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.
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.
An enantioselective synthesis of an intermediate in the Tanino total synthesis of solanoeclepin A has been developed. The key step was an intramolecular [2+2] photocycloaddition, which led to the tricyclo[5.2.1.0(1, 6)] decane core in six steps. The first photosubstrate, prepared through an indium-mediated Barbier-type reaction, gave an excellent [2+2] cycloaddition, but it could not be obtained in sufficient enantiopurity. The second photosubstrate, prepared through an asymmetric allene diborylation in high enantiomeric excess, gave the [2+2] cycloaddition product in high yield on irradiation at 365 nm on 20 g scale in a flow system. Other important steps were the replacement of a boronate group at the quaternary carbon by a vinyl group and diastereoselective cyclopropanation of an allylic alcohol.
This report describes intramolecular [2+2] photocycloadditions of several butenolides with an allenylmethyl substituent at the 5-position. These photosubstrates were prepared from 2-(silyloxy)furans through silver-mediated reactions with allenylmethyl bromides. Two cases were studied where the lactone was replaced by an N-Boc-lactam. Irradiations of the photosubstrates were carried out with 300 nm UV-light in acetonitrile/acetone mixtures. Crossed cycloadducts were produced in good yields via cycloaddition of the heterocyclic double bond with the allene internal double bond. The products were γ-lactones (γ-lactams) containing the strained 5-methylenebicyclo[2.1.1]hexane skeleton. In some cases the
An enantioselective synthesis of the right‐hand substructure of solanoeclepin A has been developed. The key step was an intramolecular [2+2] photocycloaddition between an allene and a butenolide providing a methylenecyclobutane with three quaternary carbon atoms in a complex tetracyclic framework. Other crucial steps included an enantioselective Noyori transfer hydrogenation of a ketone, a diastereoselective silver‐mediated silyl dienolate allylation, and a diastereoselective cyclopropanation of an allylic alcohol. The installation of the bridgehead methyl group by reduction of the lactone moiety proved to be troublesome.
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