Relative Stereochemical Determination and Synthesis of the C17–C25 δ‑Lactone Fragment of Hemicalide

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined the relative stereochemistry of the C8–C13 hexad by synthesizing the C1–C13 fragment. Presently, we report the assignment of the C17–C25 δ-lactone fragment. NMR analysis of authentic hemicalide along with a computational conformation study allowed us to reduce the number of putative relative isomers from 16 to 4. Concise syntheses of the four candidate diastereomers were achieved using a common strategy based on a Dias aldehyde allylation reaction, an intramolecular Horner–Wadsworth–Emmons olefination, and a dihydroxylation reaction. Finally, thorough NMR comparisons enabled us to deduce the relative stereochemistry of the C1–C17 fragment with high certainty

Intramolecular Diels–Alder Approaches to the Decalin Core of Verongidolide: The Origin of the <i>exo</i>-Selectivity, a DFT Analysis

Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, <i>Verongidolae</i>. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, <i>Neosiphonia superstes</i>. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the ¹H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a <i>cis</i>-decalin core and we hypothesize that the relative configuration of the <i>cis</i>-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels–Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels–Alder reactions was <i>exo</i> and an in-depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity

Synthetic Studies toward the C32–C46 Segment of Hemicalide. Assignment of the Relative Configuration of the C36–C42 Subunit

The synthesis of five diastereomeric model compounds incorporating the C32–C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,β-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia–Kocienski olefination. Comparison of the ¹H and ¹³C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36–C42 subunit

Elaboration of Sterically Hindered δ‑Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1–C27 Fragment of Hemicalide

The synthesis of the C1–C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework

Synthetic Studies on Hemicalide: Development of a Convergent Approach toward the C1–C25 Fragment

Synthetic studies on hemicalide, a recently isolated marine natural product displaying highly potent antiproliferative activity and a unique mode of action, have highlighted a reliable Horner–Wadsworth–Emmons olefination to create the C6–C7 alkene and a remarkable efficient Suzuki–Miyaura coupling to form the C15–C16 bond, resulting in the development of a convergent approach toward the C1–C25 fragment

Synthetic Studies on Hemicalide: Development of a Convergent Approach toward the C1–C25 Fragment

Synthetic studies on hemicalide, a recently isolated marine natural product displaying highly potent antiproliferative activity and a unique mode of action, have highlighted a reliable Horner–Wadsworth–Emmons olefination to create the C6–C7 alkene and a remarkable efficient Suzuki–Miyaura coupling to form the C15–C16 bond, resulting in the development of a convergent approach toward the C1–C25 fragment

Proteasome Inhibitors from <i>Neoboutonia melleri</i>

Thirty new cycloartane derivatives (<b>1</b>–<b>3</b>, <b>5</b>–<b>12</b>, <b>14</b>–<b>32</b>) have been isolated from the leaves of <i>Neoboutonia melleri</i>. Their novelty stems from the loss of one of the C-4 methyl groups (<b>1</b>–<b>3</b>, <b>5</b>–<b>12</b>, <b>14</b>–<b>25</b>, and <b>32</b>) and from the presence of an “extra” carbon atom in the side chain (<b>1</b>–<b>3</b>, <b>5</b>–<b>12</b>,<b> 14</b>–<b>20</b>, <b>26</b>–<b>29</b>, and <b>30</b>–<b>32</b>). Furthermore, compound <b>32</b> possesses a rare triterpene skeleton with the cyclopropane ring fused onto C-1 and C-10, instead of C-9 and C-10. The structures were determined by spectrometric means, chemical correlations, and X-ray crystallography of derivative <b>1c</b>. The substitution pattern in ring A, with a cyclopropyl ring conjugated with an α,β-unsaturated carbonyl moiety, confers to the molecule a particular reactivity, giving rise to a formal inversion of the stereochemistry of the cyclopropane ring under UV irradiation. These compounds showed an interesting level of activity on the proteasome pathway, thus motivating their evaluation as possible anticancer agents. The large number of isolated compounds permitted a structure–activity relationship analysis, which showed that the presence of the two enone functions was a requirement for the activity