Synthesis of Secosterols as an Arena for C–H Functionalization and C–C Manipulation Tactics

Synlett ◽  
2017 ◽  
Vol 28 (10) ◽  
pp. 1127-1133 ◽  
Author(s):  
Philipp Heretsch ◽  
Robert Heinze
Keyword(s):  
Natural Products ◽  
Chemical Synthesis ◽  
Current Literature ◽  
Ring Expansion ◽  
Biosynthetic Pathways ◽  
Radical Ring ◽  
Synthetic Intermediates ◽  
Synthetic Work ◽  
Shed Light

The chemical synthesis of secosterols is an arena for the application of C–H functionalization methods as well as C–C manipulations. Studies on the innate reactivity of synthetic intermediates to undergo C–C scissions and rearrangements can shed light on biosynthetic pathways, or, provide proof for biosynthetic proposals. Examples of the authors work (synthesis of the 14,15-secosterol strophasterol A), as well as examples from current literature (Tian’s synthetic work on 13,14:14,15-disecosterols glaucogenins C and D, and Baran’s synthesis of 9,10-secosterol cortistatin A) are discussed.1 Introduction2 The Synthesis of Strophasterol A Employing the Concept of Innate Reactivity3 Synthetic Work in the Glaucogenin Family of Natural Products4 The Synthesis of Cortistatin A Using a Radical Ring Expansion5 Conclusion

scholarly journals Unified Total Synthesis of the Brevianamide Alkaloids Enabled by Chemical Investigations into their Biosynthesis.

2021 ◽  
Author(s):  
Robert C. Godfrey ◽  
Helen E. Jones ◽  
Nicholas J. Green ◽  
Andrew L. Lawrence
Keyword(s):  
Natural Products ◽  
Chemical Synthesis ◽  
Total Synthesis ◽  
Scientific Community ◽  
Biological Activities ◽  
Focus Of Attention ◽  
Complex Structures ◽  
Biosynthetic Pathways ◽  
Synthetic Strategy ◽  
Synthetic Studies

The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad range of biological activities, their diverse biosynthetic origins, and their topologically complex structures, which combined make them enticing targets for chemical synthesis. In this article, full details of our synthetic studies into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family of bicyclo[2.2.2]diazaoctane alkaloids are disclosed. Insights into issues of reactivity and selectivity in the biosynthesis of these structures have aided the development of a unified biomimetic synthetic strategy, which has resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides and the anticipation of an as-yet-undiscovered congener.

Copper Catalyzed sp3 C-H α-Acetylation

2019 ◽  
Author(s):  
Otome Okoromoba ◽  
Eun Sil Jang ◽  
Claire McMullin ◽  
Thomas Cundari ◽  
Timothy H. Warren
Keyword(s):  
Natural Products ◽  
Dft Studies ◽  
Alkyl Radicals ◽  
Important Chemical ◽  
Alkyl Electrophiles ◽  
Synthetic Intermediates ◽  
Alkylation Reactions

<p>α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the sp<sup>3</sup> C-H α-acetylation of sp<sup>3</sup> C-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH<sub>2</sub>R at RT with <sup>t</sup>BuOO<sup>t</sup>Bu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu<sup>II</sup>](CH<sub>2</sub>C(O)Ar) that capture alkyl radicals R• to give R-CH<sub>2</sub>C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH<sub>2</sub>CH<sub>2</sub>C(O)Ar.</p>

Copper Catalyzed sp3 C-H α-Acetylation

2019 ◽  
Author(s):  
Otome Okoromoba ◽  
Eun Sil Jang ◽  
Claire McMullin ◽  
Thomas Cundari ◽  
Timothy H. Warren
Keyword(s):  
Natural Products ◽  
Dft Studies ◽  
Alkyl Radicals ◽  
Important Chemical ◽  
Alkyl Electrophiles ◽  
Synthetic Intermediates ◽  
Alkylation Reactions

<p>α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the sp<sup>3</sup> C-H α-acetylation of sp<sup>3</sup> C-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH<sub>2</sub>R at RT with <sup>t</sup>BuOO<sup>t</sup>Bu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu<sup>II</sup>](CH<sub>2</sub>C(O)Ar) that capture alkyl radicals R• to give R-CH<sub>2</sub>C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH<sub>2</sub>CH<sub>2</sub>C(O)Ar.</p>

scholarly journals Nephromyces represents a diverse and novel lineage of the Apicomplexa that has retained apicoplasts

2019 ◽  
Author(s):  
Sergio A Muñoz-Gómez ◽  
Keira Durnin ◽  
Laura Eme ◽  
Christopher Paight ◽  
Christopher E Lane ◽  
...  
Keyword(s):  
Life Style ◽  
Metabolic Pathways ◽  
Evolutionary History ◽  
Phylogenetic Analyses ◽  
Phylogenetic Position ◽  
Biosynthetic Pathways ◽  
History Of ◽  
Sea Squirts ◽  
Shed Light ◽  
Apicoplast Genome

Abstract A most interesting exception within the parasitic Apicomplexa is Nephromyces, an extracellular, probably mutualistic, endosymbiont found living inside molgulid ascidian tunicates (i.e., sea squirts). Even though Nephromyces is now known to be an apicomplexan, many other questions about its nature remain unanswered. To gain further insights into the biology and evolutionary history of this unusual apicomplexan, we aimed to (1) find the precise phylogenetic position of Nephromyces within the Apicomplexa, (2) search for the apicoplast genome of Nephromyces, and (3) infer the major metabolic pathways in the apicoplast of Nephromyces. To do this, we sequenced a metagenome and a metatranscriptome from the molgulid renal sac, the specialized habitat where Nephromyces thrives. Our phylogenetic analyses of conserved nucleus-encoded genes robustly suggest that Nephromyces is a novel lineage sister to the Hematozoa, which comprises both the Haemosporidia (e.g., Plasmodium) and the Piroplasmida (e.g., Babesia and Theileria). Furthermore, a survey of the renal sac metagenome revealed 13 small contigs that closely resemble the genomes of the non-photosynthetic reduced plastids, or apicoplasts, of other apicomplexans. We show that these apicoplast genomes correspond to a diverse set of most closely related but genetically divergent Nephromyces lineages that co-inhabit a single tunicate host. In addition, the apicoplast of Nephromyces appears to have retained all biosynthetic pathways inferred to have been ancestral to parasitic apicomplexans. Our results shed light on the evolutionary history of the only probably mutualistic apicomplexan known, Nephromyces, and provide context for a better understanding of its life style and intricate symbiosis.

scholarly journals Discovery and Biosynthesis of Natural Products from New Zealand Soil Metagenome Libraries

2021 ◽  
Author(s):  
◽  
Luke Stevenson
Keyword(s):  
Natural Products ◽  
New Zealand ◽  
Heterologous Expression ◽  
Gene Clusters ◽  
Bioinformatic Analysis ◽  
Coli Strain ◽  
Functional Screening ◽  
Functional Difference ◽  
Biosynthetic Pathways ◽  
New Members

<p>Antibiotic discovery rates dramatically declined following the “golden age” of the 1940’s to the 1960’s. The platforms that underpinned that age of discovery rested upon laboratory cultivation of a small clade of bacteria, the actinomycetes, primarily isolated from soil environments. Fermentation extracts of these isolated bacteria have provided the majority of antibiotics and anticancer small molecules still used today. By applying modern genetic analysis techniques to these same environmental sources that have previously yielded such success, we can uncover new biosynthetic pathways, and bioactive compounds. The work described in this thesis investigated New Zealand soil metagenomes for this purpose.  Four large metagenome libraries were constructed from the microbiomes of diverse soil environments. These were then interrogated by a functional screening approach in a knockout Escherichia coli strain, to recover a large collection of the biosynthetic gene clusters responsible for bacterial secondary metabolite production. Using different modes of bioinformatic analysis, these gene clusters were demonstrated to have both phylogenetic divergence, and functional difference from bacterial biosynthesis pathways previously discovered from culture based studies.  Two additional biosynthetic pathways were recovered from one of these metagenome libraries, and in each case found to have novel genetic features. These gene clusters were further studied by heterologous expression within Streptomyces albus production hosts. One of these gene clusters produced small aromatic polyketide compounds, the structure of one of which was solved by chemical analytic techniques, and found to be a new chemical entity.  The second gene cluster was demonstrated to have similarity to known aureolic acid biosynthesis gene clusters – a class of potent anticancer natural products. Heterologous expression resulted in the production of many metabolites, two of which were characterised and found to be new members of this chemical class.  The research in this thesis both validates the use of metagenomic analysis for future natural product discovery efforts, and adds to a growing body of evidence that understudied clades of bacteria have an untapped biosynthetic potential that can be accessed by metagenomic methods.</p>

Natural Products as an Inspiration for the Discovery of New High-Throughput Chemical Synthesis Tools

2006 ◽  
pp. 51-89 ◽  
Author(s):  
Steven V. Ley ◽  
Ian R. Baxendale ◽  
Deborah A. Longbottom ◽  
Rebecca M. Myers
Keyword(s):  
Natural Products ◽  
Chemical Synthesis ◽  
High Throughput

scholarly journals Unlocking Fungal Cryptic Natural Products

2009 ◽  
Vol 4 (11) ◽  
pp. 1934578X0900401 ◽  
Author(s):  
Yi-Ming Chiang ◽  
Kuan-Han Lee ◽  
James F. Sanchez ◽  
Nancy P. Keller ◽  
Clay C. C. Wang
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Analytical Methods ◽  
State Of The Art ◽  
Molecular Genetic ◽  
Biosynthetic Pathways ◽  
Fungal Metabolites ◽  
Potential Sources ◽  
Fungal Genomes

Recent published sequencing of fungal genomes has revealed that these microorganisms have a surprisingly large number of secondary metabolite pathways that can serve as potential sources for new and useful natural products. Most of the secondary metabolites and their biosynthesis pathways are currently unknown, possibly because they are produced in very small amounts and are thus difficult to detect or are produced only under specific conditions. Elucidating these fungal metabolites will require new molecular genetic tools, better understanding of the regulation of secondary metabolism, and state of the art analytical methods. This review describes recent strategies to mine the cryptic natural products and their biosynthetic pathways in fungi.

Biosynthesis of bioactive natural products from Basidiomycota

2019 ◽  
Vol 17 (5) ◽  
pp. 1027-1036 ◽  
Author(s):  
Hsiao-Ching Lin ◽  
Ranuka T. Hewage ◽  
Yuan-Chun Lu ◽  
Yit-Heng Chooi
Keyword(s):  
Natural Products ◽  
Bioactive Compounds ◽  
Biosynthetic Pathways ◽  
Bioactive Natural Products ◽  
Wide Range

The club fungi, Basidioycota, produce a wide range of bioactive compounds. Here, we describe recent studies on the biosynthetic pathways and enzymes of bioactive natural products from these fungi.

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