In the realm of natural product synthesis, the complexity of molecular architecture presents perpetual challenges that demand not only ingenuity but also precision in strategy design. Traditionally, the synthesis of terpenoids—a vast and structurally diverse family of natural compounds—has necessitated the creation of highly specific, target-oriented synthetic routes. Each unique skeletal connectivity demands a bespoke approach, often rendering the process laborious, time-consuming, and narrowly scoped. However, a recent groundbreaking study conducted by Deng, Yang, Li, and their colleagues has unveiled an innovative synthetic strategy that fundamentally shifts this paradigm, enabling access to a broad spectrum of terpenoid frameworks from a singular starting material using enzyme-assisted transformations combined with abiotic skeletal rearrangements.
This study ventures beyond the conventional wisdom by proposing a versatile synthetic platform that transcends the need for redesigning routes for structurally distinct targets. Starting with sclareolide, a sesquiterpene lactone known for its well-defined drimane skeleton, the researchers exploited a biocatalytically installed alcohol functional group not as a final modification but as a dynamic handle for further molecular manipulations. This deliberate reinterpretation of installed functionalities as synthetic footholds rather than terminal modifications marks a conceptual breakthrough in natural product synthesis.
The strategic foundation of this work rests on leveraging enzyme catalysis to introduce an alcohol moiety onto the sclareolide scaffold with high regio- and stereoselectivity. The controlled enzymatic oxidation step effectively primes the molecule for subsequent abiotic chemical transformations, which are purposefully designed to expand the molecular diversity accessible from the original drimane framework. This bio-enabled chemical strategy enables significant scaffold hopping—an approach where the core connectivity of a molecule is altered while maintaining or enhancing its biological relevance.
Skeletal rearrangements typically rely on the inherent reactivity of functional groups in a molecule; however, orchestrating such transformations in complex terpenoid frameworks without compromising stereochemical integrity is no trivial feat. The team’s method harnesses the installed hydroxyl group as a reaction locus, triggering a cascade of chemically programmed rearrangements that reorganize carbon connectivities and ring systems. These reactions are performed under controlled abiotic conditions, ensuring precise manipulation of molecular topology.
One of the most compelling aspects of this approach is its breadth of application. The researchers successfully synthesized four structurally diverse terpenoid natural products: merosterolic acid B, cochlioquinone B, (+)-daucene, and dolasta-1(15),8-diene. Each of these compounds possesses unique skeletal characteristics that historically would have required distinct synthetic schemes. Using their enzyme-enabled, scaffold-hopping methodology, the team demonstrated a unified synthetic route with variable divergence points leading to multiple complex molecules.
Merosterolic acid B, a hybrid terpenoid also bearing a prominent biological profile, was accessed by exploiting specific rearrangement pathways that modify the ring connectivity while preserving key stereochemical elements introduced via enzymatic oxidation. This achievement highlights the method’s capability to retain chiral information amidst dramatic structural transformations.
In the synthesis of cochlioquinone B, an environmentally relevant terpenoid with a sesquiterpene-quinone framework, the team showcased the adaptability of their method to install quinonoid moieties through subsequent oxidation and rearrangement sequences. This compound’s distinct fused-ring system was effectively constructed by tactically leveraging the enzymatically installed alcohol.
The access to (+)-daucene further illustrates the potential of this synthetic platform in generating hydrocarbon frameworks with altered ring junctions. By initiating rearrangements on the drimane core, the researchers navigated a molecular landscape that led to the formation of this sesquiterpene, which serves as a critical intermediate in various biosynthetic pathways.
Lastly, the synthesis of dolasta-1(15),8-diene, a diterpenoid with unique double bond placements and ring fusion patterns, underscored the strategic plasticity of the scaffold-hopping approach. The ability to manipulate multiple ring systems and unsaturation levels post enzymatic functionalization is a testament to the synthetic finesse embedded in this study.
Beyond the synthetic accomplishments, the integration of enzyme catalysis with abiotic chemical methodologies embodies the emerging paradigm of chemoenzymatic synthesis. By utilizing the selectivity and mildness of enzymatic reactions to install reactive sites, followed by robust chemical transformations to reform skeletal structures, this strategy achieves a level of molecular editing difficult to replicate by either approach alone.
This dual approach also contributes to efficiency and sustainability in complex molecule synthesis. Enzymes, as biocatalysts, offer environmentally benign alternatives to traditional chemical oxidations, often performed under harsh conditions with low selectivity. Moreover, the modularity of this method opens the door for rapid diversification of terpenoid frameworks, potentially accelerating drug discovery efforts reliant on natural product derivatives.
The implications of this research extend to synthetic biology, medicinal chemistry, and natural product-based drug development. The ability to rapidly generate multiple terpenoid skeletons from a common precursor empowers medicinal chemists to explore structure-activity relationships more swiftly and provides synthetic biologists with new tools to engineer pathways toward structurally complex molecules.
In addition, the concept of treating enzymatically installed functional groups as “synthetic handles” poised for subsequent rearrangements challenges the contemporary outlook on chemoenzymatic synthesis. Traditionally perceived as terminal functionalization sites, these handles can now be viewed as springboards for controlled structural diversity, a concept that could reshape route-planning strategies in natural product synthesis.
This strategy may also inspire parallel developments in other classes of natural products beyond terpenoids, where scaffold complexity and diversity remain significant hurdles. Extending this logic to polyketides, alkaloids, or nonribosomal peptides could lead to equally transformative synthetic methodologies.
While the study sets a high benchmark, future investigations may focus on expanding the toolkit of enzymatic transformations compatible with abiotic rearrangements, broadening substrate scopes, and improving overall synthetic yields and step-economies. Furthermore, computational design tools could be integrated to predict and optimize scaffold hops, enhancing reaction specificity and pathway selection.
Ultimately, the work by Deng and colleagues represents a landmark advance in synthetic chemistry, marrying the precision of enzymatic functionalization with the creative freedom of abiotic scaffold rearrangements to unlock unprecedented structural diversity. This approach not only challenges existing dogmas in natural product synthesis but also paves the way for more innovative, sustainable, and efficient routes to complex molecules with wide-ranging biological and pharmaceutical significance.
As synthetic strategies continue to evolve, such integrative approaches stand poised to revolutionize molecule construction, enabling chemists to access nature’s diverse chemical space in ways previously deemed impractical or impossible. This synthesis of divergent terpenoid frameworks from a common progenitor heralds a new era of creativity and efficiency in natural product chemistry.
Subject of Research: Synthesis of diverse terpenoid frameworks via enzyme-enabled abiotic scaffold hopping
Article Title: Synthesis of diverse terpenoid frameworks via enzyme-enabled abiotic scaffold hop
Article References:
Deng, H., Yang, J., Li, F. et al. Synthesis of diverse terpenoid frameworks via enzyme-enabled abiotic scaffold hop. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01852-6
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