Gold(I)‐Catalyzed Tandem Cycloisomerization and Fluorination of 1,3(4)‐Enyne Esters with NFSI: One‐Pot Assembly of 5‐Fluoro‐ Cyclopentenones

Zhou, Yuanyuan; Liu, Yuan; Yin, Dongliang; Wang, Shifa; Zhang, Xiaoxiang; Rao, Weidong

doi:10.1002/adsc.201800701

Cited by 17 publications

(13 citation statements)

References 89 publications

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“…At the same time, with an understanding that the prefunctionalization pathway was necessary, we explored the possibility of intercepting the intermediate enol pivalate 60 of the Rautenstrauch rearrangement with reactive electrophiles such that enone α-functionalization could be performed simultaneously with the cycloisomerization (Figure ). In the absence of the protic additive previously used for hydrolysis, we found several electrophilic halogenating reagents capable of installing fluorine, chlorine, bromine, and iodine with concomitant cyclization. Selectfluor in a mixture of dichloromethane and acetonitrile was found optimal given its superior yieldshigher than those even with protonationas well as the stability of the downstream α-fluoro tosylhydrazone 61 as compared with the other halogens.…”

Section: Resultsmentioning

confidence: 99%

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques

et al. 2021

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The isomalabaricanes comprise a large family of marine triterpenoids with fascinating structures that have been shown to be selective and potent apoptosis inducers in certain cancer cell lines. In this article, we describe the successful total syntheses of the isomalabaricanes stelletin A, stelletin E, and rhabdastrellic acid A, as well as the development of a general strategy to access other natural products within this unique family. High-throughput experimentation and computational chemistry methods were used in this endeavor. A preliminary structure−activity relationship study of stelletin A revealed the trans-syn-trans core motif of the isomalabaricanes to be critical for their cytotoxic activity.

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Section: Resultsmentioning

confidence: 99%

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques

et al. 2021

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“…[ 51 ] Following this concept, Rao and co‐workers developed the merging gold‐ catalyzed cycloisomerization of 1,3‐enyne acetates with electrophilic halogenation towards halogenated cyclopentenones. [ 52‐53 ] Inspired by these impressive studies and as part of ongoing efforts in developing enyne transformations, [ 54‐58 ] we envisaged that the in‐situ ‐generated cyclopentadiene intermediates from 1,3‐enyne acetates 1 might be intercepted by allylic alcohols to afford allylated cyclopentenones through gold self‐relay catalysis. Herein, we elaborate a conceptually new gold self‐relay catalysis involving Nazarov cyclization and allylic alkylation cascade that provides an expedient and regioselective access to allylated cyclopentenones bearing an all‐carbon stereocenter from simple and readily available 1,3‐enyne acetates and allylic alcohols in a one‐pot manner (Scheme 1b).…”

Section: Background and Originality Contentmentioning

confidence: 99%

Gold Self‐Relay Catalysis Enabling [3,3]‐Sigmatropic Rearrangement/Nazarov Cyclization and Allylic Alkylation Cascade for Constructing All‐Carbon Quaternary Stereocenters

Meng

Qin

et al. 2022

Chin. J. Chem.

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Molecular scaffolds endowed with all-carbon quaternary stereocenter are ubiquitous in natural products and significant bioactive molecules. However, efficient construction of this type of structure units is full of challenge due to their congested chemical environment. Herein, we report a new gold(I) self-relay catalysis merging [3,3]-sigmatropic rearrangement/Nazarov cyclization with allylic alkylation starting from 1,3-enyne acetates and allylic alcohols, producing a wide range of synthetically important allyl cyclopentenones with an all-carbon quaternary stereocenter in good yields under mild conditions. This protocol demonstrates the precise control of regioselectivity, high functional group tolerance of substrates and the low loading of gold catalyst without inert atmosphere protection, providing a catalytic and efficient entry to all-carbon quaternary stereocenters

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“…Leveraging these two principles, we developed efficient tandem reactions to bring in α-halo functionality during the cycloisomerization and replace it with the needed ethereal group during the reductive transposition. Exposure of enyne 57 to the gold(I) catalyst in the presence of Selectfluor closed down the C-ring and forged the critical C−F bond next to the ketone; 34 this intermediate was then converted to the corresponding ptoluenesulfonylhydrazone 80a for convenient purification. Notably, the yield of this fluorinative Rautenstrauch rearrangement was even higher than that with protic additives, and the diastereoselectivity was excellent.…”

Section: Isomalabaricanes: Total Synthesis Of Rhabdastrellic Acid a A...mentioning

confidence: 99%

Total Synthesis of Stelletins through an Unconventional Annulation Strategy

2021

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Conspectus Marine ecosystems present the largest source of biodiversity on the planet and an immense reservoir of novel chemical entities. Sessile marine organisms such as sponges produce a wide range of complex secondary metabolites, many of these with potent biological activity engineered for chemical defense. That such compounds exert dynamic effects outside of their native context is perhaps not surprising, and the realm of marine natural products has attracted considerable attention as a largely untapped repository of potential candidates for drug development. Only a handful of the more than 15 000 marine natural products that have been isolated to date have advanced to the clinic, and more are to be expected. The rich chemical information encoded in the intricate three-dimensional structures of many marine natural products facilitates highly discriminating interactions with cell signaling pathways, and especially within cancer cells such nuanced effects offer an exciting opportunity for the development of targeted therapies that lack the side effects and general toxicity of conventional chemotherapeutics. The isomalabaricanes are a rare class of marine triterpenoids that have been hailed as promising cytotoxic lead compounds for the treatment of cancer, and they have attracted a flurry of excitement from researchers because of their potent cytotoxicity in certain human cancer cell lines along with a range of other antineoplastic effects. Most notably, their inhibitory activity is highly cell-selective, characterized by large deviations from their mean GI50 concentrations across 3 orders of magnitude in the NCI-60 Human Tumor Cell Lines screen, suggesting mechanistic specificity rather than general and unbridled toxicity. Despite these auspicious preliminary reports, the isomalabaricane scaffold remains largely unexplored as a potential anticancer lead because of lack of material. This Account describes our recent efforts to develop a general, modular synthesis of the isomalabaricanes, as exemplified by the successful total syntheses of rhabdastrellic acid A, stelletin E, and stelletin A. The unorthodox trans-syn-trans configuration of their perhydrobenz[e]indene core severely circumscribes the synthetic methods available for its construction and required several generations of strategy to assemble. Ultimately, a series of unconventional transformations were identified that were capable of building this highly strained motif, and the syntheses of rhabdastrellic acid A and stelletin E were completed in racemic fashion. Subsequently, a second-generation approach to these natural products was developed, rendering the synthesis enantioselective as well as providing access to stelletin A. These synthetic efforts were greatly assisted by computational techniques such as 13C NMR prediction, which enabled structural assignments of hydrocarbon diastereomers, as well as relaxed surface scan conformational analysis, which informed a campaign for directed hydrogenation of an alkene. High-throughput experimentation met...

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Gold(I)‐Catalyzed Tandem Cycloisomerization and Fluorination of 1,3(4)‐Enyne Esters with NFSI: One‐Pot Assembly of 5‐Fluoro‐ Cyclopentenones

Cited by 17 publications

References 89 publications

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques

Gold Self‐Relay Catalysis Enabling [3,3]‐Sigmatropic Rearrangement/Nazarov Cyclization and Allylic Alkylation Cascade for Constructing All‐Carbon Quaternary Stereocenters

Total Synthesis of Stelletins through an Unconventional Annulation Strategy

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