Palladium-Catalyzed Trimethylenemethane Research Articles

Catalytic Asymmetric Synthesis of the Pentacyclic Core of (+)-Citrinadin A.

The synthesis of the pentacylic core of (+)-citrinadin A is described. Our strategy harnesses the power of palladium-catalyzed trimethylenemethane chemistry (Pd-TMM) to form the key spirooxindole motif in a catalytic, asymmetric fashion. Upon the conversion of this spirooxindole to a vinyl epoxide electrophile, the piperidine ring is directly added via a diastereoselective metalation followed by an SN2' addition. The final ring of the pentacyclic core is then formed through an intramolecular SN2 displacement of the resulting activated alcohol.

Celebrating Professor Barry M. Trost's 80th Birthday

Celebrating Professor Barry M. Trost's 80^th Birthday

Forging Odd-Membered Rings: Palladium-Catalyzed Asymmetric Cycloadditions of Trimethylenemethane.

The catalytic asymmetric synthesis of complex molecules has been the focus of our research program for several decades because such strategies have significant utility for the construction of chiral building blocks for drug development as well as the total synthesis of natural products. Cycloaddition reactions are very powerful transformations in organic synthesis providing access to highly functionalized motifs from simple starting materials. In concert with this central interest, four decades ago, we reported the palladium-catalyzed trimethylenemethane (TMM) cycloaddition for forging odd-membered ring systems. In recent years, we focused our attention on the development of powerful ligand scaffolds which enable the preparation of valuable products with complete control of chemo-, regio-, diastereo-, and enantioselectivity, thereby addressing several limitations in the field of palladium-catalyzed asymmetric cycloadditions. The first section of this Account will outline the discovery of a new class of highly modular pyrrolidine-based phosphoramidite and diamidophosphite chiral ligands which facilitate [3 + 2] cycloadditions of TMM donors, opening a new area in asymmetric construction of five-membered rings.The formation of the Pd-TMM zwitterionic intermediates is driven by the unique charge distribution of the cationic π-allyl motif, in which the most electropositive central carbon stabilizes the neighboring carbanion generated by either desilylation or deprotonation. The second section of this Account summarizes the scope of cycloadditions between Pd-TMM zwitterionic intermediates generated via desilylation and a variety of electron-deficient acceptors to access cyclopentanes, pyrrolidines and tetrahydrofurans. This section also includes the use of nitrile-, vinyl-, alkynyl- and allene-substituted TMM donors to rapidly generate cycloadducts with high molecular complexity. The extension of this strategy to include [6 + 3] cycloadditions and dearomative processes will also be presented. The third section will discuss a new generation of TMM donors substituted with electron-withdrawing groups such as nitrile, benzophenone imine, trifluoromethyl, and phosphonate, where the Pd-TMM zwitterionic intermediates are generated via deprotonation of the acidic C-H bond adjacent to the π-allyl motif. This new strategy has enabled the synthesis of heterocycles with increased numbers of functional groups in highly asymmetric and atom-economic fashion.Throughout this Account, we will describe the implementation of these transformations toward the rapid assembly of drug candidates and the total synthesis of natural products such as (-)-marcfortine C. We will also give details of mechanistic studies regarding relevant intermediates within the catalytic cycles of the different strategies, which allowed us to better understand the origin of selectivity with various donors.

Palladium-Catalyzed Trimethylenemethane Cycloaddition of Olefins Activated by the σ-Electron-Withdrawing Trifluoromethyl Group.

α-Trifluoromethyl-styrenes, trifluoromethyl-enynes, and dienes undergo palladium-catalyzed trimethylenemethane cycloadditions under mild reaction conditions. The trifluoromethyl group serves as a unique σ-electron-withdrawing group for the activation of the olefin toward the cycloaddition. This method allows for the formation of exomethylene cyclopentanes bearing a quaternary center substituted by the trifluoromethyl group, compounds of interest for the pharmaceutical, agrochemical, and materials industries. In the diene series, the cycloaddition operates in a [3 + 4] and/or [3 + 2] manner to give rise to seven- and/or five-membered rings. This transformation greatly improves the scope of the TMM cycloaddition technology and provides invaluable insights into the reaction mechanism.

Enantioselective Total Synthesis of Pinnaic Acid and Halichlorine

The enantioselective total synthesis of the bioactive marine natural products pinnaic acid and halichlorine is reported in detail. Our total synthesis features the construction of the five-membered ring and C9 and C13 stereogenic centers through a palladium-catalyzed trimethylenemethane [3+2] cyclization; the installation of the nitrogen atom through a regioselective Beckmann rearrangement of a poorly reactive ketone; the stereoselective cyclization of the spiro ring through a four-step, one-pot hydrogenation-cyclization; and efficient connection of the sterically hindered lower chain through a reduced-pressure cross olefin metathesis reaction.

Regio- and Enantioselective Synthesis of Pyrrolidines Bearing a Quaternary Center by Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Trimethylenemethanes

Herein we describe the first use of disubstituted donors in the palladium-catalyzed trimethylenemethane (TMM) cycloaddition resulting in an enantioselective synthesis of highly substituted pyrrolidines. These cyanoalkyl donors 1 form all-carbon quaternary centers in a catalytic, asymmetric, and intermolecular manner uniquely using diamidophosphite ligands L2 and L3, generating synthetically important chiral building blocks in good yields and selectivities.

Enantioselective Palladium‐Catalyzed Trimethylenemethane [3+2] Cycloadditions

Enantioselective Palladium‐Catalyzed Trimethylenemethane [3+2] Cycloadditions

Enantioselective Construction of Spirocyclic Oxindolic Cyclopentanes by Palladium-Catalyzed Trimethylenemethane-[3+2]-Cycloaddition

The palladium catalyzed [3+2] trimethylenemethane (TMM) cycloaddition is an efficient method for the construction of cyclopentanes. Herein, we report a catalytic asymmetric protocol for the synthesis of spirocyclic oxindolic cyclopentanes in excellent yields and enantioselectivities, allowing for the first time the construction of up to three adjacent stereogenic centers. In this process, the chiral ligand controls the diastereo- as well as enantioselectivity.

A selectivity control element for palladium-catalyzed trimethylenemethane cycloaddition

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA selectivity control element for palladium-catalyzed trimethylenemethane cycloadditionBarry M. Trost and Michael C. MatelichCite this: J. Am. Chem. Soc. 1991, 113, 23, 9007–9009Publication Date (Print):November 1, 1991Publication History Published online1 May 2002Published inissue 1 November 1991https://doi.org/10.1021/ja00023a094RIGHTS & PERMISSIONSArticle Views488Altmetric-Citations39LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (367 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Palladium-catalyzed trimethylenemethane reaction to form methylenetetrahydrofurans. Reactions of substituted TMM precursors and mechanistic interpretation

Palladium-catalyzed trimethylenemethane reaction to form methylenetetrahydrofurans. Reactions of substituted TMM precursors and mechanistic interpretation

Palladium-catalyzed trimethylenemethane reaction to form methylenetetrahydrofurans. Aldehyde and ketone substrates and the tin effect

Le meilleur cocatalyseur est l'(acetoxy trimethyl) stannane. L'acetate de trimethylsilylmethyl-2 allyle est utilise comme precurseur du trimethylenemethane