Synthesis of the C1–C18 Fragment of Rhizopodin: Late-State Introduction of the Oxazole

The synthesis of the C1–C18 fragment of the myxobacteria metabolite rhizopodin is described. Initial attempts at installing the <i>E</i>,<i>E</i>-diene via cross coupling with an oxazole fragment gave poor results. An alternative approach, in which the diene was formed prior and the oxazole introduced by an acylation/<i>O,N</i>-shift protocol, gave the C1–C18 fragment <b>2</b> of rhizopodin (<b>1</b>)

Total Synthesis of the Proposed Structure of 8‑Deshydroxyajudazol A: A Modified Approach to 2,4-Disubstituted Oxazoles

The total synthesis of the proposed structure for the minor myxobacterial metabolite 8-deshydroxyajudazol A (<b>3</b>) is described. The isochromanone moiety present in the eastern fragment was constructed by an intramolecular-Diels–Alder (IMDA). Difficulties were encountered with the formation of the 2,4-disubstituted oxazole, so this was synthesized via a modified approach. This involved selective acylation of the diol <b>7</b> with acid <b>8</b>, azide displacement of the secondary alcohol, and subsequent azide reduction in the presence of base which induced an <i>O,N</i> shift to give the hydroxyamide <b>23</b>. Cyclodehydration then gave the desired oxazole <b>24</b> and deprotection followed by mesylation and elimination produced the C15 alkene <b>5</b>. Sonogashira coupling with the eastern fragment vinyl iodide <b>6</b> and partial reduction yielded 8-deshydroxyajudazol A (<b>3</b>)

Formal Total Synthesis of Spirangien A

A formal total synthesis of the spiroketal containing cytotoxic myxobacteria metabolite spirangien A (<b>1</b>) is described. The approach utilizes a late introduction of the C20 alcohol that mirrors the biosynthesis of this compound. The key steps involved a high yielding cross metathesis reaction between enone <b>6</b> and alkene <b>7</b> to give <i>E</i>-enone <b>4</b> and a Mn-catalyzed conjugate reduction α-oxidation reaction to introduce the C20 hydroxyl group. Acid treatment of the α-hydroxyketone <b>4</b> gave spiroketal <b>19</b> which was converted into known spirangien A (<b>1</b>) advanced intermediate spiroketal <b>3</b>

Towards the Synthesis of Dihydrooxepino[4,3‑<i>b</i>]pyrrole-Containing Natural Products via Cope Rearrangement of Vinyl Pyrrole Epoxides

An approach to the dihydrooxepino­[4,3-<i>b</i>]­pyrrole core of diketopiperazine natural products which utilizes a vinyl pyrrole epoxide Cope rearrangement was investigated. It was found that an ester substituent on the epoxide was essential for the [3,3]-rearrangement to occur. Density functional calculations with M06-2X provided explanations for the effects of the pyrrole and ester groups on these rearrangements

Synthesis of Biotinylated Episilvestrol: Highly Selective Targeting of the Translation Factors eIF4AI/II

Silvestrol (<b>1</b>) and episilvestrol (<b>2</b>) are protein synthesis inhibitors, and the former has shown efficacy in multiple mouse models of cancer; however, the selectivity of these potent cytotoxic natural products has not been described. Herein, it is demonstrated that eukaryotic initiation factors eIF4AI/II were the only proteins detected to bind silvestrol (<b>1</b>) and biotinylated episilvestrol (<b>9</b>) by affinity purification. Our study demonstrates the remarkable selectivity of these promising chemotherapeutics

Total Synthesis of 2‴,5‴-Diepisilvestrol and Its C1‴ Epimer: Key Structure Activity Relationships at C1‴ and C2‴

The first total synthesis of the low-abundance natural product 2‴,5‴-diepisilvestrol (<b>4</b>) is described. The key step involved a Mitsunobu coupling between cyclopenta­[<i>b</i>]­benzofuran phenol <b>7</b> and dioxane lactol <b>6</b>. Deprotection then gave a 1:2.6 ratio of natural product 2‴,5‴-diepisilvestrol (<b>4</b>) and its C1 epimer 1‴,2‴,5‴-triepisilvestrol (<b>15</b>) in 50% overall yield. An in vitro protein translation inhibition assay showed that 2‴,5‴-diepisilvestrol (<b>4</b>) was considerably less active than episilvestrol (<b>2</b>), while the unnatural isomer 1‴,2‴,5‴-triepisilvestrol (<b>15</b>) was essentially inactive, showing that the configuration at C1‴ and C2‴ has a large effect on the biological activity