A total synthesis of the Aspidosperma alkaloids (+)-fendleridine (1) and (+)-1-acetylaspidoalbidine (2) is detailed, providing access to both enantiomers of the natural products and establishing their absolute configuration. Central to the synthetic approach is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole in which the pentacyclic skeleton and all the stereochemistry of the natural products are assembled in a reaction that forms three rings, four C-C bonds, five stereogenic centers including three contiguous quaternary centers, and introduces the correct oxidation state at C19 in a single synthetic operation. The final tetrahydrofuran bridge is subsequently installed in one-step, enlisting an intramolecular alcohol addition to an iminium ion generated by nitrogen assisted opening of the cycloadduct oxido bridge, with a modification that permits release of useful functionality (a ketone) at the cleavage termini.
A powerful tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles initiated by a transannular [4+2] cycloaddition is detailed. An impressive four rings, four carbon-carbon bonds, and six stereocenters are set on each site of the newly formed central six-membered ring in a cascade thermal reaction that proceeds at temperatures as low as 80 °C. The resulting cycloadducts provide the basis for the synthesis of unique analogues of vinblastine containing metabolically benign deep-seated cyclic modifications at the C3/C4 centers of the vindoline-derived subunit of the natural product.
A remarkably concise 7–8 step total synthesis of a systematic
series of key vinblastine derivatives is detailed and used to characterize the
importance and probe the role of the C5 ethyl substituent (R = H, Me,
Pr, CH=CH2, C≡CH, CH2OH, CHO vs Et). The
analogues, bearing deep-seated structural changes accessible only by total
synthesis, were prepared using a powerful intramolecular
[4+2]/[3+2] cycloaddition
cascade of 1,3,4-oxadiazoles ideally suited for use in the assemblage of the
vindoline-derived lower subunit followed by their incorporation into the
vinblastine analogues enlisting a single step biomimetic coupling with
catharanthine. The evaluation of the series revealed that the tubulin binding
site surrounding this C5 substituent is exquisitely sensitive to the presence
(Et > H, 10-fold), size (Me ≤ Et > Pr, 10-fold), shape (Et >
CH=CH2 and C≡CH, >4-fold), and polarity (Et
> CHO > CH2OH, >10–20-fold) of this substituent, and
that on selected occasions only a C5 methyl group may provide analogues that
approach the activity observed with the naturally occurring C5 ethyl group.
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