Protecting-Group-Free Syntheses of <i>ent</i>-Kaurane Diterpenoids: [3+2+1] Cycloaddition/Cycloalkenylation Approach

Wang, Jin; Hong, Bo; Hu, Dachao; Kadonaga, Yuichiro; Tang, Ruyao; Lei, Xiaoguang

doi:10.1021/jacs.9b13722

Cited by 39 publications

(12 citation statements)

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“…Consequently, we planned to elaborate the required tetracyclic intermediate 10 through a stereoselective intramolecular Michael addition of the ketone 11 , which could in turn be provided by a Cu-mediated conjugate addition of enones 12 and iodide 13 . Encouraged by our synthetic experience with ent -kaurane diterpenoids, the bicyclo[3.2.1]octane motif 13 would be assembled using Toyota’s Pd-catalyzed cycloalkenylation of a silyl enol ether generated from olefin 14 . The quaternary stereocenter of enone 14 could be built through Stoltz’s Pd-catalyzed decarboxylative allylation reaction of β-keto ester 15 , which could be further derived from the two simple compounds 16 and 17 via an asymmetric S N 2 process.…”

Section: Resultsmentioning

confidence: 99%

Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (−)-Napelline, (+)-Dehydronapelline, (−)-Songorine, (−)-Songoramine, (−)-Acoapetaldine D, and (−)-Liangshanone

Jin

Zhao

2022

J. Am. Chem. Soc.

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The napelline-type alkaloids possess an azabicyclo[3.2.1]octane moiety and an ent-kaurane-type tetracyclic skeleton (6/6/6/5) along with varied oxidation patterns embedded in the compact hexacyclic framework. Herein, we disclose a divergent entry to napelline-type alkaloids that hinges on convergent assembly of the ent-kaurane core using a diastereoselective intermolecular Cu-mediated conjugate addition and subsequent intramolecular Michael addition reaction as well as rapid construction of the azabicyclo[3.2.1]octane motif via an intramolecular Mannich cyclization. The power of this strategy has been demonstrated through efficient asymmetric total syntheses of eight napelline-type alkaloids, including (−)-napelline, (−)-12-epi-napelline, (+)-dehydronapelline, (+)-12-epi-dehydronapelline, (−)-songorine, (−)-songoramine, (−)-acoapetaldine D, and (−)-liangshanone.

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Section: Resultsmentioning

confidence: 99%

Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (−)-Napelline, (+)-Dehydronapelline, (−)-Songorine, (−)-Songoramine, (−)-Acoapetaldine D, and (−)-Liangshanone

Jin

Zhao

2022

J. Am. Chem. Soc.

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“…More recently, the same strategy was used by the same group in the protecting-group-free total synthesis of entkaurane diterpenoids such as 35 (Scheme 8, b). 56 These three examples demonstrate that the advantages of the conjugate addition methodology employing organozirconium nucleophiles are being recognized by the broader synthetic community. It was also shown that it was possible to tackle several synthetic challenges arising from the use of conventional organometallics.…”

Section: Scheme 7 Synthesis Of Fulvestrant (30)mentioning

confidence: 94%

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

Némethová

Šebesta

2020

Synthesis

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The search for mild, user-friendly, easily accessible, and robust organometallic reagents is an important feature of organometallic chemistry. Ideally, new methodologies employing organometallics should be developed with respect to practical applications in syntheses of target compounds. In this short review, we investigate if organozirconium reagents can fulfill these criteria. Organozirconium compounds are typically generated via in situ hydrozirconation of alkenes or alkynes with the Schwartz reagent. Alkyl and alkenylzirconium reagents have proven to be convenient in conjugate additions, allylic substitutions, cross-coupling reactions, and additions to carbonyls or imines. Furthermore, the Schwartz reagent itself is a useful reducing agent for polar functional groups.1 Introduction2 Synthesis and Generation of the Schwartz Reagent3 Structure and Properties of Cp2Zr(H)Cl4 Reactivity of Organozirconium Reagents4.1 Asymmetric Conjugate Addition4.2 Asymmetric Allylic Alkylations4.3 Desymmetrization Reactions4.4 Cross-Coupling Reactions4.5 1,2-Additions5 Conclusions

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“…Following previous discussions, we will showcase how sequential C–H functionalizations, radical-based transformations, and a functional group pairing strategy can contribute to our total synthesis of polysubstituted aromatics ( 1 – 4 , Figure ), , ent -kaurane diterpenoids ( 5 – 13 , Figure ), ,, and Lycopodium alkaloids ( 14 – 17 , Figure ), respectively. More importantly, our total synthesis acts as the driving force for the discovery of bioactive compounds as well as a deep understanding of their mechanism of action (MOA).…”

Section: Introductionmentioning

confidence: 90%

“…Since then, the synthesis of an assortment of biologically active ent -kauranes as well as their biological evaluations have been reported by our laboratory (Figure ). ,, …”

Section: Total Syntheses Of Ent-kaurane Diterpenoids Through Radical ...mentioning

confidence: 99%

New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products

et al. 2020

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Metrics & MoreArticle Recommendations CONSPECTUS: Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C−H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors.During the last two decades, a series of remarkable advances in C−H functionalization have led to the emergence of many new approaches to directly functionalize C−H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step-and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C−H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C−H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.Recently, we have also completed the total syntheses for a number of skeletally diverse tetracyclic Isodon diterpenoids inspired by their biogenesis and radical-based retrosynthetic disconnections. Radical transformations are strategically and tactically utilized in our syntheses, and radical-based reactions, including organo-SOMO catalysis, Birch reduction, regioselective 1,6-dienyne reductive cyclization, visible-light-mediated Schenck ene reaction, and photoradical-mediated late-stage skeletal rearrangement, play significant roles in our synthetic endeavors. Protecting-group-free and scalable syntheses are also built into our work to achieve the "ideal" synthesis. Furthermore, our synthetic work reveals that late-stage skeletal rearrangement through a photo radical process is possible in a biological setting in complement with nature's carbocation chemistry in complex natural product biosynthesis.Lycopodium alkaloids are a large family of structurally unique polycyclic natural products with impressive biological activities. Owing to their fascinating polycyclic architectures and diverse biological activities, these alkaloids have continued to serve as targets as well as inspirations for the synthetic community for decades. To access these bioactive natural products or natural product-like molecules for biological exploration and drug discovery, we applied a novel functional ...

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Protecting-Group-Free Syntheses of ent-Kaurane Diterpenoids: [3+2+1] Cycloaddition/Cycloalkenylation Approach

Cited by 39 publications

References 75 publications

Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (−)-Napelline, (+)-Dehydronapelline, (−)-Songorine, (−)-Songoramine, (−)-Acoapetaldine D, and (−)-Liangshanone

Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (−)-Napelline, (+)-Dehydronapelline, (−)-Songorine, (−)-Songoramine, (−)-Acoapetaldine D, and (−)-Liangshanone

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products

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