Formal Total Synthesis of the Algal Toxin (−)‐Polycavernoside A

Abstract

A concise and largely catalysis-based approach to the potent algal toxin polycavernoside A (1) is described that intercepts a late-stage intermediate of a previous total synthesis; from there on, this challenging target can be reached in a small number of steps. Key to success was a sequence of a molybdenum-catalyzed ring-closing alkyne metathesis (RCAM) reaction to forge the macrocyclic frame, followed by a gold-catalyzed and strictly regioselective transannular hydroalkoxylation of the resulting cycloalkyne that allows the intricate oxygenation pattern of the macrolactone ring of 1 to be properly set. The required cyclization precursor 5 was assembled by the arguably most advanced fragment coupling process based on an Evans-Tishchenko redox esterification known to date, which was optimized to the extent that the precious coupling partners could be used in an almost equimolar ratio (6/7 1:1.3). The preparation of these building blocks features, inter alia, the power of the Sc(OTf)(3)-catalyzed Leighton crotylation as well as the superb selectivities of alkene cross metathesis, asymmetric keto-ester hydrogenation, and the Jacobsen epoxidation/epoxide resolution technologies.

Katalyse und Totalsynthese: eine persönliche Zwischenbilanz

“…So wäre ohne Verständnis für die Konkurrenz aus gem-Diaurierung und Protodeaurierung wohl keine gute Lçsung für die neue, goldkatalysierte Synthese von 2-Pyronen gefunden worden, der bei der Totalsynthese des außerordentlich labilen marinen Naturstoffs Neurymenolid A eine Schlüsselrolle zufallen sollte. [40] ¾hnlich verhält es sich mit den transannularen Reaktionen, die zu Spirastrellolid F, [41] Amphidinolid F [42] und Polycavernosid A [43] führten und massiv von der gewachsenen Einsicht in die Elementarschritte der Hydroalkoxylierung von Alkinen profitiert haben. Ferner sei an dieser Stelle erwähnt, dass die Totalsynthesen von Cubeben und verwandten Cyclopropanderivaten -obgleich strukturell wesentlich einfacher als die eben erwähnten Zielverbindungen -den carbenoiden Charakter der reaktiven Zwischenstufen besonders augenfällig machen; zudem zeigen sie die Mçglichkeit, Alkine als vic-Dicarbensynthone zu nutzen.…”

Gold(I)‐Catalyzed C−O/C−C Bond‐Forming Domino Reactions and Their Synthetic Applications

“…Another recent example of synthetic application of a gold catalyzed intramolecular hydroalkoxylation came from Fürstner's laboratory, where JohnPhosAu(NCMe)SbF 6 catalyst selectively promoted 6‐ endo‐dig cyclization of macrocyclic intermediate 22 , affording the macrolide 23 in 84 % yield (Figure ). This key intermediate was converted in 8 steps to polycavernoside A ( 24 ), a toxin responsible for accidental fatal poisoning resulting from the ingestion of edible red algae in Philippines in 2002–2003.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…In synthesis [83,84] of the complex macrocyclic spermine alkaloid (-)-ephedradine A (123) that is one of the hypotensive components of the traditional Chinese drug Mao-con, the closure of the 16-membered ring of polyamine (124) was also carried out under Mitsunobu conditions, and construction of the 13-membered ring of macro-lactam (125) included cyclization of precursor (126) with an activated ester group using the Staudinger/intramolecular aza-Wittig reaction (Scheme 29).…”

“…[124] The formation of the dihydropyran fragment occurs in the intramolecular interaction of the triple bond with the hydroxyl group, which is applicable to synthesis of bryastatines of sea mats Bigula neritina [125] and polycavernoside (252) that is glycosylated macrolide of poisonous red algae Gracilaria edulis (Polycavernosa tsudai). [126] Thus, metathesis cyclization of diyne (253) over a molybdenum catalyst (254) forms the required macrocycle (255), and transannular reaction therein over alkynophile gold catalyst (256) -an additional six-membered cycle. Further transformations of the resulting tricycle (257) (oxidation of the double bond and decreasing the pyranone cycle to hydroxyfurane) proceeded stereoselectively (Scheme 56).…”