An Eleven‐Step Synthesis of Galanthamine from Commercially Available Materials

Abstract

Narwedine, an immediate precursor to the therapeutically valuable alkaloid (–)‐galanthamine, has been synthesised by engaging an iodinated isovanillin derivative in an intermolecular Mitsunobu reaction with a 2‐cyclohexen‐1‐ol derivative. The resulting aryl ether participated in an exceptionally efficient intramolecular Heck reaction to give a tetracyclic lactol after the hydrolysis of the primary cyclisation product. This last compound is an advanced intermediate associated with the Magnus synthesis of narwedine and could be elaborated to narwedine itself under reductive amination conditions. As a result, an eleven‐step synthesis of galanthamine has been established.

Reductive Amination in the Synthesis of Pharmaceuticals

“…Nugent and Banwell also published a protocol involving azepine ring formation via reductive amination (Scheme ). The authors carried out the reduction of the tosyl group in intermediate 2.28.m with sodium naphthalenide, followed by the addition of 1.5 equiv of sodium triacetoxyborohydride. The reaction proceeded in an overall yield of 29% and with 6% RME (50 mg of the product).…”

Intramolecular Heck Reaction in Total Synthesis of Natural Products: An Update

“…This was reduced further using NaBH 4 to form intermediate 69 which finally was transformed to the titled compound. Banwell et al [26b] . in 2016 was also reported the synthesis of (−)‐galanthamine ( 70 ) using intramolecular Heck reaction as one of the strategic steps from the Heck intermediates 72 and 74 which were synthesized from precursors 71 and 73 , respectively, in good yield (Scheme 8).…”

The Synthesis of Certain Derivatives and Analogues of (−)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase

“…Magnus and co-workers have described a related and highly effective approach. Intramolecular Heck reactions have provided another means for assembling the tetracyclic framework of galanthamine, including those accomplished in an enantioselective manner, while various chirons (corresponding to the A-ring) have been employed for the assembly in either enantiomeric form of the alkaloid. , New routes to (−)-galanthamine continue to be reported, including approaches from our group …”

“…As part of an ongoing program to establish concise routes to the tetracyclic framework of galanthamine, , we now report chemoenzymatic syntheses of two oxygenated derivatives, 2 and 3 , as well as analogues 4 – 9 of the natural or (−)-form of the alkaloid (Figure ). …”