Polycyclic diterpenes exhibit many important biological activities, but de novo synthetic access to these molecules is highly challenging because of their structural complexity. Semisynthetic access has also been limited by the lack of chemical tools for scaffold modifications. We report a chemoenzymatic platform to access highly oxidized diterpenes by a hybrid oxidative approach that strategically combines chemical and enzymatic oxidation methods. This approach allows for selective oxidations of previously inaccessible sites on the parent carbocycles and enables abiotic skeletal rearrangements to additional underlying architectures. We synthesized a total of nine complex natural products with rich oxygenation patterns and skeletal diversity in 10 steps or less from ent-steviol.
Meroterpenoids are natural products of hybrid biosynthetic origins-derived from both terpenoid and polyketide pathways-with a wealth of biological activities. Given their therapeutic potential, a general strategy to access these natural products in a concise and divergent fashion is highly desirable. Here, we report a modular synthesis of a suite of oxidized meroterpenoids using a hybrid synthetic strategy that is designed to harness the power of both biocatalytic and radicalbased retrosynthetic logic. This strategy enables direct introduction of key hydroxyl groups and rapid construction of key bonds and stereocenters, facilitating the development of a concise route (7-12 steps from commercial materials) to eight oxidized meroterpenoids from two common molecular scaffolds. This work lays the foundation for rapid access to a wide range of oxidized meroterpenoids through the use of similar hybrid strategy that combines two synthetic approaches. Multistep chemical synthesis relies almost exclusively on the use of retrosynthetic analysis. 1 Using this conceptual framework, a target molecule is disconnected through a series of reverse reactions to arrive finally at greatly simplified or commercial starting materials. As each disconnection needs to be sensible in the forward synthetic direction, the choice of bond(s) to disconnect is highly dependent on the contemporary synthetic transformations available at the practitioner's disposal. Throughout the history of organic chemistry, polar disconnections, due to their perceived robustness, permeate much of the discourse in the field. More recently, the emergence of new technologies in chemical synthesis has led to the formulation of alternative retrosynthetic strategies. Biocatalytic retrosynthesis 2 has flourished into a highly powerful principle for multistep syntheses due to the unparalleled selectivity of enzymatic transformations and the ever-growing tools of protein engineering and directed evolution. 3 Similarly, radical-based retrosynthetic disconnections 4,5 have become increasingly popular, owing to the unique chemoselectivity and chemofidelity 6 of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Nature has produced a diverse range of oxygenases for the modification of secondary metabolites with selectivity profiles that are unmatched by conventional man-made catalysts. In the past two decades, organic chemists have begun to harness the synthetic potential of these biocatalysts to develop efficient chemoenzymatic synthesis of complex natural products. Judicious combination of synthetic and enzymatic transformations in multistep synthesis can often result in powerful disconnections that compare favorably with contemporary chemical strategies for accessing the target natural products, while at the same time presenting opportunities to innovate. This Perspective highlights strategic applications of enzymatic hydroxylation to simplify problems in natural product synthesis. Finally, newly discovered enzymes that would facilitate further developments in this field are discussed.
A combination of genomic and metabolomic approaches recently resulted in the identification of a nonribosomal tetrapeptide tambromycin, which possesses promising antiproliferative activity and several unusual structural features, including a densely substituted indole, a methyloxazoline ring, and an unusual pyrrolidine-containing amino acid called tambroline. In this work, we identify a concise synthetic route to access tambromycin, which relies on the strategic use of biocatalytic and chemocatalytic C-H functionalization methods to prepare two key precursors to the natural product in an efficient and scalable manner. The success of our study highlights the benefits of applying the principles of biocatalytic retrosynthesis as well as C-H functionalization logic to the synthesis of complex molecular scaffolds.
We report a modular approach to access a range of oxidized meroterpenoids using a novel hybrid synthetic strategy involving enzymatic hydroxylation and radical based transformations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.