Synthetic Studies on Amphidinolide F: Exploration of Macrocycle Construction by Intramolecular Stille Coupling

Abstract

Exploration of an ambitious new strategy for the total synthesis of the cytotoxic marine natural product amphidinolide F is described, which features fabrication of the core structure from four readily accessible fragments and macrocycle construction through C9–C10 bond formation by intramolecular Stille coupling between an alkenyl iodide and alkenyl stannane. Efficient stereoselective synthesis of each of the four building-blocks and subsequent coupling of them to produce the requisite cyclization precursor has been accomplished, but suitable conditions for high-yielding palladium-mediated closure of the macrocycle to produce the fully protected amphidinolide F ring system have yet to be identified.

Advances Toward Amphidinolides C, F and U: Isolations, Synthetic Studies and Total Syntheses

“…Therefore, they used a third approach to reach AMPÀ F (5). [87] One of the most significant modifications was using the Mukaiyama oxidative cyclization, [51] with Pagenkopf's improvement, [53] to build the 2,5-trans-THF motif between C 19 and C 24 .…”

“…Firstly, stannane 203 was transformed either in alcohol 228 by removal of the pivaloyl group or in carboxylic acid 229 by oxidation of 228 (Scheme 31). [87] Therefore, different cross‐coupling attempts under Fürstner conditions [86] could be tried between 227 b and 228 or 229 . However, all attempts drove to no coupling reaction.…”

“…Thus, homoallyl alcohol 218 underwent a cyclization with oxygen under Pagenkopf's cobalt catalysis [53] (see Section 3.5.1) (Scheme 30). [87] The introduction of an acetylene function was performed in three steps and according to Clark's previous studies (see Scheme 28), Sonogashira cross‐coupling, directed reduction of the alkyne in E ‐olefin, and diastereoselective reduction of the ketone at C 24 position with Luche conditions afforded compound 222 . Alkylation of the dithiane 223 with iodide 222 gave rise to 224 in acceptable yield after ethoxyethyl (OEE) protecting group removal.…”

Macrocyclization Strategies Towards the Synthesis of Amphidinolide Natural Products

“…The latter upon a subsequent intramolecular Stille coupling reaction under similar conditions efficiently cyclized to the target macrolide 6 (44%) (Scheme 21). Recently, Clark and Decultot applied intramolecular Stille coupling for the construction of amphidinolide F, but the methods didn't work effectively [42] …”

“…Recently, Clark and Decultot applied intramolecular Stille coupling for the construction of amphidinolide F, but the methods didn't work effectively. [42]…”