Synthesis of the Taxol Core via Catalytic Asymmetric 1,4-Addition of an Alkylzirconium Nucleophile

Wang, Jiao Yu Joseph; Fletcher, Stephen P.

doi:10.1021/acs.orglett.0c01165

Cited by 7 publications

(7 citation statements)

References 46 publications

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“…Earlier works in this field focused on using these enolates in aldol, Mannich, Michael additions, or nucleophilic substitutions [21] . Recent effort of the research community focuses on utilizing either less explored enolates, [22] substrates, [23] or trapping reactions [24] . Our lab's interest in expanding this methodology aims on using carbocations or their equivalents in Cu‐catalyzed ACAs of organometallic reagents.…”

Section: Methodsmentioning

confidence: 99%

“…[21] Recent effort of the research community focuses on utilizing either less explored enolates, [22] substrates, [23] or trapping reactions. [24] Our lab's interest in expanding this methodology aims on using carbocations or their equivalents in Cu-catalyzed ACAs of organometallic reagents. We have shown that stabilized carbocations such as tropylium or sulfur-stabilized cations are compatible with Grignard or organozirconium reagents.…”

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confidence: 99%

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Asymmetric Tandem Conjugate Addition and Reaction with Carbocations on Unsaturated Heterocycles

et al. 2022

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Heterocycles possessing multiple substituents and stereogenic centers are important structural motifs in many compounds of interest. We present here stereoselective tandem transformation based on Cu‐catalyzed conjugate addition of Grignard reagents to heterocyclic Michael acceptors, which is followed by one‐pot trapping of in situ formed enolates with stabilized carbocations or their equivalents. The transformations are highly enantio‐ and diastereoselective with Josiphos‐type ferrocene ligand. The reaction of chiral metal enolates with onium compounds allows the installation of structurally attractive substituents on chromenone or piperidinone core. Moreover, cycloheptatrienyl and benzodithiolyl substituents can be further modified, thus expanding synthetic possibilities of this methodology.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Asymmetric Tandem Conjugate Addition and Reaction with Carbocations on Unsaturated Heterocycles

et al. 2022

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“…In 2020, Fletcher and co-workers 152 reported a concise and enantioselective approach to Taxol core (Scheme 29D). Type II IMDA cycloaddition of intermediate 211 with TiCl 4 afforded the tricyclic compound 212 in 35% yield, albeit as a 1:1 mixture of diastereomers at C1.…”

Section: Model Studiesmentioning

confidence: 99%

Strategies and Lessons Learned from Total Synthesis of Taxol

et al. 2023

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Taxol (paclitaxel), the most well-known taxane diterpenoid, is the best-selling natural-source anticancer drug ever produced and one of the most common prescriptions in the treatment of breast, lung, and ovarian cancers, saving countless lives around the world. Structurally, Taxol possesses a highly oxygenated [6−8−6−4] core bearing 11 stereocenters, seven of which are contiguous chiral centers. Moreover, the extremely strained bicyclo[5.3.1] undecane ring system with a bridgehead double bond is a unique structural feature. All these features make Taxol a highly challenging synthetic target. Tremendous synthetic efforts from more than 60 research groups around the world have already culminated in ten total syntheses and three formal syntheses, as well as more than 60 synthetic model studies of Taxol. This review is intended to provide a long-overdue appraisal of the great achievements in the total syntheses of Taxol reported in the last few decades. In doing so, we summarize the development of synthesis toward Taxol from 1994 to 2022, including the evolution of synthetic strategy for accessing this complex molecular scaffold and key lessons learned from such endeavors. Finally, we briefly discuss the future of the research in this area.

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“…66 This reaction was recently employed in the total synthesis of taxol core derivative 47 (Scheme 13). 67 This work improved on Baran's elegant synthesis of taxadienone, 68 which utilized the ACA of Me 3 Al using Alexakis's protocol. 69 The advantage of the use of organozirconium reagents was in the streamlined installation of the alkenyl side chain at the C3-position.…”

Section: Scheme 12 the First Zr-enolate Trapping Reactions Initiated mentioning

confidence: 99%

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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Synthesis of the Taxol Core via Catalytic Asymmetric 1,4-Addition of an Alkylzirconium Nucleophile

Cited by 7 publications

References 46 publications

Asymmetric Tandem Conjugate Addition and Reaction with Carbocations on Unsaturated Heterocycles

Asymmetric Tandem Conjugate Addition and Reaction with Carbocations on Unsaturated Heterocycles

Strategies and Lessons Learned from Total Synthesis of Taxol

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

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