Divergent synthesis of complex diterpenes through a hybrid oxidative approach

Zhang, Xiao; King-Smith, Emma; Dong, Liao-Bin; Yang, Li‐Cheng; Rudolf, Jeffrey D.; Shen, Ben; Renata, Hans

doi:10.1126/science.abb8271

Cited by 133 publications

(123 citation statements)

References 60 publications

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“…Recent advances in synthetic chemistry permit the biomimetic generation of natural product structures. These advances facilitate methods to access plant polyketides and strained cyclic terpenoids that previous methods could not easily synthesize ( 50 , 51 , 52 , 53 ).Chemoenzymatic methods have enabled the synthesis of a variety of oxygenated terpenoids ( 54 ), and breakthroughs in peptide synthesis using flow chemistry facilitate the rapid production of longer peptides than earlier methodologies ( 55 , 56 ). In addition, bacterial fermentations and engineered cocultures of Escherichia coli with other bacteria and yeast can now produce plant-derived secondary metabolites such as alkaloids and phenylpropanoids ( 57 , 58 ).…”

mentioning

confidence: 99%

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Parthasarathy

Borrego

Savka

et al. 2021

Journal of Biological Chemistry

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For millennia, humanity has relied on plants for its medicines, and modern pharmacology continues to reexamine and mine plant metabolites for novel compounds and to guide improvements in biological activity, bioavailability, and chemical stability. The critical problem of antibiotic resistance and increasing exposure to viral and parasitic diseases has spurred renewed interest into drug treatments for infectious diseases. In this context, an urgent revival of natural product discovery is globally underway with special attention directed toward the numerous and chemically diverse plant defensive compounds such as phytoalexins and phytoanticipins that combat herbivores, microbial pathogens, or competing plants. Moreover, advancements in “ omics ,” chemistry, and heterologous expression systems have facilitated the purification and characterization of plant metabolites and the identification of possible therapeutic targets. In this review, we describe several important amino acid–derived classes of plant defensive compounds, including antimicrobial peptides ( e.g. , defensins, thionins, and knottins), alkaloids, nonproteogenic amino acids, and phenylpropanoids as potential drug leads, examining their mechanisms of action, therapeutic targets, and structure–function relationships. Given their potent antibacterial, antifungal, antiparasitic, and antiviral properties, which can be superior to existing drugs, phytoalexins and phytoanticipins are an excellent resource to facilitate the rational design and development of antimicrobial drugs.

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mentioning

confidence: 99%

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Parthasarathy

Borrego

Savka

et al. 2021

Journal of Biological Chemistry

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“…Although the C2-oxygenation of (+)-stemar-13-ene (1) 41 is a biosynthetically viable process 27,42,43 to generate (+)-2-oxostemar-13-ene (2), 44 given the high competitiveness of allylic positions (C8 and C17) present in 1 during the C2-H oxygenation with chemical oxidants, we postulated that compound 6 would be a more superior substrate for C2-H oxygenation than 1. The C2-H oxygenations of a less complicated system sclareolide have been well studied in recent years.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

et al. 2022

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A unified protecting-group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first time via chemical synthesis. Starting from a common intermediate, two distinct tetracyclic frameworks containing diastereoisomeric bridged bicycles were constructed by divergent ring reorganization strategy. Late-stage C−H functionalization through xanthylation-oxygenation protocol furnished the corresponding oxygenated stereocenters or oxo functionality in high regio-and diastereoselective fashion within a complex hydrocarbon system. The stereochemical puzzles in (-)-2-acetoxybetaer-13(17)-ene and (+)-7-acetoxybetaer-13(17)-ene were first predicted by the comparison of DFT-NMR data with the reported data and later were unambiguously addressed through the total syntheses of natural products and three diastereomers.

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“…183,184 Likewise, native 2OG-dependent hydroxylases and halogenases have been utilized by the Renata Lab and others in the synthesis and tailoring of natural product compounds. [185][186][187][188][189][190][191][192][193][194][195] A few examples of the abiological transformations enabled by these platforms have already surfaced: the cyclopropyl core structures of the approved drugs levomilnacipran, ticagrelor, tranylcypromine, and tasimelteon, as well as a TRPV1 antagonist drug candidate, have been constructed with engineered P450s and globins. [196][197][198] Enzyme engineers ultimately aspire to see the products of their creativity and labor used directly in the manufacture of valuable compounds.…”

Section: Iron-dependent Oxygenases In Organic Synthesismentioning

confidence: 99%

Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases

2020

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Iron is an especially important redox-active cofactor in biology because of its ability to mediate reactions with atmospheric O 2 . Iron-dependent oxygenases exploit this earthabundant transition metal for the insertion of oxygen atoms into organic compounds. Throughout the astounding diversity of transformations catalyzed by these enzymes, the protein framework directs reactive intermediates toward the precise formation of products, which, in many cases, necessitates the cleavage of strong C-H bonds. In recent years, members of several iron-dependent oxygenase families have been engineered for new-to-nature transformations that offer advantages over conventional synthetic methods. In this Perspective, we first explore what is known about the reactivity of heme-dependent cytochrome P450 oxygenases and nonheme iron-dependent oxygenases bearing the 2-His-1-carboxylate facial triad by reviewing mechanistic studies with an emphasis on how the protein scaffold maximizes the catalytic potential of the iron-heme and iron cofactors. We then review how these cofactors have been repurposed for abiological transformations by engineering the protein frameworks of these enzymes. Finally, we discuss contemporary challenges associated with engineering these platforms and comment on their roles in biocatalysis moving forward.

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Divergent synthesis of complex diterpenes through a hybrid oxidative approach

Cited by 133 publications

References 60 publications

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases

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