Aquatolide has been reisolated from its natural source, and its structure has been revised on the basis of quantum-chemical NMR calculations, extensive experimental NMR analysis, and crystallography.
The
first asymmetric insertion reactions of donor–donor
carbenoids, i.e., those with no pendant electron-withdrawing groups,
are reported. This process enables the synthesis of densely substituted
benzodihydrofurans with high levels of enantio- and diastereoselectivity.
Preliminary results show similar efficiency in the preparation of
indanes. This new method is used in the first enantioselective synthesis
of an oligoresveratrol natural product (E-δ-viniferin).
Metal carbenes appended with two electron-donating groups, known as "donor/donor" carbenes, undergo diastereo- and enantioselective rhodium-catalyzed C-H insertion reactions with ether substrates to form benzodihydrofurans. Unlike the reactions of metal carbenes with electron-withdrawing groups attached, the attenuated electrophilicity enables these reactions to be conducted in Lewis basic solvents (e.g., acetonitrile) and in the presence of water. The diazo precursors for these species are prepared in situ from hydrazone using a mild and chemoselective oxidant (MnO ). Although this sequence often can be performed in one-pot, control experiments have elucidated why a "two-pot" process is often more efficient. A thorough screening of achiral catalysts demonstrated that sterically encumbered catalysts are optimal for diastereoselective reactions. Although efficient insertion into allylic and propargylic C-H bonds is observed, competing dipolar cycloaddition processes are noted for some substrates. The full substrate scope of this useful method of benzodihydrofuran synthesis, mechanisms of side reactions, and computational support for the origins of stereoselectivity are described.
The revision of the structure of
the sesquiterpene aquatolide from
a bicyclo[2.2.0]hexane to a bicyclo[2.1.1]hexane 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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