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Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables Bioinspired Syntheses of Neonectrolides B-E and Analogues.

ABSTRACT: Development of a synthetic route to the oxaphenalenone (OP) natural products neonectrolides B-E is described. The synthesis relies on gold-catalyzed 6-endo-dig hydroarylation of an unusual enynol substrate as well as a one-pot Rieche formylation/cyclization/deprotection sequence to efficiently construct the tricyclic oxaphenalenone framework in the form of a masked ortho-quinone methide (o-QM). A tandem cycloisomerization/[4 + 2] cycloaddition strategy was employed to quickly construct molecules resembling the neonectrolides. The tricyclic OP natural product SF226 could be converted to corymbiferan lactone E and a related masked o-QM. Our study culminates with the application of the tandem reaction sequence to syntheses of neonectrolides B-E as well as previously unreported exo-diastereomers.

SUBMITTER: Purgett TJ

PROVIDER: S-EPMC6761007 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables Bioinspired Syntheses of Neonectrolides B-E and Analogues.

Purgett Thomas J TJ Dyer Matthew W MW Bickel Bryce B McNeely James J Porco John A JA

Journal of the American Chemical Society 20190912 38

Development of a synthetic route to the oxaphenalenone (OP) natural products neonectrolides B-E is described. The synthesis relies on gold-catalyzed 6-endo-dig hydroarylation of an unusual enynol substrate as well as a one-pot Rieche formylation/cyclization/deprotection sequence to efficiently construct the tricyclic oxaphenalenone framework in the form of a masked ortho-quinone methide (o-QM). A tandem cycloisomerization/[4 + 2] cycloaddition strategy was employed to quickl ...[more]

PMID: 31469554

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Project description:The combination of two or more unsaturated structural units to form cyclic organic compounds is commonly referred to as cycloaddition, and the combination of two unsaturated structural units that forms a six-membered ring is formally either a [5 + 1]-, [4 + 2]-, [2 + 2 + 2]-, or [3 + 3]-cycloaddition. Occurring as concerted or stepwise processes, cycloaddition reactions are among the most useful synthetic constructions in organic chemistry. Of these transformations, the concerted [4 + 2]-cycloaddition, the Diels-Alder reaction, is by far the best known and most widely applied. However, although symmetry disallowed as a concerted process and lacking certifiable examples until recently, stepwise [3 + 3]-cycloadditions offer advantages for the synthesis of a substantial variety of heterocyclic compounds, and they are receiving considerable attention. In this Account, we present the development of stepwise [3 + 3]-cycloaddition reactions from virtual invisibility in the 1990s to a rapidly growing synthetic methodology today, involving organocatalysis or transition metal catalysis. With origins in organometallic or vinyliminium ion chemistry, this area has blossomed into a viable synthetic transformation for the construction of six-membered heterocyclic compounds containing one or more heteroatoms. The development of [3 + 3]-cycloaddition transformations has been achieved through identification of suitable and compatible reactive dipolar adducts and stable dipoles. The reactive dipolar species is an energetic dipolar intermediate that is optimally formed catalytically in the reaction. The stepwise process occurs with the reactive dipolar adduct reacting as an electrophile or as a nucleophile to form the first covalent bond, and this association provides entropic assistance for the construction of the second covalent bond and the overall formal [3 + 3]-cycloaddition. Organocatalysis is well developed for both inter- and intramolecular synthetic transformations, but the potential of transition metal catalysis for [3 + 3]-cycloaddition has only recently emerged. The key to the rapid development of the transition metal-based methodology has been recognition that certain catalytically generated vinylcarbenes are effective dipolar adducts for reactions with stable dipolar compounds, including aryl and vinyl ylides. In particular, metallo-enolcarbenes that are generated catalytically from conveniently prepared stable enoldiazoacetates or from donor-acceptor cyclopropenes are highly effective dipolar adducts for [3 + 3]-cycloaddition. The electron-donating oxygen of the silyl ether enhances electrophilic ring closure to the metal-bound carbon of the initial adduct from vinylogous addition, and this enhancement inhibits the alternative [3 + 2]-cycloaddition across the carbon-carbon double bond of the vinylcarbene. Catalytically generated metallo-enolcarbenes react under mild conditions with a broad spectrum of compatible stable dipoles, including nitrones, azomethine imines, ylides, and certain covalent precursors of stable dipoles, to form [3 + 3]-cycloaddition products having the β-ketoester functionality (in dihydrooxazines, tetrahydropyridazines, pyrazolidinone and pyraxole derivatives, dihydroquinolines, and quinolizidines, for example) in high yield. Two ways to access these metallo-enolcarbenes, either by dinitrogen extrusion from enoldiazoacetate esters or by rearrangement of donor-acceptor cyclopropenes, enhance the versatility of the process. The [3 + 3]-cycloaddition methodology is a complementary strategy to [4 + 2]-cycloaddition for the synthesis of heterocyclic compounds having six-membered rings. High levels of enantioselectivity are obtained with the use of chiral ligands on transition metal catalysts that include those on dirhodium(II) and silver(I).

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Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables Bioinspired Syntheses of Neonectrolides B-E and Analogues.

Publications

Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables Bioinspired Syntheses of Neonectrolides B-E and Analogues.

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