Total Synthesis Establishes the Biosynthetic Pathway to the Naphterpin and Marinone Natural Products

Murray, Lauren A. M.; McKinnie, Shaun M. K.; Pepper, Henry P.; Erni, Reto; Miles, Zachary D.; Cruickshank, Michelle C.; López-Pérez, Borja; Moore, Bradley S.; George, Jonathan H.

doi:10.1002/anie.201804351

Cited by 46 publications

(54 citation statements)

References 52 publications

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“…Identification and reconstruction of new vHPOs from other natural product biosynthetic gene clusters such as recently identified vHPOs from naphterpin and marinone biosynthetic cluster and from unexplored cyanobacterial species will shed more light in this direction. [103,104,105,106]…”

Section: Reconstructed Biosynthetic and Natural Product Pathways Withmentioning

confidence: 99%

Halogenases for biosynthetic pathway engineering: Toward new routes to naturals and non-naturals

2020

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Nature's repertoire of bio-halogenase enzymes is intriguing with halogenases from various natural product biosynthetic clusters that carry out site and region-specific halogenation of diverse bioactive precursors and molecules. Currently, we have a comprehensive catalogue of cryptic and non-cryptic halogenases that act on simple to complex aliphatic and aromatic molecular scaffolds. This will open up further synthetic and biosynthetic opportunities for C-H activation, ring formation and functionalization of different molecular structures. In fact, halogenases were exploited over the years for these potential applications, to replace traditional chemical halogenation chemistries toward creating economical and environmentally benign methodologies and also for biosynthetic pathways. This review will discuss our advances in utilizing biohalogenases to generate both in vivo and in vitro biosynthetic pathways; summarizing all naturals and non-naturals that are synthesized with a direct bio-halogenase incorporation.

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Section: Reconstructed Biosynthetic and Natural Product Pathways Withmentioning

confidence: 99%

Halogenases for biosynthetic pathway engineering: Toward new routes to naturals and non-naturals

2020

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“…CL190 ( Fig. 1a), where it has been recently proposed to transfer a geranyl group onto the C4 position of the putative substrate 1,3,6,8-tetrahydroxynaphthalene (Murray et al 2018). Beyond this natural activity, though, NphB is known to exhibit a high degree of promiscuity toward phenolic acceptors, including flavonoids, isoflavonoids, plant polyketides, and various naphthols (Fig.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…In 2017, the enzyme was recombinantly expressed in the yeast Komagataella phaffii with tetrahydrocannabinolic acid synthase from Cannabis sativa. The resulting lysate was shown to produce Δ 9 -tetrahydrocannabinolic acid from GPP and olivetolic acid (Zirpel et al 2017), demonstrating the viability of NphB as a biocatalyst in the production of (Murray et al 2018). b Known substrates of NphB.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Acceptor substrate determines donor specificity of an aromatic prenyltransferase: expanding the biocatalytic potential of NphB

Johnson

Scull

Dimas

et al. 2020

Appl Microbiol Biotechnol

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Aromatic prenyltransferases are known for their extensive promiscuity toward aromatic acceptor substrates and their ability to form various carbon-carbon and carbon-heteroatom bonds. Of particular interest among the prenyltransferases is NphB, whose ability to geranylate cannabinoid precursors has been utilized in several in vivo and in vitro systems. It has therefore been established that prenyltransferases can be utilized as biocatalysts for the generation of useful compounds. However, recent observations of non-native alkyl-donor promiscuity among prenyltransferases indicate the role of NphB in biocatalysis could be expanded beyond geranylation reactions. Therefore, the goal of this study was to elucidate the donor promiscuity of NphB using different acceptor substrates. Herein, we report distinct donor profiles between NphB-catalyzed reactions involving the known substrate 1,6-dihydroxynaphthalene and an FDA-approved drug molecule sulfabenzamide. Furthermore, we report the first instance of regiospecific, NphB-catalyzed N-alkylation of sulfabenzamide using a library of non-native alkyl-donors, indicating the biocatalytic potential of NphB as a late-stage diversification tool. Key Points • NphB can utilize the antibacterial drug sulfabenzamide as an acceptor. • The donor profile of NphB changes dramatically with the choice of acceptor. • NphB performs a previously unknown regiospecific N-alkylation on sulfabenzamide. • Prenyltransferases like NphB can be utilized as drug-alkylating biocatalysts.

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“…George et al., reported a biosynthetic pathway for the total synthesis of marinone and iso ‐marinone natural products 246 from a tetralone based α,α‐dichloroketone 247 (Scheme C). The dichloroketone 247 was converted to a α‐hydroxyketone 248 through thermal rearrangement after heating.…”

Section: The Gem‐dihaloketones In the Synthesis Of Heterocyclic Framementioning

confidence: 99%

The α,α‐Dihalocarbonyl Building Blocks: An Avenue for New Reaction Development in Organic Synthesis

Sadhukhan

Santhi

Baire

2020

Chemistry A European J

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The α,α‐dihalocarbonyl moiety is a bifunctional system with a gem‐dihalocarbon and a carbonyl carbon in 1,2‐fashion. This is one of the privileged scaffolds in medicinal chemistry due to its chemical and metabolic stability and lipophilicity. They have also been found in numerous structurally divergent natural products and most of their fabricated structures have already been in medicinal use. Apart from their important use in medicinal chemistry, the α,α‐dihalocarbonyl groups have been employed as key building blocks for the development of novel synthetic strategies and utilized as intermediates in total synthesis. In addition to the traditional transformations such as oxidations, reductions, and C−C bond formations, recently several new and non‐classical reactions have also been developed. This review provides short description of existing methods for their synthesis and detailed discussion on the efforts for the discovery and development of new reactions by employing α,α‐dihaloketones as synthetic building blocks. We have presented their use as key functional groups for the synthesis of polycyclic systems of medicinal and material importance and natural products.

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Total Synthesis Establishes the Biosynthetic Pathway to the Naphterpin and Marinone Natural Products

Cited by 46 publications

References 52 publications

Halogenases for biosynthetic pathway engineering: Toward new routes to naturals and non-naturals

Halogenases for biosynthetic pathway engineering: Toward new routes to naturals and non-naturals

Acceptor substrate determines donor specificity of an aromatic prenyltransferase: expanding the biocatalytic potential of NphB

The α,α‐Dihalocarbonyl Building Blocks: An Avenue for New Reaction Development in Organic Synthesis

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