Monoterpenoid indole alkaloids are the major class of tryptamine‐derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic ...chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.
Dearomatization strategy: Aspidosperma‐ and Strychnos‐type alkaloids have been attractive targets for natural product synthesis due to their challenging structures. Inspired by nature, many dearomatization strategies have been reported over the past seven decades. Nevertheless, this field has maintained substantial interest and, therefore, it is important to provide a comprehensive historical perspective, which presents an essential guideline for the future of this field.
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A palladium‐catalyzed intermolecular cascade (4+3) cyclocondensation of salicylaldehydes and vinylcyclopropanes is reported. A key feature of the reaction is the use of a phosphonate group as an ...acceptor moiety on the cyclopropane, exploiting its propensity to undergo olefination with aldehydes. Subsequent O‐allylation enabled the formation of a range of substituted benzoxepinsWith a novel chiral ligand, the products were obtained in generally good yield and with reasonable enantioselectivity.
Enantiomerically enriched benzoxepins were synthesized from phosphonate‐functionalized vinylcyclopropanes and salicylaldehydes by palladium‐catalyzed ring opening followed by Horner–Wadsworth–Emmons olefination and subsequent O‐allylation (see scheme). In contrast to existing cycloaddition reactions of donor–acceptor cyclopropanes, the two bonds are each formed in a separate event, thus allowing greater flexibility in reaction design.
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The N‐iodosuccinimide‐mediated spirocyclization of tryptamine‐derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible ...handles for follow‐up chemistry. Nucleophilic addition typically occurs chemoselectively on the imine moiety with complete diastereoselectivity, providing opportunities for the construction of complex molecular frameworks. The synthetic potential of the method was showcased in the formal total synthesis of (±)‐aspidofractinine.
I make(s) spirocycles: Iodospirocyclization of tryptamine‐derived isocyanides affords highly substituted spiroindolenine imidoyl iodides. The imine functionality can undergo a variety of diastereoselective addition reactions, including in situ reduction, while the imidoyl iodide functionality is remarkable stable. The utility of the method was demonstrated by the formal total synthesis of (±)‐aspidofractinine.
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We report a highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochemically complex spiroindolines from tryptamine-derived isocyanides. ...The reaction is facilitated by using fluorinated alcohols (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.
Monoterpenoid indole alkaloids are the major class of tryptamine‐derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic ...chemists. In their Review on page 8916 ff., J. M. Saya, R. V. A. Orru, and E. Rujter discuss the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles.
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Dearomatization of indoles through a charge transfer complex constitutes a powerful tool for synthesizing three-dimensional constrained structures. However, the implementation of this strategy for ...the dearomatization of tryptamine-derived isocyanides to generate spirocyclic scaffolds remains underdeveloped. In this work, we have demonstrated the ability of tryptamine-derived isocyanides to form aggregates at higher concentration, enabling a single electron transfer step to generate carbon-based-radical intermediates. Optical, HRMS and computational studies have elucidated key aspects associated with the photophysical properties of tryptamine-derived isocyanides. The developed protocol is operationally simple, robust and demonstrates a novel approach to generate conformationally constrained spirocyclic scaffolds, compounds with high demand in various fields, including drug discovery.
Tryptamine-derived isocyanides form aggregates at higher concentration that can form a charge transfer complex under visible light irradiation thus enabling a crucial single electron transfer step to generate carbon-based-radical intermediates.
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A new Passerini-type reaction in which hexafluoroisopropanol functions as the acid component is reported. The reaction tolerates a broad range of isocyanides and aldehydes, and the formed imidates ...can be reduced toward β-amino alcohols under mild and metal-free conditions. In addition, the imidate products were shown to undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic information about the Passerini reaction and its variations.
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Total Synthesis of Aquatolide Saya, Jordy M; Vos, Klaas; Kleinnijenhuis, Roel A ...
Organic letters,
08/2015, Volume:
17, Issue:
15
Journal Article
Peer reviewed
Open access
A total synthesis of the sesquiterpene lactone aquatolide has been accomplished. The central step is an intramolecular 2 + 2-photocycloaddition of an allene onto an α,β-unsaturated δ-lactone. Other ...key steps are an intramolecular Horner–Wadsworth–Emmons reaction to close the lactone and an intramolecular Mukaiyama-type aldol reaction to cyclize the eight-membered ring. Racemic aquatolide has been resolved using preparative HPLC.
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The revision of the structure of the sesquiterpene aquatolide from a bicyclo2.2.0hexane to a bicyclo2.1.1hexane structure using compelling NMR data, X-ray crystallography, and the recent ...confirmation via full synthesis exemplify that the achievement of “structural correctness” depends on the completeness of the experimental evidence. Archived FIDs and newly acquired aquatolide spectra demonstrate that archiving and rigorous interpretation of 1D 1H NMR data may enhance the reproducibility of (bio)chemical research and curb the growing trend of structural misassignments. Despite being the most accessible NMR experiment, 1D 1H spectra encode a wealth of information about bonds and molecular geometry that may be fully mined by 1H iterative full spin analysis (HiFSA). Fully characterized 1D 1H spectra are unideterminant for a given structure. The corresponding FIDs may be readily submitted with publications and collected in databases. Proton NMR spectra are indispensable for structural characterization even in conjunction with 2D data. Quantum interaction and linkage tables (QuILTs) are introduced for a more intuitive visualization of 1D J-coupling relationships, NOESY correlations, and heteronuclear experiments. Overall, this study represents a significant contribution to best practices in NMR-based structural analysis and dereplication.
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Tryptamine-derived isocyanides are valuable building blocks in the construction of spirocyclic indolenines and indolines via dearomatization of the indole moiety. We report the ...Bu4NFe(CO)3NO-catalyzed carbene transfer of α-diazo esters to 3-(2-isocyanoethyl)indoles, leading to ketenimine intermediates that undergo spontaneous dearomative spirocyclization. The utility of this iron-catalyzed carbene transfer/spirocyclization cascade was demonstrated by its use as a key step in the formal total synthesis of monoterpenoid indole alkaloids (±)-aspidofractinine, (±)-limaspermidine, (±)-aspidospermidine, and (±)-17-demethoxy-N-acetylcylindrocarine.
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