Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

International audienceTerpene compounds probably represent the most diversified class of secondary metabolites. Some classes of terpenes, mainly diter-penes (C20) and sesterterpenes (C25) and to a lesser extent sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki-Hiyama-Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson-Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddi-tion and biocatalysis

Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines

International audienceFunction-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification

Pd-Catalysed Coupling Reactions: (Z)-Vinyl (N,N-Diisopropyl)Carbamate Group as an Efficient Precursor of a (Z)-Vinyl triflate Function

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Preparation of the Three C1-C7, C8-C15, and C16-N22 Fragments of the Hsp90 Inhibitor Herbimycin A

International audienceThe construction of the three C16-N22 2, C1-C7 6 (as 23) and C8-C15 5 (as 32) segments of the Hsp90 inhibitor herbimycin A (1) is reported. 1-Iodo-3-nitro-2,5-diphenol compound 2 was obtained in 55% yield for 3 steps from the commercially available diiodo derivative 7. Reaction between 1,1-dibromo-alkene 22 and vinyltin 17a using Pd(PPh3)4 or Pd(CH3CN)2Cl2/CuI/diisopropylethylamine, in toluene or DMF at 85 °C, led to enyne 23 in 63% yield (19% overall yield from isopropylidene glyceraldehyde). The synthesis of the C8-C15 sub-unit 32 was performed in 3.4% overall yield for 13 steps, from the commercially available ester 24, with a Hoppe crotylation as a key step

α-Oxygenated Crotyltitanium and Dyotropic Rearrangement in the Total Synthesis of Discodermolide

International audienceThe total synthesis of discodermolide relies on the elaboration of syn–anti stereotriads linked to a Z-O-enecarbamate group, its direct transformation into the terminal Z diene, and stereocontrolled generation of the trisubstituted Z double bond by a dyotropic rearrangement (see scheme; OCb=N,N-diisopropylcarbamoyloxy). The synthesis was achieved in 21 steps with 1.6 % overall yield

Progress on PPAPs cyclization: Guttiferone A as a case study

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Functional characterization of the GATA-type transcription factor PaNsdD in the filamentous fungus Podospora anserina and its interplay with the sterigmatocystin pathway

International audienceThe model ascomycete Podospora anserina, featured by its strict sexual development, is a prolific but yet unexploited reservoir of natural products. The GATA-type transcription factor NsdD has been characterized by the role in balancing asexual and sexual reproduction, and governing secondary metabolism in filamentous fungi. In the present study, we functionally investigated the NsdD ortholog PaNsdD in P. anserina. Compared to the wild-type strain, vegetative growth, ageing processes, sexual reproduction, stress tolerance and interspecific confrontations in the mutant were drastically impaired, owing to the loss of function of PaNsdD. In addition, the production of 3-acetyl-4-methylpyrrole, a new metabolite identified in P. anserina in this study, was significantly inhibited in the ΔPaNsdD mutant. We also demonstrated the interplay of PaNsdD with the sterigmatocystin biosynthetic gene pathway, especially as the deletion of PaNsdD triggered the enhanced red-pink pigment biosynthesis that only occurs in the presence of the core polyketide synthase-encoding gene PaStcA of the sterigmatocystin pathway. Taken together, these results contribute to a better understanding of the global regulation mediated by PaNsdD in P. anserina, especially with regard to its unexpected involvement in fungal ageing process and its interplay with sterigmatocystin pathway. Importance Fungal transcription factors play an essential role in coordinating multiple physiological processes. Yet, little is known about the functional characterization of transcription factors in the filamentous fungus P. anserina. In this study, a GATA-type regulator PaNsdD was investigated in P. anserina. The results showed that PaNsdD was a key factor that can control the fungal ageing process, vegetative growth, pigmentation, stress response, interspecific confrontations, and positively regulate the production of 3-acetyl-4-methylpyrrole. Meanwhile, a molecular interaction was implied between PaNsdD and the sterigmatocystin pathway. Overall, loss of function of PaNsdD seems to be highly disadvantageous for P. anserina, which relies on pure sexual reproduction in limited lifespan. Therefore, PaNsdD is clearly indispensable for the survival and propagation of P. anserina in its complex ecological niches

Complementary Strategies to Unlock Biosynthesis Gene Clusters Encoding Secondary Metabolites in the Filamentous Fungus <i>Podospora anserina</i>

The coprophilous ascomycete Podospora anserina is known to have a high potential to synthesize a wide array of secondary metabolites (SMs). However, to date, the characterization of SMs in this species, as in other filamentous fungal species, is far less than expected by the functional prediction through genome mining, likely due to the inactivity of most SMs biosynthesis gene clusters (BGCs) under standard conditions. In this work, our main objective was to compare the global strategies usually used to deregulate SM gene clusters in P. anserina, including the variation of culture conditions and the modification of the chromatin state either by genetic manipulation or by chemical treatment, and to show the complementarity of the approaches between them. In this way, we showed that the metabolomics-driven comparative analysis unveils the unexpected diversity of metabolic changes in P. anserina and that the integrated strategies have a mutual complementary effect on the expression of the fungal metabolome. Then, our results demonstrate that metabolite production is significantly influenced by varied cultivation states and epigenetic modifications. We believe that the strategy described in this study will facilitate the discovery of fungal metabolites of interest and will improve the ability to prioritize the production of specific fungal SMs with an optimized treatment

Complementary Strategies to Unlock Biosynthesis Gene Clusters Encoding Secondary Metabolites in the Filamentous Fungus Podospora anserina

International audienceThe coprophilous ascomycete Podospora anserina is known to have a high potential to synthesize a wide array of secondary metabolites (SMs). However, to date, the characterization of SMs in this species, as in other filamentous fungal species, is far less than expected by the functional prediction through genome mining, likely due to the inactivity of most SMs biosynthesis gene clusters (BGCs) under standard conditions. In this work, our main objective was to compare the global strategies usually used to deregulate SM gene clusters in P. anserina, including the variation of culture conditions and the modification of the chromatin state either by genetic manipulation or by chemical treatment, and to show the complementarity of the approaches between them. In this way, we showed that the metabolomics-driven comparative analysis unveils the unexpected diversity of metabolic changes in P. anserina and that the integrated strategies have a mutual complementary effect on the expression of the fungal metabolome. Then, our results demonstrate that metabolite production is significantly influenced by varied cultivation states and epigenetic modifications. We believe that the strategy described in this study will facilitate the discovery of fungal metabolites of interest and will improve the ability to prioritize the production of specific fungal SMs with an optimized treatment

Total Synthesis of Discodermolide: Optimization of the Effective Synthetic Route

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