A Concise Total Synthesis of (+)‐Pancratistatin from D‐Glucose Featuring the Henry Reaction

Abstract

Pancratistatin (PST, Scheme 1) is a natural compound that was first isolated [1] from Spider Lily, a plant native to Hawaii that belongs to the Amaryllidaceae family. As well as antiviral and antiparasitic activities, PST has very strong antitumor activity. [2] Furthermore, PST can act as an antitumor secondary metabolite that can induce apoptosis in tumor cells by targeting their mitochondria while leaving normal cells unaffected. [3] Therefore, as well as being a challenging compound to synthetic chemists, a facile large-scale synthesis of PST and its analogs would be of great importance in pharmaceutical sciences. [4,5] However, despite many attempts to synthesize PST and its analogs (various epimers and/or deoxy derivatives, Scheme 1), [4g,h,j] a practical and scalable synthesis of from readily available starting compounds has remained elusive.We have been engaged in the total syntheses of naturally occurring branched-chain cyclitol compounds, such as cyclophellitol, mytillitol, laminitol, and (À)-tetrodotoxin (TTX), [6] by using d-glucose as the starting material. Herein, we describe the concise stereoselective total synthesis of (+)-PST from d-glucose, which features both inter-and intramolecular Henry reactions [7] (nitroaldol reactions) as key transformations. As shown in the retrosynthetic plan (Scheme 2), the key intermediate C-aryl nitrocyclitol B can be prepared from D by the intramolecular [a] Assoc. Scheme 1. Pancratistatin (PST) and its related compounds. Scheme 2. Retrosynthetic analysis of (+)-PST from d-glucose featuring an intramolecular Henry reaction.

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

“…[22] Thekey steps involved the construction of the ring C from d-glucose and the coupling of ring Awith fragment 37 by Michael addition. [22] Thekey steps involved the construction of the ring C from d-glucose and the coupling of ring Awith fragment 37 by Michael addition.…”

“…[21] Fort he synthesis of (+ +)-pancratistatin (1), Alonso [21] and Sato [22] both employed classical reactions,s uch as the aldol reaction, and Michael addition, while Cho [20] utilized Diels-Alder chemistry in his synthesis to achieve the required stereochemistry. Out of these four syntheses, Alonsos reported in 2012, was the shortest, comprising 14 steps and accomplished in 8.2 %o verall yield.…”

“…[21] Fort he synthesis of (+ +)-pancratistatin (1), Alonso [21] and Sato [22] both employed classical reactions,s uch as the aldol reaction, and Michael addition, while Cho [20] utilized Diels-Alder chemistry in his synthesis to achieve the required stereochemistry. Sato and co-workers [22] adopted the chirality from d-glucose and elaborated it further to build the natural product 1,t hus fulfilling the 7th principle of Green Chemistry (i.e.u se of renewable feedstocks). [37] In Madsens synthesis [19] of (+ +)-pancratistatin (1), ring closing metathesis (RCM) [38] was exploited to construct ring C, which could lead to ah igher cost.…”

Synthese von Inhaltsstoffen der Amaryllisgewächse und nichtnatürlichen Derivaten

“…Eine Strategie unter Nutzung des chiralen Pools wurde in der von Sato und Mitarbeitern 2003 beschriebenen Totalsynthese von (+)‐Pancratistatin ( 1 ) angewendet . Die wesentlichen Schritte umfassten den Aufbau des C‐Rings aus d ‐Glucose und die Verknüpfung des A‐Rings mit dem Fragment 37 durch Michael‐Addition.…”

“…Von diesen vier Synthesen war die 2012 von Alonso veröffentlichte die kürzeste Synthese, die 14 Schritte umfasste und mit 8.2 % Gesamtausbeute abgeschlossen wurde . Für die Synthese von (+)‐Pancratistatin ( 1 ) nutzten sowohl Alonso als auch Sato klassische Reaktionen, wie die Aldolreaktion und die Michael‐Addition, während Cho in seiner Synthese die Diels‐Alder‐Reaktion anwendete, um die benötigte Stereochemie zu erzielen. Sato und Mitarbeiter übernahmen die Chiralität von d ‐Glucose und entwickelten sie weiter, um den Naturstoff 1 aufzubauen, womit sie das 7.…”