Scientists Break Century-Old Barrier to Synthesizing Anti-Bredt Olefins

Anti-Bredt olefins: delving into the world of molecular structures © Sirisook- stock.adobe.com

For nearly a century, chemists have considered anti-Bredt olefins (ABOs) nearly impossible to synthesize and harness due to their inherent instability and unconventional bond geometries. The twist and pyramidal distortion of the ABO π-bonds, which are central to their chemical reactivity, have historically deterred successful synthesis. However, in an innovative leap, a research team from the University of California, Los Angeles (UCLA) has successfully synthesized ABOs and demonstrated their potential as reactive intermediates in chemical synthesis. Their findings, detailed in Science, could inspire new methodologies and applications in synthetic chemistry (1–2).

The Challenge of Anti-Bredt Olefins

The idea that ABOs were out of reach for chemists dates back to the early 20th century when Julius Bredt, studying camphane and pinane ring systems, proposed that double bonds could not form at the branching positions of certain carbon-bridge structures. This idea became known as “Bredt’s rule,” which essentially made ABOs inaccessible intermediates within traditional synthetic chemistry. Since then, there have been attempts to synthesize ABOs, but their inherent instability and tendency to decompose have deterred consistent success (1–2).

UCLA’s team, including researchers Luca McDermott, Zach G. Walters, Sarah A. French, Allison M. Clark, Jiaming Ding, Andrew V. Kelleghan, K. N. Houk, and Neil K. Garg, set out to challenge this paradigm. Their work aimed to develop a practical method for synthesizing and capturing ABOs, a task that, if successful, could open entirely new avenues for chemical synthesis (1).

NMR Measurements Were Key for Problem Solving

Nuclear magnetic resonance (NMR) spectroscopy was essential to confirming the successful synthesis and structure of anti-Bredt olefins (ABOs) in the UCLA team’s research. NMR provided detailed insights into the geometric distortions of the ABO π-bonds, specifically their twisting and pyramidalization. By analyzing chemical shifts, coupling constants, and splitting patterns, the researchers could directly observe the unique electronic environments within the ABOs, supporting the computational predictions about their highly strained structure (1).

Additionally, NMR helped track the stereochemical aspects of reactions involving ABOs, such as the transfer of point chirality from a precursor molecule to a chiral cycloadduct via an axially chiral intermediate. This stereochemical verification indicated that ABOs are able retain and transmit chirality in synthetic reactions, highlighting their potential as intermediates for constructing complex, chiral molecules. Altogether, NMR played a critical role in validating both the structural and stereochemical characteristics of ABOs, underpinning this significant breakthrough in synthetic chemistry (1).

Novel Approach to ABO Synthesis

Inspired by methods used to synthesize other strained molecules, the team used a strategy involving silyl (pseudo)halide precursors. These precursors, when treated with a fluoride source (such as Bu4NF or CsF/Bu4NBr), generated ABOs in situ that could be quickly trapped by various cycloaddition reactions. Using this technique, the team was able to synthesize ABOs within several bicyclic ring systems, including [3.2.1], [2.2.2], and [2.2.1] configurations, successfully stabilizing them long enough to carry out further chemical reactions (1).

Bicyclic ring systems, such as [3.2.1], [2.2.2], and [2.2.1] configurations, are molecular structures where two rings share atoms, creating strained frameworks. The numbers in these notations indicate the atoms in each bridge between the shared bridgehead atoms. For example, the bicyclo[3.2.1] system, as in bicyclo[3.2.1]octane, has a seven-membered ring and notable geometric strain, while bicyclo[2.2.2]octane forms a symmetric eight-membered ring with moderate stability. The bicyclo[2.2.1] structure, seen in norbornane, includes a single-atom bridge that adds significant strain. These systems' unique geometries and reactivity make them valuable in studying synthetic intermediates, as shown in the UCLA research on anti-Bredt olefins (1).

Central to their research was an analysis of ABO geometries. Using density functional theory (DFT) computations, the team confirmed that the alkenes in ABOs indeed exhibit twisting and pyramidalization. This geometric distortion is key to their heightened reactivity. These distorted alkenes, in a [2.2.1] ABO configuration, were shown to undergo a range of trapping experiments, including (4+2), (2+2), (3+2), and (5+2) cycloadditions, which resulted in structurally complex products. Many of these products also included functional handles that could be further modified, adding versatility to their potential applications (1).

Computational and Experimental Insights

Beyond experimental synthesis, the researchers used computational modeling to understand why ABOs are so reactive. Focusing on the [2.2.1] structure, their studies revealed that ABOs display distinctly olefinic character and can react in concerted, asynchronous cycloadditions with dienes, such as anthracene. These findings confirmed that ABOs could be viable intermediates for reactions that have traditionally relied on more stable alkenes (1).

Interestingly, the team’s stereochemical studies with the [2.2.2] system revealed another promising characteristic of ABOs. They found that chirality in the starting material could be retained through cycloaddition reactions involving ABOs, resulting in chiral products. This phenomenon was attributed to the intermediate’s axial chirality, further underscoring the olefinic nature of ABOs and supporting the team’s broader findings on their potential applications (1).

Conclusion and Future Implications

The UCLA team’s research offers a groundbreaking solution to the longstanding challenge of ABO synthesis, disproving the idea that ABOs are too unstable for practical application. Their findings suggest that these highly strained molecules could become valuable intermediates in synthetic chemistry, particularly for creating complex, functionally diverse products.

The success of this work is not just a scientific achievement but a potential harbinger for new developments in chemistry, where researchers can leverage the unique reactivity of geometrically distorted alkenes. For now, the UCLA team’s research challenges one of organic chemistry’s most entrenched rules, hinting at the possibility of more breakthroughs that redefine established concepts and inspire fresh approaches to complex synthesis problems (1).

References

(1) McDermott, L.; Walters, Z. G.; French, S. A.; Clark, A. M.; Ding, J.; Kelleghan, A.V.; Houk, K. N.; Garg, N. K. 2024. A Solution to the Anti-Bredt Olefin Synthesis Problem. Science 2024, 386 (6721), eadq3519. DOI: 10.1126/science.adq3519

(2) Krenske, E. H.; Williams, C. M. Do Anti‐Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability. Angew. Chem. Int. Ed. 2015, 54 (36), 10608–10612. DOI: 10.1002/anie.201503822