Total Synthesis of the Hamigerans

Li, Xiaojun; Xue, Dongsheng; Wang, Cheng; Gao, Shuanhu

doi:10.1002/anie.201604070

Cited by 31 publications

(33 citation statements)

References 47 publications

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“…While a combination of Pd(OAc) 2 and dppb ligand could afford the product in moderate yield (entry 7), a large scale synthesis was problematic owing to an elongated reaction time, leading to partial hydrolysis of 15a . To compare with the prior literature 27 – 31 , the low coupling efficiency is probably due to the excessively congested structure of 15a with the additional presence of a bulky OTBS. To overcome this obstacle, we turned to examine the catalytic efficiency of phosphinamide-derived palladacycle 18 , which was developed in our previous studies toward synthesizing P-stereogenic compounds through C–H arylation of phosphinamide 32 , 33 and exhibited excellent catalytic activity for Suzuki cross-coupling of aryl (pseudo)halides under mild conditions 34 .…”

Section: Resultsmentioning

confidence: 87%

“…The Suzuki-Miyaura cross-coupling involving sterically congested nonactivated enolate substrates was relatively rare. Initial scouting of the conditions for coupling triflate 15a with 16a was carried out by examining an array of conditions reported in literature 27 – 31 (Table 1 ). Unfortunately, most of the reactions were less effective, affording the coupled product 17a in low yields (entries 1−6).…”

Section: Resultsmentioning

confidence: 99%

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Total synthesis of cyrneines A–B and glaucopine C

Zhang

Tan

et al. 2018

Nat Commun

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The cyrneine diterpenoids represent a structurally intriguing subfamily of cyathane diterpenoids and could significantly induce neurite outgrowth. Therefore, the efficient synthesis of these natural products is of great importance. Herein, we present a route for the collective synthesis of cyrneines A, B, and glaucopine C. As the key precursor, the 5-6-6-tricyclic scaffold is efficiently constructed by employing a mild Suzuki coupling of heavily substituted nonactivated cyclopentenyl triflate and a chelation-controlled regiospecific Friedel-Crafts cyclization as key transformations. The stereoselective installation of the all-carbon quaternary center at C6 ring junction of the tricycle is achieved via Birch reductive methylation. Subsequently, a carbenoid-mediated ring expansion furnishes the essential 5-6-7-tricyclic core. Finally, manipulation of this core by several appropriately orchestrated conversions accomplishes a more step-economic synthesis of cyrneine A (20 steps), and the first synthesis of cyrneine B (24 steps) and glaucopine C (23 steps).

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Total synthesis of cyrneines A–B and glaucopine C

Zhang

Tan

et al. 2018

Nat Commun

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“…Very recently, our group discovered a series of novel natural cyathane diterpenoids with neurotrophic and anti-neuroinflammatory effects from higher basidiomycetes such as Cyathus africanus, Sarcodon scabrosus [20,21], such as sarcodonin G (3), striatoid B (4), cyafricanin C (5), and allocyathin B2 (6). The two small families of natural products have aroused considerable interest from the research communities of natural products, pharmacology, and synthetic chemistry because of their unique structures with intriguing biological potential [22][23][24][25]. Many synthetic endeavors have been devoted to the synthesis of hamigeran B (2), and our group achieved the total synthesis of hamigeran B in 2018 [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators

Han

et al. 2020

Marine Drugs

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We describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs (23 new members in all), structurally related to cyathane diterpenoid scaffold, and their anti-neuroinflammatory and neurite outgrowth-stimulating (neurotrophic) activity. Compounds 9a, 9h, 9o, and 9q exhibited moderate nerve growth factor (NGF)-mediated neurite-outgrowth promoting effects in PC-12 cells at the concentration of 20 μm. Compounds 9b, 9c, 9o, 9q, and 9t showed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, of which 9c and 9q were the most potent inhibitors, with IC50 values of 5.85 and 6.31 μm, respectively. Two derivatives 9q and 9o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers. Cytotoxicity experiments, H2O2-induced oxidative injury assay, and ELISA reaction speculated that compounds may inhibit the TNF-α pathway to achieve anti-inflammatory effects on nerve cells. Moreover, molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives (like 9c, 9q) with the active site of iNOS protein. The structure-activity relationships (SARs) were also discussed. These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.

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“…This dearth in syntheses is presumably due to the relative scarcity of methods for the synthesis of seven-membered rings as compared to their six-membered counterparts. Hamigeran D has been synthesized recently by Gao and coworkers via a biomimetic skeletal rearrangement from a 6-6-5 tricycle, 15 and thus our strategy of directly targeting the seven-membered ring structure remains unique ( vide infra ).…”

Section: Introductionmentioning

confidence: 99%

Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core

2017

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The hamigeran family of natural products has been the target of numerous synthetic efforts due to its biological activity and interesting structural properties. Herein we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members due to their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products.

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Total Synthesis of the Hamigerans

Cited by 31 publications

References 47 publications

Total synthesis of cyrneines A–B and glaucopine C

Total synthesis of cyrneines A–B and glaucopine C

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators

Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core

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