Natural Product-like Combinatorial Libraries Based on Privileged Structures. 1. General Principles and Solid-Phase Synthesis of Benzopyrans

Nicolaou, K. C.; Pfefferkorn, Jeffrey A.; Roecker, Anthony J.; Cao, Gengyu; Barluenga, and S.; Mitchell, Helen J.

doi:10.1021/ja002033k

Cited by 676 publications

(369 citation statements)

References 82 publications

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“…[1][2][3] This nucleus is considered a privileged structure that is very common in bioactive natural products, such as coumarins, flavones, tocopherols (vitamin E) and tetrahydrocannabinoids. 4,5 The benzopyran moieties, 2H-chromenes and chromanes, isolated from Piper gaudichaudianum and Peperomia obtusifolia, respectively, have been demonstrated as potent trypanocidal compounds. 6,7 Curiously, both classes of compounds occur as racemic mixtures in these species, though their formation follows two distinct biosynthetic routes.…”

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confidence: 99%

Biosynthetic Insights into p-Hydroxybenzoic Acid-Derived Benzopyrans in Piper gaudichaudianum

Batista¹,

Batista²,

Souza-Moreira³

et al. 2017

J. Braz. Chem. Soc.

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Piper gaudichaudianum Kunth (Piperaceae) accumulates gaudichaudianic acid, a prenylated benzopyran, as its major component. Interestingly, this trypanocidal compound occurs as a racemic mixture. Herein, transcriptomic investigations of Piper gaudichaudianum using the RNAseq approach are reported, and from the analysis of the transcripts expressed it was possible to propose a complete biosynthetic pathway for the production of gaudichaudianic acid, including the steps that originate its precursor, p-hydroxybenzoic acid. Peperomia obtusifolia (L.) A. Dietr. (Piperaceae) also accumulates racemic benzopyrans, however, its chromanes originate from the polyketide pathway, while the chromenes from Piper derives from the shikimate pathway. Recent transcriptomic and proteomic studies of the former species did not identify polyketide synthases involved in the production of the benzopyran moiety, but revealed the expression of tocopherol cyclase, which may be responsible for the cyclization of the 3,4-dihydro-2H-pyran ring. The analysis of the enzymes involved in the secondary metabolism of Piper gaudichaudianum and the comparison with the data previously obtained from Peperomia obtusifolia can provide valuable information on how these compounds are biosynthesized.Keywords: Piperaceae, chromene, transcriptome, RNA-seq, de novo assembly, biosynthesis IntroductionChromanes and chromenes, which are secondary metabolites commonly found in some species from Piper and Peperomia genera (Piperaceae), are characterized by the presence of a benzopyran ring with various levels of oxidation. [1][2][3] This nucleus is considered a privileged structure that is very common in bioactive natural products, such as coumarins, flavones, tocopherols (vitamin E) and tetrahydrocannabinoids. 4,5 The benzopyran moieties, 2H-chromenes and chromanes, isolated from Piper gaudichaudianum and Peperomia obtusifolia, respectively, have been demonstrated as potent trypanocidal compounds. 6,7 Curiously, both classes of compounds occur as racemic mixtures in these species, though their formation follows two distinct biosynthetic routes. 6,8,9 In Piper gaudichaudianum, chromenes originate from the shikimate pathway and use p-hydroxybenzoic acid (p-HBA) as a precursor. 10 In the case of Peperomia obtusifolia, chromanes are formed through the polyketide pathway and use orsellinic acid as a precursor. 1,11 Additionally, the formation of both classes of metabolites involves the condensation of an aromatic unit (p-HBA or orsellinic acid) and an isoprene unit (dimethylallyl pyrophosphate, isopentenyl pyrophosphate or geranyl pyrophosphate), followed by cyclization that gives rise to the benzopyran ring. During cyclization, the carbon atom at C-2 becomes a stereogenic center and, different from other benzopyrans such as vitamin E, both enantiomers are biosynthesized (Figure 1). Thus, the study of the proteins and genes possibly responsible for the biosynthesis of benzopyrans in these species, as well as the comparison between them, may provide new insights into how...

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confidence: 99%

Biosynthetic Insights into p-Hydroxybenzoic Acid-Derived Benzopyrans in Piper gaudichaudianum

Batista¹,

Batista²,

Souza-Moreira³

et al. 2017

J. Braz. Chem. Soc.

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“…[10][11][12] Toward this end, several natural product-like templates have been tethered to a solidsupport utilizing an intramolecular, selenium-mediated cycloaddition procedure. Encouraged by their success in developing chemistry and technology to produce natural productlike libraries of oxygen-containing heterocycles and carbocyclic frameworks [13][14][15][16] and due to the potential utility of such libraries in chemical biology investigations, 17,18) they sought to expand the scope of this selenium-based solid-phase chemistry to include nitrogen-containing heterocycles.…”

Section: Selenium-based Solid-phase Chemistry To Include Nitrogen-conmentioning

confidence: 99%

Solid-phase organic synthesis of heterocyclic compounds

Izumi

2006

J. Pestic. Sci.

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The establishment of an efficient method of synthesizing heterocycles is required for the development of pharmaceuticals and agrochemicals, since many bioactive compounds have a heterocyclic ring. It is also necessary to prepare libraries of small organic compounds for investigations of function and the discovery of more bioactive compounds in pharmaceutical and agrochemical chemistry. Combinatorial and parallel synthetic methodologies provide the main driving force for the preparation of libraries for applications in the discovery of lead compounds and high-throughput medicinal chemistry within the pharmaceutical industry. [1][2][3] Many different formats of high-throughput chemistry are available and solid-phase organic synthesis (SPOS) plays a pivotal role allowing the convenient handling of large numbers of synthetic intermediates. 4,5) Since the combinatorial chemistry first appeared in the early 1990s, the way drugs are discovered has changed dramatically. The SPOS strategy has been a strong tool for high throughput synthesis and combinatorial chemistry.6-9) Synthetic intermediates are retained on the support and can be, therefore, quickly separated from the reaction mixture without extraction, concentration, and purification. SPOS is thus particularly advantageous for multi-step iterative synthesis. Various solid-phase automated synthesizers have been developed and are now commercially available. Even though several synthesizers for solution synthesis have been developed, automation is essentially easier in solid-phase synthesis than solution synthesis. In particular, the automated synthesis of peptides and oligonucleotides has allowed their facile and rapid preparation and greatly contributed to the elucidation of their functions. However, SPOS is not without its drawbacks since often extended development times are required to optimize new solid-phase chemical reactions. Actually, many laboratories have been engaged in the development of novel solidphase linking strategies and chemical technologies. This paper describes recent findings in, and a useful method for, the synthesis of heterocycle and nitrogen heterocycle compounds. Selenium-based solid-phase chemistry to include nitrogen-containing heterocyclesNicolaou and co-workers have been engaged in the development of novel solid-phase linking strategies and chemical technologies aimed at the construction of discovery-oriented, natural product-like libraries. [10][11][12] Toward this end, several natural product-like templates have been tethered to a solidsupport utilizing an intramolecular, selenium-mediated cycloaddition procedure. Encouraged by their success in developing chemistry and technology to produce natural productlike libraries of oxygen-containing heterocycles and carbocyclic frameworks [13][14][15][16] and due to the potential utility of such libraries in chemical biology investigations, 17,18) they sought to expand the scope of this selenium-based solid-phase chemistry to include nitrogen-containing heterocycles. Recently, they reported t...

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“…However, 1,4-dimethoxybenzene (8) has been prenylated utilizing the DoM protocol to produce 9 in 69% yield (Scheme 1b). 12 The addition of catalytic CuI improves the yield of 9 to 71%.…”

Section: Directed Ortho-metalation (Dom) and Alkylationmentioning

confidence: 99%

Strategies for the Preparation of Differentially Protectedortho-Prenylated Phenols

Hoarau¹,

Pettus²

2002

Synlett

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A new process for ortho-prenylation of phenols is presented within the context of known methods. All of the processes are briefly assessed with regards to the substitution patterns and accompanying functional groups tolerated by each strategy. The conclusion reached is that a new procedure using ortho-quinone methides, for which an experimental protocol is provided, offers the greatest generality and flexibility in the preparation of ortho-prenylated phenol derivatives.

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Natural Product-like Combinatorial Libraries Based on Privileged Structures. 1. General Principles and Solid-Phase Synthesis of Benzopyrans

Cited by 676 publications

References 82 publications

Biosynthetic Insights into p-Hydroxybenzoic Acid-Derived Benzopyrans in Piper gaudichaudianum

Biosynthetic Insights into p-Hydroxybenzoic Acid-Derived Benzopyrans in Piper gaudichaudianum

Solid-phase organic synthesis of heterocyclic compounds

Strategies for the Preparation of Differentially Protectedortho-Prenylated Phenols

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