermediates can abstract hydrogen atoms from DNA, making them promising for anticancer therapies 1 .
More recent investigations reveal that the mechanism is nuanced, with some substrates favoring ionic pathways depending on reaction conditions and substrate design 5 .
One of the most intriguing aspects of the GB cyclization is the ongoing investigation into its precise mechanism. Whether the reaction proceeds through a diradical or ionic pathway has been the subject of extensive research, with evidence supporting both possibilities depending on reaction conditions and substrate design 1 .
A 2016 computational study examined how the mechanism varies across different substrates:
To illustrate the practical application of GB cyclization, let's examine a specific experiment aimed at synthesizing phenanthridine derivatives—privileged structures found in numerous bioactive natural products and pharmaceuticals .
The research team designed a retrosynthetic approach where phenanthridine derivatives would be obtained through GB cyclization of bis-propargylic ethers . These ethers, in turn, would be synthesized via base-mediated O-alkylation of corresponding propargyl alcohols, which could be prepared through Sonogashira coupling of 3-bromo quinoline or 4-bromo isoquinoline with appropriate alkynes .
Preparation of necessary quinoline and isoquinoline precursors.
Key bis-propargyl ether substrates were prepared.
Reaction conditions: potassium tert-butoxide (t-BuOK) in DMSO at 80°C .
Products purified using column chromatography and characterized through NMR spectroscopy and mass spectrometry .
The GB cyclization successfully produced dihydroisofuran-fused phenanthridine derivatives in moderate to good yields (50-75%) . The reaction proceeded via a mono-allene intermediate rather than a bis-allene, attributed to the significant difference in acidity between the propargylic hydrogens in the two arms when electron-withdrawing quinoline or isoquinoline systems were incorporated .
| Compound | Binding Constant (K) (M⁻¹) | Relative Binding Affinity |
|---|---|---|
| 51 | 2.5 × 10⁵ | Highest |
| 53a | 1.8 × 10⁵ | High |
| 53b | 1.6 × 10⁵ | High |
| 54 | Not determined | Very weak |
| 59 | Not determined | Very weak |
| Property | Finding |
|---|---|
| Primary Binding Mode | Intercalation |
| Compounds with Weak Binding | 54, 59 |
| Most Promising Compounds | 51, 53a, 53b |
| Additional Significance | Fused isofuran moiety provides handle for further functionalization |
Beyond synthetic utility, the resulting phenanthridine derivatives showed promising DNA-binding affinities through predominantly intercalative modes . This DNA interaction is significant because it suggests potential biological applications for these compounds, particularly in anticancer drug development where DNA-targeting agents play a crucial role.
| Reagent/Category | Function in GB Cyclization |
|---|---|
| Bis-propargyl Sulfones | Common substrates; undergo fast isomerization followed by slower cyclization 5 |
| Bis-propargyl Ethers | Alternative substrates; undergo slow isomerization followed by easier cyclization 5 |
| Potassium tert-butoxide | Commonly used strong base to initiate the reaction |
| Dimethyl Sulfoxide (DMSO) | Polar aprotic solvent frequently used for GB cyclizations |
| Deuterated Solvents | Essential for NMR characterization of products and mechanistic studies |
| DNA Restriction Fragments | Used to study biological activity and DNA-binding properties of products 1 |
The true value of the Garratt-Braverman cyclization lies in its diverse applications across multiple fields of chemistry and medicine.
The diradicals generated during GB cyclization have shown significant potential as anticancer agents 1 . Research has demonstrated that bis-propargyl sulfones can interact with DNA either as DNA alkylators or through diradical-mediated DNA cleavage 1 .
Although GB is a self-quenching process, diradicals with lesser reactivity and longer half-lives can survive long enough to abstract hydrogen from DNA backbones, resulting in DNA damage 1 . This dual mechanism of action—direct alkylation and radical-mediated cleavage—makes these compounds particularly interesting for cancer therapy development.
The extended aromatic systems accessible through GB cyclization have found applications in the development of conducting polymers and materials with interesting photochemical and photophysical properties 1 .
The ability to create complex, conjugated systems in a relatively straightforward manner makes this reaction valuable for designing new organic semiconductors and light-emitting materials .
Furthermore, the biaryl skeletons generated through GB cyclization possess a chiral axis, opening up possibilities for creating axially chiral molecules that could have applications in asymmetric synthesis and the development of chiral ligands or catalysts 1 .
The Garratt-Braverman cyclization represents a powerful and versatile tool in the synthetic chemist's arsenal. From its intriguing mechanistic duality to its practical applications in drug discovery and materials science, this reaction continues to reveal new dimensions more than four decades after its initial discovery.
As research advances, we can expect to see further refinement of the reaction conditions, expansion of substrate scope, and increased understanding of the factors controlling the diradical versus ionic pathways.
The integration of GB cyclization with other transformations—such as the one-pot Garratt-Braverman cyclization and Scholl oxidation route to acene-helicene hybrids developed by Mitra and colleagues—demonstrates how this reaction can be combined with other processes to access increasingly complex molecular architectures 4 .
In the endless quest for efficient methods to construct carbon-carbon bonds—the very backbone of organic molecules—the Garratt-Braverman cyclization stands out as a testament to the power of fundamental chemical exploration to yield practical solutions with far-reaching implications across multiple scientific disciplines.