Saragossasäure A/Squalestatin S1: synthetische und retrosynthetische Untersuchungen

Abstract

Schritt um Schritt zur ersten Totalsynthese: Saragossasäuren/Squalestatine können möglicherweise als Therapeutica für die Senkung des Serum‐Cholesterinspiegels eingesetzt werden. Die wichtigste Verbindung dieser neuartigen Naturstoffklasse, der wirkungsvolle Squalensynthase‐ Inhibitor Saragossasäure A/Squalestatin S1 1, wurde nun über die Schlüsselzwischenstufen 2und 3 synthetisiert. Zunächst wurden dazu die Schlußsequenz (2 → 1) erarbeitet und die Seitenketten an C1 und C6 in effizienten asymmetrischen Synthesen hergestellt. Die erste Synthese des hochoxygenierten Gerüstes der Saragossasäuren/Squalestatine gelang ausgehend von einem einfachen prochiralen Dien über die Zwischenstufe 3. Darauf aufbauend wurde ein Syntheseweg 3 → 2 entwickelt, so daß die Totalsynthese erfolgreich abgeschlossen werden konnte. Bb = Benzyl, PMB = para‐Methoxybenzyl, TMS = Trimethylsilyl.magnified image

Redox Economy in Organic Synthesis

“…In comparison, three other syntheses of zaragozic acid C occur in 22 steps with eight redox operations, [36] 30 steps with 11 redox operations (one of which is strategic), [37] and 36 steps with 13 redox operations (two of which are strategic); [38] a synthesis of zaragozic acid A (which differs only in the side chains) occurs in 33 steps with eight redox operations (three being strategic). [39] This is additionally impressive in the case of such a highly oxidized target.…”

Stereoselective Total Synthesis of Zaragozic Acid A based on an Acetal [1,2] Wittig Rearrangement

“…Therefore, it is not surprising that the these compounds have elicited considerable attention from numerous synthetic chemists. [3,4] Zaragozic acid A (squalestatin S1; 1) is a representative example of this novel class of compounds. Herein, we report the efficient, convergent synthesis of 1 by highlighting the acetal [1,2] Wittig rearrangement [5] for forming the C4ÀC5 bond together with the simultaneous creation of the contiguous quaternary carbon atoms as the key step.…”

Stereoselective Total Synthesis of Zaragozic Acid A based on an Acetal [1,2] Wittig Rearrangement

“…[1a, 2a] All the zaragozic acids and squalestatins have a common 2,8-dioxabicy-clo[3.2.1]octane core with an array of six stereogenic centers including contiguous quarternary carbon atoms, and are different only at the alkyl and acyl side chains at C1 and C6, respectively. [3,4] Zaragozic acid A (squalestatin S1; 1) is a representative example of this novel class of compounds. [3,4] Zaragozic acid A (squalestatin S1; 1) is a representative example of this novel class of compounds.…”